U.S. patent application number 14/772481 was filed with the patent office on 2016-02-11 for s1p and/or atx modulating agents.
The applicant listed for this patent is BIOGEN MA INC.. Invention is credited to Gnanasambandam Kumaravel, Hairuo Peng, Lihong Sun, Art Taveras, Deping Wang, Zhili Xin, Lei Zhang.
Application Number | 20160039825 14/772481 |
Document ID | / |
Family ID | 50639967 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160039825 |
Kind Code |
A1 |
Peng; Hairuo ; et
al. |
February 11, 2016 |
S1P AND/OR ATX MODULATING AGENTS
Abstract
Compounds of formula (I), and pharmaceutically acceptable salts
thereof, can modulate the activity of one or more SIP receptors
and/or the activity of autotaxin (ATX). ##STR00001##
Inventors: |
Peng; Hairuo; (Cambridge,
MA) ; Xin; Zhili; (Cambridge, MA) ; Zhang;
Lei; (Cambridge, MA) ; Sun; Lihong;
(Cambridge, MA) ; Kumaravel; Gnanasambandam;
(Cambridge, MA) ; Taveras; Art; (Cambridge,
MA) ; Wang; Deping; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOGEN MA INC. |
Cambridge |
MA |
US |
|
|
Family ID: |
50639967 |
Appl. No.: |
14/772481 |
Filed: |
March 14, 2014 |
PCT Filed: |
March 14, 2014 |
PCT NO: |
PCT/US2014/027664 |
371 Date: |
September 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61790281 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
514/210.18 ;
514/221; 514/230.5; 514/233.2; 514/249; 540/543; 540/567; 540/568;
544/105; 544/117; 544/349; 544/350 |
Current CPC
Class: |
A61K 36/9068 20130101;
A61P 11/06 20180101; A61P 25/00 20180101; A61P 29/00 20180101; A61P
35/00 20180101; A61P 19/02 20180101; C07D 487/04 20130101; C07D
519/00 20130101; A61K 31/198 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 519/00 20060101 C07D519/00 |
Claims
1. A compound represented by formula (I): ##STR00548## or a
pharmaceutically acceptable salt thereof, wherein: L is --C(O)--,
--O--C(O)--, --NR.sup.6--C(O)--, or --S(O).sub.2--; L.sup.2 is a
bond, --O--, or --NR--; provided that L.sup.2 is not --O-- when
R.sup.2 is structure (iv); R, for each occurrence, is independently
hydrogen or a C.sub.1-4alkyl; R.sup.1 is a C.sub.1-8alkylene;
R.sup.2 is selected form the group consisting of: ##STR00549##
##STR00550## R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15, --O--P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH, --C(O)NHCN, a 5 to 14
membered heteroaryl, a 3 to 15 membered heterocyclyl, or
-L.sup.1-R.sup.4; where in the heteroaryl and heterocyclyl are
optionally substituted with one to four R.sup.5; provided that when
R.sup.2 is structure (ii), (iii), (iv), or (xi), R.sup.3 is not
hydrogen; and provided that when R.sup.2 is structure (iv), R.sup.3
is not pyrrolidinyl, piperidinyl, an N-methylpyrrolidinyl, an
N-acetyl-pyrrolidinyl, an N-methylpiperidinyl, or an
N-acetyl-piperidinyl; L.sup.1 is C.sub.1-8alkylene, --C(O)--,
--C(O)O--, --C(O)NR--, --S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--;
R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5; R.sup.5 is halo, cyano,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2--,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.6 is hydrogen or a
C.sub.1-8alkyl; R.sup.7, for each occurrence, is independently
selected from the group consisting of halo, hydroxyl, oxo, nitro,
cyano, carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.8, for each occurrence, is independently selected from the
group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.9, for each occurrence, is independently selected from the
group consisting of halo, cyano, hydroxyl, carboxy, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; R.sup.9a is hydrogen or R.sup.9; or
R.sup.9a and R.sup.6, together with the intervening atoms, form a
3- to 8-membered heterocyclyl which is optionally substituted with
from one to three R.sup.9; R.sup.10 and R.sup.11, for each
occurrence, are independently hydrogen, halo, hydroxyl, carboxy,
C.sub.1-4alkyl, or C.sub.1-4haloalkyl; R.sup.15 for each occurrence
is independently selected from the group consisting of hydrogen,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to
14 membered heteroaryl, and a 3 to 15 membered heterocyclyl;
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein
R.sup.15 may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.16 is C.sub.1-8alkoxy, or
R.sup.15; or two R.sup.16 together with the nitrogen atom to which
they are attached form a 5 to 14 membered heteroaryl or a 3 to 15
membered heterocyclyl, wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein the heteroaryl or heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
h is 0, 1, or 2; n, for each occurrence, is independently 0, 1, 2,
3, or 4; m, for each occurrence, is independently 0 or an integer
from 1 to 6; p is 0, 1, 2, or 3; q is 1, 2, 3, or 4; r is 1, 2, or
3; and t is 0 or 1, provided that the compound is not:
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz-
in-2-yl)propanoic acid;
2-(2,3-difluorophenyl)-1-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazin-5(4H)-yl)ethanone;
3-(5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid;
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid;
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazin-2-yl)propanoic acid;
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]p-
yrazine-5(4H)-carboxamide;
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-3-(p-tolyl)propan-1-one; methyl
5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-
-carboxylate; methyl
5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate;
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepin-2-yl)propanoic acid;
1-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-
-2-(3-(trifluoromethyl)phenyl)ethanone;
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(3-(trifluoromethyl)phenyl)ethanone;
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(2-fluorophenyl)ethanone;
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-5(6H)-carboxamide;
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid;
1-(2-((1,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)--
yl)-2-(4-methoxyphenyl)ethanone;
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid;
3-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)propan-1-one;
2-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)ethanone;
2-(4-ethoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-5(6H)-yl)ethanone; methyl
5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate;
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-2,-
5(4H)-dicarboxamide;
5-((1-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxylic acid;
4-(4-chlorophenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl-
)butan-1-one;
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-c-
arboxamide;
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(4-ethoxyphenyl-
)ethanone;
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(o-to-
lyl)ethanone;
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carb-
oxamide;
1-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyra-
zine-2(1H)-carboxamide;
N-(4-fluorobenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide;
1-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1-
H)-carboxamide;
1-ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide;
2-(2-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone;
2-(4-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone;
N-(3-methoxybenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2-
(1H)-carboxamide;
1-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-
-2(1H)-carboxamide;
1-isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
e-2(1H)-carboxamide;
6-methyl-N-(4-methylbenzyl)-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide;
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-
-b]pyrrole-4-carboxylic acid;
2-(3-bromophenyl)-2-methyl-1-(2-methyl-5,6-dihydro-[1,2,4]triazolo[1,5-a]-
pyrazin-7(8H)-yl)propan-1-one;
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl-
)ethanone;
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]tria-
zolo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)ethanone;
3-(m-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one;
3-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one;
2-(2-chloro-6-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7(8H)-yl)ethanone;
4-(3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propyl)benzonitrile;
2-(2-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyraz-
in-7(8H)-yl)-2-methylpropan-1-one;
3-(2-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propan-1-one;
2-(3,4-dimethoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyr-
azin-7(8H)-yl)ethanone;
2-(3-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7(8H)-yl)ethanone;
2-(2-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7(8H)-yl)ethanone;
3-(4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7 (8H)-yl)propan-1-one;
3-(3-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7 (8H)-yl)propan-1-one;
2-(2-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin--
7 (8H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7 (8H)-yl)ethanone;
1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)-2-(2-fluorophenyl)-2-methylpropan-1-one;
3-(3-chloro-4-methylphenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7 (8H)-yl)propan-1-one;
3-(2,5-dimethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7 (8H)-yl)propan-1-one;
3-(3-chloro-4-methylphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7 (8H)-yl)propan-1-one;
1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)-5-(p-tolyl)pentan-1-one;
2-(2-chloro-6-fluorophenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7 (8H)-yl)ethanone;
3-(2-ethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)propan-1-one;
3-(2-methoxyphenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]tri-
azolo[4,3-d][1,4]diazepin-7(6H)-yl)propan-1-one;
2-(3,4-dichlorophenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]-
triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-([1,1'-biphenyl]-4-yl)-1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone;
2-(3-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]-
diazepin-7(6H)-yl)ethanone;
1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-y-
l)-2-(4-(methylthio)phenyl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triaz-
olo[4,3-a]pyrazin-7(8H)-yl)ethanone;
2-(2-chlorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone;
5-(4-bromophenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridi-
n-5(4H)-yl)pentan-1-one;
3-(4-ethoxyphenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyrid-
in-5(4H)-yl)propan-1-one;
2-(2-ethoxyphenoxy)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyri-
din-5(4H)-yl)ethanone;
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy-
)ethanone;
3-(5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyra-
zolo[1,5-a][1,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid;
2-(4-ethylphenoxy)-1-(2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-5(6H)-yl)ethanone;
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-2-(m-tolyloxy)ethanone; methyl
5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carboxylate;
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonitrile;
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonitrile;
1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4-fluor-
ophenyl)ethanone;
2-(2-chloro-6-fluorophenyl)-1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]-
pyridin-5(4H)-yl)ethanone; methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate; methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate;
3-(5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid;
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazin-2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-2-yl)propanoic acid; methyl
5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxylate;
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxamide;
2-(2-hydroxyphenyl)-1-(2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-
-a]pyrazin-5(4H)-yl)ethanone;
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-
-2-carboxamide;
2-(3-chloro-4-hydroxyphenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepi-
n-8(9H)-yl)ethanone;
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanon-
e; or
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)pro-
pan-1-one.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected form the group consisting of:
##STR00551##
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein p is 0, 1, or 2.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein p is 1, and r is 1 or 2.
5-12. (canceled)
13. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound is represented by formula (II):
##STR00552##
14. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein L is --C(O)--, --O--C(O)--, or --NR--C(O)--.
15. (canceled)
16. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound is represented by structural formula
(III): ##STR00553## wherein: R.sup.1 is a C.sub.1-8alkylene;
R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15, --O--P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH, --C(O)NHCN, a 5 to 14
membered heteroaryl, a 3 to 15 membered heterocyclyl, or
L.sup.1-R.sup.4; where in the heteroaryl and heterocyclyl are
optionally substituted with one to four R.sup.5; L.sup.1 is
C.sub.1-8alkylene, --C(O)--, --C(O)O--, --C(O)NR--,
--S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--; R, for each
occurrence, is independently hydrogen or C.sub.1-4alkyl; R.sup.4 is
C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15 membered
heterocyclyl, wherein R.sup.4 may be optionally substituted with
from one to four R.sup.5; R.sup.5 is halo, cyano, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.9, for each
occurrence, is independently selected from the group consisting of
halo, cyano, hydroxyl, carboxy, C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; R.sup.10 and R.sup.11, for each
occurrence, are independently hydrogen, halo, hydroxyl, carboxy,
C.sub.1-4alkyl, or C1-4haloalkyl; R.sup.15 for each occurrence is
independently selected from the group consisting of hydrogen,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to
14 membered heteroaryl, and a 3 to 15 membered heterocyclyl;
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein
R.sup.15 may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.16 is C.sub.1-8alkoxy, or
R.sup.15; or two R.sup.16 together with the nitrogen atom to which
they are attached form a 5 to 14 membered heteroaryl or a 3 to 15
membered heterocyclyl, wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein the heteroaryl or heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy, cyano,
nitro, hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
m, for each occurrence, is independently 0 or an integer from 1 to
6; and q is 1, 2, 3, or 4.
17. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2, a 5 to 14
membered heteroaryl, or L.sup.1-R.sup.4; where in the heteroaryl
and heterocyclyl are optionally substituted with one to four
R.sup.5.
18. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.16, for each occurrence, is independently
selected from the group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.3-8cycloalkyl, or two R.sup.16 together with the nitrogen
atom to which they are attached form a 5 to 14 membered heteroaryl
or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or
heterocyclyl comprises from 1 to 10 heteroatoms independently
selected from O, N, or S; and wherein the heteroaryl or
heterocyclyl may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl.
19.-28. (canceled)
29. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein L is --O--C(O)--, --NR.sup.6--C(O)--, or --C(O)--;
L.sup.2 is a bond, --O--, or --NR--; R.sup.1 is C.sub.1-4alkylene;
R.sup.2 is selected form the group consisting of: ##STR00554## p is
1 or 2; and r is 1 or 2.
30. The compound of claim 29, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is methylene or ethylene; and R.sup.2 is
selected from ##STR00555##
31. (canceled)
32. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7, for each occurrence, is independently
selected from the group consisting of halo, hydroxyl, cyano,
carboxy, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, C.sub.1-8alkoxycarbonyl,
C.sub.1-8alkanoyloxy, carbamoyl, N--(C.sub.1-8alkyl)carbamoyl,
N,N-di-(C.sub.1-8alkyl)carbamoyl, and C.sub.1-8alkylamido; R.sup.8,
for each occurrence, is independently selected from the group
consisting of halo, hydroxyl, cyano, carboxy, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, C.sub.1-8alkoxycarbonyl,
C.sub.1-8alkanoyloxy, carbamoyl, N--(C.sub.1-8alkyl)carbamoyl,
N,N-di-(C.sub.1-8alkyl)carbamoyl, and C.sub.1-8alkylamido; h is 0
or 1; n is 0 or 1; and t is 0 or 1.
33.-35. (canceled)
36. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.9, for each occurrence, is independently
selected from the group consisting of halo, cyano, hydroxyl,
carboxy, C.sub.1-8alkoxy, C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy,
C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy,
carbamoyl, N--(C.sub.1-8alkyl)carbamoyl,
N,N-di-(C.sub.1-8alkyl)carbamoyl, C.sub.1-8alkylamido, mercapto,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, and C.sub.1-8alkoxy-C.sub.1-6alkyl; and q is 1, 2,
or 3.
37-40. (canceled)
41. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R is hydrogen or C.sub.1-4alkyl; R.sup.6 is
hydrogen or a C.sub.1-4alkyl; R.sup.9a is hydrogen or R.sup.9; or
R.sup.9a and R.sup.6, together with the intervening atoms, form a
3- to 8-membered heterocyclyl which is optionally substituted with
from one to three R.sup.9.
42.-43. (canceled)
44. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--C(O)NHS(O).sub.2R.sup.15, a 5 to 14 membered heteroaryl, a 3 to
15 membered heterocyclyl, or -L.sup.1-R.sup.4; where in the
heteroaryl and heterocyclyl are optionally substituted with one to
four R.sup.5 groups selected from C.sub.1-4alkyl, --OH,
C.sub.1-4alkoxy, hydroxy(C.sub.1-4alkyl), --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl; L.sup.1 is C.sub.1-8alkylene,
--C(O)--, --C(O)O--, --C(O)NR--, --S(O).sub.2NR--, or
--C(O)NR--S(O).sub.2--; R, for each occurrence, is independently
hydrogen or a C.sub.1-4alkyl; R.sup.4 is C.sub.1-8alkyl,
C.sub.3-8cycloalkyl, a 5 to 14 membered heteroaryl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5 groups selected from
halo, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl, --COOH,
--C(O)O--(C.sub.1-4alkyl), C.sub.1-4alkoxy, --OH,
hydroxyC.sub.1-4alkyl, --NH.sub.2, (C.sub.1-4alkyl)amino,
C.sub.3-8cycloalkyl, and a 3 to 15 membered heterocyclyl selected
from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl,
piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be
optionally substituted with one or two substituents independently
selected from the group consisting of optionally substituted with
C.sub.1-4alkyl, --OH, and COOH; R.sup.10 and R.sup.11, for each
occurrence, are independently hydrogen, carboxy, C.sub.1-4alkyl, or
C.sub.1-4haloalkyl; R.sup.15 for each occurrence is independently
selected from the group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, wherein
R.sup.15 may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, and
carboxyl; Each R.sup.16 is independently selected from hydrogen,
C.sub.1-8alkoxy, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, a 5 to 14 membered
heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the
heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms
independently selected from O, N, or S; and wherein R.sup.16 may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, and C.sub.1-4alkylamidol; or two
R.sup.16 together with the nitrogen atom to which they are attached
form a 5 to 14 membered heteroaryl or a 3 to 15 membered
heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from
1 to 10 heteroatoms independently selected from O, N, or S; and
wherein the heteroaryl or heterocyclyl may be optionally
substituted with from 1 to 3 substituents independently selected
from the group consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl,
cyano, nitro, hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, and
C.sub.1-4alkylamidol; and m, for each occurrence, is independently
0 or 1.
45.-46. (canceled)
47. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein L is --O--C(O)--, --NR.sup.6--C(O)--, or --C(O)--;
L.sup.2 is a bond; R.sup.1 is C.sub.1-4alkylene; R.sup.2 is
##STR00556## R.sup.3 is --(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
a 3 to 15 membered heterocyclyl selected from
8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl,
3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl,
4,7-diazaspiro[2.5]octanyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole,
octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl,
piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein
heterocyclyl is optionally substituted with one to four groups
selected from C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl; or -L.sup.1-R.sup.4; L.sup.1 is
--C(O)--, R.sup.4 is 3 to 15 membered heterocyclyl selected from
9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl,
3,6-diazabicyclo[3.2.1]octanyl, 6,9-diazaspiro[4.5]decanyl,
2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl,
4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl,
morpholinyl, octahydropyrrolo[1,2-a]pyrazinyl,
octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl,
octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl,
piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl,
tetrahydro-2H-pyranyl, wherein the heterocyclyl may be optionally
substituted with from one to four groups selected from halo, --CN,
C.sub.1-4alkyl, --CF.sub.3, --COOH, --COOCH.sub.3, --COO-t-butyl,
--OH, --CH.sub.2CH.sub.2OH, --OCH.sub.3, --NH.sub.2, and
--NHCH.sub.3; each R.sup.9 is independently selected from halo and
C.sub.1-8haloalkyl; R.sup.9a is hydrogen; R.sup.10 and R.sup.11,
for each occurrence, are independently hydrogen or C.sub.1-4alkyl;
R.sup.15 is hydrogen or C.sub.1-4alkyl; m is 0 or 1; n is 0 or 1; q
is 1, 2, or 3; p is 1 or 2; r is 1 or 2; and t is 0 or 1.
48. The compound of any one of claim 1, or a pharmaceutically
acceptable salt thereof, wherein L is --O--C(O)-- L.sup.2 is a
bond; R.sup.1 is methylene; R.sup.2 is ##STR00557## R.sup.3 is
--C(O)OR.sup.15; --CR.sup.10R.sup.11--C(O)OR.sup.15 a 3 to 15
membered heterocyclyl selected from azetidinyl, morpholinyl,
piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, and
octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], wherein
the heterocyclyl is optionally substituted with one to four groups
selected from C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl; or -L.sup.1-R.sup.4; L.sup.1 is
--C(O)--, R.sup.4 is 3 to 15 membered heterocyclyl selected
azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl,
piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the heterocyclyl
may be optionally substituted with from one to four groups selected
from halo, C.sub.1-4alkyl, --CF.sub.3, --COOH, --COOCH.sub.3,
--COO-t-butyl; each R.sup.9 is independently selected from halo and
C.sub.1-4haloalkyl; R.sup.9a is hydrogen; R.sup.10 and R.sup.11,
for each occurrence, are independently hydrogen or C.sub.1-4alkyl;
R.sup.15 is hydrogen or C.sub.1-4alkyl; and q is 1, 2, or 3.
49. (canceled)
50. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or excipient and a compound of claim 1, or a
pharmaceutically acceptable salt thereof.
51. A method of preventing, treating, or reducing symptoms of a
condition mediated by ATX activity in a mammal comprising
administering to said mammal an effective amount of a compound
represented by formula (I): ##STR00558## or a pharmaceutically
acceptable salt thereof, wherein: L is --C(O)--, --O--C(O)--,
--NR.sup.6--C(O)--, or --S(O).sub.2--; L.sup.2 is a bond, --O--, or
--NR--; R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl; R.sup.1 is a C.sub.1-8alkylene; R.sup.2 is selected
form the group consisting of: ##STR00559## ##STR00560## R.sup.3 is
hydrogen, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15, --O--P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH, --C(O)NHCN, a 5 to 14
membered heteroaryl, a 3 to 15 membered heterocyclyl, or
-L.sup.1-R.sup.4; where in the heteroaryl and heterocyclyl are
optionally substituted with one to four R.sup.5; L.sup.1 is
C.sub.1-8alkylene, --C(O)--, --C(O)O--, --C(O)NR--, S(O).sub.2NR--,
or C(O)NR--S(O).sub.2--; R.sup.4 is C.sub.1-8alkyl,
C.sub.3-8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein
R.sup.4 may be optionally substituted with from one to four
R.sup.5; R.sup.5 is halo, cyano, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.6 is hydrogen or a
C.sub.1-8alkyl; R.sup.7, for each occurrence, is independently
selected from the group consisting of halo, hydroxyl, oxo, nitro,
cyano, carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.8, for each occurrence, is independently selected from the
group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.9, for each occurrence, is independently selected from the
group consisting of halo, cyano, hydroxyl, carboxy, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; R.sup.9a is hydrogen or R.sup.9; or
R.sup.9a and R.sup.6, together with the intervening atoms, form a
3- to 8-membered heterocyclyl which is optionally substituted with
from one to three R.sup.9; R.sup.10 and R.sup.11, for each
occurrence, are independently hydrogen, halo, hydroxyl, carboxy,
C.sub.1-4alkyl, or a C.sub.1-4haloalkyl; R.sup.15 for each
occurrence is independently selected from the group consisting of
hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to
14 membered heteroaryl, and a 3 to 15 membered heterocyclyl;
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein
R.sup.15 may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.16 is C.sub.1-8alkoxy, or
R.sup.15; or two R.sup.16 together with the nitrogen atom to which
they are attached form a 5 to 14 membered heteroaryl or a 3 to 15
membered heterocyclyl, wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein the heteroaryl or heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
h is 0, 1, or 2; n, for each occurrence, is independently 0, 1, 2,
3, or 4; m, for each occurrence, is independently 0 or an integer
from 1 to 6; p is 0, 1, 2, or 3; q is 1, 2, 3, or 4; r is 1, 2, or
3; and t is 0 or 1.
52.-62. (canceled)
63. A method of preventing, treating, or reducing chronic pain in a
mammal comprising administering to said mammal an effective amount
of a compound represented by formula (I): ##STR00561## or a
pharmaceutically acceptable salt thereof, wherein: L is --C(O)--,
--O--C(O)--, --NR--C(O)--, or --S(O).sub.2--; R, for each
occurrence, is independently hydrogen or a C.sub.1-4alkyl; R.sup.1
is a C.sub.1-8alkylene; R.sup.2 is selected form the group
consisting of: ##STR00562## ##STR00563## R.sup.3 is hydrogen, --CN,
C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15, --O--P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH, --C(O)NHCN, a 5 to 14
membered heteroaryl, a 3 to 15 membered heterocyclyl, or
-L.sup.1-R.sup.4; where in the heteroaryl and heterocyclyl are
optionally substituted with one to four R.sup.5; L.sup.1 is
C.sub.1-8alkylene, --C(O)--, --C(O)O--, --C(O)NR--,
--S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--; R.sup.4 is
C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15 membered
heterocyclyl, wherein R.sup.4 may be optionally substituted with
from one to four R.sup.5; R.sup.5 is halo, cyano, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.7, for each
occurrence, is independently selected from the group consisting of
halo, hydroxyl, oxo, nitro, cyano, carboxy, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.1-8alkoxy, C.sub.1-8haloalkoxy, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.8, for each occurrence, is independently selected from the
group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
R.sup.9, for each occurrence, is independently selected from the
group consisting of halo, cyano, hydroxyl, carboxy, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; R.sup.10 and R.sup.11, for each
occurrence, are independently hydrogen, halo, hydroxyl, carboxy,
C.sub.1-4alkyl, or a C.sub.1-4haloalkyl; R.sup.15 for each
occurrence is independently selected from the group consisting of
hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to
14 membered heteroaryl, and a 3 to 15 membered heterocyclyl;
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein
R.sup.15 may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl; R.sup.16 is C.sub.1-8alkoxy, or
R.sup.15; or two R.sup.16 together with the nitrogen atom to which
they are attached form a 5 to 14 membered heteroaryl or a 3 to 15
membered heterocyclyl, wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein the heteroaryl or heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
h is 0, 1, or 2; n, for each occurrence, is independently 0, 1, 2,
3, or 4; m, for each occurrence, is independently 0 or an integer
from 1 to 6; p is 0, 1, 2, or 3; q is 1, 2, 3, or 4; r is 1, 2, or
3; and t is 0 or 1, provided that the compound is not
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone.
64.-76. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/790,281, filed Mar. 15, 2013, the entire
contents of which are hereby incorporated by reference.
[0002] Provided are agents that modulate S1P and/or ATX, and
methods of making and using such agents.
[0003] Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator
that evokes a variety of cellular responses by stimulation of five
members of the endothelial cell differentiation gene (EDG) receptor
family. The EDG receptors are G-protein coupled receptors (GPCRs)
and on stimulation propagate second messenger signals via
activation of heterotrimeric G-protein alpha (G.sub..alpha.)
subunits and beta-gamma (G.sub..beta..gamma.) dimers. Ultimately,
this S1P-driven signaling results in cell survival, increased cell
migration and, often, mitogenesis. The recent development of
agonists targeting S1P receptors has provided insight regarding the
role of this signaling system in physiologic homeostasis. For
example, the immunomodulating agent, FTY720
(2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol), that
following phosphorylation, is an agonist at 4 of 5 S1P receptors,
revealed that affecting S1P receptor activity influences lymphocyte
trafficking. Further, S1P type 1 receptor (S1P.sub.1) antagonists
cause leakage of the lung capillary endothelium, which suggests
that S1P may be involved in maintaining the integrity of the
endothelial barrier in some tissue beds. S1P type 4 receptors
(S1P.sub.4) are expressed mainly in leukocytes, and specifically
S1P.sub.4 mediates immunosuppressive effects of S1P by inhibiting
proliferation and secretion of effector cytokines, while enhancing
secretion of the suppressive cytokine IL-10. See, for example,
Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which is
incorporated by reference in its entirety. S1P type 5 receptors
(S1P.sub.5) are exclusively expressed in oligodendrocytes and
oligodendrocyte precursor cells (OPCs) and are vital for cell
migration. Stimulation of S1P.sub.5 inhibits OPC migration, which
normally migrate considerable distances during brain development.
See, for example, Novgorodov, A. et al., (2007) FASEB J, 21:
1503-1514, which is incorporated by reference in its entirety.
[0004] S1P has been demonstrated to induce many cellular processes,
including those that result in platelet aggregation, cell
proliferation, cell morphology, tumor-cell invasion, endothelial
cell chemotaxis and angiogenesis. For these reasons, S1P receptors
are good targets for therapeutic applications such as wound
healing, tumor growth inhibition, and autoimmune diseases.
[0005] Sphingosine-1-phosphate signals cells in part via a set of G
protein-coupled receptors named S1P.sub.1, S1P.sub.2, S1P.sub.3,
S1P.sub.4, and S1P.sub.5 (formerly EDG1, EDG5, EDG3, EDG6 and
EDGE). The EDG receptors are G-protein coupled receptors (GPCRs)
and on stimulation propagate second messenger signals via
activation of heterotrimeric G-protein alpha (G.sub..alpha.)
subunits and beta-gamma (G.sub..beta..gamma.) dimers. These
receptors share 50-55% amino acid sequence identity and cluster
with three other receptors (LPA.sub.1, LPA.sub.2, and LPA.sub.3
(formerly EDG2, EDG4 and EDG7) for the structurally related
lysophosphatidic acid (LPA).
[0006] A conformational shift is induced in the G-Protein Coupled
Receptor (GPCR) when the ligand binds to that receptor, causing GDP
to be replaced by GTP on the .alpha.-subunit of the associated
G-proteins and subsequent release of the G-proteins into the
cytoplasm. The .alpha.-subunit then dissociates from the
.beta..gamma.-subunit and each subunit can then associate with
effector proteins, which activate second messengers leading to a
cellular response. Eventually the GTP on the G-proteins is
hydrolyzed to GDP and the subunits of the G-proteins reassociate
with each other and then with the receptor. Amplification plays a
major role in the general GPCR pathway. The binding of one ligand
to one receptor leads to the activation of many G-proteins, each
capable of associating with many effector proteins leading to an
amplified cellular response.
[0007] S1P receptors make good drug targets because individual
receptors are both tissue and response specific. Tissue specificity
of the S1P receptors is desirable because development of an agonist
or antagonist selective for one receptor localizes the cellular
response to tissues containing that receptor, limiting unwanted
side effects. Response specificity of the S1P receptors is also of
importance because it allows for the development of agonists or
antagonists that initiate or suppress certain cellular responses
without affecting other responses. For example, the response
specificity of the S1P receptors could allow for an S1P mimetic
that initiates platelet aggregation without affecting cell
morphology.
[0008] Sphingosine-1-phosphate is formed as a metabolite of
sphingosine in its reaction with sphingosine kinase and is stored
in abundance in the aggregates of platelets where high levels of
sphingosine kinase exist and sphingosine lyase is lacking. S1P is
released during platelet aggregation, accumulates in serum, and is
also found in malignant ascites. Reversible biodegradation of S1P
most likely proceeds via hydrolysis by ectophosphohydrolases,
specifically the sphingosine-1-phosphate phosphohydrolases.
Irreversible degradation of S1P is catalyzed by S1P lyase yielding
ethanolamine phosphate and hexadecenal.
[0009] Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely
present in biological fluids, including blood, cancer ascites,
synovial, pleural and cerebrospinal fluids, originally isolated
from the supernatant of melanoma cells as an autocrine motility
stimulation factor (Stracke, M. L., et al. Identification,
purification, and partial sequence analysis of autotaxin, a novel
motility-stimulating protein. J Biol Chem 267, 2524-2529 (1992),
which is incorporated by reference in its entirety). ATX is encoded
by a single gene on human chromosome 8 (mouse chromosome 15) whose
transcription, regulated by diverse transcription factors (Hoxal3,
NFAT-1 and v-jun), results in four alternatively spliced isoforms
(.alpha., .beta., .gamma., and .delta.). See, for example, Giganti,
A., et al Murine and Human Autotaxin alpha, beta, and gamma
Isoforms: Gene organization, tissue distribution and biochemical
characterization. J Biol Chem 283, 7776-7789 (2008); and van
Meeteren, L. A. & Moolenaar, W. H. Regulation and biological
activities of the autotaxin-LPA axis. Prog Lipid Res 46, 145-160
(2007); Hashimoto, et al, "Identification and Biochemical
Charaterization of a Novel Autotaxin Isoform, ATX.delta.," J. of
Biochemistry Advance Access (Oct. 11, 2011); each of which is
incorporated by reference in its entirety.
[0010] ATX is synthesized as a prepro-enzyme, secreted into the
extracellular space after the proteolytic removal of its N-terminal
signal peptide (Jansen, S., el al Proteolytic maturation and
activatio of autotaxin (NPP2), a secreted metastasis-enhancing
lysophospho lipase D. J Cell Sci 118, 3081-3089 (2005), which is
incorporated by reference in its entirety). ATX is a member of the
ectonucleotide pyrophosphatase/phosphodiesterase family of
ectoenzymes (E-NPP) that hydrolyze phosphodiesterase (PDE) bonds of
various nucleotides and derivatives (Stefan, C, Jansen, S. &
Bollen, M. NPP-type ectophosphodiesterases: unity in diversity.
Trends Biochem Sci 30, 542-550 (2005), which is incorporated by
reference in its entirety). The enzymatic activity of ATX was
enigmatic, until it was shown to be identical to lysophospholipase
D (lysoPLD) (Umezu-Goto, M., et al. Autotaxin has lysophospholipase
D activity leading to tumor cell growth and motility by
lysophosphatidic acid production. J Cell Biol 158, 227-233 (2002),
which is incorporated by reference in its entirety), which is
widely present in biological fluids. Since ATX is a constitutively
active enzyme, the biological outcome of ATX action will largely
depend on its expression levels and the local availability of its
substrates. The major lysophospholipid substrate for ATX,
lysophosphatidylcholine (LPC), is secreted by the liver and is
abundantly present in plasma (at about 100 .mu.M) as a
predominantly albumin bound form (Croset, M., Brossard, N.,
Polette, A. & Lagarde, M. Characterization of plasma
unsaturated lysophosphatidylcholines in human and rat Biochem J 345
Pt 1, 61-67 (2000), which is incorporated by reference in its
entirety). LPC is also detected in tumor-cell conditioned media
(Umezu-Goto, M., et al.), presumably as a constituent of shed
microvesicles. ATX, through its lysoPLD activity converts LPC to
lysophosphatidic acid (LPA).
[0011] LPC is an important inflammatory mediator with recognized
effects in multiple cell types and pathophysiological processes. It
is a major component of oxidized low density lipoprotein (oxLDL)
and it can exist in several other forms including free, micellar,
bound to hydrophobic proteins such as albumin and incorporated in
plasma membranes. It is produced by the hydrolysis of
phosphatidylcholine (PC) by PLA2 with concurrent release of
arachidonic acid and in turn of other pro-inflammatory mediators
(prostaglandins and leukotrienes). Moreover, LPC externalization
constitutes a chemotactic signal to phagocytic cells, while
interaction with its receptors can also stimulate lymphocytic
responses. LPC has been shown to have therapeutic effects in
experimental sepsis, possibly by suppressing endotoxin-induced
HMGB1 release from macrophages/monocytes.
[0012] LPA is a bioactive phospholipid with diverse functions in
almost every mammalian cell line (Moolenaar, W. H., van Meeteren,
L. A. & Giepmans, B. N. The ins and outs of lysophosphatidic
acid signaling. Bioessays 28, 870-881 (2004), which is incorporated
by reference in its entirety). LPA is a major constituent of serum
bound tightly to albumin, gelsolin and possibly other as yet
unidentified proteins. See, e.g., Goetzl, E. J., et al Gelsolin
binding and. cellular presentation of lysophosphatidic acid. J Biol
Chem 275, 14573-14578 (2000); and Tigyi, G. & Miledi, R,
Lysophosphatidates bound to serum albumin activate membrane
currents in Xenopus oocytes and neurite retraction in PC12
pheochromocytoma cells. J Biol Chem 267, 21360-21367 (1992); each
of which is incorporated by reference in its entirety.
[0013] LPA is also found in other biofluids, such as saliva and
follicular fluid, and has been implicated in a wide array of
functions, such as wound healing, tumor invasion and metastasis,
neurogenesis, myelination, astrocytes outgrowth and neurite
retraction. The long list of LPA functions was also explained with
the discovery that it signals through G-protein coupled receptors
(GPCRs), via classical second messenger pathways. Five mammalian
cell-surface LPA receptors have been identified so far. The best
known are LPA1-3 (namely Edg-2, Edg-4 and Edg7) which are all
members of the so-called `endothelial differentiation gene` (EDG)
family of GPCRs (Contos, J. J., Ishii, I. & Chun, J.
Lysophosphatidic acid receptors. Mol Pharmacol 58, 1188-1196
(2000), which is incorporated by reference in its entirety). LPA
receptors can couple to at least three distinct G proteins
(G.sub.q, G.sub.i and G.sub.12/13), which, in turn, feed into
multiple effector systems. LPA activates G.sub.q and thereby
stimulates phospholipase C (PLC), with subsequent
phosphatidylinositol--bisphosphate hydrolysis and generation of
multiple second messengers leading to protein kinase C activation
and changes in cytosolic calcium. LPA also activates G.sub.i, which
leads to at least three distinct signaling routes: inhibition of
adenylyl cyclase with inhibition of cyclic AMP accumulation;
stimulation of the mitogenic RAS-MAPK (mitogen-activated protein
kinase) cascade; and activation of phosphatidylinositol 3-kinase
(PI3K), leading to activation of the guanosine
diphosphate/guanosine triphosphate (GDP/GTP) exchange factor TIAM1
and the downstream RAC GTPase, as well as to activation of the
AKT/PKB antiapoptotic pathway. Finally, LPA activates G.sub.12/13,
leading to activation of the small GTPase RhoA, which drives
cytoskeletal contraction and cell rounding. So, LPA not only
signals via classic second messengers such as calcium,
diacylglycerol and cAMP, but it also activates RAS- and RHO-family
GTPases, the master switches that control cell proliferation,
migration and morphogenesis.
[0014] LPA signaling through the RhoA-Rho kinase pathway mediates
neurite retraction and inhibition of axon growth. Interfering with
LPA signaling has been shown to promote axonal regeneration and
functional recovery after CNS injury or cerebral ischemia. (See
Broggini, et al., Molecular Biology of the Cell (2010),
21:521-537.) It has been reported that addition of LPA to dorsal
root fibers in ex vivo culture causes demyelination, whereas LPC
fails to cause significant demyelination of nerve fibers in ex vivo
cultures without further addition of recombinant ATX to the culture
which when added caused significant demyelination at equivalent
levels to LPA presumable due to conversion of LPC to LPA through
the enzymatic activity of ATX. Moreover, injury induced
demyelination was attenuated by about 50% in atx.sup.+/- mice
(Nagai, et al., Molecular Pain (2010), 6:78).
[0015] A number of diseases or disorders involve demyelination of
the central or peripheral nervous system which can occur for a
number of reasons such as immune dysfunction as in multiple
sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic
inflammatory demyelinating polyneuropathy (CIDP), transverse
myelitis, and optic neuritis; demyelination due to injury such as
spinal cord injury, traumatic brain injury, stroke, acute ischemic
optic neuropathy, or other ischemia, cerebral palsy, neuropathy
(e.g. neuropathy due to diabetes, chronic renal failure,
hypothyroidism, liver failure, or compression of the nerve (e.g. in
Bell's palsy)), post radiation injury, and central pontine
myelolysis (CPM); inherited conditions such as Charcot-Marie-Tooth
disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe
disease, Canavan disease, Alexander disease, Friedreich's ataxia,
Pelizaeus Merzbacher disease, Bassen-Kornzweig syndrome,
metachromatic leukodystrophy (MLD), adrenoleukodystrophy, and nerve
damage due to pernicious anemia; viral infection such as
progressive multifocal leukoencephalopathy (PML), Lyme disease, or
tabes dorsalis due to untreated syphilis; toxic exposure due to
chronic alcoholism (which is a possible cause of
Marchiafava-Bignami disease), chemotherapy, or exposure to
chemicals such as organophosphates; or dietary deficiencies such as
vitamin B12 deficiency, vitamin E deficiency and copper deficiency.
Other demyelination disorders may have unknown causes or multiple
causes such as trigeminal neuralgia, Marchiafava-Bignami disease
and Bell's palsy. One practically successful approach to treating
demyelination disorders which are caused by autoimmune dysfunction
has been to attempt to limit the extent of demyelination by
treating the patient with immunoregulatory drugs. However,
typically this approach has merely postponed but not avoided the
onset of disability in these patients. Patients with demyelination
due to other causes have even fewer treatment options. Therefore,
the need exists to develop new treatments for patients with
demyelination diseases or disorders.
SUMMARY
[0016] Provided are agents that can modulate S1P and/or ATX, e.g.,
an S1P4 antagonist and/or ATX inhibitor. Without wishing to be
bound by any theory, it is believed that LPA inhibits remyelination
of neurons that have suffered demyelination due to injury or
disease and that inhibition of ATX will prevent the conversion of
LPC to LPA and thus allow remyelination to occur. In addition,
activation of PLC, ERK and Rho via LPA receptors results in cell
proliferation, cell survival and changes in cell morphology.
Therefore, inhibition of ATX is expected to be useful for treating
demyelination due to injury or disease, as well as for treating
proliferative disorders such as cancer.
[0017] Provided is a compound represented by formula (I), or a
pharmaceutically acceptable salt thereof:
##STR00002## [0018] or a pharmaceutically acceptable salt thereof,
wherein: [0019] L is --C(O)--, --O--C(O)--, --NR.sup.6--C(O)--, or
--S(O).sub.2--; [0020] L.sup.2 is a bond, --O--, or --NR--;
provided that L.sup.2 is not --O-- when R.sup.2 is structure (iv);
[0021] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl; [0022] R.sup.1 is a C.sub.1-8alkylene; [0023]
R.sup.2 is selected form the group consisting of:
[0023] ##STR00003## ##STR00004## [0024] R.sup.3 is hydrogen, --CN,
C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or -L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four R.sup.5;
provided that when R.sup.2 is structure (ii), (iii), (iv), or (xi),
R.sup.3 is not hydrogen; and provided that when R.sup.2 is
structure (iv), R.sup.3 is not pyrrolidinyl, piperidinyl, an
N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an
N-methylpiperidinyl, or an N-acetyl-piperidinyl; [0025] L.sup.1 is
C.sub.1-8alkylene, --C(O)--, --C(O)O--, --C(O)NR--,
--S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--; [0026] R.sup.4 is
C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15 membered
heterocyclyl, wherein R.sup.4 may be optionally substituted with
from one to four R.sup.5; [0027] R.sup.5 is halo, cyano,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; [0028] R.sup.6 is hydrogen
or a C.sub.1-8alkyl; [0029] R.sup.7, for each occurrence, is
independently selected from the group consisting of halo, hydroxyl,
oxo, nitro, cyano, carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
[0030] R.sup.8, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
[0031] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; [0032] R.sup.9a is hydrogen or R.sup.9;
or R.sup.9a and R.sup.6, together with the intervening atoms, form
a 3- to 8-membered heterocyclyl which is optionally substituted
with from one to three R.sup.9; [0033] R.sup.10 and R.sup.11, for
each occurrence, are independently hydrogen, halo, hydroxyl,
carboxy, C.sub.1-4alkyl, or a C.sub.1-4haloalkyl; [0034] R.sup.15
for each occurrence is independently selected from the group
consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl, N--(C.sub.1-4
alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; [0035] R.sup.16 is
C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16 together with the
nitrogen atom to which they are attached form a 5 to 14 membered
heteroaryl or a 3 to 15 membered heterocyclyl, wherein the
heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms
independently selected from O, N, or S; and wherein the heteroaryl
or heterocyclyl may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0036] h is 0, 1, or 2; [0037] n, for each occurrence, is
independently 0, 1, 2, 3, or 4; [0038] m, for each occurrence, is
independently 0 or an integer from 1 to 6; [0039] p is 0, 1, 2, or
3; [0040] q is 1, 2, 3, or 4; [0041] r is 1, 2, or 3; and [0042] t
is 0 or 1, provided that the compound is not: [0043]
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz-
in-2-yl)propanoic acid; [0044]
2-(2,3-difluorophenyl)-1-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazin-5(4H)-yl)ethanone; [0045]
3-(5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid; [0046]
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid; [0047]
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazin-2-yl)propanoic acid; [0048]
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]p-
yrazine-5(4H)-carboxamide; [0049]
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-3-(p-tolyl)propan-1-one; [0050] methyl
5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-
-carboxylate; [0051] methyl
5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate; [0052]
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepin-2-yl)propanoic acid; [0053]
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid; [0054]
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepin-2-yl)propanoic acid; [0055]
1-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-
-2-(3-(trifluoromethyl)phenyl)ethanone; [0056]
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(3-(trifluoromethyl)phenyl)ethanone; [0057]
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(2-fluorophenyl)ethanone; [0058]
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-5(6H)-carboxamide; [0059]
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide; [0060]
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid; [0061]
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid; [0062]
1-(2-((1,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)--
yl)-2-(4-methoxyphenyl)ethanone; [0063]
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid; [0064]
3-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)propan-1-one; [0065]
2-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)ethanone; [0066]
2-(4-ethoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-5(6H)-yl)ethanone; [0067] methyl
5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate; [0068]
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-2,-
5(4H)-dicarboxamide; [0069]
5-((1-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxylic acid; [0070]
4-(4-chlorophenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl-
)butan-1-one; [0071]
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-c-
arboxamide; [0072]
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(4-ethoxyphenyl-
)ethanone; [0073]
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethano-
ne; [0074]
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine--
8(9H)-carboxamide; [0075]
1-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1-
H)-carboxamide; [0076]
N-(4-fluorobenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0077]
1-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1-
H)-carboxamide; [0078]
1-ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0079]
2-(2-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone; [0080]
2-(4-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone; [0081]
N-(3-methoxybenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2-
(1H)-carboxamide; [0082]
1-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-
-2(1H)-carboxamide; [0083]
1-isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
e-2(1H)-carboxamide; [0084]
6-methyl-N-(4-methylbenzyl)-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0085]
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-
-b]pyrrole-4-carboxylic acid; [0086]
2-(3-bromophenyl)-2-methyl-1-(2-methyl-5,6-dihydro-[1,2,4]triazolo[1,5-a]-
pyrazin-7(8H)-yl)propan-1-one; [0087]
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl-
)ethanone; [0088]
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone; [0089]
2-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)ethanone; [0090]
3-(m-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one; [0091]
3-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one; [0092]
2-(2-chloro-6-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7(8H)-yl)ethanone; [0093]
4-(3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propyl)benzonitrile; [0094]
2-(2-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyraz-
in-7(8H)-yl)-2-methylpropan-1-one; [0095]
3-(2-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propan-1-one; [0096]
2-(3,4-dimethoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyr-
azin-7(8H)-yl)ethanone; [0097]
2-(3-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7(8H)-yl)ethanone; [0098]
2-(2-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7(8H)-yl)ethanone; [0099]
3-(4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propan-1-one; [0100]
3-(3-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propan-1-one; [0101]
2-(2-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin--
7(8H)-yl)ethanone; [0102]
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone; [0103]
1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(2-fluor-
ophenyl)-2-methylpropan-1-one; [0104]
3-(3-chloro-4-methylphenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7(8H)-yl)propan-1-one; [0105]
3-(2,5-dimethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one; [0106]
3-(3-chloro-4-methylphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7(8H)-yl)propan-1-one; [0107]
1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-(p-toly-
l)pentan-1-one; [0108]
2-(2-chloro-6-fluorophenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7(8H)-yl)ethanone; [0109]
3-(2-ethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-
(8H)-yl)propan-1-one; [0110]
3-(2-methoxyphenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]tri-
azolo[4,3-d][1,4]diazepin-7(6H)-yl)propan-1-one; [0111]
2-(3,4-dichlorophenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]-
triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone; [0112]
2-([1,1'-biphenyl]-4-yl)-1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone; [0113]
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone; [0114]
2-(3-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]-
diazepin-7(6H)-yl)ethanone; [0115]
1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-y-
l)-2-(4-(methylthio)phenyl)ethanone; [0116]
2-(2-chloro-6-fluorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triaz-
olo[4,3-a]pyrazin-7(8H)-yl)ethanone;
[0117]
2-(2-chlorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazol-
o[4,3-a]pyrazin-7(8H)-yl)ethanone; [0118]
5-(4-bromophenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridi-
n-5(4H)-yl)pentan-1-one; [0119]
3-(4-ethoxyphenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyrid-
in-5(4H)-yl)propan-1-one; [0120]
2-(2-ethoxyphenoxy)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyri-
din-5(4H)-yl)ethanone; [0121]
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy-
)ethanone; [0122]
3-(5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepin-2-yl)propanoic acid; [0123]
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid; [0124]
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid; [0125]
2-(4-ethylphenoxy)-1-(2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-5(6H)-yl)ethanone; [0126]
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-2-(m-tolyloxy)ethanone; [0127] methyl
5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carboxylate; [0128]
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonitrile; [0129]
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonitrile; [0130]
1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4-fluor-
ophenyl)ethanone; [0131]
2-(2-chloro-6-fluorophenyl)-1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]-
pyridin-5(4H)-yl)ethanone; [0132] methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate; [0133] methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate; [0134]
3-(5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid; [0135]
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid; [0136]
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazin-2-yl)propanoic acid; [0137]
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-2-yl)propanoic acid; [0138] methyl
5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxylate; [0139]
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxamide; [0140]
2-(2-hydroxyphenyl)-1-(2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-
-a]pyrazin-5(4H)-yl)ethanone; [0141]
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-
-2-carboxamide; [0142]
2-(3-chloro-4-hydroxyphenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepi-
n-8(9H)-yl)ethanone; [0143]
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanon-
e; or [0144]
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)propan-1-
-one.
[0145] Also provided is a pharmaceutical composition comprising at
least one compound represented by structural formula (I), or a
pharmaceutically acceptable salt thereof:
##STR00005##
[0146] or a pharmaceutically acceptable salt thereof, wherein:
[0147] L is --C(O)--, --O--C(O)--, --NR.sup.6--C(O)--, or
--S(O).sub.2--;
[0148] L.sup.2 is a bond, --O--, or --NR--;
[0149] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl;
[0150] R.sup.1 is a C.sub.1-8alkylene;
[0151] R.sup.2 is selected form the group consisting of:
##STR00006## ##STR00007##
[0152] R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.2--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or -L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four
R.sup.5;
[0153] L.sup.1 is C.sub.1-8alkylene, --C(O)--, --C(O)O--,
--C(O)NR--, --S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--;
[0154] R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5;
[0155] R.sup.5 is halo, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0156] R.sup.6 is hydrogen or a C.sub.1-8alkyl;
[0157] R.sup.7, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0158] R.sup.8, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0159] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl;
[0160] R.sup.9a is hydrogen or R.sup.9; or R.sup.9a and R.sup.6,
together with the intervening atoms, form a 3- to 8-membered
heterocyclyl which is optionally substituted with from one to three
R.sup.9;
[0161] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, halo, hydroxyl, carboxy, C.sub.1-4alkyl, or
a C.sub.1-4haloalkyl;
[0162] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0163] R.sup.16 is C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16
together with the nitrogen atom to which they are attached form a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein the
heteroaryl or heterocyclyl may be optionally substituted with from
1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4 alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0164] h is 0, 1, or 2;
[0165] n, for each occurrence, is independently 0, 1, 2, 3, or
4;
[0166] m, for each occurrence, is independently 0 or an integer
from 1 to 6;
[0167] p is 0, 1, 2, or 3;
[0168] q is 1, 2, 3, or 4;
[0169] r is 1, 2, or 3; and
[0170] t is 0 or 1, provided that the compound is not
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone;
[0171] and at least one pharmaceutically acceptable carrier or
excipient.
[0172] Also provided is a method of preventing, treating, or
reducing symptoms of a condition mediated by S1P activity and/or
ATX activity in a mammal comprising delivering (e.g.,
administering) to said mammal an effective amount of a compound
represented by structural formula (I):
##STR00008##
[0173] or a pharmaceutically acceptable salt thereof, wherein:
[0174] L is --C(O)--, --O--C(O)--, --NR.sup.6--C(O)--, or
--S(O).sub.2--;
[0175] L.sup.2 is a bond, --O--, or --NR--;
[0176] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl;
[0177] R.sup.1 is a C.sub.1-8alkylene;
[0178] R.sup.2 is selected form the group consisting of:
##STR00009## ##STR00010##
[0179] R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or -L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four
R.sup.5;
[0180] L.sup.1 is C.sub.1-8alkylene, --C(O)--, --C(O)O--,
--C(O)NR--, --S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--;
[0181] R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5;
[0182] R.sup.5 is halo, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4 alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4 alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0183] R.sup.6 is hydrogen or a C.sub.1-8alkyl;
[0184] R.sup.7, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0185] R.sup.8, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0186] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8 alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8 alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl;
[0187] R.sup.9a is hydrogen or R.sup.9; or R.sup.9a and R.sup.6,
together with the intervening atoms, form a 3- to 8-membered
heterocyclyl which is optionally substituted with from one to three
R.sup.9;
[0188] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, halo, hydroxyl, carboxy, C.sub.1-4alkyl, or
a C.sub.1-4haloalkyl;
[0189] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl, C.sub.1-4
alkylsulfonamido, sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0190] R.sup.16 is C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16
together with the nitrogen atom to which they are attached form a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein the
heteroaryl or heterocyclyl may be optionally substituted with from
1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0191] h is 0, 1, or 2;
[0192] n, for each occurrence, is independently 0, 1, 2, 3, or
4;
[0193] m, for each occurrence, is independently 0 or an integer
from 1 to 6;
[0194] p is 0, 1, 2, or 3;
[0195] q is 1, 2, 3, or 4;
[0196] r is 1, 2, or 3; and
[0197] t is 0 or 1.
[0198] The condition can be selected from the group consisting of
an inflammatory disorder, an autoimmune disorder, a fibrosis of the
lung, or a malignancy of the lung. The inflammatory disorder can be
rheumatoid arthritis. The autoimmune disorder can be multiple
sclerosis. The method can further include administering to said
mammal an effective amount of one or more drugs selected from the
group consisting of: a corticosteroid, a bronchodilator, an
antiasthmatic, an antiinflammatory, an antirheumatic, an
immunosuppressant, an antimetabolite, an immunomodulator, an
antipsoriatic, and an antidiabetic.
[0199] Also provided is a method of promoting myelination or
remyelination in a mammal in need thereof, comprising administering
to cells an effective amount of at least one compound, or a
pharmaceutically acceptable salt thereof, described herein.
[0200] Also provided is a method of preventing, treating, or
reducing chronic pain in a mammal comprising delivering (e.g.,
administering) to said mammal an effective amount of at least one
compound, or a pharmaceutically acceptable salt thereof,
represented by formula (I):
##STR00011##
[0201] or a pharmaceutically acceptable salt thereof, wherein:
[0202] L is --C(O)--, --O--C(O)--, --NR--C(O)--, or
--S(O).sub.2--;
[0203] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl;
[0204] R.sup.1 is a C.sub.1-8alkylene;
[0205] R.sup.2 is selected form the group consisting of:
##STR00012##
[0206] R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or -L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four
R.sup.5;
[0207] L.sup.1 is C.sub.1-8alkylene, --C(O)--, --C(O)O--,
--C(O)NR--, --S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--;
[0208] R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5;
[0209] R.sup.5 is halo, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0210] R.sup.7, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0211] R.sup.8, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and
C.sub.1-8alkylsulfonamido;
[0212] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl;
[0213] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, halo, hydroxyl, carboxy, C.sub.1-4alkyl, or
a C.sub.1-4haloalkyl;
[0214] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0215] R.sup.16 is C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16
together with the nitrogen atom to which they are attached form a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein the
heteroaryl or heterocyclyl may be optionally substituted with from
1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0216] h is 0, 1, or 2;
[0217] n, for each occurrence, is independently 0, 1, 2, 3, or
4;
[0218] m, for each occurrence, is independently 0 or an integer
from 1 to 6;
[0219] p is 0, 1, 2, or 3;
[0220] q is 1, 2, 3, or 4;
[0221] r is 1, 2, or 3; and
[0222] t is 0 or 1, provided that the compound is not
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone.
[0223] In some embodiments, the chronic pain can be inflammatory
pain or neuropathic pain.
[0224] Other features or advantages will be apparent from the
following detailed description of several embodiments, and also
from the appended claims.
[0225] As used in the present specification, the following words,
phrases and symbols are generally intended to have the meanings as
set forth below, except to the extent that the context in which
they are used indicates otherwise.
[0226] As used herein, the term "alkyl" refers to a fully saturated
branched or unbranched hydrocarbon moiety. In some embodiments, the
alkyl comprises 1 to 20 carbon atoms, such as 1 to 16 carbon atoms,
1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
or n-decyl.
[0227] As used herein, the term "alkylene" refers to a divalent
alkyl group. Examples of alkylene groups include methylene,
ethylene, propylene, n-butylene, and the like. The alkylene is
attached to the rest of the molecule through a single bond and to
the radical group through a single bond. The points of attachment
of the alkylene to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
carbon chain.
[0228] As used herein, the term "haloalkyl" refers to an alkyl, as
defined herein, that is substituted by one or more halo groups as
defined herein. In some embodiments, the haloalkyl can be
monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
A monohaloalkyl can have one iodo, bromo, chloro or fluoro
substituent. Dihaloalkyl and polyhaloalkyl groups can be
substituted with two or more of the same halo atoms or a
combination of different halo groups. Non-limiting examples of
haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A
perhaloalkyl refers to an alkyl having all hydrogen atoms replaced
with halo atoms. In some embodiments, a haloalkyl group is
trifluoromethyl or difluoromethyl.
[0229] As used herein, the term "halogen" or "halo" may be fluoro,
chloro, bromo or iodo.
[0230] "Alkenyl" refers to an unsaturated hydrocarbon group which
may be linear or branched and has at least one carbon-carbon double
bond. Alkenyl groups with 2-8 carbon atoms can be preferred. The
alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds, or
more. Examples of alkenyl groups include ethenyl, n-propenyl,
isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.
[0231] "Alkynyl" refers to an unsaturated hydrocarbon group which
may be linear or branched and has at least one carbon-carbon triple
bond. Alkynyl groups with 2-8 carbon atoms can be preferred. The
alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, or
more. Examples of alkynyl groups include ethynyl, n-propynyl,
n-but-2-ynyl, n-hex-3-ynyl and the like.
[0232] As used herein, the term "alkoxy" refers to alkyl-O--,
wherein alkyl is defined herein above. Representative examples of
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,
cyclopropyloxy-, cyclohexyloxy- and the like. Alternatively,
representative examples of alkoxy include, but are not limited to,
methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy,
pentyloxy, and hexyloxy, and the like. In some embodiments, alkoxy
groups have about 1-6 carbon atoms, such as about 1-4 carbon
atoms.
[0233] As used herein, the term "haloalkoxy" refers to
haloalkyl-O--, wherein haloalkyl is defined herein above.
Representative example of haloalkoxy groups are trifluoromethoxy,
difluoromethoxy, and 1,2-dichloroethoxy. In some embodiments,
haloalkoxy groups have about 1-6 carbon atoms, such as about 1-4
carbon atoms.
[0234] As used herein, the term "alkylthio" refers to alkyl-S--,
wherein alkyl is defined herein above.
[0235] As used herein, the term "carbocyclyl" refers to saturated
or partially unsaturated (but not aromatic) monocyclic, bicyclic or
tricyclic hydrocarbon groups of 3-14 carbon atoms, such as 3-9, for
example, 3-8 carbon atoms. Carbocyclyls include fused or bridged
ring systems. The term "carbocyclyl" encompasses cycloalkyl groups.
The term "cycloalkyl" refers to completely saturated monocyclic,
bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, such
as 3-9, for example, 3-8 carbon atoms. Exemplary monocyclic
carbocyclyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.
Exemplary bicyclic carbocyclyl groups include bornyl,
decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl.
Exemplary tricyclic carbocyclyl groups include adamantyl.
[0236] As used herein, the term "halocycloalkyl" refers to a
cycloalkyl, as defined herein, that is substituted by one or more
halo groups as defined herein. In some embodiments the
halocycloalkyl can be monohalocycloalkyl, dihalocycloalkyl or
polyhalocycloalkyl including perhalocycloalkyl. A
monohalocycloalkyl can have one iodo, bromo, chloro or fluoro
substituent. Dihalocycloalkyl and polyhalocycloalkyl groups can be
substituted with two or more of the same halo atoms or a
combination of different halo groups.
[0237] As used herein, the term "cycloalkoxy" refers to
cycloalkyl-O--, wherein cycloalkyl is defined herein above.
[0238] As used herein, the term "halocycloalkoxy" refers to
halocycloalkyl-O--, wherein halocycloalkyl is defined herein
above.
[0239] As used herein, the term "the term "aryl" refers to
monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups
having from 6 to 14 carbon atoms in the ring portion. In some
embodiments, the term aryl refers to monocyclic and bicyclic
aromatic hydrocarbon groups having from 6 to 10 carbon atoms.
Representative examples of aryl groups include phenyl, naphthyl,
fluorenyl, and anthracenyl.
[0240] The term "aryl" also refers to a bicyclic or tricyclic group
in which at least one ring is aromatic and is fused to one or two
non-aromatic hydrocarbon ring(s). Nonlimiting examples include
tetrahydronaphthalene, dihydronaphthalenyl and indanyl.
[0241] As used herein, the term "heterocyclyl" refers to a
saturated or unsaturated, non-aromatic monocyclic, bicyclic or
tricyclic ring system which has from 3- to 15-ring members at least
one of which is a heteroatom, and up to 10 of which may be
heteroatoms, wherein the heteroatoms are independently selected
from O, S and N, and wherein N and S can be optionally oxidized to
various oxidation states. In some embodiments, a heterocyclyl is a
3-8-membered monocyclic. In some embodiments, a heterocyclyl is a
6-12-membered bicyclic. In some embodiments, a heterocyclycyl is a
10-15-membered tricyclic ring system. The heterocyclyl group can be
attached at a heteroatom or a carbon atom. Heterocyclyls include
fused or bridged or spiro ring systems. The term "heterocyclyl"
encompasses heterocycloalkyl groups. The term "heterocycloalkyl"
refers to completely saturated monocyclic, bicyclic or tricyclic
heterocyclyl comprising 3-15 ring members, at least one of which is
a heteroatom, and up to 10 of which may be heteroatoms, wherein the
heteroatoms are independently selected from O, S and N, and wherein
N and S can be optionally oxidized to various oxidation states.
Examples of heterocyclyls include dihydrofuranyl, [1,3]dioxolane,
1,4-dioxane, 1,4-dithiane, 1,3-dioxolane, imidazolidinyl,
imidazolinyl, dihydropyran, oxathiolane, dithiolane, I,3-dioxane,
1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl, aziridinyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl,
oxapinyl, oxazepinyl and diazepinyl. Further examples of
heterocyclyls include azepanyl, azetidinyl, 1,4-diazepanyl,
4,5-dihydrothiazolyl, morpholinyl, oxetanyl, piperidinyl,
piperidin-2-one, piperazinyl, piperazin-2-one, pyrrolidinyl,
tetrahydro-2H-pyranyl, 1,2,3,6-tetrahydropyridinyl,
3-azabicyclo[3.1.0]hexanyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[2,3-b]pyrrolyl,
octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl,
octahydropyrrolo[3,4-c]pyrrolyl, 9-azabicyclo[3.3.1]nonanyl,
8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl,
2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl,
3,9-diazabicyclo[3.3.1]nonanyl, 2,8-diazaspiro[4.5]decane,
5,8-diazaspiro[3.5]nonane, 4,7-diazaspiro[2.5]octane, and
6,9-diazaspiro[4.5]decane.
[0242] As used herein, the term "heteroaryl" refers to a 5-14
membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1
to 10 heteroatoms independently selected from N, O or S, wherein N
and S can be optionally oxidized to various oxidation states, and
wherein at least one ring in the ring system is aromatic. In one
embodiment, the heteroaryl is monocyclic and has 5 or 6 ring
members. Examples of monocyclic heteroaryl groups include pyridyl,
thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl and tetrazolyl. Examples of monocyclic heteroaryl
groups further include imidazolyl, oxadiazolyl, pyridinyl (or
pyridyl), pyrazolyl, thiazolyl, and tetrazolyl. In another
embodiment, the heteroaryl is bicyclic and has from 8 to 10 ring
members. Examples of bicyclic heteroaryl groups include indolyl,
benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl,
isoindolyl, indolizinyl, benzamidazolyl, quinolinyl,
5,6,7,8-tetrahydroquinoline and
6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
[0243] As used herein, the term "amino" refers to a group having
the formula NH.sub.2. The term N-(alkyl)amino is an amino group in
which one of the hydrogen atoms is replaced with an alkyl group.
The term N,N-(dialkyl)amino is an amino group in which each
hydrogen atoms is replaced with an alkyl group which may be the
same or different.
[0244] As used herein, the term "alkanoyl" refers to
alkyl-C(.dbd.O)--, where alkyl is defined herein above.
[0245] As used herein, the term "alkoxycarbonyl" refers to
alkyl-O--C(.dbd.O)--, where alkyl is defined herein above.
[0246] As used herein, the term "alkanoyloxy" refers to
alkyl-C(.dbd.O)--O--, where alkyl is defined herein above.
[0247] As used herein, the term "alkylamido" refers to
alkyl-C(.dbd.O)--NH--, where alkyl is defined herein above.
[0248] As used herein, the term "carbamoyl" refers to
--C(.dbd.O)--NH.sub.2. The term N-alkylcarbamoyl refers to a
carbamoyl group in which one of the hydrogen atoms is replaced with
an alkyl group. The term N,N-dialkylcarbamoyl refers to a carbamoyl
group in which each hydrogen atoms is replaced with an alkyl group
which may be the same or different.
[0249] As used herein, the term "carboxy" or "carboxyl" refers to
--C(.dbd.O)--OH.
[0250] As used herein, the term "bridged ring system," is a ring
system that has a carbocyclyl or heterocyclyl ring wherein two
non-adjacent atoms of the ring are connected (bridged) by one or
more (such as from one to three) atoms. A bridged ring system can
have more than one bridge within the ring system (e.g., adamantyl).
A bridged ring system may have from 6-10 ring members, such as from
7-10 ring members. Examples of bridged ring systems include
adamantly, 9-azabicyclo[3.3.1]nonan-9-yl,
8-azabicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,
3-azabicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl,
(1R,5S)-bicyclo[3.2.1]octanyl, 3-azabicyclo[3.3.1]nonanyl, and
bicyclo[2.2.1]heptanyl. In some embodiments, the bridged ring
system is selected from 9-azabicyclo[3.3.1]nonan-9-yl,
8-azabicyclo[3.2.1]octanyl, and bicyclo[2.2.2]octanyl. In some
embodiments, the bridged ring system is selected from
9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl,
8-azabicyclo[3.2.1]oct-2-enyl, 2,5-diazabicyclo[2.2.1]heptanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl,
3,6-diazabicyclo[3.2.1]octanyl, and
3,9-diazabicyclo[3.3.1]nonanyl.
[0251] As used herein, the term "spiro ring system," is a ring
system that has a carbocyclyl or heterocyclyl with rings connected
through just one atom. The rings can be different in nature or
identical. A spiro ring system may have from 6-12 ring members,
such as from 8-10 ring members. Examples of spiro ring systems
include 2,8-diazaspiro[4.5]decane, 5,8-diazaspiro[3.5]nonane,
4,7-diazaspiro[2.5]octane, and 6,9-diazaspiro[4.5]decane.
[0252] The number of carbon atoms in a group is specified herein by
the prefix "C.sub.X-xx", wherein x and xx are integers. For
example, "C.sub.1-4alkyl" is an alkyl group which has from 1 to 4
carbon atoms; C.sub.1-6alkoxy is an alkoxy group having from 1 to 6
carbon atoms; C.sub.6-10aryl is an aryl group which has from 6 to
10 carbon atoms; C.sub.1-4haloalkyl is a haloalkyl group which has
from 1 to 4 carbon atoms; and N,N-di-C.sub.1-6alkylamino is a
N,N-dialkylamino group in which the nitrogen is substituted with
two alkyl groups each of which is independently from 1 to 6 carbon
atoms.
[0253] The disclosed compounds, or pharmaceutically acceptable
salts thereof, can contain one or more asymmetric centers in the
molecule. In accordance with the present disclosure any structure
that does not designate the stereochemistry is to be understood as
embracing all the various optical isomers (e.g., diastereomers and
enantiomers) in pure or substantially pure form, as well as
mixtures thereof (such as a racemic mixture, or an enantiomerically
enriched mixture). It is well known in the art how to prepare such
optically active forms (for example, resolution of the racemic form
by recrystallization techniques, synthesis from optically-active
starting materials, by chiral synthesis, or chromatographic
separation using a chiral stationary phase). The disclosed
compounds may exist in tautomeric forms and mixtures and separate
individual tautomers are contemplated. In addition, some compounds
may exhibit polymorphism.
[0254] By way of clarity, compounds of the invention included all
isotopes of the atoms present in formula (I) and any of the
examples or embodiments disclosed herein. For example, H (or
hydrogen) represents any isotopic form of hydrogen including
.sup.1H, .sup.2H (D), and .sup.3H (T); C represents any isotopic
form of carbon including .sup.12C, .sup.13C, and .sup.14C; O
represents any isotopic form of oxygen including .sup.16O, .sup.17O
and .sup.18O; N represents any isotopic form of nitrogen including
.sup.13N, .sup.14N and .sup.15N; P represents any isotopic form of
phosphorous including .sup.31P and .sup.32P; S represents any
isotopic form of sulfur including .sup.32S and .sup.35S; F
represents any isotopic form of fluorine including .sup.19F and
.sup.18F; Cl represents any isotopic form of chlorine including
.sup.35Cl, .sup.37Cl and .sup.36Cl; and the like. In a preferred
embodiment, compounds represented by formula (I) comprises isotopes
of the atoms therein in their naturally occurring abundance.
However, in certain instances, it is desirable to enrich one or
more atom in a particular isotope which would normally be present
in less abundance. For example, .sup.1H would normally be present
in greater than 99.98% abundance; however, a compound of the
invention can be enriched in .sup.2H or .sup.3H at one or more
positions where H is present. In particular embodiments of the
compounds of formula (I), when, for example, hydrogen is enriched
in the deuterium isotope, the symbol "D" may be used to represent
the enrichment in deuterium. In one embodiment, when a compound of
the invention is enriched in a radioactive isotope, for example
.sup.3H and .sup.14C, they may be useful in drug and/or substrate
tissue distribution assays. It is to be understood that the
invention encompasses all such isotopic forms which modulate ATX or
S1P receptor activity.
[0255] Provided is a compound represented by formula (I), or a
pharmaceutically acceptable salt thereof:
##STR00013## [0256] or a pharmaceutically acceptable salt thereof,
wherein: [0257] L is --C(O)--, --O--C(O)--, --NR.sup.6--C(O)--, or
--S(O).sub.2--; [0258] L.sup.2 is a bond, --O--, or NR--; provided
that L.sup.2 is not --O-- when R.sup.2 is structure (iv); [0259] R,
for each occurrence, is independently hydrogen or a C.sub.1-4alkyl;
[0260] R.sup.1 is a C.sub.1-8alkylene; [0261] R.sup.2 is selected
form the group consisting of:
[0261] ##STR00014## ##STR00015## [0262] R.sup.3 is hydrogen, --CN,
C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four R.sup.5;
provided that when R.sup.2 is structure (ii), (iii), (iv), or (xi),
R.sup.3 is not hydrogen; and provided that when R.sup.2 is
structure (iv), R.sup.3 is not pyrrolidinyl, piperidinyl, an
N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an
N-methylpiperidinyl, or an N-acetyl-piperidinyl; [0263] L.sup.1 is
C.sub.1-8alkylene, --C(O)--, --C(O)O--, --C(O)NR--, S(O).sub.2NR--,
or C(O)NR--S(O).sub.2--; [0264] R.sup.4 is C.sub.1-8alkyl,
C.sub.3-8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein
R.sup.4 may be optionally substituted with from one to four
R.sup.5; [0265] R.sup.5 is halo, cyano, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; [0266] R.sup.6 is hydrogen
or a C.sub.1-8alkyl; [0267] R.sup.7, for each occurrence, is
independently selected from the group consisting of halo, hydroxyl,
oxo, nitro, cyano, carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkoxy,
C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
[0268] R.sup.8, for each occurrence, is independently selected from
the group consisting of halo, hydroxyl, nitro, cyano, carboxy,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl,
C.sub.3-8halocycloalkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkoxy,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, and C.sub.1-8alkylsulfonamido;
[0269] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl; [0270] R.sup.9a is hydrogen or R.sup.9;
or R.sup.9a and R.sup.6, together with the intervening atoms, form
a 3- to 8-membered heterocyclyl which is optionally substituted
with from one to three R.sup.9; [0271] R.sup.10 and R.sup.11, for
each occurrence, are independently hydrogen, halo, hydroxyl,
carboxy, C.sub.1-4alkyl, or a C.sub.1-4haloalkyl; [0272] R.sup.15
for each occurrence is independently selected from the group
consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carboxyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl; [0273] R.sup.16 is
C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16 together with the
nitrogen atom to which they are attached form a 5 to 14 membered
heteroaryl or a 3 to 15 membered heterocyclyl, wherein the
heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms
independently selected from O, N, or S; and wherein the heteroaryl
or heterocyclyl may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0274] h is 0, 1, or 2; [0275] n, for each occurrence, is
independently 0, 1, 2, 3, or 4; [0276] m, for each occurrence, is
independently 0 or an integer from 1 to 6; [0277] p is 0, 1, 2, or
3; [0278] q is 1, 2, 3, or 4; [0279] r is 1, 2, or 3; and [0280] t
is 0 or 1, provided that the compound is not: [0281]
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz-
in-2-yl)propanoic acid; [0282]
2-(2,3-difluorophenyl)-1-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazin-5(4H)-yl)ethanone; [0283]
3-(5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid; [0284]
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid; [0285]
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazin-2-yl)propanoic acid; [0286]
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]p-
yrazine-5(4H)-carboxamide; [0287]
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-3-(p-tolyl)propan-1-one; [0288] methyl
5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-
-carboxylate; [0289] methyl
5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate; [0290]
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepin-2-yl)propanoic acid; [0291]
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid; [0292]
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepin-2-yl)propanoic acid; [0293]
1-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-
-2-(3-(trifluoromethyl)phenyl)ethanone; [0294]
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(3-(trifluoromethyl)phenyl)ethanone; [0295]
1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl-
)-2-(2-fluorophenyl)ethanone; [0296]
N-(3-fluorobenzyl)-2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-5(6H)-carboxamide; [0297]
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide; [0298]
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid; [0299]
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4-
]diazepin-2-yl)propanoic acid; [0300]
1-(2-((1,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)--
yl)-2-(4-methoxyphenyl)ethanone; [0301]
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
-2-yl)propanoic acid; [0302]
3-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)propan-1-one; [0303]
2-(2-methoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepin-5(6H)-yl)ethanone; [0304]
2-(4-ethoxyphenyl)-1-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-5(6H)-yl)ethanone; [0305] methyl
5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carboxylate; [0306]
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-2,-
5(4H)-dicarboxamide; [0307]
5-((1-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxylic acid; [0308]
4-(4-chlorophenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl-
)butan-1-one; [0309]
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-c-
arboxamide; [0310]
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(4-ethoxyphenyl-
)ethanone; [0311]
1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethano-
ne; [0312]
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine--
8(9H)-carboxamide; [0313]
1-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1-
H)-carboxamide; [0314]
N-(4-fluorobenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0315]
1-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1-
H)-carboxamide; [0316]
1-ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0317]
2-(2-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone; [0318]
2-(4-aminophenyl)-1-(1,6-dimethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)--
yl)ethanone; [0319]
N-(3-methoxybenzyl)-6-methyl-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2-
(1H)-carboxamide; [0320]
1-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-
-2(1H)-carboxamide; [0321]
1-isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
e-2(1H)-carboxamide; [0322]
6-methyl-N-(4-methylbenzyl)-1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(-
1H)-carboxamide; [0323]
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-
-b]pyrrole-4-carboxylic acid; [0324]
2-(3-bromophenyl)-2-methyl-1-(2-methyl-5,6-dihydro-[1,2,4]triazolo[1,5-a]-
pyrazin-7(8H)-yl)propan-1-one; [0325]
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl-
)ethanone; [0326]
2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7(8H)-yl)ethanone; [0327]
2-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)ethanone; [0328]
3-(m-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one; [0329]
3-(p-tolyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7(8H)-yl)propan-1-one; [0330]
2-(2-chloro-6-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7(8H)-yl)ethanone; [0331]
4-(3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propyl)benzonitrile; [0332]
2-(2-fluorophenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyraz-
in-7(8H)-yl)-2-methylpropan-1-one; [0333]
3-(2-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7(8H)-yl)propan-1-one; [0334]
2-(3,4-dimethoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyr-
azin-7(8H)-yl)ethanone; [0335]
2-(3-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7 (8H)-yl)ethanone; [0336]
2-(2-chloro-4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3--
a]pyrazin-7 (8H)-yl)ethanone; [0337]
3-(4-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7 (8H)-yl)propan-1-one; [0338]
3-(3-methoxyphenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
-7 (8H)-yl)propan-1-one; [0339]
2-(2-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin--
7 (8H)-yl)ethanone; [0340]
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a-
]pyrazin-7 (8H)-yl)ethanone; [0341]
1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)-2-(2-fluorophenyl)-2-methylpropan-1-one; [0342]
3-(3-chloro-4-methylphenyl)-1-(3-isopropyl-5,6-dihydro-[1,2,4]triazolo[4,-
3-a]pyrazin-7 (8H)-yl)propan-1-one; [0343]
3-(2,5-dimethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyra-
zin-7 (8H)-yl)propan-1-one; [0344]
3-(3-chloro-4-methylphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7 (8H)-yl)propan-1-one; [0345]
1-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)-5-(p-tolyl)pentan-1-one; [0346]
2-(2-chloro-6-fluorophenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]-
pyrazin-7 (8H)-yl)ethanone; [0347]
3-(2-ethoxyphenyl)-1-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl)propan-1-one; [0348]
3-(2-methoxyphenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]tri-
azolo[4,3-d][1,4]diazepin-7(6H)-yl)propan-1-one; [0349]
2-(3,4-dichlorophenyl)-1-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[1,2,4]-
triazolo[4,3-d][1,4]diazepin-7(6H)-yl)ethanone; [0350]
2-([1,1'-biphenyl]-4-yl)-1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone; [0351]
2-(2-chloro-6-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,-
3-d][1,4]diazepin-7(6H)-yl)ethanone; [0352]
2-(3-fluorophenyl)-1-(3-methyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]-
diazepin-7(6H)-yl)ethanone; [0353]
1-(3-isopropyl-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-y-
l)-2-(4-(methylthio)phenyl)ethanone; [0354]
2-(2-chloro-6-fluorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triaz-
olo[4,3-a]pyrazin-7(8H)-yl)ethanone;
[0355]
2-(2-chlorophenyl)-1-(3-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazol-
o[4,3-a]pyrazin-7(8H)-yl)ethanone; [0356]
5-(4-bromophenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridi-
n-5(4H)-yl)pentan-1-one; [0357]
3-(4-ethoxyphenyl)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyrid-
in-5(4H)-yl)propan-1-one; [0358]
2-(2-ethoxyphenoxy)-1-(1-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyri-
din-5(4H)-yl)ethanone; [0359]
1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy-
)ethanone; [0360]
3-(5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepin-2-yl)propanoic acid; [0361]
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid; [0362]
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azin-2-yl)propanoic acid; [0363]
2-(4-ethylphenoxy)-1-(2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-5(6H)-yl)ethanone; [0364]
1-(2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(-
4H)-yl)-2-(m-tolyloxy)ethanone; [0365] methyl
5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carboxylate; [0366]
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonitrile; [0367]
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonitrile; [0368]
1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4-fluor-
ophenyl)ethanone; [0369]
2-(2-chloro-6-fluorophenyl)-1-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]-
pyridin-5 (4H)-yl)ethanone; [0370] methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate; [0371] methyl
3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c-
]pyridine-6-carboxylate; [0372]
3-(5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepin-2-yl)propanoic acid; [0373]
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zin-2-yl)propanoic acid; [0374]
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazin-2-yl)propanoic acid; [0375]
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepin-2-yl)propanoic acid; [0376] methyl
5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxylate; [0377]
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carboxamide; [0378]
2-(2-hydroxyphenyl)-1-(2-(pyrrolidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-
-a]pyrazin-5 (4H)-yl)ethanone; [0379]
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-
-2-carboxamide; [0380]
2-(3-chloro-4-hydroxyphenyl)-1-(6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepi-
n-8 (9H)-yl)ethanone; [0381] 1-(5,6-dihydroimidazo[1,5-a]pyrazin-7
(8H)-yl)-2-(2-hydroxyphenoxy)ethanone; or [0382]
1-(5,6-dihydroimidazo[1,5-a]pyrazin-7
(8H)-yl)-3-(2-hydroxyphenyl)propan-1-one.
[0383] In some embodiments, R.sup.2 is selected form the group
consisting of:
##STR00016##
[0384] In some embodiments, p is 0, 1, or 2.
[0385] In some embodiments, p is 1, and r is 1 or 2. In some
embodiments, p is 2, and r is 1.
[0386] In some embodiments, n is 1, and R.sup.7 is C.sub.1-8alkyl.
In some embodiments, n is 0.
[0387] In some embodiments, t is 1 and R.sup.8 is halo. In some
embodiments, t is 0.
[0388] In some embodiments, L.sup.2 is a bond.
[0389] In some embodiments, when L.sup.2 is O or NR, R.sup.1 is
C.sub.2-8alkylene.
[0390] In some embodiments, R.sup.6 is hydrogen.
[0391] In some embodiments, R.sup.9a is hydrogen.
[0392] In some embodiments, the compound of formula (I) is
represented by formula (II):
##STR00017##
[0393] In some embodiments, L is --C(O)--, --O--C(O)--, or
--NR--C(O)--.
[0394] In some embodiments, L is --O--C(O)--.
[0395] Provided is a compound represented by formula (III), or a
pharmaceutically acceptable salt thereof:
##STR00018##
[0396] or a pharmaceutically acceptable salt thereof, wherein:
[0397] R.sup.1 is a C.sub.1-8alkylene;
[0398] R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2NHS(O).sub.2R.sup.15,
--C(O)N(R.sup.15)--S(O).sub.2R.sup.15, --S(O).sub.2OR.sup.15,
--C(O)NHC(O)R.sup.15, --Si(O)OH, --B(OH).sub.2,
--N(R.sup.15)S(O).sub.2R.sup.15).sub.2, --P(O)(OR.sup.15).sub.2,
--S(O).sub.2NHC(O)R.sup.15, --C(O)NHS(O).sub.2R.sup.15, --C(O)NHOH,
--C(O)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered
heterocyclyl, or -L.sup.1-R.sup.4; where in the heteroaryl and
heterocyclyl are optionally substituted with one to four
R.sup.5;
[0399] L.sup.1 is C.sub.1-8alkylene, --C(O)--, --C(O)O--,
--C(O)NR--, --S(O).sub.2NR--, or --C(O)NR--S(O).sub.2--;
[0400] R, for each occurrence, is independently hydrogen or
C.sub.1-4alkyl;
[0401] R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or a 3 to 15
membered heterocyclyl, wherein R.sup.4 may be optionally
substituted with from one to four R.sup.5;
[0402] R.sup.5 is halo, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--C(O)N(R.sup.16).sub.2, --C(O)N(R.sup.15)--S(O).sub.2R.sup.15,
--S(O).sub.2OR.sup.15, --C(O)NHC(O)R.sup.15, --Si(O)OH,
--B(OH).sub.2, --N(R.sup.15)S(O).sub.2R.sup.15,
--S(O).sub.2N(R.sup.15).sub.2, O P(O)(OR.sup.15).sub.2,
--P(O)(OR.sup.15).sub.2, --S(O).sub.2NHC(O)R.sup.15,
--C(O)NHS(O).sub.2R.sup.15, C(O)NHOH, C(O)NHCN, --C(O)R.sup.15, a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl may be optionally
substituted with one to four substituents independently selected
from the group consisting of halo, hydroxyl, .dbd.O,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, cyano, nitro,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonamido, sulfamoyl, N--C.sub.1-4alkylsulfamoyl,
and N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0403] R.sup.9, for each occurrence, is independently selected from
the group consisting of halo, cyano, hydroxyl, carboxy,
C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl,
C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, C.sub.1-8alkanoyl,
amino, N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8alkyl)sulfamoyl, C.sub.1-8alkylsulfonamido,
C.sub.6-10aryl, C.sub.1-8alkoxy-C.sub.1-6alkyl, and
tri-(C.sub.1-8alkyl)silyl;
[0404] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, halo, hydroxyl, carboxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl;
[0405] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.6-10aryl, a 5 to 14 membered heteroaryl, and a 3 to 15
membered heterocyclyl; wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein R.sup.15 may be optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halo, C.sub.1-4alkoxy, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4 alkylsulfonamido,
sulfamoyl, N--(C.sub.1-4alkyl)sulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0406] R.sup.16 is C.sub.1-8alkoxy, or R.sup.15; or two R.sup.16
together with the nitrogen atom to which they are attached form a 5
to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl,
wherein the heteroaryl or heterocyclyl comprises from 1 to 10
heteroatoms independently selected from O, N, or S; and wherein the
heteroaryl or heterocyclyl may be optionally substituted with from
1 to 3 substituents independently selected from the group
consisting of halo, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylsulfonamido,
sulfamoyl, N--C.sub.1-4alkylsulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl;
[0407] m, for each occurrence, is independently 0 or an integer
from 1 to 6; and
[0408] q is 1, 2, 3, or 4.
[0409] In some embodiments, R.sup.3 is hydrogen, --CN,
C.sub.1-8alkyl, C.sub.1-8haloalkyl,
--(CR.sup.10R.sup.11).sub.m--N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2, a 5 to 14
membered heteroaryl, or -L.sup.1-R.sup.4; where in the heteroaryl
and heterocyclyl are optionally substituted with one to four
R.sup.5.
[0410] In some embodiments, R.sup.16, for each occurrence, is
independently selected from the group consisting of hydrogen,
C.sub.1-8alkyl, C.sub.3-8cycloalkyl, or two R.sup.16 together with
the nitrogen atom to which they are attached form a 5 to 14
membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the
heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms
independently selected from O, N, or S; and wherein the heteroaryl
or heterocyclyl may be optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl,
amino, N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino,
carboxyl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido,
C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl,
N--C.sub.1-4alkylsulfamoyl, and
N,N--(C.sub.1-4dialkyl)-sulfamoyl.
[0411] In some embodiments, R.sup.15 is H or C.sub.1-8alkyl.
[0412] In some embodiments, m is 0.
[0413] In some embodiments, R.sup.3 is --C(O)OH.
[0414] In some embodiments, q is 1 or 2.
[0415] In some embodiments, R.sup.9, for each occurrence, is
independently selected from the group consisting of halo,
C.sub.1-8alkyl, C.sub.1-8haloalkyl, and C.sub.6-10aryl.
[0416] In some embodiments, R.sup.9, for each occurrence, is
independently selected from the group consisting of fluoro, chloro,
bromo, methyl, trifluoromethyl, and phenyl.
[0417] In some embodiments, R.sup.1 is methylene or ethylene.
[0418] In some embodiments, R.sup.1 is methylene.
[0419] In some embodiments, provided is a compound selected from
the group consisting of: [0420] 5-(3,5-Dichlorobenzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate;
[0421] 5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate;
[0422] 7-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate; [0423]
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxylate; [0424]
7-(3,5-Bis(trifluoromethyl)benzyl) 3-methyl
8,9-dihydro-5H-imidazo[1,2-d][1,4]diazepine-3,7(6H)-dicarboxylate;
[0425] 5-(3,5-Bis(trifluoromethyl)benzyl) 3-ethyl
7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-3,5(6H)-dicarboxylate-
; [0426]
5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyraz-
olo[1,5-a][1,4]diazepine-2-carboxylic acid; [0427]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0428]
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydroimida-
zo[1,2-a]pyrazine-2-carboxylic acid; [0429]
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-6,7,8,9-tetrahydro-5H-i-
midazo[1,2-d][1,4]diazepine-3-carboxylic acid; [0430]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-[-
1,2,3]triazolo[1,5-a][1,4]diazepine-3-carboxylic acid; [0431]
3,5-Dichlorobenzyl
2-(9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-5(6H)-carboxylate; [0432] 3,5-Dichlorobenzyl
2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate; [0433] 3,5-Dichlorobenzyl
2-(tert-butylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate; [0434] 3,5-Dichlorobenzyl
2-(cyclobutylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate; [0435] 3,5-Dichlorobenzyl
2-(cyclopentylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6-
H)-carboxylate; [0436] 3,5-Dichlorobenzyl
2-(cyclohexylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate; [0437] 3,5-Dichlorobenzyl
2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate; [0438] 3,5-Dichlorobenzyl
2-(piperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate; [0439] 3,5-Dichlorobenzyl
2-(4-fluoropiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0440] 3,5-Dichlorobenzyl
2-(4-methylpiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0441] 3,5-Dichlorobenzyl
2-(4-(trifluoromethyl)piperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5--
a][1,4]diazepine-5(6H)-carboxylate; [0442] 3,5-Dichlorobenzyl
2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate; [0443] 3,5-Dichlorobenzyl
2-(piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate; [0444] 3,5-Dichlorobenzyl
2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0445] 3,5-Dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate; [0446] 3,5-Dichlorobenzyl
2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-ca-
rboxylate; [0447] 3,5-Dichlorobenzyl
2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)--
carboxylate; [0448] 3,5-Dichlorobenzyl
2-(ethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate; [0449] 3,5-Bis(trifluoromethyl)benzyl
2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate; [0450] 3,5-Bis(trifluoromethyl)benzyl
2-(4-hydroxypiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate; [0451] 3,5-Bis(trifluoromethyl)benzyl
2-(4-fluoropiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0452] 3,5-Bis(trifluoromethyl)benzyl
2-(piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate; [0453]
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
[0454]
9-(5-((3-chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; [0455]
9-(5-((3-(trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,-
5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0456]
9-(5-((4-Chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
[0457]
9-(5-((4-(Trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,-
5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0458]
9-(5-((3-Chloro-5-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0459]
9-(5((3,5-Difluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0460]
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0461]
9-(5-(((3-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,-
5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0462]
9-(5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydro-
pyrazolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0463]
9-(5-(((4-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
[0464]
9-(5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0465]
9-(5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0466]
9-(5-(((3,5-Difluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
[0467]
9-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0468]
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0469]
9-(5-(3-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0470]
9-(5-(3-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-py-
razolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carbo-
xylic acid; [0471]
9-(5-(4-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]-
diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
[0472]
9-(5-(4-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0473]
9-(5-(3-Chloro-5-fluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0474]
9-(5-(3,5-Difluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0475]
9-(5-((3,5-Dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyraz-
olo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxyl-
ic acid; [0476]
9-(5-((3-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0477]
9-(5-((3-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-c-
arboxylic acid; [0478]
9-(5-((4-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0479]
9-(5-((4-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-c-
arboxylic acid; [0480]
9-(5-((3-Chloro-5-fluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazol-
o[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0481]
9-(5-((3,5-Trifluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid; [0482]
9-(5-((3,5-Bis(trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H--
pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-car-
boxylic acid; [0483]
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0484]
5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0485]
5-(((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0486]
5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazo-
lo[1,5-a][1,4]diazepine-2-carboxylic acid; [0487]
5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo-
[1,5-a][1,4]diazepine-2-carboxylic acid; [0488]
5-(((3,5-Difluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepine-2-carboxylic acid; [0489]
5-(((3,4,5-Trifluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carboxylic acid; [0490]
5-(((3-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0491]
5-(((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0492]
5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazo-
lo[1,5-a][1,4]diazepine-2-carboxylic acid; [0493]
5((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carboxylic acid; [0494]
5-(((3-Bromo-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-2-carboxylic acid; [0495]
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0496]
5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carboxylic acid; [0497]
5-(7-Chloro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-
-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0498]
5-(7-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-
-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid;
[0499]
5-(5-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-
-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid;
[0500]
5-(5-Chloro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-
-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0501]
5-(3-(3,5-bis(Trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyr-
azolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0502]
5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carboxylic acid; [0503]
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carboxamido)propanoic acid; [0504]
(cis)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyra-
zolo[1,5-a][1,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid;
[0505]
(trans)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-py-
razolo[1,5-a][1,4]diazepine-2-carboxamido)cyclohexanecarboxylic
acid; [0506]
1-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyr-
azolo[1,5-a][1,4]diazepine-2-carbonyl)piperidine-4-carboxylic acid;
[0507]
1-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carbonyl)piperidine-3-carboxylic acid; [0508]
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid; [0509]
5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-2-carboxylic acid; [0510]
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
[0511]
8-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]p-
yrazine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
[0512]
1-(2-(9-Azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyr-
azin-5(4H)-yl)-3-(3,5-dichlorophenyl)propan-1-one; [0513]
3,5-Dichlorobenzyl
2-(3-(methoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro--
4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate; [0514]
3-(3,5-Dichlorophenyl)-1-(2-(morpholine-4-carbonyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazin-5(4H)-yl)propan-1-one; [0515]
8-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic
acid; [0516] 2-(3,5-Dichlorobenzyl) 7-ethyl
3,4-dihydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate; [0517]
2-(3,5-Dichlorobenzyl) 8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate;
[0518]
2-(((3,5-Dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a-
][1,4]diazepine-8-carboxylic acid; [0519] 3,5-Dichlorobenzyl
2-(4-hydroxypiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate; [0520] 3,5-Dichlorobenzyl
2-carbamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e; [0521]
9-(2-4(3,5-dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1H-py-
rrolo[1,2-a][1,4]diazepine-8-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxy-
lic acid; [0522] 3,5-Bis(trifluoromethyl)benzyl
2-carbamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e; [0523] 2-Ethyl 5-(3-methyl-5-(trifluoromethyl)benzyl)
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate;
[0524] 2-(3,5-Bis(trifluoromethyl)benzyl) 8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate;
[0525] 5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
7-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxyla-
te; [0526] 5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxyla-
te; [0527]
5-(((3-Methyl-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-t-
etrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid;
[0528]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-5,6,7,8-tetrah-
ydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0529]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-7-methyl-5,6,7,8-tetrah-
ydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0530]
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-chloro-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxylate;
[0531]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-4,5,6,7-tetrah-
ydropyrazolo[1,5-a]pyrazine-2-carboxylic acid; [0532]
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylat-
e;
[0533]
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-bromo-5,6,7,8--
tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid;
[0534]
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0535]
5-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyraz-
olo[1,5-a][1,4]diazepine-2-carboxylic acid; [0536]
3,5-Bis(trifluoromethyl)benzyl
2-(3-methyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0537] 3,5-Bis(trifluoromethyl)benzyl
2-(5-methyl-1,3,4-oxadiazol-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate; [0538]
5-(((5-Fluoro-[1,1'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0539]
3,5-Dichlorobenzyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0540] 3,5-Dichlorobenzyl
2-cyano-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0541] 3,5-Dichlorobenzyl
2-(1H-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-c-
arboxylate; [0542] 3,5-Bis(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0543] 3,5-Bis(trifluoromethyl)benzyl
2-cyano-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0544] 3-Fluoro-5-(trifluoromethyl)benzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate;
[0545] 3,5-Bis(trifluoromethyl)benzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate;
[0546] 3-Fluoro-5-(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0547] 3-Fluoro-5-(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0548] 3,5-Dichlorobenzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0549] 3,5-Dichlorobenzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate;
[0550] 3,5-Bis(trifluoromethyl)benzyl
6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxylate;
[0551] 3,5-Dichlorobenzyl
6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxylate;
[0552] 3,5-Bis(trifluoromethyl)benzyl
3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carb-
oxylate; [0553] 3-Chloro-5-(trifluoromethyl)benzyl
3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carb-
oxylate; [0554] 3,5-Bis(trifluoromethyl)benzyl
2-(1H-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-c-
arboxylate; [0555] 3-Chloro-5-(trifluoromethyl)benzyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0556]
3-(3,5-Bis(trifluoromethyl)phenyl)-1-(7,8-dihydro-4H-pyrazolo[1,5-a][1,4]-
diazepin-5(6H)-yl)propan-1-one; [0557]
5-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate;
[0558]
5-((1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)carbonyl)-5,6,7,8-tet-
rahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0559]
5-(3,5-Bis(trifluoromethyl)phenethyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate;
[0560]
5-((3,5-Bis(trifluoromethyl)phenethoxy)carbonyl)-5,6,7,8-tetrahydr-
o-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid; [0561]
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-2-carboxylic acid; [0562]
3,5-Bis(trifluoromethyl)benzyl
2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-
-5(6H)-carboxylate; [0563] 3,5-Bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate;
[0564] 3,5-Bis(trifluoromethyl)benzyl
2-(1-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate; [0565] 3,5-Bis(trifluoromethyl)benzyl
2-(1-aminoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbo-
xylate; [0566] 3,5-Bis(trifluoromethyl)benzyl
2-(1-(piperidin-1-yl)ethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine--
5(6H)-carboxylate; and [0567]
1-(1-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydr-
o-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic
acid;
[0568] or a pharmaceutically acceptable salt thereof.
[0569] In some embodiments, L is --O--C(O)--, --NR.sup.6--C(O)--,
or --C(O)--; L.sup.2 is a bond, --O--, or --NR--; R.sup.1 is
C.sub.1-4alkylene; R.sup.2 is selected form the group consisting
of:
##STR00019##
[0570] p is 1 or 2; and r is 1 or 2.
[0571] In some embodiments, R.sup.1 is methylene or ethylene;
R.sup.2 is selected from
##STR00020##
[0572] In some embodiments, L is --O--C(O); L.sup.2 is a bond;
R.sup.1 is methylene; and
R.sup.2 is
##STR00021##
[0574] In some embodiments, R.sup.7, for each occurrence, is
independently selected from the group consisting of halo, hydroxyl,
cyano, carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.1-8alkoxy, C.sub.1-8haloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl, and
C.sub.1-8alkylamido; R.sup.8, for each occurrence, is independently
selected from the group consisting of halo, hydroxyl, cyano,
carboxy, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkoxy, C.sub.1-8alkanoyl, amino,
N--(C.sub.1-8alkyl)amino, N,N-di-(C.sub.1-8alkyl)amino,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl, and
C.sub.1-8alkylamido; h is 0 or 1; n is 0 or 1; and t is 0 or 1.
[0575] In some embodiments, R.sup.7, for each occurrence, is
independently selected from the group consisting of halo, hydroxyl,
carboxy, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4haloalkoxy, C.sub.1-8alkoxycarbonyl, and
C.sub.1-8alkanoyloxy; R.sup.8, for each occurrence, is
independently selected from the group consisting of halo, cyano,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, amino, N--(C.sub.1-8
alkyl)amino, N,N-di-(C.sub.1-8 alkyl)amino, and
C.sub.1-8alkylamido; h is 0 or 1; n is 0 or 1; and t is 0 or 1.
[0576] In some embodiments, R.sup.7, for each occurrence, is
independently selected from the group consisting of hydroxyl,
carboxy, C.sub.1-4alkyl, and C.sub.1-8alkoxycarbonyl; R.sup.8, for
each occurrence, is independently selected from the group
consisting of halo, cyano, C.sub.1-4alkyl, C.sub.1-4haloalkyl, and
C.sub.1-8alkylamido; h is 0 or 1; n is 0 or 1; and t is 0 or 1.
[0577] In some embodiments, R.sup.7 is methyl, --OH, --COOH,
--COOCH.sub.3 or --COOCH.sub.2CH.sub.3; R.sup.8 is chloro, bromo,
CN, methyl, CF.sub.3, or NHC(O)CH.sub.3; h is 0 or 1; n is 0 or 1;
and t is 0 or 1.
[0578] In some embodiments, R.sup.9, for each occurrence, is
independently selected from the group consisting of halo, cyano,
hydroxyl, carboxy, C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8haloalkyl, C.sub.1-8haloalkoxy, C.sub.1-8alkanoyl,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoyloxy, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N-di-(C.sub.1-8alkyl)carbamoyl,
C.sub.1-8 alkylamido, mercapto, C.sub.1-8alkylthio,
C.sub.1-8alkylsulfonyl, sulfamoyl, N--(C.sub.1-8alkyl)sulfamoyl,
N,N-di-(C.sub.1-8 alkyl)sulfamoyl, C.sub.1-8 alkylsulfonamido,
C.sub.6-10 aryl, and C.sub.1-8 alkoxy-C.sub.1-6alkyl; and q is 1,
2, or 3.
[0579] In some embodiments, R.sup.9, for each occurrence, is
independently selected from the group consisting of halo, cyano,
carboxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8haloalkyl,
C.sub.1-8haloalkoxy, C.sub.6-10aryl, and
C.sub.1-8alkoxy-C.sub.1-6alkyl; and q is 1, 2, or 3.
[0580] In some embodiments, R.sup.9, for each occurrence, is
independently selected from the group consisting of halo,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, and phenyl; and q is 1, 2, or
3.
[0581] In some embodiments, each R.sup.9 is independently selected
from methyl, fluoro, chloro, bromo, trifluoromethyl, and phenyl; q
is 1, 2, or 3.
[0582] In some embodiments, each R.sup.9 is independently selected
from methyl, fluoro, chloro, bromo, and trifluoromethyl; and q is
1, 2, or 3.
[0583] In some embodiments, R is hydrogen or C.sub.1-4alkyl;
R.sup.6 is hydrogen or a C.sub.1-4alkyl; R.sup.9a is hydrogen or
R.sup.9; or R.sup.9a and R.sup.6, together with the intervening
atoms, form a 3- to 8-membered heterocyclyl which is optionally
substituted with from one to three R.sup.9.
[0584] In some embodiments, R is hydrogen or methyl; R.sup.9a is
hydrogen and R.sup.6 is hydrogen; or R.sup.9a and R.sup.6, together
with the intervening atoms, form a tetrahydroisoquinolinyl
ring.
[0585] In some embodiments, R.sup.9a is hydrogen.
[0586] In some embodiments, t is 0. Alternatively, t is 1. In some
embodiments, n is 0. Alternatively, n is 1. In some embodiments, h
is 0. Alternatively, h is 1.
[0587] In some embodiments,
[0588] R.sup.3 is hydrogen, --CN, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --(CR.sup.10R.sup.11)m--N(R.sup.16).sup.2,
--(CR.sup.10R.sup.11).sub.m--OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15,
--(CR.sup.10R.sup.11).sub.m--C(O)N(R.sup.16).sub.2,
--(CR.sup.10R.sup.11).sub.m--S(O).sub.2N(R.sup.16).sub.2,
--C(O)NHS(O).sub.2R.sup.15, a 5 to 14 membered heteroaryl, a 3 to
15 membered heterocyclyl, or -L.sup.1-R.sup.4; where in the
heteroaryl and heterocyclyl are optionally substituted with one to
four R.sup.5 groups selected from C.sub.1-4alkyl, --OH,
C.sub.1-4alkoxy, hydroxy(C.sub.1-4alkyl), --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl;
[0589] L.sup.1 is C.sub.1-8alkylene, --C(O)--, --C(O)O--,
--C(O)NR--, S(O).sub.2NR--, or C(O)NR--S(O).sub.2--;
[0590] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl;
[0591] R.sup.4 is C.sub.1-8alkyl, C.sub.3-8cycloalkyl, a 5 to 14
membered heteroaryl, or a 3 to 15 membered heterocyclyl, wherein
R.sup.4 may be optionally substituted with from one to four R.sup.5
groups selected from halo, cyano, C.sub.1-8alkyl,
C.sub.1-8haloalkyl, --COOH, --C(O)O--(C.sub.1-4alkyl), --OH,
hydroxyC.sub.1-4alkyl, --NH.sub.2, (C.sub.1-4alkyl)amino,
C.sub.3-8cycloalkyl, and a 3 to 15 membered heterocyclyl selected
from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl,
piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be
optionally substituted with one or two substituents independently
selected from the group consisting of optionally substituted with
C.sub.1-4alkyl, --OH, and COOH;
[0592] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, carboxy, C.sub.1-4alkyl, or
C.sub.1-4haloalkyl;
[0593] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, wherein R.sup.15 may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, and carboxyl;
[0594] Each R.sup.16 is independently selected from hydrogen,
C.sub.1-8alkoxy, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, a 5 to 14 membered
heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the
heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms
independently selected from O, N, or S; and wherein R.sup.16 may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, and C.sub.1-4alkylamidol;
[0595] or two R.sup.16 together with the nitrogen atom to which
they are attached form a 5 to 14 membered heteroaryl or a 3 to 15
membered heterocyclyl, wherein the heteroaryl or heterocyclyl
comprises from 1 to 10 heteroatoms independently selected from O,
N, or S; and wherein the heteroaryl or heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino,
N--(C.sub.1-4alkyl)amino, N,N-di-(C.sub.1-4alkyl)amino, carboxyl,
carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di-(C.sub.1-4alkyl)carbamoyl, and C.sub.1-4alkylamidol; and
[0596] m, for each occurrence, is independently 0 or 1.
[0597] In some embodiments,
[0598] R.sup.3 is hydrogen, --CN, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, --N(R.sup.16).sub.2,
--CR.sup.10R.sup.11--N(R.sup.16).sub.2, --OR.sup.15,
--CR.sup.10R.sup.11--OR.sup.15, --C(O)OR.sup.15,
--CR.sup.10R.sup.11--C(O)OR.sup.15, --C(O)N(R.sup.16).sub.2,
--CR.sup.10R.sup.11--C(O)N(R.sup.16).sub.2,
--S(O).sub.2N(R.sup.16).sub.2, C(O)NHS(O).sub.2R.sup.15, a 5 to 14
membered heteroaryl selected from 1,2,4-oxadiazolyl, pyridinyl,
pyrazolyl, and tetrazolyl; a 3 to 15 membered heterocyclyl selected
from 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl,
3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl,
4,7-diazaspiro[2.5]octanyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole,
octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl,
piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein the
heteroaryl and heterocyclyl are optionally substituted with one to
four groups selected from C.sub.1-4alkyl, --OH, C.sub.1-4alkoxy,
hydroxyC.sub.1-4alkyl, --COOH, --COO--C.sub.1-4alkyl,
--CH.sub.2COOH, and --CH.sub.2COO--C.sub.1-4alkyl; or
-L.sup.1-R.sup.4;
[0599] L.sup.1 is --CH.sub.2--, --CH(CH.sub.3)--, --C(O)--,
--C(O)O--, --C(O)NR--, --S(O).sub.2NR--, or
--C(O)NR--S(O).sub.2--;
[0600] R, for each occurrence, is independently hydrogen or a
C.sub.1-4alkyl;
[0601] R.sup.4 is C.sub.1-4alkyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or a 3 to 15 membered heterocyclyl
selected from 3-azabicyclo[3.1.0]hexanyl,
9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl,
3,6-diazabicyclo[3.2.1]octanyl, 6,9-diazaspiro[4.5]decanyl,
2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl,
4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl,
morpholinyl, octahydropyrrolo[1,2-a]pyrazinyl,
octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl,
octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl,
piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl,
tetrahydro-2H-pyranyl, wherein the R.sup.4 may be optionally
substituted with from one to four groups selected from halo, --CN,
C.sub.1-4alkyl, --CF.sub.3, --COOH, --COOCH.sub.3, --COO-t-butyl,
--OH, --CH.sub.2CH.sub.2OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
cyclopropyl, and 3 to 15 membered heterocyclyl selected from
3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl,
or pyrrolidinyl, wherein the heterocyclyl may be optionally
substituted with one or two substituents independently selected
from the group consisting of optionally substituted with
C.sub.1-4alkyl, --OH, and COOH;
[0602] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen, carboxy, methyl, or CF.sub.3;
[0603] R.sup.15 for each occurrence is independently selected from
the group consisting of hydrogen, C.sub.1-4alkyl;
[0604] Each R.sup.16 is independently selected from hydrogen,
C.sub.1-4alkoxy, C.sub.1-4alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and 3 to 15 membered heterocyclyl selected from
8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, azepanyl,
4,5-dihydroimidazolyl, 4,5-dihydrothiazolyl, oxetanyl, piperidinyl,
tetrahydro-2H-pyranyl; and wherein R.sup.16 may be optionally
substituted with from 1 to 3 substituents independently selected
from the group consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl,
hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, and carboxyl;
[0605] or two R.sup.16 together with the nitrogen atom to which
they are attached a 3 to 15 membered heterocyclyl selected from
9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl,
3,6-diazabicyclo[3.2.1]octanyl, 2,8-diazaspiro[4.5]decanyl
6,9-diazaspiro[4.5]decanyl, 4,7-diazaspiro[2.5]octanyl,
5,8-diazaspiro[3.5]nonanyl, 1,4-diazepanyl, morpholinyl,
octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl,
octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,
octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, piperidinyl,
piperizinyl, and pyrrolidinyl and wherein the heterocyclyl may be
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halo, C.sub.1-4alkoxy,
C.sub.1-4alkyl, cyano, hydroxyl, amino, N--(C.sub.1-4alkyl)amino,
N,N-di-(C.sub.1-4alkyl)amino, and carboxyl.
[0606] In some embodiments, R.sup.3 is hydrogen; --CN; --CH.sub.3;
--CF.sub.3; --CH.sub.2Br; --NH.sub.2; --NH--CH(CH.sub.3)COOH;
--NHCH(CH.sub.2CH.sub.3)COOH; --NHCH(CH(CH.sub.3).sub.2)COOH;
--NH-8-azabicyclo[3.2.1]octanyl; --NH-9-azabicyclo[3.3.1]nonanyl;
--NH-azepanyl; --NH-piperidinyl optionally substituted with 1 or 2
groups selected from methyl, ethyl, isopropyl or t-butyl;
--CH.sub.2NH.sub.2; --CH(COOH)NH.sub.2; --CH.sub.2NHCH.sub.3;
--CH.sub.2N(CH.sub.3).sub.2; --CH(CH.sub.3)NH.sub.2;
--CH.sub.2NH-cyclopropyl; --CH.sub.2NH-cyclobutyl optionally
substituted with 1, 2 or 3 groups selected from methyl or carboxyl;
--CH.sub.2NH-cyclohexyl optionally substituted with carboxyl;
--CH(CH.sub.3)NH-cyclopropyl; --CH.sub.2-8-azabicyclo[3.2.1]octanyl
optionally substituted with carboxy;
--CH.sub.2-9-azabicyclo[3.3.1]nonane optionally substituted with
carboxy; --CH.sub.2NH-4,5-dihydroimidazolyl;
--CH.sub.2NH-4,5-dihydrothiazolyl; --CH.sub.2NH-oxetanyl;
--CH.sub.2-piperidinyl optionally substituted with halo;
--CH.sub.2-piperizinyl optionally substituted with methyl;
--CH(CH.sub.3)-3,8-diazabicyclo[3.2.1]octanyl optionally
substituted with methyl or --COO-t-butyl;
--CH(CH.sub.3)-9-azabicyclo[3.3.1]nonane optionally substituted
with COOH; --CH(CH.sub.3)NH-4,5-dihydroimidazolyl;
--CH(CH.sub.3)NH-4,5-dihydrothiazolyl; --CH(CH.sub.3)NH-oxetanyl;
--CH(CH.sub.3)-piperdinyl optionally substituted with COOH,
hydroxyl, or halo; --CH(CH.sub.3)-piperizinyl optionally
substituted with methyl or --COO-t-butyl;
--CH(CH.sub.3)-pyrrolidinyl; --COOH; --COOCH.sub.3;
--COOCH.sub.2CH.sub.3; --CH.sub.2COOH;
--CH.sub.2COOCH.sub.2CH.sub.3; --CH(CH.sub.3)COOH;
--CH(CH.sub.3)COOCH.sub.2CH.sub.3; --C(CH.sub.3).sub.2COOH;
--C(CH.sub.3).sub.2COOCH.sub.2CH.sub.3; --CH.sub.2OH;
--CH.sub.2OCH.sub.3; --CH(CH.sub.3)OH; --CH(CF.sub.3)OH;
--CONH.sub.2; --C(O)NHCH.sub.3; --C(O)NHCH.sub.2CH.sub.3;
--CO--NHCH.sub.2CH.sub.2CH.sub.3; --C(O)NHCH(CH.sub.3)CH.sub.3;
--C(O)NHCH(CH.sub.3).sub.2; --C(O)NHC(CH.sub.3).sub.3;
--CON(CH.sub.3).sub.2; --C(O)NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CCH;
--C(O)NHCH.sub.2CH.sub.2NH.sub.2;
--C(O)NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2;
--C(O)NHCH.sub.2CH.sub.2COOH; --CONHCH.sub.2CH.sub.2OH;
--CONHCH(CH.sub.3)CH.sub.2OH; --C(O)N(CH.sub.3)OCH.sub.3;
--C(O)NH-cyclopropyl; --C(O)NH-cyclobutyl optionally substituted
with hydroxyl; --C(O)NH-cyclopentyl; --C(O)NH-cyclohexyl optionally
substituted with COOH; --C(O)NH-4,5-dihydrothiazolyl;
--C(O)NH-oxetanyl; --C(O)NH-tetrahydro-2H-pyran;
--C(O)NHCH.sub.2-cyclopropyl; --C(O)-8-azabicyclo[3.2.1]octanyl
optionally substituted with --COOH;
--C(O)-9-azabicyclo[3.3.1]nonanyl optionally substituted with
--COOH; --C(O)-azetidinyl optionally substituted with NH.sub.2,
NHCH.sub.3, or OH; --C(O)-2,5-diazabicyclo[2.2.1]heptanyl;
--C(O)-3,9-diazabicyclo[3.3.1]nonanyl optionally substituted with
methyl; --C(O)-2,5-diazabicyclo[2.2.2]octanyl optionally
substituted with methyl; --C(O)-3,8-diazabicyclo[3.2.1]octanyl
optionally substituted with methyl or --COO-t-butyl;
--C(O)-3,6-diazabicyclo[3.2.1]octanyl;
--C(O)-6,9-diazaspiro[4.5]decanyl optionally substituted with
methyl; --C(O)-4,7-diazaspiro[2.5]octanyl optionally substituted
with methyl or ethyl; --C(O)-2,8-diazaspiro[4.5]decanyl;
--C(O)-5,8-diazaspiro[3.5]nonanyl octane optionally substituted
with methyl; --CO-1,4-diazepanyl; --C(O)-- morpholinyl,
--C(O)-octahydropyrrolo[1,2-a]pyrazinyl;
--C(O)-octahydropyrrolo[3,4-b]pyrrolyl;
--C(O)-octahydropyrrolo[3,2-b]pyrrolyl;
--C(O)-octahydropyrrolo[3,4-c]pyrrolyl;
--C(O)-octahydropyrrolo[2,3-b]pyrrolyl; --C(O)-piperazin-2-one;
--C(O)-- pyrrolidinyl optionally substituted with NHCH.sub.3;
--C(O)-- piperidinyl optionally substituted with methyl, halo,
CF.sub.3, hydroxyl, COOH, COOCH.sub.3, or amino; --C(O)-piperazinyl
optionally substituted with 1, 2 or 3 groups selected from methyl,
ethyl, carboxyl, cyano, hydroxyl, hydroxyethyl, CF.sub.3, or
--COO-t-butyl; --CONHSO.sub.2CH.sub.3; --SO.sub.2NH.sub.2;
--SO.sub.2N(CH.sub.3).sub.2; --SO.sub.2-8-azabicyclo[3.2.1]octanyl;
--SO.sub.2-9-azabicyclo[3.3.1]nonanyl; --SO.sub.2-piperidinyl;
--SO.sub.2-piperizinyl optionally substituted with methyl;
--C(O)CH.sub.3; --C(O)CH.sub.2-3-azabicyclo[3.1.0]hexanyl;
--C(O)CH.sub.2-azetidinyl optionally substituted with COOH;
--C(O)CH.sub.2-morpholino optionally substituted with 1 or 2 methyl
groups; --C(O)CH.sub.2-piperidinyl; --C(O)CH.sub.2-pyrrolidinyl
optionally substituted with methyl orhydroxyl; 1,2,4-oxadiazolyl
optionally substituted with methyl; pyridinyl optionally
substituted with methyl; pyrazolyl optionally substituted with
CH.sub.2COOH; tetrazolyl; 8-azabicyclo[3.2.1]octanyl optionally
substituted with methyl; 8-azabicyclo[3.2.1]oct-2-enyl optionally
substituted with methyl; 3,8-diazabicyclo[3.2.1]octanyl;
1,4-diazepanyl optionally substituted with methyl;
4,7-diazaspiro[2.5]octanyl optionally substituted with methyl;
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl;
octahydropyrido[2,1-c][1,4]oxazinyl;
octahydropyrrolo[1,2-a]pyrazinyl; octahydropyrrolo[3,2-b]pyrrole
optionally substituted methyl; octahydropyrrolo[3,4-c]pyrrolyl
optionally substituted with methyl or ethyl; piperizinyl optionally
substituted with 1 or 2 groups independently selected from methyl,
ethyl, propyl, isopropyl or hydroxyethyl; piperidinyl optionally
substituted with 1 or 2 groups independently selected from methyl
or --COO-t-butyl; piperidin-2-one; pyrrolidinyl optionally
substituted with methyl or --COO-t-butyl;
1,2,3,6-tetrahydropyridinyl optionally substituted with 1 or 2
groups independently selected from methyl or
--COO--C.sub.1-4alkyl.
[0607] In some embodiments, L is --O--C(O)--, --NR.sup.6--C(O)--,
or --C(O)--;
[0608] L.sup.2 is a bond;
[0609] R.sup.1 is C.sub.1-4alkylene;
[0610] R.sup.2 is
##STR00022##
[0611] R.sup.3 is --(CR.sup.10R.sup.11).sub.m--C(O)OR.sup.15, a 3
to 15 membered heterocyclyl selected from
8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl,
3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl,
4,7-diazaspiro[2.5]octanyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole,
octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl,
piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein
heterocyclyl is optionally substituted with one to four groups
selected from C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl; or -L.sup.1-R.sup.4;
[0612] L.sup.1 is --C(O)--,
[0613] R.sup.4 is 3 to 15 membered heterocyclyl selected from
9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl,
3,6-diazabicyclo[3.2.1]octanyl, 6,9-diazaspiro[4.5]decanyl,
2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl,
4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl,
morpholinyl, octahydropyrrolo[1,2-a]pyrazinyl,
octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl,
octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl,
piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl,
tetrahydro-2H-pyranyl, wherein the heterocyclyl may be optionally
substituted with from one to four groups selected from halo, --CN,
C.sub.1-4alkyl, --CF.sub.3, --COOH, --COOCH.sub.3, --COO-t-butyl,
--OH, --CH.sub.2CH.sub.2OH, --OCH.sub.3, --NH.sub.2, and
--NHCH.sub.3;
[0614] each R.sup.9 is independently selected from halo and
C.sub.1-8haloalkyl;
[0615] R.sup.9a is hydrogen;
[0616] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen or C.sub.1-4alkyl;
[0617] R.sup.15 is hydrogen or C.sub.1-4alkyl; [0618] m is 0 or 1;
[0619] n is 0 or 1; [0620] q is 1, 2, or 3; [0621] p is 1 or 2;
[0622] r is 1 or 2; and [0623] t is 0 or 1.
[0624] In some embodiments, L is --O--C(O)--;
[0625] L.sup.2 is a bond;
[0626] R.sup.1 is methylene;
[0627] R.sup.2 is
##STR00023##
[0628] R.sup.3 is --C(O)OR.sup.15;
--CR.sup.10R.sup.11--C(O)OR.sup.15 a 3 to 15 membered heterocyclyl
selected from azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl,
piperidinyl, piperizinyl, pyrrolidinyl,
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
octahydropyrido[2,1-c][1,4]oxazinyl,
octahydropyrrolo[1,2-a]pyrazinyl, and
octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], wherein
the heterocyclyl is optionally substituted with one to four groups
selected from C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, --COOH,
--COO--C.sub.1-4alkyl, --CH.sub.2COOH, and
--CH.sub.2COO--C.sub.1-4alkyl; or -L.sup.1-R.sup.4;
[0629] L.sup.1 is --C(O)--,
[0630] R.sup.4 is 3 to 15 membered heterocyclyl selected
azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl,
piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the heterocyclyl
may be optionally substituted with from one to four groups selected
from halo, C.sub.1-4alkyl, --CF.sub.3, --COOH, --COOCH.sub.3,
--COO-t-butyl;
[0631] each R.sup.9 is independently selected from halo and
C.sub.1-4haloalkyl;
[0632] R.sup.9a is -hydrogen;
[0633] R.sup.10 and R.sup.11, for each occurrence, are
independently hydrogen or C.sub.1-4alkyl;
[0634] R.sup.15 is hydrogen or C.sub.1-4alkyl; and
[0635] q is 1, 2, or 3.
[0636] In some embodiments, n R.sup.3 is --C(O)OH;
--CH.sub.2C(O)OH, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl,
piperizinyl; --C(O)-piperizinyl, wherein the piperizinyl is
optionally substituted with 1, 2 or 3 C.sub.1-4alkyl groups.
[0637] In another embodiment, the invention is any one the
compounds disclosed in the Exemplification section as a neutral
compound or a pharmaceutically acceptable salt thereof.
[0638] In cases where a compound provided herein is sufficiently
basic or acidic to form stable nontoxic acid or base salts,
preparation and administration of the compounds as pharmaceutically
acceptable salts may be appropriate. Examples of pharmaceutically
acceptable salts are organic acid addition salts formed with acids
which form a physiological acceptable anion, for example, tosylate,
methanesulfonate, acetate, citrate, malonate, tartarate, succinate,
benzoate, ascorbate, .alpha.-ketoglutarate, or
.alpha.-glycerophosphate. Inorganic salts may also be formed,
including hydrochloride, sulfate, nitrate, bicarbonate, and
carbonate salts.
[0639] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0640] Pharmaceutically-acceptable base addition salts can be
prepared from inorganic and organic bases. Salts from inorganic
bases, can include but are not limited to, sodium, potassium,
lithium, ammonium, calcium or magnesium salts. Salts derived from
organic bases can include, but are not limited to, salts of
primary, secondary or tertiary amines, such as alkyl amines,
dialkyl amines, trialkyl amines, substituted alkyl amines,
di(substituted alkyl) amines, tri(substituted alkyl) amines,
alkenyl amines, dialkenyl amines, trialkenyl amines, substituted
alkenyl amines, di(substituted alkenyl) amines, tri(substituted
alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines,
tri(cycloalkyl) amines, substituted cycloalkyl amines,
disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines,
cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)
amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl
amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl
amines, triaryl amines, heteroaryl amines, diheteroaryl amines,
triheteroaryl amines, heterocyclic amines, diheterocyclic amines,
triheterocyclic amines, or mixed di- and tri-amines where at least
two of the substituents on the amine can be different and can be
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl, or heterocyclic and the like. Also included are
amines where the two or three substituents, together with the amino
nitrogen, form a heterocyclic or heteroaryl group. Non-limiting
examples of amines can include, isopropylamine, trimethyl amine,
diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline,
betaine, ethylenediamine, glucosamine, N-alkylglucamines,
theobromine, purines, piperazine, piperidine, morpholine, or
N-ethylpiperidine, and the like. Other carboxylic acid derivatives
can be useful, for example, carboxylic acid amides, including
carboxamides, lower alkyl carboxamides, or dialkyl carboxamides,
and the like.
[0641] A compound of formula (I), or a pharmaceutically acceptable
salt thereof, can modulate the activity of S1P receptors. A
compound provided herein, or a pharmaceutically acceptable salt
thereof, can have S1P receptor agonist or antagonist activity. The
compound, or a pharmaceutically acceptable salt thereof, can be
selective for the S1P4 receptor. The compound, or a
pharmaceutically acceptable salt thereof, can be a selective S1P4
antagonist. Being selective can mean that the compound, or a
pharmaceutically acceptable salt thereof, binds to the receptor (or
relatively small group of related molecules or proteins) in a
complex mixture, or in other words, when exposed to a variety of
closely related receptor types, the compound, or a pharmaceutically
acceptable salt thereof, can bind preferentially to just one of the
receptor types.
[0642] The compound, or a pharmaceutically acceptable salt thereof,
can have a greater affinity for the S1P4 receptor, by at by at
least 100-fold, by at least 50-fold, by at least 10-fold, by at
least 5-fold or by at least 2-fold, than for S1P1 receptor, S1P2
receptor, S1P3 receptor, or SIP5 receptor.
[0643] An inhibitor of S1P4 mediated activity can block S1P
interaction with an S1P4 receptor. For example, the inhibitor can
be an antagonist of an S1P4 receptor. An antagonist can be a
molecule that has affinity for the receptor but does not induce
activity or a specific activity from the receptor. The antagonist
can bind with an S1P4 receptor with an IC.sub.50 value of less than
1 .mu.M, less than 750 nM, less than 500 nM, less than 250 nM or
less than 100 nM. The antagonist can bind with an S1P4 receptor
with an IC.sub.50 value in a range between 1 nM and 1 .mu.M,
between 1 nM and 500 nM, between 10 nM and 250 nM, between 25 nm
and 100 nM, or between 50 nM and 100 nM.
[0644] The compound, or a pharmaceutically acceptable salt thereof,
can also promote oligodendrocyte progenitor cell differentiation.
The compound, or a pharmaceutically acceptable salt thereof, can
promote myelination or remyelination.
[0645] An "S1P modulating agent" refers a compound, or a
pharmaceutically acceptable salt thereof, or composition that is
capable of inducing a detectable change in SIP receptor activity in
vivo or in vitro (e.g., at least 10% increase or decrease in S1P
activity as measured by a given assay such as the assays described
in the examples and known in the art. "S1P receptor," refers to all
of the S1P receptor subtypes (for example, the S1P receptors S1P1,
S1P2, S1P3, S1P4, or SIP5), unless the specific subtype is
indicated. It is well known in the art how to determine S1P agonist
or antagonist activity using the standard tests described herein,
or using other similar tests which are well known in the art. In
some cases, depending on the cell type and conditions used, an S1P
modulating agent can have agonist or antagonist activity, even at
the same receptor subtype.
[0646] The biological effects of an S1P modulating agent vary
depending on whether the compound, or a pharmaceutically acceptable
salt thereof, has S1P receptor agonist or antagonist activity.
Potential uses of an S1P modulating agent include, but are not
limited to, prevention or treatment of a pathological condition or
symptom in a mammal. For example, the condition can include asthma,
an inflammatory neuropathies, arthritis, lupus erythematosis,
psoriasis, an ischemia reperfusion injury, a solid tumor, a tumor
metastasis, a disease associated with angiogenesis, a vascular
disease, a pain condition, an acute viral disease, or
insulin-dependent diabetes, and non-insulin dependent diabetes. The
condition can alter lymphocyte trafficking as a method of treatment
for neuropathic pain, inflammation-induced pain (e.g., where
prostaglandins are involved) or treatment of autoimmune pathologies
such as uveitis, type I diabetes, rheumatoid arthritis, chronic
inflammatory disorders, inflammatory bowel diseases (e.g., Crohn's
disease and ulcerative colitis), multiple sclerosis, and in
drug-eluting stents. Additional uses can include treatment of brain
degenerative diseases, heart diseases, cancers, or hepatitis C.
See, for example, WO 2005/085295, WO 2004/010987, WO 03/097028, and
WO 2006/072562, each of which is incorporated by reference in its
entirety. A class of S1P receptor agonists are described in
provisional U.S. Application No. 60/956,111, filed Aug. 15, 2007,
and PCT/US2008/073378, filed Aug. 15, 2008, each of which is
incorporated by reference in its entirety. See also provisional
U.S. Application No. 61/231,539, filed Aug. 5, 2009, and
PCT/US2010/44607, filed Aug. 5, 2010, each of which is incorporated
by reference in its entirety. See also provisional U.S. Application
No. 61/440,254, filed Feb. 7, 2011, and PCT/US2012/23799 filed Feb.
6, 2012, each of which is incorporated by reference in its
entirety.
[0647] Additional potential uses of an S1P modulating agent
include, but are not limited to, prevention or treatment of a
pathological condition or symptom in a mammal. For example, the
condition can include inhibited cell migration of oligodendrocyte
precursor cells (OPCs).
[0648] Potential uses of an S1P receptor antagonist, and S1P4
receptor type selective antagonists particularly, include, but are
not limited to, prevention or treatment of a pathological condition
or symptom in a mammal.
[0649] LPA has been shown to be involved in lymphocyte trafficking
and helps promote entry of lymphocytes into secondary lymphoid
organs (see Kanda, et al., Nat. Immunology (2008), 9:415-423).
Therefore, the disclosed compounds and salts thereof are expected
to be useful for altering lymphocyte trafficking as a method for
prolonging allograft survival, for example transplantation
including solid organ transplants, treatment of graft vs. host
disease, bone marrow transplantation, and the like.
[0650] An "ATX modulating agent" refers a compound, or a
pharmaceutically acceptable salt thereof, or composition that is
capable of inducing a detectable change in ATX activity in vivo or
in vitro (e.g., at least 10% increase or decrease in ATX activity
as measured by a given assay such as the assays described in the
examples and known in the art. The compound, or a pharmaceutically
acceptable salt thereof, be an ATX modulating agent, i.e., it can
modulate the activity of ATX. For example, the compound, or a
pharmaceutically acceptable salt thereof, can be an ATX inhibitor.
The compound, or a pharmaceutically acceptable salt thereof, can be
a selective ATX modulating agent. Being selective can mean that the
compound, or a pharmaceutically acceptable salt thereof, binds to
ATX preferentially when exposed to a variety of potential binding
partners. The compound, or a pharmaceutically acceptable salt
thereof, can have a greater affinity for the ATX, by at by at least
100-fold, by at least 50-fold, by at least 10-fold, by at least
5-fold or by at least 2-fold, than for other binding partners.
Affinity can be measured, for example, as a dissociation constant
(K.sub.d), as an inhibition constant (such as IC.sub.50), or
another measure; provided that affinity is measured in a consistent
fashion between ATX and the other binding partners it is compared
to.
[0651] An inhibitor of ATX mediated activity can block interaction
of ATX with its native substrate(s), such as LPC. For example, the
inhibitor can show an IC.sub.50 value of less than 1 .mu.M, less
than 750 nM, less than 500 nM, less than 250 nM, less than 100 nM,
less than 50 nM, less than 25 nM, or less than 10 nM, when measured
in a FRET-based assay using FS-3 substrate (see, e.g., Ferguson, C.
G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, which is
incorporated by reference in its entirety).
[0652] Some substrates and inhibititors of ATX are described in WO
2011/151461, which is incorporated by reference in its
entirety.
[0653] Potential uses of an ATX modulating agent include, but are
not limited to, prevention or treatment of a pathological condition
or symptom in a mammal. The pathological disorder can be an
inflammatory disorder, an autoimmune disorder, a fibrosis of the
lung, or a malignancy of the lung. The pathological disorder can
also be an inflammatory disorder, an autoimmune disorder, a
fibrosis of the lung, a malignancy of the lung, liver fibrosis, or
renal fibrosis. In one embodiment, the pathological disorder is a
fibrotic disease, including, for example, a fibrosis of the lung,
liver fibrosis, kidney fibrosis, and scleroderma. Prevention or
treatment of the pathological condition or symptom can include
administering to the mammal an effective amount of an ATX
modulating agent, e.g., an ATX inhibitor, to prevent, treat or
reduce symptoms of the inflammatory disorder, autoimmune disorder,
the fibrosis of the lung, or the malignancy of the lung. Prevention
or treatment of the pathological condition or symptom can also
include administering to the mammal an effective amount of an ATX
modulating agent, e.g., an ATX inhibitor, to prevent, treat or
reduce symptoms of the inflammatory disorder, autoimmune disorder,
the fibrosis of the lung, the malignancy of the lung, liver
fibrosis, or renal fibrosis. Prevention or treatment of the
pathological condition or symptom can also include administering to
the mammal an effective amount of an ATX modulating agent, e.g., an
ATX inhibitor, to prevent, treat or reduce symptoms of the fibrotic
disease, including, for example, a fibrosis of the lung, liver
fibrosis, kidney fibrosis, and scleroderma. In one embodiment, the
inflammatory disorder is rheumatoid arthritis (RA). In another
embodiment, the inflammatory disorder is asthma. In another
embodiment, the inflammatory disorder is periodontal disease. In
another embodiment, the autoimmune disorder is multiple sclerosis
(MS). In another embodiment, the autoimmune disorder is
scleroderma. A particular example of lung fibrosis is an
interstitial lung disease, for instance, pulmonary fibrosis. See,
for example, WO 2011/151461, which is incorporated by reference in
its entirety.
[0654] In some embodiments, an ATX inhibitor of the present
invention can be used to treat or prevent a demyelinating disease
or disorder. Demyelinating diseases or disorders include multiple
sclerosis, Guillain-Barre Syndrome, chronic inflammatory
demyelinating polyneuropathy (CIDP), transverse myelitis, and optic
neuritis, spinal cord injury, stroke or other ischemia, cerebral
palsy, Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome,
Refsum disease, Krabbe disease, Canavan disease, Alexander disease,
nerve damage due to pernicious anemia, progressive multifocal
leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to
untreated syphilis, demyelination due to exposure to an
organophosphates, demyelination due to vitamin B12 deficiency or
copper deficiency.
[0655] In addition, disclosed compounds and salts can be useful as
antagonists of the cannabinoid CB.sub.1 receptor. CB.sub.1
antagonism is associated with a decrease in body weight and an
improvement in blood lipid profiles. The CB.sub.1 antagonism could
be in concert with S1P receptor activity, or be independent of
activity at any S1P receptor.
[0656] In addition, disclosed compounds and salts can be useful for
inhibition of group IVA cytosolic PLA.sub.2 (cPLA.sub.2).
cPLA.sub.2 catalyzes the release of eicosanoic acids (e.g.,
arachidonic acid). The eicosanoic acids are transformed to
pro-inflammatory eicosanoids such as prostaglandins and
leukotrienes. Thus, disclosed compounds and salts may be useful as
anti-inflammatory agents. This inhibition could be in concert with
S1P receptor activity, or be independent of activity at any S1P
receptor.
[0657] In addition, disclosed compounds and salts may be useful for
inhibition of the multiple substrate lipid kinase (MuLK). MuLK is
highly expressed in many human tumor cells and thus its inhibition
might slow the growth or spread of tumors.
Neurological Disorders
[0658] MS can begin with a relapsing-remitting pattern of
neurologic involvement, which then can progress to a chronic phase
with increasing neurological damage. MS can be associated with the
destruction of myelin, oligodendrocytes or axons localized to
chronic lesions. The demyelination observed in MS may not always
permanent and remyelination has been documented in early stages of
the disease. Remyelination of neurons can require
oligodendrocytes.
[0659] Axons and dendrites can extend from neurons. The distal tip
of an extending axon or neurite can include a specialized region,
known as the growth cone. Growth cones can sense the local
environment and can guide axonal growth toward a neuron's target
cell. Growth cones can respond to environmental cues, for example,
surface adhesiveness, growth factors, neurotransmitters and
electric fields. The growth cones can advance at a rate of one to
two millimeters per day. The growth cone can explore the area ahead
of it and on either side, by means of elongations classified as
lamellipodia and filopodia. When an elongation contacts an
unfavorable surface, it can withdraw. When an elongation contacts a
favorable growth surface, it can continue to extend and guides the
growth cone in that direction. When the growth cone reaches an
appropriate target cell a synaptic connection can be created.
[0660] Nerve cell function can be influenced by contact between
neurons and other cells in their immediate environment
(Rutishauser, et al., 1988, Physiol. Rev. 68:819, which is
incorporated by reference in its entirety). These cells can include
specialized glial cells, oligodendrocytes in the central nervous
system (CNS), and Schwann cells in the peripheral nervous system
(PNS), which can sheathe the neuronal axon with myelin (Lemke,
1992, in An Introduction to Molecular Neurobiology, Z. Hall, Ed.,
p. 281, Sinauer, each of which is incorporated by reference in its
entirety). LPA causes the collapse of the neuron growth cone and
tends to inhibit or reverse the morphological differentiation of
many neuronal cell lines (see Gendaszewska-Darmach, Acta Biochimica
Polonica (2008), 55(2):227-240). Since ATX activity is involved in
the generation of LPA, inhibitors of ATX should increase the
ability of the nervous system to make synaptic connections. Thus,
ATX inhibitors may be useful in treating neurodegenerative
disorders such as Alzheimer's disease, Huntington's disease,
Parkinson's disease (including Parkinson's dementia), Lewy Body
Dementia, amylotrophic lateral sclerosis (ALS), Friedreich's
ataxia, spinal muscular atrophy.
[0661] CNS neurons can have the inherent potential to regenerate
after injury, but they can be inhibited from doing so by inhibitory
proteins present in myelin (Brittis et al., 2001, Neuron 30:11-14;
Jones et al., 2002, J. Neurosci. 22:2792-2803; Grimpe et al., 2002,
J. Neurosci.: 22:3144-3160, each of which is incorporated by
reference in its entirety).
[0662] Several myelin inhibitory proteins found on oligodendrocytes
have been characterized. Known examples of myelin inhibitory
proteins can include NogoA (Chen et al., Nature, 2000, 403,
434-439; Grandpre et al., Nature 2000, 403, 439-444, each of which
is incorporated by reference in its entirety), myelin associated
glycoprotein (MAG) (McKerracher et al., 1994, Neuron 13:805-811;
Mukhopadhyay et al., 1994, Neuron 13:757-767, each of which is
incorporated by reference in its entirety) or oligodendrocyte
glycoprotein (OM-gp), Mikol et al., 1988, J. Cell. Biol.
106:1273-1279, each of which is incorporated by reference in its
entirety). Each of these proteins can be a ligand for the neuronal
Nogo receptor-1 (NgR1 (Wang et al., Nature 2002, 417, 941-944;
Grandpre et al., Nature 2000, 403, 439-444; Chen et al., Nature,
2000, 403, 434-439; Domeniconi et al., Neuron 2002, published
online Jun. 28, 2002, each of which is incorporated by reference in
its entirety).
[0663] Nogo receptor-1 (NgR1) is a GPI-anchored membrane protein
that contains 8 leucine rich repeats (Fournier et al., 2001, Nature
409:341-346, which is incorporated by reference in its entirety).
Upon interaction with inhibitory proteins (e.g., NogoA, MAG and
OM-gp), the NgR1 complex can transduce signals that lead to growth
cone collapse and inhibition of neurite outgrowth.
[0664] There is a need for molecules and methods for inhibiting
NgR1-mediated growth cone collapse and the resulting inhibition of
neurite outgrowth. Additionally, there is a need for molecules
which increase neuronal survival and axon regeneration,
particularly for the treatment of disease, disorders or injuries
that involve axonal injury, neuronal or oligodendrocyte cell death,
demyelination or dymyelination or generally relate to the nervous
system.
[0665] Such diseases, disorders or injuries can include, but are
not limited to, multiple sclerosis (MS), progressive multifocal
leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine
myelolysis (CPM), adrenoleukodystrophy, Alexander's disease,
Pelizaeus Merzbacher disease (PMZ), Globoid cell Leucodystrophy
(Krabbe's disease) and Wallerian Degeneration, optic neuritis,
transverse myelitis, amylotrophic lateral sclerosis (ALS),
Huntington's disease, Alzheimer's disease, Parkinson's disease,
spinal cord injury, traumatic brain injury, post radiation injury,
neurologic complications of chemotherapy, stroke, acute ischemic
optic neuropathy, vitamin E deficiency, isolated vitamin E
deficiency syndrome, AR, Bassen-Kornzweig syndrome,
Marchiafava-Bignami syndrome, metachromatic leukodystrophy,
trigeminal neuralgia, or Bell's palsy. Among these diseases, MS may
the most widespread, affecting approximately 2.5 million people
worldwide.
[0666] Various disease-modifying treatments may be available for
MS, including the use of corticosteroids and immunomodulating
agents such as interferon beta or Tysabri.RTM.. In addition,
because of the central role of oligodendrocytes and myelination in
MS, there have been efforts to develop therapies to increase
oligodendrocyte numbers or enhance myelination. See, e.g., Cohen et
al., U.S. Pat. No. 5,574,009; Chang et al., N. Engl. J. Med. 346:
165-73 (2002), each of which is incorporated by reference in its
entirety. However, there remains an urgent need to devise
additional therapies for MS and other demyelination and
dismyelination disorders.
[0667] A compound provided herein, or a pharmaceutically acceptable
salt thereof, can promote myelination or remyelination. A method
can include administering a compound provided herein, or a
pharmaceutically acceptable salt thereof, to cells. A method of
promoting oligodendrocyte progenitor cell differentiation can
include administering a compound provided herein, or a
pharmaceutically acceptable salt thereof, to cells. A method of
treating multiple sclerosis can include administering a compound
provided herein, or a pharmaceutically acceptable salt thereof, to
a subject.
[0668] A number of studies have shown that ATX is expressed in
non-pathological conditions, throughout development, with high
expression levels in the CNS among other tissues. ATX mRNA was
identified as highly upregulated during oligodendrocyte
differentiation and ATX protein expression is also apparent in
maturing ODCs, temporally correlated with the process of
myelination. Finally, in the adult brain ATX is expressed in
secretory epithelial cells, such as the choroid plexus, ciliary,
iris pigment, and retinal pigment epithelial cells, whereas there
is evidence for ATX expression in leptomenigneal cells and cells of
the CNS vasculature. See, for example, Fuss, B., et al., J Neurosci
17, 9095-9103 (1997); Kawagoe, H., et al. Genomics 30, 380-384
(1995); Lee, H. Y., et al. J Biol Chem 271, 24408-24412 (1996);
Narita, M., et al., J Biol Chem 269, 28235-28242 (1994); Bachner,
D., et al., Mechanisms of Development 84, 121-125 (1999);
Awatramani, R., et al., Nat Genet 35, 70-75 (2003); Li, Y., et al.,
J Neurol Sci 193, 137-146 (2002); Dugas, J. C., et al., J Neurosci
26, 10967-10983 (2006); Fox, M. A., et al., Molecular and Cellular
Neuroscience 27, 140-150 (2004); Hoelzinger, D. B., et al.,
Neoplasia 7, 7-16 (2005); and Sato, K., et al., J Neurochem 92,
904-914 (2005); each of which is incorporated by reference in its
entirety.
[0669] Although neurons and astrocytes do not seem to express ATX
under physiological conditions, ATX is highly upregulated in
astrocytes following brain lesion. Two hallmarks of reactive
astrogliosis can be induced by LPA itself: hypertrophy of
astrocytes and stress fiber formation. This may indicate an
autoregulation loop of astrocytic activation, in which astrocytes
upregulate the LPA-generating enzyme ATX and become activated by
its metabolite LPA, while increased amounts of the metabolite
inhibit the catalytic activity of ATX. See, e.g., Savaskan, N. E.,
et al., Cell Mol Life Sci 64, 230-243 (2007); Ramakers, G. J, &
Moolenaar, W. H., Exp Cell Res 245, 252-262 (1998); and van
Meeteren, L. A., et al., J Biol Chem 280, 21155-21161 (2005); each
of which is incorporated by reference in its entirety.
[0670] ATX expression levels were shown to be elevated in
glioblastoma multiform samples, and ATX was shown to augment
invasiveness of cells transformed with ras, a key signaling
molecule that promotes gliomagenesis. ATX expression was also
detected in primary tumor tissues from neuroblastoma patients and
retinoic acid induced expression of ATX in N-myc-amplified
neuroblastoma cells.
[0671] There is significant evidence for ATX signaling in
demyelination processes and in other neurodegenerative conditions.
As noted above, it has been reported that addition of LPA to dorsal
root fibers in ex vivo culture causes demyelination, whereas LPC
fails to cause significant demyelination of nerve fibers in ex vivo
cultures without further addition of recombinant ATX to the
culture. Addition of recombinant ATX caused significant
demyelination at equivalent levels to LPA presumable due to
conversion of LPC to LPA through the enzymatic activity of ATX. In
addition, injury induced demyelination was attenuated by about 50%
in atx.sup.+/- mice over their wild type counterparts (Nagai, et
al., Molecular Pain (2010), 6:78).
[0672] ATX protein levels were found deregulated in an animal model
of MS (experimental autoimmune encephalitis; EAE) at the onset of
clinical symptoms. See, e.g., Hoelzinger, D. B., et al. Neoplasia
7, 7-16 (2005); Nam, S. W., et al., Oncogene 19, 241-247 (2000);
Kawagoe, H., et al., Cancer Res 57, 2516-2521 (1997);
Dufner-Beattie, J., et al., Mol Carcinog 30, 181-189 (2001);
Umemura, K., et al., Neuroscience Letters 400, 97-100 (2006); and
Fuss, B., et al., J Neurosci 17, 9095-9103 (1997); each of which is
incorporated by reference in its entirety. Moreover, significant
ATX expression was been detected in the cerebrospinal fluid of
patients suffering with multiple sclerosis (MS), while completely
lacking from the control samples, suggesting a role for ATX in
maintenance of cerebrospinal fluid homeostasis during
pathological/demyelinating conditions. Hammack, B. N., et al.
Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult
Scler 10, 245-260 (2004); and Dennis, J., et al., J Neurosci Res
82, 737-742 (2005); each of which is incorporated by reference in
its entirety.
[0673] Interestingly, ATX mRNA expression was found to be elevated
in the frontal cortex of Alzheimer-type dementia patients
indicating a potential involvement for ATX signaling in
neurodegenerative diseases. LPA receptors are enriched in the CNS
and their expression patterns suggest their potential involvement
in developmental process including neurogenesis, neuronal
migration, axon extension and myelination. Noteworthy, only two
receptors have the same spatiotemporal expression as ATX in the CNS
(Contos, J. J., et al., Mol Cell Biol 22, 6921-6929 (2002);
Jaillard, C, ei al, Edg8/S1 P5: an oligodendroglial receptor with
dual function on process retraction and cell survival. J Neurosci
25, 1459-1469 (2005); and Saba, J. D. Journal of cellular
biochemistry 92, 967-992 (2004); each of which is incorporated by
reference in its entirety). LPAi and SIP5 are specific for ODCs,
and their expression highly correlates with the process of
myelination. LPA1 is expressed in restricted fashion within the
neuroblasts of the neuroproliferatve Ventricular Zone (VZ) of the
developing cortex, in the dorsal olfactory bulb, along the pial
cells of neural crest origin, and in developing facial bone tissue.
Expression is observed during E11-E18, corresponding to a time
period during which neurogenesis occurs. LPA1 expression is
undetectable in the VZ after this point, to reappear during the
first postnatal week within ODCs. Notably, Schwann cells (the
myelinating cells of the Peripheral Nervous System; PNS) express
high levels of LPA1 early in development and persistently
throughout life, suggesting an influence of LPA on myelinating
processes (Weiner. J. A. & Chun, J., Proc Natl Acad Sci USA 96,
5233-5238 (1999), which is incorporated by reference in its
entirety).
[0674] The above data strongly support a critical role for ATX and
LPA signaling in neuronal development, oligodendrocyte
differentiation and myelination, as well as possibly in the
autoregulation of astrocyte activation. Moreover, the regulation of
ATX and thus LPA production at local sites of CNS injury,
inflammatory or autoimmune, could contribute to tissue homeostasis
through the numerous effects of LPA. As demyelination and
deregulated cerebrospinal fluid homeostasis are the hallmarks of
multiple sclerosis, a role of ATX and LPA signaling in the
pathophysiology of multiple sclerosis seems very likely.
[0675] The S1P modulating agents and/or ATX modulating agents of
formula (I) can be used to various forms of MS including
relapsing-remitting, secondary-progressive, primary-progressive,
and progressive-relapsing forms. In addition, S1P modulating agents
and/or ATX modulating agents of formula (I) can be used alone or in
conjunction with other agents to treat or prevent MS. In some
embodiments, the compounds and salts described herein can be used
to treat or prevent MS in combination with an immunomodulating
therapy such as corticosteroids, beta interferon-1a (such as
Avonex.RTM. or Rebif.RTM.), beta interferon-lb (Betaseron.RTM.),
natalizumab (Tysabri.RTM.), glatiramer, and mitoxantrone.
[0676] Promoting myelination, remyelination or oligodendrocyte
progenitor cell differentiation can prevent or can treat a
pathological condition or symptom in a mammal. A number of diseases
or disorders involve demyelination of the central or peripheral
nervous system which can occur for a number of reasons such as
immune dysfunction as in multiple sclerosis, encephalomyelitis,
Guillain-Barre Syndrome, chronic inflammatory demyelinating
polyneuropathy (CIDP), transverse myelitis, and optic neuritis;
demyelination due to injury such as spinal cord injury, traumatic
brain injury, stroke, acute ischemic optic neuropathy, or other
ischemia, cerebral palsy, neuropathy (e.g. neuropathy due to
diabetes, chronic renal failure, hypothyroidism, liver failure, or
compression of the nerve), post radiation injury, and central
pontine myelolysis (CPM); inherited conditions such as
Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum
disease, Krabbe disease, Canavan disease, Alexander disease,
Friedreich's ataxia, PelizaeusMerzbacher disease, Bassen-Kornzweig
syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy,
and nerve damage due to pernicious anemia; viral infection such as
progressive multifocal leukoencephalopathy (PML), Lyme disease, or
tabes dorsalis due to untreated syphilis; toxic exposure due to
chronic alcoholism (which is a possible cause of
Marchiafava-Bignami disease), chemotherapy, or exposure to
chemicals such as organophosphates; or dietary deficiencies such as
vitamin B12 deficiency, vitamin E deficiency, and copper
deficiency. Some demyelination disorders can have unknown or
multiple causes such as trigeminal neuralgia, Marchiafava-Bignami
disease and Bell's palsy. In addition, demyelination can contribute
to neuropathic pain. Compounds and salts described herein are
expected to be useful in treating demyelination disorders.
Inflammatory Disorders
[0677] Since LPA is a proinflammatory factor reducing the amount of
LPA producted by inhibiting ATX is useful for treating inflammatory
disorders such as asthma, allergies, arthritis, inflammatory
neuropathies, transplantation rejection, Crohn's disease,
ulcerative colitis, lupus erythematosis, psoriasis, an inflammatory
bowel condition, and diabetes.
Pain Mediation
[0678] Pain experienced by mammals can be divided into two main
categories: acute pain (or nociceptive) and chronic pain which can
be subdivided into chronic inflammatory pain and chronic
neuropathic pain. Acute pain is a response to stimulus that causes
tissue injury and is a signal to move away from the stimulus to
minimize tissue damage. Chronic pain, on the other hand, serves no
biological function and develops as a result of inflammation caused
by tissue damage (inflammatory pain) or by damage to the nervous
system such as demyelination (neuropathic pain). Chronic pain is
generally characterized by stimulus-independent, persistent pain or
by abnormal pain perception triggered by innocuous stimuli.
[0679] LPA has been found to be a mediator of both inflammatory
pain and neuropathic pain. The transient receptor potential channel
TRPV 1 is known to be the originator of inflammatory pain. LPA has
been shown to directly activate TRPV 1 thereby creating pain
stimulus by binding to its intracellular C-terminus (Tigyi, Nature
Chemical Biology (January 2012), 8:22-23). Thus, compounds and
salts which inhibit the formation of LPA by inhibiting the action
of ATX would be useful in treating inflammatory pain.
[0680] LPA has also been shown to play a role in neuropathic pain.
For example, sciatic nerve injury has been shown to induce
demyelination, down-regulation of myelin-associated glycoprotein
(MAG) and damage to Schwann cell partitioning of C-fiber-containing
Remak bundles in the sciatic nerve and dorsal root. However,
demyelination, MAG down-regulation and Remak bundle damage in the
dorsal root were abolished in LPA.sub.1 receptor-deficient
(Lpar1.sup.-/-) mice (Nagai, et al., Molecular Pain (2010), 6:78).
These results indicate that compounds and salts that inhibit the
formation of LPA by inhibiting the action of ATX would decrease
dorsal root demyelination following nerve injury and decrease or
eliminate neuropathic pain.
[0681] Additionally, the pathological disorder can be selected from
pain, acute pain, chronic pain, neuropathic pain, visceral pain,
nociceptive pain including post-surgical pain, and mixed pain types
involving the viscera, gastrointestinal tract, cranial structures,
musculoskeletal system, spine, urogenital system, cardiovascular
system and CNS, including cancer pain, back and orofacial pain; and
pain associated with dysmenorrhea, pelvic pain, cystitis,
pancreatitis, migraine, cluster and tension headaches, diabetic
neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia,
causalgia, and conditions of lower urinary tract dysfunction. (See,
for example, WO2013061297, which is incorporated by reference in
its entirety)
[0682] Thus the compounds and salts described herein are useful in
treating or preventing chronic pain such as inflammatory pain and
neuropathic pain in mammals.
Rheumatoid Arthritis (RA)
[0683] Studies in human and animal models of RA suggest that ATX
plays a role in the development and progress of the disease. For
example, increased ATX mRNA expression was detected in synovial
fibroblasts (SFs) from animal models of RA during differential
expression profiling, and human RA SFs were shown to express mRNA
for both ATX and LPARs (Aidinis, V., et al., PLoS genetics 1, e48
(2005); Zhao, C, et al., Molecular pharmacology 73, 587-600 (2008);
each of which is incorporated by reference in its entirety). ATX is
overexpressed from activated SFs in arthritic joints, both in
animal models and human patients (see WO 2011/151461). ATX
expression was shown to be induced from TNF, the major
pro-inflammatory factor driving RA.
[0684] Disease development was assessed in well-established animal
models of RA. When ATX expression was conditionally ablated
specifically in SFs, the lack of ATX expression in the joints
resulted in marked decreased inflammation and synovial hyperplasia.
This suggested an active involvement of the ATX-LPA axis in the
pathogenesis of the disease. Similar results were also obtained
with pharmacologic inhibition of ATX enzymatic activity and LPA
signaling. A series of ex vivo experiments on primary SFs revealed
that ATX, through LPA production, stimulates rearrangements of the
actin cyto skeleton, proliferation and migration to the
extracellular matrix (ECM), as well as the secretion of
proinflammatory cytokines and matrix metalloproteinases (MMPs).
Moreover, the LPA effect was shown to be synergistic with TNF and
dependent on the activation of MAPK cellular signaling pathways.
See, e.g., Armaka, M., et al., The Journal of experimental medicine
205, 331-337 (2008); which is incorporated by reference in its
entirety.
[0685] In one embodiment a method for treating an individual with
RA or the individual at risk of suffering thereof comprises
administering to said individual an SIP modulating agent and/or ATX
modulating agent of formula (I) in conjunction with an anti-TNF
antibody for use in the treatment of RA. Examples of suitable
anti-TNF antibodies are adalimumab, etanercept, golimumab, and
infliximab (Taylor P C, Feldmann M. Anti-TNF biologic agents: still
the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol.
2009 October; 5(10):578-82).
Asthma
[0686] The ATX-LPA pathway appears to have role in the pathogenesis
of asthma, for example, see Park, et al., Am J Respir Crit Care Med
Vol 188, Iss. 8, pp 928-940, 2013, the entire teachings of which
are incorporated herein by reference. Thus the compounds and salts
described herein are useful in preventing, treating, or reducing
symptoms of asthma in a mammal in need thereof.
Periodontal Disease
[0687] Elevated levels of LPA may contribute to the pathogenesis
and progression of periodontal diseases, see Bathena, et al.,
Journal of Pharmaceutical and Biomedical Analysis 56 (2011)
402-407, the entire teachings of which are incorporated herein by
reference. Thus the compounds and salts described herein are useful
in preventing, treating, or reducing symptoms of periodontal
disease in a mammal in need thereof.
Pulmonary Fibrosis
[0688] Evidence also suggests a role for ATX in pulmonary fibrosis.
Mice lacking lysophosphatidic acid (LPA) receptor 1 (LPAR1) were
protected from Bleomycin (BLM)-induced pulmonary fibrosis and
mortality, suggesting a major role for LPA in disease
pathophysiology. The majority of circulating LPA is produced by the
phospholipase D activity of Autotaxin (ATX) and the hydrolysis of
lysophosphatidylcholine (LPC). Increased ATX expression has been
previously reported in the hyperplastic epithelium of fibrotic
lungs of human patients and animal models. See, for example, Sakai,
et al., Inflammation and Regeneration Vol 33, No. 2 (2013), 78-89;
and Budd, et al., Future Med. Chem. (2013) 5(16), 1935-1952, the
entire teachings of both are incorporated herein by reference.
[0689] Therefore, we hypothesized that genetic or pharmacologic
inhibition of ATX activity would reduce local or circulating LPA
levels and hence attenuate disease pathogenesis. Thus the compounds
and salts described herein are useful in preventing, treating, or
reducing symptoms of pulmonary fibrosis in a mammal in need
thereof.
Liver Fibrosis
[0690] Subjects with liver fibrosis may exhibit increased ATX and
LPA levels in the blood, see, for example, Ikeda, et al., Clinica
Chimica Acta 413 (2012) 1817-1821; and Budd, et al., Future Med.
Chem. (2013) 5(16), 1935-1952, the entire teachings of both are
incorporated herein by reference. Thus the compounds and salts
described herein are useful in preventing, treating, or reducing
symptoms of liver fibrosis in a mammal in need thereof.
Renal Fibrosis
[0691] Evidence also suggests a role for ATX in renal fibrosis, see
for example, Sakai, et al., Inflammation and Regeneration Vol 33,
No. 2 (2013), 78-89, and Budd, et al., Future Med. Chem. (2013)
5(16), 1935-1952, the entire teachings of both are incorporated
herein by reference. Thus the compounds and salts described herein
are useful in preventing, treating, or reducing symptoms of renal
fibrosis in a mammal in need thereof.
Scleroderma
[0692] Evidence also suggests a role for ATX in
scleroderma/systemic sclerosis, see, for example, Sakai, et al.,
Inflammation and Regeneration Vol 33, No. 2 (2013), 78-89, the
entire teachings of which are incorporated herein by reference.
Thus the compounds and salts described herein are useful in
preventing, treating, or reducing symptoms of scleroderma in a
mammal in need thereof.
Cancer
[0693] Increased ATX expression has been detected in a large number
of malignancies, including mammary, thyroid, hepatocellular and
renal cell carcinomas, glioblastoma and neuroblastoma, as well as
NSCLC. Strikingly, transgenic overexpression of ATX was shown to
induce spontaneous mammary carcinogenesis. In accordance, in vitro
ATX overexpression in various cell types promotes proliferation and
metastasis while inhibiting apoptosis. LPA's actions are concordant
with many of the "hallmarks of cancer", indicating a role for LPA
in the initiation or progression of malignant disease. Indeed LPA
levels are significantly increased in malignant effusions, and its
receptors are aberrantly expressed in several human cancers.
[0694] LPA has been shown to be involved in wound healing and
stimulates the proliferation and migration of endothelial cells
promoting processes such as angiogenesis. However, these same
processes when deregulated can promote tumor growth and metastasis,
and LPA is thought to contribute to the development, progression,
and metastasis of several types of cancer including ovarian,
prostate, melanoma, breast, head and neck cancers (see
Gendaszewska-Darmach, Acta Biochimica Polonica (2008),
55(2):227-240). In addition, since ATX is located outside the cell
in circulation, ATX inhibitors are expected to be of most benefit
outside the cell. Therefore, ATX inhibitors are expected to be
useful in treating cancer, particularly multidrug resistant (MDR)
cancers where drug efflux mechanisms are the largest contributor to
the drug resistance.
[0695] See, for example: Euer, N., et al., Anticancer Res 22,
733-740 (2002); Liu, S., et al., Cancer Cell 15, 539-550 (2009);
Zhang, G., et al., Chin Med J (Engl) 112, 330-332 (1999); Stassar,
M. J., et al., Br J Cancer 85. 1372-1382 (2001); Kishi, Y., et al.,
J Biol Chem 281, 17492-17500 (2006); Kawagoe, H., et al., Cancer
Res 57, 2516-2521 (1997); Yang, Y., et al., Am J Respir Cell Mol
Biol 21, 216-222 (1999); and Toews, M. L., et al. Biochim Biophys
Acta 1582, 240-250 (2002); each of which is incorporated by
reference in its entirety.
Additional Diseases
[0696] Additionally, the pathological disorder can be selected from
renal conditions, liver conditions, inflammatory conditions,
conditions of the nervous system, conditions of the respiratory
system, vascular and cardiovascular conditions, fibrotic diseases,
cancer, angiogenesis, and tumor metastasis and progression, ocular
conditions, metabolic conditions, cholestatic and other forms of
chronic pruritus and acute and chronic organ transplant rejection.
(See, for example, WO2013186159 and WO2013061297, both of which are
incorporated by reference in its entirety).
[0697] Renal conditions include, but are not limited to, acute
kidney injury and chronic renal disease with and without
proteinuria including end-stage renal disease (ESRD). In more
detail, this includes decreased creatinine clearance and decreased
glomerular filtration rate, microalbuminuria, albuminuria and
proteinuria, glomerulosclerosis with expansion of reticulated
mesangial matrix with or without significant hypercellularity
(particularly diabetic nephropathy and amyloidosis), focal
thrombosis of glomerular capillaries (particularly thrombotic
microangiopathies), global fibrinoid necrosis, ischemic lesions,
malignant nephrosclerosis (such as ischemic retraction, reduced
renal blood flow and renal arteriopathy), swelling and
proliferation of intracapillary (endothelial and mesangial) and/or
extracapillary cells (crescents) like in glomerular nephritis
entities, focal segmental glomerular sclerosis, IgA nephropathy,
vasculitides/systemic diseases as well as acute and chronic kidney
transplant rejection and chronic allograft nephropathy.
[0698] Liver conditions include, but are not limited to, liver
cirrhosis, hepatic congestion, cholestatic liver disease including
pruritus, nonalcoholic steatohepatitis and acute and chronic liver
transplant rejection.
[0699] Inflammatory conditions include, but are not limited to,
arthritis, osteoarthritis, systemic lupus erythematodes, psoriasis,
chronic inflammation, inflammatory bowel disease, irritable bowel
syndrome, functional bowel disorders, abnormal evacuation disorder
and the like as well as inflammatory airways diseases such as
idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary
disease (COPD) or chronic asthma bronchiale.
[0700] Conditions of the respiratory system include, but are not
limited to, other diffuse parenchymal lung diseases of different
etiologies including iatrogenic drug-induced fibrosis, occupational
and/or environmental induced fibrosis, systemic diseases and
vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity
pneumonia), collagen vascular disease, alveolar proteinosis,
Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited
diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis,
neurofibromatosis, metabolic storage disorders, familial
interstitial lung disease), radiation induced fibrosis, silicosis,
asbestos induced pulmonary fibrosis or acute respiratory distress
syndrome (ARDS).
[0701] Conditions of the nervous system include, but are not
limited to, schizophrenia, neuro-inflammation (e.g. astrogliosis),
peripheral and/or autonomic (diabetic) neuropathies, neuropathies
and the like.
[0702] Vascular conditions include, but are not limited to,
atherosclerosis, thrombotic vascular disease as well as thrombotic
micro angiopathies, proliferative arteriopathy (such as swollen
myointimal cells surrounded by mucinous extracellular matrix and
nodular thickening), decreased vascular compliance (such as
stiffness, reduced ventricular compliance and reduced vascular
compliance), endothelial dysfunction and the like.
[0703] Cardiovascular conditions include, but are not limited to,
acute coronary syndrome, coronary heart disease, myocardial
infarction, arterial and pulmonary hypertension, thrombosis, stroke
and other vascular damage.
[0704] Fibrotic diseases include, but are not limited to myocardial
and vascular fibrosis, organ fibrosis, renal fibrosis, liver
fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and
encapsulating peritonitis. In some embodiments, the fibrotic
disease is renal tubulo-interstitial fibrosis or
glomerulosclerosis. In another embodiment, the fibrotic disease is
idiopathic pulmonary fibrosis. In another embodiment, the fibrotic
disease is non-alcoholic liver steatosis, liver fibrosis or liver
cirrhosis. Additionally, fibrotic diseases include endomyocardial
fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal
fibrosis, nephrogenic systemic fibrosis, Keloid, atherofibrosis and
adhesive capsulitis.
[0705] Cancer and cancer metastasis include, but are not limited
to, lung cancer, mesothelioma, glioma, hepatic carcinoma,
gastrointestinal cancers and progression and metastatic
aggressiveness thereof.
[0706] Ocular conditions include, but are not limited to,
proliferative and non-proliferative (diabetic) retinopathy, dry and
wet age-related macular degeneration (AMD), macular edema, central
arterial/venous occlusion, traumatic injury, glaucoma and the
like.
[0707] Metabolic conditions include, but are not limited to,
obesity and diabetes.
[0708] Pharmaceutical compositions can include a compound of
formula (I), or a pharmaceutically acceptable salt thereof. More
particularly, such compounds and salts can be formulated as
pharmaceutical compositions using standard pharmaceutically
acceptable carriers, fillers, solubilizing agents and stabilizers
known to those skilled in the art. For example, a pharmaceutical
composition including a compound of formula (I), or a
pharmaceutically acceptable salt thereof, as described herein, is
used to administer the appropriate compound, or a pharmaceutically
acceptable salt thereof, to a subject.
[0709] The compounds of formula (I), or a pharmaceutically
acceptable salt thereof, are useful for treating a disease or
disorder associated with S1P receptor activity, and/or ATX
activity. In one embodiment, a therapeutically effective amount of
a compound of formula (I), or a pharmaceutically acceptable salt
thereof, is delivered (e.g. administered) to a subject in need
thereof. In another embodiment, a pharmaceutical composition
comprising a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically-acceptable carrier is administered to a subject in
need thereof.
[0710] The compounds and salts described herein can be used in
combination with at least one further active ingredient, such as a
medicament used in the treatment of multiple sclerosis such as
Tysabri.RTM., dimethyl fumarate, an interferon (such as pegylated
or non-pegylated interferons, such as interferon .beta.-1a or
pegylated interferon .beta.-1a), glatiramer acetate, a compound
improving vascular function, an immunomodulating agent (such as
Fingolimod, cyclosporins, rapamycins or ascomycins, or their
immunosuppressive analogs, e.g. cyclosporine A, cyclosporine G,
FK-506, ABT-281, ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin
etc.); corticosteroids; cyclophosphamide; azathioprine;
mitoxanthrone, methotrexate; leflunomide; mizoribine; mycophenolic
add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone
valerate; difluprednate; Alclometasone dipropionate; amcinonide;
amsacrine; asparaginase; azathioprine; basiliximab; beclometasone
dipropionate; betamethasone; betamethasone dipropionate;
betamethasone phosphate sodique; betamethasone valerate;
budesonide; captopril; chlormethine chlorhydrate; clobetasol
propionate; cortisone acetate; cortivazol; cyclophosphamide;
cytarabine; daclizumab; dactinomycine; desonide; desoximetasone;
dexamethasone; dexamethasone acetate; dexamethasone isonicotinate;
dexamethasone metasulfobenzoate sodique; dexamethasonephosphate;
dexamethasone tebutate; dichlorisone acetate; doxorubicinee
chlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide;
fludrocortisone acetate; fludroxycortide; flumetasone pivalate;
flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone;
fluocortolone hexanoate; fluocortolone pivalate; fluorometholone;
fluprednidene acetate; fluticasone propionate; gemcitabine
chlorhydrate; halcinonide; hydrocortisone; hydrocortisone acetate;
hydrocortisone butyrate; hydrocortisone hemisuccinate; melphalan;
meprednisone; mercaptopurine; methylprednisolone;
methylprednisolone acetate; methylprednisolone hemisuccinate;
misoprostol; muromonab-cd3; mycophenolate mofetil; paramethansone
acetate; prednazoline, prednisolone; prednisolone acetate;
prednisolone caproate; prednisolone metasulfobenzoate sodique;
prednisolone phosphate sodique; prednisone; prednylidene;
rifampicine; rifampicine sodique; tacrolimus; teriflunomide;
thalidomide; thiotepa; tixocortol pivalate; triamcinolone;
triamcinolone acetonide hemisuccinate; triamcinolone benetonide;
triamcinolone diacetate; triamcinolone hexacetonide;
immunosuppressive monoclonal antibodies, e.g., monoclonal
antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7,
CD20 (e.g., rituximab and ocrelizumab), CD25, CD28, B7, CD40, CD45,
CD56 (e.g., daclizumab), or CD58 or their ligands; or other
immunomodulating agenty compounds, e.g. CTLA41g, or other adhesion
molecule inhibitors, e.g. mAbs or low molecular weight inhibitors
including Selectin antagonists and VLA-4 antagonists (such as
Tysabri.RTM.); remyelinating agents such as BIIB033. Compounds and
salts described herein can also be used in combination with agents
which treat the symptoms of multiple sclerosis such as
fampridine.
[0711] The dose of a compound provided herein, or a
pharmaceutically acceptable salt thereof, administered to a subject
can be less than 10 .mu.g, less than 25 .mu.g, less than 50 .mu.g,
less than 75 .mu.g, less than 0.10 mg, less than 0.25 mg, less than
0.5 mg, less than 1 mg, less than 2.5 mg, less than 5 mg, less than
10 mg, less than 15 mg, less than 20 mg, less than 50 mg, less than
75 mg, less than 100 mg, or less than 500 mg.
[0712] Delivering a compound of formula (I) to a mammal comprises
any delivery method whereby the compound comes in contact with any
part of the mammal's body. Delivering a compound of formula (I) to
a mammal includes administering a compound of formula (I)
topically, enterally, parenterally, transdermally, transmucosally,
via inhalation, intracisternally, epidurally, intravaginally,
intravenously, intramuscularly, subcutaneously, intradermally or
intravitreally to the mammal. Delivering a compound of formula (I)
to a mammal also includes administering topically, enterally,
parenterally, transdermally, transmucosally, via inhalation,
intracisternally, epidurally, intravaginally, intravenously,
intramuscularly, subcutaneously, intradermally or intravitreally to
a mammal a compound that metabolizes within or on a surface of the
body of the mammal to a compound of formula (I).
[0713] The duration of administering can be less than 30 seconds,
less than 1 minute, about 1 minute, between 1 minute and 5 minutes,
between 5 minutes and 10 minutes, between 10 minutes and 20
minutes, between 20 minutes and 30 minutes, between 30 minutes and
1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours,
between 6 hours and 12 hours, between 12 hours and 24 hours or for
more than 24 hours.
[0714] Administering the compound, or a pharmaceutically acceptable
salt thereof, can include multiple administrations. The duration
between administrations can be less than 30 seconds, less than 1
minute, about 1 minute, between 1 minute and 5 minutes, between 5
minutes and 10 minutes, between 10 minutes and 20 minutes, between
20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1
hour and 3 hours, between 3 hours and 6 hours, between 6 hours and
12 hours, between 12 hours and 24 hours or for more than 24
hours.
[0715] The duration between successive administrations can be less
than 30 seconds, less than 1 minute, about 1 minute, between 1
minute and 5 minutes, between 5 minutes and 10 minutes, between 10
minutes and 20 minutes, between 20 minutes and 30 minutes, between
30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours
and 6 hours, between 6 hours and 12 hours, between 12 hours and 24
hours, between 24 hours and 48 hours, between 48 hours and 72
hours, between 72 hours and 1 week or between 1 week and 2
weeks.
[0716] Administering the compound, or a pharmaceutically acceptable
salt thereof, to cells can include cells of an in vitro or in vivo
system or model. The cells can be part of a cell line. The cell
line can be a primary or secondary cell line. The cell line can be
an immortal cell line. The cells can be ruptured and be in the form
of a cell lysate. The cells can be part of a living organism, i.e.,
a subject, for example, a mammal. A mammal can include a rat, a
mouse, a gerbil, a hamster, a rabbit or a human. The human can be a
subject or a patient.
[0717] A method can further include monitoring a property of a
sample or a subject. A sample can be removed from a subject. For
instance, a sample can include a sample of cells or a tissue from a
subject. A sample can include blood, plasma, or neuronal tissue
including neurons or glial cells. A sample can also remain in the
subject. For example, a sample can be a tissue or cells that are
observed within the patient.
[0718] A method can further include providing untreated control
cells, sample or subject and measuring a property of a sample of
the untreated control cells, sample or subject.
[0719] A property can include the presence or absence of a
molecule, the concentration of a molecule, for example myelin basic
protein, myelin associated glycoprotein or myelin oligodendrocyte
glycoprotein. In some embodiments, determining the presence of a
molecule can include determining the concentration of the molecule,
determining the purity of the molecule or determining the quantity
of the molecule.
[0720] A property can be the conductivity of a tissue or cell. A
property can be an emission, for example, electromagnetic
radiation.
[0721] Monitoring a property can include observing the property of
the sample or subject alone. Monitoring a property can include
monitoring the property before the sample or subject has been
administered a compound provided herein, or a pharmaceutically
acceptable salt thereof. Monitoring a property can include
monitoring the property after the sample or subject has been
administered a compound, or a pharmaceutically acceptable salt
thereof. Monitoring a property can include monitoring a property
after the sample or subject has been administered a known
concentration of a compound, or a pharmaceutically acceptable salt
thereof.
[0722] Monitoring a property of a sample or subject can include
observing the property through a microscope. Monitoring a property
of the composition can include measuring the property using a
microscope. Monitoring a property of the composition can include
monitoring the property using still photography or movies. The
photography or movies can be on film media or digital form.
Monitoring a property can include taking a scan, for example, an
MRI or CT scan.
[0723] A compound of formula (I), or a pharmaceutically acceptable
salt thereof, formulated as a pharmaceutical composition and
administered to a mammalian host, such as a human patient in a
variety of forms adapted to the chosen route of administration,
e.g., orally or parenterally, as eyedrops, by intravenous,
intramuscular, topical or subcutaneous routes.
[0724] Thus, compound provided herein, or a pharmaceutically
acceptable salt thereof, may be systemically administered, e.g.,
orally, in combination with a pharmaceutically acceptable vehicle
such as an inert diluent or an assimilable edible carrier. They may
be enclosed in hard or soft shell gelatin capsules, may be
compressed into tablets, or may be incorporated directly with the
food of the patient's diet. For oral therapeutic administration,
the active compound, or a pharmaceutically acceptable salt thereof,
may be combined with one or more excipients and used in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, or wafers, and the like. Such compositions and
preparations should contain at least about 0.1% of active compound,
or a pharmaceutically acceptable salt thereof. The percentage of
the compositions and preparations may, of course, be varied and may
conveniently be between about 2 to about 60% of the weight of a
given unit dosage form. The amount of active compound, or a
pharmaceutically acceptable salt thereof, in such therapeutically
useful compositions can be such that an effective dosage level will
be obtained.
[0725] The tablets, troches, pills, capsules, and the like can
include the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; or a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, or a pharmaceutically acceptable salt thereof,
sucrose or fructose as a sweetening agent, methyl or propylparabens
as preservatives, a dye and flavoring such as cherry or orange
flavor. Of course, any material used in preparing any unit dosage
form should be pharmaceutically acceptable and substantially
non-toxic in the amounts employed. In addition, the active
compound, or a pharmaceutically acceptable salt thereof, may be
incorporated into sustained-release preparations and devices.
[0726] The active compound, or a pharmaceutically acceptable salt
thereof, may also be administered intravenously or
intraperitoneally by infusion or injection. Solutions of the active
compound or its salts can be prepared in water, optionally mixed
with a nontoxic surfactant. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use,
these preparations can contain a preservative to prevent the growth
of microorganisms.
[0727] Exemplary pharmaceutical dosage forms for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form should be
sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol
(for example, glycerol, propylene glycol, liquid polyethylene
glycols, and the like), vegetable oils, or nontoxic glyceryl
esters, and mixtures thereof. The proper fluidity can be
maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, or thimerosal, and the like. In
many cases, isotonic agents, for example, sugars, buffers or sodium
chloride, will be included. Prolonged absorption of the injectable
compositions can be brought about by the use in the compositions of
agents delaying absorption, for example, aluminum monostearate or
gelatin.
[0728] Sterile injectable solutions can be prepared by
incorporating the active compound, or a pharmaceutically acceptable
salt thereof, in the required amount in the appropriate solvent
with various of the other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile
powders for the preparation of sterile injectable solutions, the
methods of preparation can be vacuum drying and the freeze drying
techniques, which can yield a powder of the active ingredient plus
any additional desired ingredient present in the previously
sterile-filtered solutions.
[0729] For topical administration, a compound provided herein, or a
pharmaceutically acceptable salt thereof, may be applied in pure
form, e.g., when they are liquids. However, it can be generally be
desirable to administer them to the skin as compositions or
formulations, in combination with a dermatologically acceptable
carrier, which may be a solid or a liquid.
[0730] Exemplary solid carriers can include finely divided solids
such as talc, clay, microcrystalline cellulose, silica, alumina and
the like. Useful liquid carriers include water, alcohols or glycols
or water-alcohol/glycol blends, in which the present compounds and
salts can be dissolved or dispersed at effective levels, optionally
with the aid of non-toxic surfactants. Adjuvants such as fragrances
and additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0731] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts or esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0732] Examples of useful dermatological compositions which can be
used to deliver the compounds provided herein, or a
pharmaceutically acceptable salt thereof, to the skin are known to
the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),
Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No.
4,559,157) and Wortzman (U.S. Pat. No. 4,820,508), each of which is
incorporated by reference in its entirety.
[0733] Useful dosages of the compounds provided herein, or a
pharmaceutically acceptable salt thereof, can be determined by
comparing their in vitro activity, and in vivo activity in animal
models. Methods for the extrapolation of effective dosages in mice,
and other animals, to humans are known to the art; for example, see
U.S. Pat. No. 4,938,949, which is incorporated by reference in its
entirety.
[0734] Generally, the concentration of the compound(s) provided
herein, or a pharmaceutically acceptable salt thereof, in a liquid
composition, such as a lotion, can be from about 0.1 to about 25
weight percent, such as from about 0.5-10 weight percent. The
concentration in a semi-solid or solid composition such as a gel or
a powder can be about 0.1-5 wt-%, such as about 0.5-2.5 weight
percent based on the total weight of the composition.
[0735] The amount of the compound, or a pharmaceutically acceptable
salt thereof, required for use in treatment can vary not only with
the particular salt selected but also with the route of
administration, the nature of the condition being treated and the
age and condition of the patient and can be ultimately at the
discretion of the attendant physician or clinician. In general,
however, a dose can be in the range of from about 0.1 to about 10
mg/kg of body weight per day.
[0736] The compound, or a pharmaceutically acceptable salt thereof,
can be conveniently administered in unit dosage form; for example,
containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per
unit dosage form. In some embodiments, a dose of 5 mg/kg or less
can be suitable.
[0737] The active ingredient can be administered so as to achieve a
desired peak plasma concentration of the active compound, or a
pharmaceutically acceptable salt thereof. The desired peak plasma
concentration can be from about 0.5 .mu.M to about 75 .mu.M, such
as, about 1 .mu.M to 50 .mu.M, or about 2 .mu.M to about 30 .mu.M.
This may be achieved, for example, by the intravenous injection of
a 0.05 to 5% solution of the active ingredient, optionally in
saline, or orally administered as a bolus containing between about
1 mg to about 100 mg of the active ingredient.
[0738] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four, or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0739] The disclosed method can include a kit comprising a compound
provided herein, or a pharmaceutically acceptable salt thereof, and
instructional material which can describe administering the
compound, or a pharmaceutically acceptable salt thereof, or a
composition comprising the compound, or a pharmaceutically
acceptable salt thereof, to a cell or a subject. This should be
construed to include other embodiments of kits that are known to
those skilled in the art, such as a kit comprising a (such as
sterile) solvent for dissolving or suspending the compound, or a
pharmaceutically acceptable salt thereof, or composition prior to
administering the compound or composition to a cell or a subject.
In some embodiments, the subject can be a human.
[0740] In accordance with the disclosed methods, as described above
or as discussed in the Examples below, there can be employed
conventional chemical, cellular, histochemical, biochemical,
molecular biology, microbiology, and in vivo techniques which are
known to those of skill in the art. Such techniques are explained
fully in the literature.
EXAMPLES
[0741] The compounds provided herein, or a pharmaceutically
acceptable salt thereof, can be prepared from readily available
starting materials using the following general methods and
procedures. It will be appreciated that where typical or preferred
process conditions (i.e., reaction temperatures, times, mol ratios
of reactants, solvents, pressures, etc.) are given, other process
conditions can also be used unless otherwise stated. Optimum
reaction conditions may vary with the particular reactants or
solvent used, but such conditions can be determined by one skilled
in the art by routine optimization procedures.
[0742] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions.
Suitable protecting groups for various functional groups as well as
suitable conditions for protecting and deprotecting particular
functional groups are well known in the art. For example, numerous
protecting groups are described in T. W. Greene and G. M. Wuts,
Protecting Groups in Organic Synthesis, Third Edition, Wiley, New
York, 1999, and references cited therein.
[0743] Furthermore, the compounds provided herein may contain one
or more chiral centers. Accordingly, if desired, such compounds can
be prepared or isolated as pure stereoisomers, i.e., as individual
enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
All such stereoisomers (and enriched mixtures) are included, unless
otherwise indicated. Pure stereoisomers (or enriched mixtures) may
be prepared using, for example, optically active starting materials
or stereoselective reagents well-known in the art. Alternatively,
racemic mixtures of such compounds can be separated using, for
example, chiral column chromatography, chiral resolving agents and
the like.
[0744] The compounds of formula (I) can be prepared by the
synthetic protocols illustrated in Scheme 1, where L, L.sup.2,
R.sup.1, R.sup.2, R.sup.9, R.sup.9a and q are as defined
herein.
##STR00024##
[0745] Compound 1-1 is reacted with at least a stoichiometric
amount and in some embodiments an excess of H--R.sup.2. The
reaction is typically conducted under conventional coupling
conditions well known in the art. In one embodiment, the reaction
is conducted with the use of a coupling agent such as
carbonyldiimidazole (for compounds whereing L is --OC(O)--) and
HATU (for compounds wherein L is --C(O)--) in the presence of
triethylamine in a suitable solvent, such as DMF. The reaction is
continued until substantially complete which typically occurs
within about 1 to 12 hours. Upon reaction completion, compound (I)
can be recovered by conventional techniques such as neutralization,
extraction, precipitation, chromatography, filtration and the
like.
[0746] For compounds wherein one of R.sup.3, R.sup.6 and/or R.sup.8
comprise an amide or a carboxyl group (either a carboxilic acid or
ester functionality), the coupling reaction of Scheme 1 can be
performed either before or after the installation of such groups.
For the amide, the reaction is typically conducted under
conventional coupling conditions well known in the art. In one
embodiment, the reaction is conducted with the use of a coupling
agent such as DIAD in the presence of PPh.sub.3 in a suitable
solvent, such as toluene. The reaction is continued until
substantially complete which typically occurs within about 1 to 12
hours. Upon reaction completion, the final compound can be
recovered by conventional techniques such as neutralization,
extraction, precipitation, chromatography, filtration and the
like.
TABLE-US-00001 List of Abbreviations and Acronyms Abbreviation
Meaning .degree. C. Degree Celsius Ac Acetate aq. Aqueous i-OPr
Isopropoxide ng Nanograms sat. Saturated bs/br Broad singlet Bu
Butyl d Doublet dba dibenzylideneacetone DCM Dichloromethane DIAD
Diisopropyl azodicarboxylate DMF Dimethylformamide DMSO
Dimethylsulfoxide DIPEA N,N-Diisopropylethylamine EA Ethylacetate
EGTA Ethylene glycol tetraacetic acid eq Equivalents Et Ethyl g
Grams h Hours HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HPCD Hydroxypropyl-.beta.-cyclodextrin HPLC
High-performance liquid chromatography Hz Hertz IC.sub.50 The half
maximal inhibitory concentration J Coupling constant Kg Kilogram
LCMS Liquid chromatography-mass spectrometry LPC Lysolecithin M
Molar m multiplet m/z mass-to-charge ratio M + H Mass peak plus
hydrogen Me Methyl mg Milligram MHz Megahertz min Minute mL
Milliliter mM Millimolar mmol Millimole MS Mass spectrometry MW
Microwave N Normal nL Nanoliter nm Nanometer NMR Nuclear magnetic
resonance PBS Phosphate buffered saline Ph Phenyl prep Preparative
q Quartet rt Room temperature s Singlet sec Second t Triplet TFA
Trifluoroacetic acid THF Tetrahydrofuran .delta. Chemical shift
.mu.g Microgram .mu.L Microliter .mu.M Micromolar
Example 1
5-(3,5-Dichlorobenzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00025##
[0748] To a mixture of (3,5-dichloro-phenyl)-methanol (97 mg, 0.55
mmol) and N,N-carbonyldiimidazole (89 mg, 0.55 mmol) in DMF (2 mL)
was added triethylamine (139 .mu.L, 1.00 mmol). The reaction
mixture was stirred at rt for 1 h. It was then added a solution of
ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
(105 mg, 0.50 mmol) in DMF (1 mL). The reaction mixture was stirred
at rt over weekend. It was purified by prep-HPLC (MeCN/H.sub.2O
with 0.1% TFA) to get the desired ester as a white powder after
lyophilization (68 mg, yield 33%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.11-7.42 (m, 3H), 6.72, 6.66 (s, s, 1H),
5.10, 5.06 (s, s, 2H), 4.65, 4.53 (s, s, 2H), 4.46-4.54 (m, 2H),
4.32 (q, J=7.03 Hz, 2H), 3.69-3.94 (m, 2H), 1.85-1.95 (m, 2H), 1.35
(t, J=7.03 Hz, 3H); LCMS m/z 411.9 [M+H].sup.+.
Example 2
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00026##
[0750] The titled compound was synthesized according to the
procedure described in Example 1 (1.49 g, yield 78%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.78-8.16 (m, 3H), 6.65, 6.59
(s, s, 1H), 5.25, 5.22 (s, s, 2H), 4.66, 4.57 (s, s, 2H), 4.43-4.54
(m, 2H), 4.14-4.31 (m, 2H), 3.64-3.86 (m, 2H), 1.72-1.86 (m, 2H),
1.25 (t, J=6.90 Hz, 3H); LCMS m/z 480.2 [M+H].sup.+.
Example 3
7-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate
##STR00027##
[0752] The titled compound was synthesized according to the
procedure described in Example 1 (159 mg, yield 67%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.05 (s, 2H), 7.96 (s, 1H),
7.76 (s, 1H), 5.36 (s, 2H), 4.79-4.74 (m, 2H), 4.31 (q, J=7.2 Hz,
2H), 4.15 (t, J=4.8 Hz, 2H), 3.97 (bs, 2H), 1.35 (t, J=7.2 Hz, 3H);
LCMS m/z 466.1 [M+H].sup.+.
Example 4
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxylate
##STR00028##
[0754] The titled compound was synthesized according to the
procedure described in Example 1 (116 mg, yield 58%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.03 (s, 2H), 7.94 (s, 1H),
6.63 (s, 1H), 5.34 (s, 2H), 4.82-4.76 (m, 2H), 4.33 (q, J=7.2 Hz,
2H), 4.26-3.21 (m, 2H), 4.02 (bs, 2H), 1.35 (t, J=7.2 Hz, 3H); LCMS
m/z 466.1 [M+H].sup.+.
Example 5
7-(3,5-Bis(trifluoromethyl)benzyl) 3-methyl
8,9-dihydro-5H-imidazo[1,2-d][1,4]diazepine-3,7(6H)-dicarboxylate
##STR00029##
[0756] The titled compound was synthesized according to the
procedure described in Example 1 (121 mg, yield 61%). LCMS m/z
466.1 [M+H].sup.+.
Example 6
5-(3,5-Bis(trifluoromethyl)benzyl) 3-ethyl
7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-3,5(6H)-dicarboxylate
##STR00030##
[0758] The titled compound was synthesized according to the
procedure described in Example 1 (115 mg, yield 59%). LCMS m/z
481.1 [M+H].sup.+.
Example 7
5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-2-carboxylic acid
##STR00031##
[0760] To the above ethyl ester (65 mg, 0.16 mmol) in MeOH (0.8 mL)
and THF (0.8 mL) was added 3 N NaOH (0.2 mL, 0.6 mmol). The
reaction mixture was stirred at rt for 2 h. It was acidified by
adding 2N HCl (pH-3.about.4), and purified by prep-HPLC
(MeCN/H.sub.2O with 0.1% TFA) to get the desired acid as a white
solid (55 mg, yield 91%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.13-7.42 (m, 3H), 6.71, 6.66 (s, s, 1H), 5.10, 5.07 (s, s,
2H), 4.66, 4.53 (s, s, 2H), 4.46-4.54 (m, 2H), 3.74-3.96 (m, 2H),
1.85-1.96 (m, 2H); LCMS m/z 383.9 [M+H].sup.+.
Example 8
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-py-
razolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00032##
[0762] To 5-(3,5-bis(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(2.98 g, 6.22 mmol) in THF (20 mL) was added 3 N NaOH (8 mL, 20
mmol), followed by MeOH (4 mL). The reaction mixture was stirred at
rt for 1.5 h. It was acidified by adding 2N HCl (pH-3.about.4),
diluted with brine, and extracted with EtOAc. The organic phase was
dried over MgSO.sub.4, filtered and concentrated to get
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid as a white solid
(2.79 g, yield 99%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.75-8.01 (m, 3H), 6.71, 6.62 (s, s, 1H), 5.27, 5.25 (s, s,
2H), 4.67, 4.61 (s, s, 2H), 4.41-4.55 (m, 2H), 3.71-3.97 (m, 2H),
1.78-1.99 (m, 2H); LCMS m/z 452.1 [M+H].sup.+.
Example 9
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydroimidaz-
o[1,2-a]pyrazine-2-carboxylic acid
##STR00033##
[0764] The titled compound was synthesized according to the
procedure described in Example 7 (17 mg, yield 14%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.04 (s, 2H), 7.96 (s, 1H),
7.68 (s, 1H), 5.35 (s, 2H), 4.80-4.73 (m, 2H), 4.14 (t, J=5.6 Hz,
2H), 3.96 (bs, 2H); LCMS m/z 438.1 [M+H].sup.+.
Example 10
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-6,7,8,9-tetrahydro-5H-im-
idazo[1,2-d][1,4]diazepine-3-carboxylic acid
##STR00034##
[0766] The titled compound was synthesized according to the
procedure described in Example 7 (30 mg, yield 26%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.03 (s, 2H), 7.95 (s, 1H),
7.46 (s, 1H), 5.34 (s, 2H), 4.88-4.84 (m, 2H), 3.85-3.73 (m, 4H),
3.15-3.14 (m, 2H); LCMS m/z 452.1 [M+H].sup.+.
Example 11
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-[1-
,2,3]triazolo[1,5-a][1,4]diazepine-3-carboxylic acid
##STR00035##
[0768] The titled compound was synthesized according to the
procedure described in Example 7 (10 mg, yield 10%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.95-7.83 (m, 3H), 5.24 (s,
2H), 5.17-5.11 (m, 2H), 4.72-4.67 (m, 2H), 3.90-3.79 (m, 2H),
2.02-1.98 (m, 2H); LCMS m/z 453.1 [M+H].sup.+.
Example 12
3,5-Dichlorobenzyl
2-(9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-5(6H)-carboxylate
##STR00036##
[0770] To a mixture of
5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepine-2-carboxylic acid (12 mg, 0.031 mmol) and
9-azabicyclo[3.3.1]nonane hydrochloride (6.0 mg, 0.037 mmol) in DMF
(0.5 mL) was added HATU (14 mg, 0.037 mmol), followed by
N,N-diisopropylethylamine (22 .mu.L, 0.12 mmol). The mixture was
stirred at room temperature for 1 h, and purified by prep HPLC (TFA
method) to provide the desired product as a white solid (11 mg,
yield 72%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.21-7.40 (m, 3H), 6.50, 6.47 (s, s, 1H), 5.08, 5.07 (s, s, 2H),
4.55-4.79 (m, 4H), 4.39-4.52 (m, 2H), 3.76-3.96 (m, 2H), 2.10-2.30
(m, 2H), 1.57-2.00 (m, 12H); LCMS m/z 491.0 [M+H].sup.+.
Example 13
3,5-Dichlorobenzyl
2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate
##STR00037##
[0772] The titled compound was synthesized according to the
procedure described in Example 12 (65 mg, yield 65%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.28 (m, 2H), 7.16 (s,
1H), 6.66-6.63 (m, 1H), 5.10-5.06 (m, 2H), 4.65-4.59 (m, 2H),
4.52-4.49 (m, 2H), 4.19-4.12 (m, 1H), 3.86-3.81 (m, 2H), 1.91 (bs,
2H), 1.23 (d, J=6.8 Hz, 6H); LCMS m/z 425.1 [M+H].sup.+.
Example 14
3,5-Dichlorobenzyl
2-(tert-butylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00038##
[0774] The titled compound was synthesized according to the
procedure described in Example 12 (74 mg, yield 72%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.32 (m, 1H), 7.27 (s,
1H), 7.15 (s, 1H), 6.62-6.60 (m, 1H), 5.09-5.06 (m, 2H), 4.65-4.59
(m, 2H), 4.49 (t, J=5.2 Hz, 2H), 3.85-3.80 (m, 2H), 1.90 (bs, 2H),
1.43 (s, 9H); LCMS m/z 439.1 [M+H].sup.+.
Example 15
3,5-Dichlorobenzyl
2-(cyclobutylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00039##
[0776] The titled compound was synthesized according to the
procedure described in Example 12 (77 mg, yield 84%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.16 (m, 3H), 6.65-6.62
(m, 1H), 5.09-5.06 (m, 2H), 4.64-4.59 (m, 2H), 4.51-4.45 (m, 3H),
3.86-3.81 (m, 2H), 2.33-2.31 (m, 2H), 2.12-2.07 (m, 2H), 1.91 (bs,
2H), 1.78-1.74 (m, 2H); LCMS m/z 437.1 [M+H].sup.+.
Example 16
3,5-Dichlorobenzyl
2-(cyclopentylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6-
H)-carboxylate
##STR00040##
[0778] The titled compound was synthesized according to the
procedure described in Example 12 (78 mg, yield 83%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.16 (m, 3H), 6.66-6.64
(m, 1H), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H),
4.30-4.26 (m, 1H), 3.86-3.81 (m, 2H), 2.04-1.91 (m, 4H), 1.77-1.54
(m, 6H); LCMS m/z 451.1 [M+H].sup.+.
Example 17
3,5-Dichlorobenzyl
2-(cyclohexylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00041##
[0780] The titled compound was synthesized according to the
procedure described in Example 12 (76 mg, yield 69%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.16 (m, 3H), 6.66-6.64
(m, 1H), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H),
3.86-3.81 (m, 3H), 1.93-1.91 (m, 4H), 1.81-1.78 (m, 2H), 1.69-1.65
(m, 1H), 1.43-1.25 (m, 5H); LCMS m/z 465.1 [M+H].sup.+.
Example 18
3,5-Dichlorobenzyl
2-(pyrrolidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate
##STR00042##
[0782] The titled compound was synthesized according to the
procedure described in Example 12 (71 mg, yield 65%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.39-7.21 (m, 3H), 6.67-6.63
(m, 1H), 5.10-5.07 (m, 2H), 4.66-4.62 (m, 2H), 4.53-4.51 (m, 2H),
3.91-4.82 (m, 4H), 3.59 (t, J=6.8 Hz, 2H), 1.99-1.92 (m, 6H); LCMS
m/z 437.1 [M+H].sup.+.
Example 19
3,5-Dichlorobenzyl
2-(piperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00043##
[0784] The titled compound was synthesized according to the
procedure described in Example 12 (66 mg, yield 62%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37-7.27 (m, 3H), 6.51-6.49
(m, 1H), 5.09-5.08 (m, 2H), 4.66-4.62 (m, 2H), 4.51-4.48 (m, 2H),
3.88-3.82 (m, 4H), 3.68 (t, J=4.2 Hz, 2H), 1.93-1.92 (m, 2H),
1.74-1.70 (m, 2H), 1.64-1.59 (m, 4H); LCMS m/z 451.1
[M+H].sup.+.
Example 20
3,5-Dichlorobenzyl
2-(4-fluoropiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00044##
[0786] The titled compound was synthesized according to the
procedure described in Example 12 (48 mg, yield 43%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.39-7.26 (m, 3H), 6.56-6.54
(m, 1H), 5.09-5.07 (m, 2H), 4.96-4.83 (m, 1H), 4.67-4.62 (m, 2H),
4.50 (t, J=5.6 Hz, 2H), 4.03-3.71 (m, 6H), 1.99-1.86 (m, 6H); LCMS
m/z 469.1 [M+H].sup.+.
Example 21
3,5-Dichlorobenzyl
2-(4-methylpiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00045##
[0788] The titled compound was synthesized according to the
procedure described in Example 12 (60 mg, yield 55%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.37 (s, 1H), 7.30-7.26 (m,
2H), 6.50-6.48 (m, 1H), 5.09-5.07 (m, 2H), 4.66 (s, 1H), 4.61-4.56
(m, 3H), 4.49 (t, J=5.2 Hz, 2H), 3.88-3.82 (m, 2H), 3.11-3.09 (m,
1H), 2.81-2.79 (m, 1H), 1.93-1.92 (m, 2H), 1.78-1.66 (m, 3H),
1.18-1.15 (m, 2H), 0.98 (d, J=4.2 Hz, 3H); LCMS m/z 465.1
[M+H].sup.+.
Example 22
3,5-Dichlorobenzyl
2-(4-(trifluoromethyl)piperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5--
a][1,4]diazepine-5(6H)-carboxylate
##STR00046##
[0790] The titled compound was synthesized according to the
procedure described in Example 12 (80 mg, yield 65%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 0.05 TFA as mobile
phase; from 5% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.39-7.36 (m, 1H), 7.31-7.25 (m, 2H), 6.57-6.55 (m, 1H),
5.10-5.08 (m, 2H), 4.88-4.79 (m, 1H), 4.74-4.62 (m, 3H), 4.52-4.50
(m, 2H), 3.88-3.82 (m, 2H), 3.18-3.12 (m, 1H), 2.85-2.79 (m, 1H),
2.59-2.50 (m, 1H), 2.01-1.93 (m, 4H), 1.61-1.48 (m, 2H); LCMS m/z
519.1 [M+H].sup.+.
Example 23
3,5-Dichlorobenzyl
2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00047##
[0792] The titled compound was synthesized according to the
procedure described in Example 12 (59 mg, yield 56%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.39-7.37 (m, 1H), 7.30 (s,
1H), 7.25 (s, 1H), 6.59-6.57 (m, 1H), 5.10-5.07 (m, 2H), 4.67-4.62
(m, 2H), 4.51-4.49 (m, 2H), 4.06-4.01 (m, 2H), 3.88-3.81 (m, 2H),
3.73-3.69 (m, 6H), 1.93-1.92 (m, 2H); LCMS m/z 453.0
[M+H].sup.+.
Example 24
3,5-Dichlorobenzyl
2-(piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00048##
[0794] The titled compound was synthesized according to the
procedure described in Example 12 (80 mg, yield 75%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.38-7.37 (m, 1H), 7.30-7.25
(m, 2H), 6.56-6.54 (m, 1H), 5.10-5.07 (m, 2H), 4.67-4.62 (m, 2H),
4.51-4.49 (m, 2H), 3.97-3.83 (m, 4H), 3.70 (bs, 2H), 2.87-2.84 (m,
4H), 1.93-1.92 (m, 2H); LCMS m/z 452.1 [M+H].sup.+.
Example 25
3,5-Dichlorobenzyl
2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00049##
[0796] The titled compound was synthesized according to the
procedure described in Example 12 (72 mg, yield 66%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.38-7.37 (m, 1H), 7.30-7.25
(m, 2H), 6.56-6.65 (m, 1H), 5.09-5.07 (m, 2H), 4.66-4.61 (m, 2H),
4.50 (t, J=5.0 Hz, 2H), 4.04 (bs, 2H), 3.88-3.82 (m, 2H), 3.75 (bs,
2H), 2.50-2.47 (m, 4H), 2.33 (s, 3H), 1.93-1.92 (m, 2H); LCMS m/z
466.1 [M+H].sup.+.
Example 26
3,5-Dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate
##STR00050##
[0797] Step 1
3,5-Dichlorobenzyl
2-(4-((tert-butoxycarbonyl)amino)piperidine-1-carbonyl)-7,8-dihydro-4H-py-
razolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00051##
[0799] The titled compound was synthesized according to the
procedure described in Example 12 (121 mg, yield 82%); LCMS m/z
566.1 [M+H].sup.+.
Step 2
3,5-Dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate
##STR00052##
[0801] A mixture of 3,5-dichlorobenzyl
2-(4-((tert-butoxycarbonyl)amino)piperidine-1-carbonyl)-7,8-dihydro-4H-py-
razolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (120 mg, 0.21 mmol),
TFA (2 mL) in dichloromethane (4 mL) was stirred at rt for 3 h. The
mixture was evaporated in vacuo, the residue was dissolved in
dichloromethane (50 mL), washed with saturated aqueous NaHCO.sub.3
solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in
vacuo to give the crude product, which was purified by prep-HPLC
(MeCN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as mobile phase; from
5% to 95%) to afford 3,5-dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate as a brown solid (36 mg, yield 36%). .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.38-6.37 (m, 1H),
7.31-7.26 (m, 2H), 6.53-6.51 (m, 1H), 5.10-5.07 (m, 2H), 4.68-4.53
(m, 4H), 4.50 (t, J=5.6 Hz, 2H), 3.88-3.82 (m, 2H), 3.21-3.15 (m,
1H), 2.95-2.85 (m, 2H), 1.94-1.83 (m, 4H), 1.38-1.32 (m, 2H); LCMS
m/z 466.1 [M+H].sup.+.
Example 27
3,5-Dichlorobenzyl
2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-ca-
rboxylate
##STR00053##
[0803] The titled compound was synthesized according to the
procedure described in Example 12 (70 mg, yield 75%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.38-7.18 (m, 3H), 6.64-6.61
(m, 1H), 5.09-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H),
3.86-3.81 (m, 2H), 2.88 (s, 3H), 1.92-1.91 (m, 2H); LCMS m/z 397.1
[M+H].sup.+.
Example 28
3,5-Dichlorobenzyl
2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)--
carboxylate
##STR00054##
[0805] The titled compound was synthesized according to the
procedure described in Example 12 (68 mg, yield 70%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.29-7.17 (m, 3H), 6.59-6.54
(m, 1H), 5.03 (s, 2H), 4.55-4.54 (m, 2H), 4.45-4.43 (m, 2H), 3.78
(t, J=4.8 Hz, 2H), 3.31 (bs, 3H), 3.07 (s, 3H), 1.98-1.97 (m, 2H);
LCMS m/z 411.1 [M+H].sup.+.
Example 29
3,5-Dichlorobenzyl
2-(ethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00055##
[0807] The titled compound was synthesized according to the
procedure described in Example 12 (68 mg, yield 70%). The mixture
was purified by pre-HPLC (MeCN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.38-7.18 (m, 3H), 6.65-6.62
(m, 1H), 5.10-5.06 (m, 2H), 4.66-4.60 (m, 2H), 4.52-4.49 (m, 2H),
3.87-3.81 (m, 2H), 3.37 (q, J=7.2 Hz, 2H), 1.92-1.91 (m, 2H), 1.20
(t, J=7.2 Hz, 3H); LCMS m/z 411.1 [M+H].sup.+.
Example 30
3,5-Bis(trifluoromethyl)benzyl
2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00056##
[0809] The titled compound was synthesized according to the
procedure described in Example 12 (63 mg, yield 55%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.94-7.89 (m, 3H), 6.58-6.55
(m, 1H), 5.27-5.26 (m, 2H), 4.68-4.62 (m, 2H), 4.51-4.49 (m, 2H),
4.05-4.01 (m, 2H), 3.90-3.83 (m, 2H), 3.73-3.68 (m, 6H), 1.93-1.92
(m, 2H); LCMS m/z 521.1 [M+H].sup.+.
Example 31
3,5-Bis(trifluoromethyl)benzyl
2-(4-hydroxypiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate
##STR00057##
[0811] The titled compound was synthesized according to the
procedure described in Example 12 (71 mg, yield 60%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.95-7.91 (m, 3H), 6.54-6.50
(m, 1H), 5.27-5.26 (m, 2H), 4.68-4.62 (m, 2H), 4.51-4.49 (m, 2H),
4.33-4.29 (m, 1H), 4.20-4.16 (m, 1H), 3.90-3.84 (m, 3H), 3.52-3.50
(m, 1H), 3.22-3.21 (m 1H), 1.93 (bs, 4H), 1.52-1.51 (m, 2H); LCMS
m/z 535.1 [M+H].sup.+.
Example 32
3,5-Bis(trifluoromethyl)benzyl
2-(4-fluoropiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00058##
[0813] The titled compound was synthesized according to the
procedure described in Example 12 (67 mg, yield 57%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.95-7.91 (m, 3H), 6.57-6.52
(m, 1H), 5.28-5.27 (m, 2H), 4.98-4.77 (m, 1H), 4.69-4.63 (m, 2H),
4.52-4.50 (m, 2H), 4.04-3.96 (m, 2H), 3.90-3.84 (m, 3H), 3.72 (bs,
1H), 1.94-1.93 (m, 6H); LCMS m/z 535.1 [M+H].sup.+.
Example 33
3,5-Bis(trifluoromethyl)benzyl
2-(piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00059##
[0815] The titled compound was synthesized according to the
procedure described in Example 12 (64 mg, yield 56%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.04 (bs, 2H), 7.97 (s, 1H),
6.45, 6.40 (s, s, 1H), 5.25, 5.23 (s, s, 2H), 4.65, 4.57 (s, s,
2H), 4.45-4.44 (m, 2H), 3.78-3.74 (m, 4H), 3.49 (bs, 2H), 2.67-2.65
(m, 4H), 1.84-1.80 (m, 2H); LCMS m/z 520.2 [M+H].sup.+.
Example 34
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00060##
[0816] Step 1
tert-Butyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00061##
[0818] To a solution of
5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbo-
xylic acid (2.3 g, 8.6 mmol) in DMF (8 mL) was added HATU (4.9 g,
12.9 mmol) and Et.sub.3N (2.6 g, 25.8 mmol). After stirring at rt
for 2 h, ethyl 9-azabicyclo[3.3.1]nonane-3-carboxylate
hydrochloride (2.2 g, 9.5 mmol) was added to the reaction solution.
The mixture was stirred at rt for 16 h, and was purified with
prep-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile phase; from 20%
to 95%) to furnish the compound tert-butyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate as a yellow solid (1.9 g,
yield 51%). LCMS m/z 447.2 [M+H].sup.+.
Step 2
Ethyl
9-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonyl)-9-azabicycl-
o[3.3.1]nonane-3-carboxylate
##STR00062##
[0820] To a solution of tert-butyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate (1.9 g, 4.26 mmol) in EtOH
(20 mL) was added SOCl.sub.2 (2.0 g, 17.04 mmol) dropwise. The
mixture was stirred at reflux for 4 h. The mixture was evaporated
and saturated aqueous NaHCO.sub.3 (10 mL) was added. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.25 mL), and the
organic layer washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removered in vacuo to afford
ethyl
9-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3-
.1]nonane-3-carboxylate (1.3 g, yield 92%) which was used without
further purification. LCMS m/z 347.2 [M+H].sup.+.
Step 3
Ethyl
9-(5-((3,5-dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate
##STR00063##
[0822] To a solution of triphosgene (35 mg, 0.12 mmol) in
dichloromethane (3 mL) was added a solution of ethyl
9-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3-
.1]nonane-3-carboxylate (100 mg, 0.29 mmol) in dichloromethane (3
mL) and Et.sub.3N (58 mg, 0.58 mmol). The mixture was stirred at rt
for 2.5 h, followed by (3,5-dichlorophenyl)methanamine (56 mg, 0.32
mmol) and Et.sub.3N (58 mg, 0.58 mmol). The mixture was stirred at
rt for 16 h. To the reaction mixture was added methanol (10 mL) and
the solvent was evaporated. The residue was purified with prep-HPLC
(MeOH/H.sub.2O with 0.05% TFA as mobile phase; from 20% to 95%) to
furnish ethyl
9-(5-((3,5-dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate as a
yellow oil (89 mg, yield 56%). LCMS m/z 548.2 [M+H].sup.+.
Step 4
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00064##
[0824] To a solution of ethyl
9-(5-((3,5-dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (89 mg,
0.16 mmol) in THF (2 mL) and H.sub.2O (0.5 mL) was added lithium
hydroxide monohydrate (27 mg, 0.64 mmol). The reaction mixture was
stirred at rt for 16 h. Then it was adjusted to pH=6 with aq. HCl
(1N). The mixture was concentrated in vacuo. The redidue was
purified by prep-HPLC (MeCN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3
as mobile phase; from 20% to 95%) to furnish
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a
yellow solid (55 mg, yield 65%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.31 (s, 1H), 7.28-7.27 (m, 2H), 6.44 (s,
1H), 4.85 (bs, 2H), 4.74 (s, 2H), 4.36 (s, 2H), 4.22 (t, J=5.2 Hz,
2H), 3.97 (t, J=5.2 Hz, 2H), 3.35-3.31 (m, 1H), 2.17-1.63 (m, 10H);
LCMS m/z 520.1 [M+H].sup.+.
Example 35
9-(5((3-chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00065##
[0826] The titled compound was synthesized according to the
procedure described in Example 34 (46 mg, yield 53%). The mixture
was purified by prep-HPLC (MeCN/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.32-7.23 (m, 4H), 6.44 (s, 1H), 4.86-4.84 (m, 2H), 4.74
(s, 2H), 4.38 (s, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.97 (t, J=5.6 Hz,
2H), 3.23-3.21 (m, 1H), 2.12-1.81 (m, 10H); LCMS m/z 486.2
[M+H].sup.+.
Example 36
9-(5-((3-(trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00066##
[0828] The titled compound was synthesized according to the
procedure described in Example 34 (46 mg, yield 51%). The mixture
was purified by prep-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.62-7.51 (m, 4H), 6.44 (s, 1H), 4.86-4.84 (m, 2H), 4.74
(s, 2H), 4.46 (s, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.98 (t, J=5.6 Hz,
2H), 3.23-3.21 (m, 1H), 2.08-1.81 (m, 10H); LCMS m/z 520.2
[M+H].sup.+.
Example 37
9-(5((4-Chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00067##
[0830] The titled compound was synthesized according to the
procedure described in Example 34 (40 mg, yield 58%). The mixture
was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as
mobile phase; from 20% to 95%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.32-7.30 (m, 4H), 6.44 (s, 1H),
4.86-4.84 (m, 2H), 4.73 (s, 2H), 4.37 (s, 2H), 4.21 (t, J=5.6 Hz,
2H), 3.96 (t, J=5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.11-1.79 (m, 10H);
LCMS m/z 486.2 [M+H].sup.+.
Example 38
9-(5-((4-(Trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00068##
[0832] The titled compound was synthesized according to the
procedure described in Example 34 (47 mg, yield 88%). The mixture
was purified by prep-HPLC (MeCN/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.60 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 6.43 (s,
1H), 4.86 (bs, 2H), 4.74 (s, 2H), 4.46 (s, 2H), 4.22 (t, J=5.2 Hz,
2H), 3.97 (t, J=5.2 Hz, 2H), 3.37-3.35 (m, 1H), 2.09-1.66 (m, 10H);
LCMS m/z 520.2 [M+H].sup.+.
Example 39
9-(5-((3-Chloro-5-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00069##
[0834] The titled compound was synthesized according to the
procedure described in Example 34 (64 mg, yield 58%). The mixture
was purified by prep-HPLC (MeCN/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.17 (s, 1H), 7.08-7.01 (m, 2H), 6.45 (s, 1H), 4.86-4.84
(m, 2H), 4.74 (s, 2H), 4.38 (s, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.97
(t, J=5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.10-1.79 (m, 10H); LCMS m/z
504.1 [M+H].sup.+.
Example 40
9-(5-((3,5-Difluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00070##
[0836] The titled compound was synthesized according to the
procedure described in Example 34 (33 mg, yield 46%). The mixture
was purified by prep-HPLC (MeCN/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 6.92-6.91 (m, 2H), 6.81-6.80 (m, 1H), 6.45 (s, 1H),
4.86-4.84 (m, 2H), 4.74 (s, 2H), 4.39 (s, 2H), 4.23 (t, J=5.6 Hz,
2H), 3.97 (t, J=5.6 Hz, 2H), 3.35-3.32 (m, 1H), 2.12-1.79 (m, 10H);
LCMS m/z 488.1 [M+H].sup.+.
Example 41
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00071##
[0837] Step 1
3,5-Dichlorobenzyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00072##
[0839] To a solution of (3,5-dichlorophenyl)methanol (153 mg, 0.87
mmol) in DMF (3 mL) was added CDI (141 mg, 0.87 mmol). After
stirring at rt for 2 h, ethyl
9-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3-
.1]nonane-3-carboxylate (100 mg, 0.29 mmol) was added to the
reaction mixture. The mixture was stirred at rt for 16 h, quenched
with brine (5 mL), and extracted with ethyl acetate (3.times.5 mL).
The combined organic phase was washed with brine (5 mL), dried over
sodium sulfate and evaporated in vacuo. The crude product was
purified by prep-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%) to furnish 3,5-dichlorobenzyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate as a yellow oil (111 mg,
yield 70%). LCMS m/z 549.2 [M+H].sup.+.
Step 2
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00073##
[0841] To a solution of 3,5-dichlorobenzyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate (111 mg, 0.21 mmol) in THF
(2 mL) and H.sub.2O (0.5 mL) was added lithium hydroxide
monohydrate (35 mg, 0.84 mmol). The reaction mixture was stirred at
rt for 5 mM, then the reaction was stored in refrigerator
(0-5.degree. C.) overnight. After that the mixture was adjusted to
pH=6 with aq. HCl (1N) under ice bath. The mixture was concentrated
in vacuo. The residue was purified by prep-HPLC (MeOH/H.sub.2O with
10 mM NH.sub.4HCO.sub.3 as mobile phase; from 20% to 95%) to
furnish the target compound
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a-
]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
as a white solid (45 mg, yield 43%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.41-7.40 (m, 3H), 6.44 (s, 1H), 4.85 (s,
2H), 4.84-4.77 (m, 4H), 4.22 (t, J=5.2 Hz, 2H), 4.02 (bs, 2H),
3.30-3.28 (m, 1H), 2.09-1.67 (m, 10H). LCMS m/z 521.2
[M+H].sup.+.
Example 42
9-(5-(((3-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00074##
[0843] The titled compound was synthesized according to the
procedure described in Example 41 (41 mg, yield 71%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 20% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.42 (s, 1H), 7.35-7.33 (m,
3H), 6.43 (s, 1H), 5.17 (bs, 2H), 4.91-4.81 (m, 4H), 4.20 (t, J=5.2
Hz, 2H), 3.99 (bs, 2H), 3.36-3.32 (m, 1H), 2.11-1.77 (m, 10H); LCMS
m/z 487.2 [M+H].sup.+.
Example 43
9-(5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo-
[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00075##
[0845] The titled compound was synthesized according to the
procedure described in Example 41 (32 mg, yield 43%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.61-7.48 (m, 4H), 6.41 (s, 1H), 5.22 (s, 2H), 4.93-4.74 (m, 4H),
4.21 (bs, 2H), 3.96 (bs, 2H), 3.34 (bs, 1H), 2.05-1.68 (m, 10H);
LCMS m/z 521.2 [M+H].sup.+.
Example 44
9-(5-(((4-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00076##
[0847] The titled compound was synthesized according to the
procedure described in Example 41 (38 mg, yield 64%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 20% to 95%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.41-7.36 (m, 4H), 6.43 (s,
1H), 5.18 (s, 2H), 4.81-4.78 (m, 4H), 4.21 (t, J=4.8 Hz, 2H), 4.00
(bs, 2H), 3.35-3.33 (m, 1H), 2.09-1.68 (m, 10H); LCMS m/z 487.2
[M+H].sup.+.
Example 45
9-(5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo-
[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00077##
[0849] The titled compound was synthesized according to the
procedure described in Example 41 (75 mg, yield 49%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.57 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.39 (s, 1H), 5.17
(s, 2H), 4.89-4.69 (m, 4H), 4.17 (bs, 2H), 3.92 (bs, 2H), 3.28 (bs,
1H), 2.03-1.64 (m, 10H); LCMS m/z 521.2 [M+H].sup.+.
Example 46
9-(5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1-
,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00078##
[0851] The titled compound was synthesized according to the
procedure described in Example 41 (20 mg, yield 31%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.15 (s, 1H), 7.07-7.05 (m, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.43 (s,
1H), 5.30 (s, 2H), 4.94-4.76 (m, 4H), 4.23 (t, J=5.2 Hz, 2H), 3.99
(bs, 2H), 3.41-3.22 (m, 1H), 2.08-1.69 (m, 10H); LCMS m/z 505.2
[M+H].sup.+.
Example 47
9-(5-(((3,5-Difluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00079##
[0853] The titled compound was synthesized according to the
procedure described in Example 41 (46 mg, yield 43%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
6.88-6.87 (m, 2H), 6.79-6.74 (m, 1H), 6.43 (s, 1H), 5.14 (s, 2H),
4.94-4.74 (m, 4H), 4.22 (t, J=5.2 Hz, 2H), 3.98-3.96 (m, 2H),
3.24-3.21 (m, 1H), 2.07-1.68 (m, 10H); LCMS m/z 489.2
[M+H].sup.+.
Example 48
9-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyr-
azolo[1,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00080##
[0855] The titled compound was synthesized according to the
procedure described in Example 41 (12 mg, yield 19%). The mixture
was purified by pre-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 8.04 (s, 2H), 7.96 (s, 1H), 6.45 (s, 1H), 5.36 (s, 2H),
4.78-4.75 (m, 4H), 4.23 (t, J=5.2 Hz, 2H), 4.03 (bs, 2H), 3.41-3.32
(m, 1H), 2.11-1.67 (m, 10H); LCMS m/z 589.2 [M+H].sup.+.
Example 49
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00081##
[0856] Step 1
9-(5-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00082##
[0858] To a solution of
5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepi-
ne-2-carboxylic acid (500 mg, 1.78 mmol) in DMF (8 mL) were added
ethyl 9-azabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (414
mg, 1.78 mmol), HATU (676 mg, 1.78 mmol) and DIPEA (918 mg, 7.12
mmol). The mixture was stirred at room temperature for 12 h. The
mixture was purified by prep-HPLC (MeCN in water from 5% to 95%) to
give
9-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a
white solid (450 mg, yield 58%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.49 (s, 1H), 4.95-4.80 (m, 4H), 4.49-4.40 (m, 2H),
3.77-3.63 (m, 2H), 3.41-3.28 (m, 1H), 1.98-1.94 (m, 9H), 1.79-1.69
(m, 3H), 1.41 (s, 9H); LCMS m/z 433.2 [M+H].sup.+.
Step 2
Ethyl
9-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-
-azabicyclo[3.3.1]nonane-3-carboxylate
##STR00083##
[0860] To a solution of
9-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid (210
mg, 0.49 mmol) in EtOH (5 mL) was added SOCl.sub.2 (230 mg, 1.90
mmol) dropwise at 0.degree. C. The reaction mixture was stirred at
80.degree. C. for 2 h. After cooling down to rt, the mixture was
basified to pH=7 with NaHCO.sub.3 (sat.), and was extracted with
Ethyl acetate (100 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to give ethyl
9-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-azab-
icyclo[3.3.1]nonane-3-carboxylate as a yellow oil (138 mg, yield
79%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.42 (s, 1H),
4.96-4.88 (m, 2H), 4.40-4.37 (m, 2H), 3.92 (s, 2H), 3.31-3.22 (m,
1H), 3.22 (t, J=5.2 Hz, 2H), 2.09-2.05 (m, 4H), 2.02-1.92 (m, 4H),
1.89-1.85 (m, 2H), 1.77-1.68 (m, 3H), 1.27-1.23 (m, 5H); LCMS m/z
361.7 [M+H].sup.+.
Step 3
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00084##
[0862] To a solution of ethyl
9-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-azab-
icyclo[3.3.1]nonane-3-carboxylate (138 mg, 0.38 mmol) in
dichlormethane (3 mL) was added triphosgene (45 mg, 0.15 mmol) and
Et.sub.3N (46 mg, 0.46 mmol) dropwise at room temperature. The
mixture was stirred at room temperature for 30 min. Then
(3,5-dichlorophenyl)methanamine (80 mg, 0.46 mmol) and Et.sub.3N
(76 mg, 0.76 mmol) were added, and the mixture was stirred at room
temperature for 12 h. The reaction mixture was purified by prep-TLC
(DCM/MeOH=10/1) to give ethyl
9-(5-((3,5-dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate.
To a mixture of above ester (100 mg, 0.18 mmol, 1.0 eq) in MeOH (5
mL) and H.sub.2O (5 mL) was added NaOH (29 mg, 0.72 mmol). The
mixture was stirred at 60.degree. C. for 2 h. The organic solvent
was removed under reduced pressure. The resulting mixture was
acidified to pH=5 with HCl (1 N). The precipitate was filtered,
washed with water (5 mL) and dried to give the target compound
9-5-((3,5-dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid as a white solid (62 mg, yield 30%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.21 (s, 1H), 7.40 (s, 1H), 7.23 (t, J=8 Hz,
1H), 7.17 (d, J=1.6 Hz, 2H), 6.53 (s, 1H), 4.964-4.963 (m, 1H),
4.69-4.68 (m, 1H), 4.569 (s, 2H), 4.19 (d, J=5.6 Hz, 2H), 4.42-4.44
(m, 2H), 3.73-3.65 (m, 2H), 3.25-3.18 (m, 1H), 1.96-1.75 (m, 11H),
1.57-1.53 (m, 1H); LCMS m/z 533.1 [M+H].sup.+.
Example 50
9-(5-(3-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]d-
iazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00085##
[0864] The titled compound was synthesized according to the
procedure described in Example 49 (61 mg, yield 44%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.27-7.09 (m, 3H), 7.11 (d, J=8
Hz, 1H), 6.58 (s, 1H), 4.83 (s, 2H), 4.63 (ABq, 2H), 4.49 (t, J=4.8
Hz, 2H), 4.30 (s, 2H), 3.88-3.75 (m, 2H), 3.30-3.23 (m, 1H),
2.18-1.61 (m, 12H); LCMS m/z 500.2 [M+H].sup.+.
Example 51
9-(5-(3-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00086##
[0866] The titled compound was synthesized according to the
procedure described in Example 49 (48 mg, yield 32%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.53-7.43 (m, 4H), 6.58 (s,
1H), 4.82 (s, 2H), 4.63 (ABq, 2H), 4.49 (t, J=4.8 Hz, 2H), 4.38 (s,
2H), 3.87-3.75 (m, 2H), 3.28-3.20 (m, 1H), 2.17-1.64 (m, 12H); LCMS
m/z 534.2 [M+H].sup.+.
Example 52
9-(5-(4-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]d-
iazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00087##
[0868] The titled compound was synthesized according to the
procedure described in Example 49 (55 mg, yield 39%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.26 (d, J=8.8 Hz, 2H), 7.16
(d, J=8.8 Hz, 2H), 6.57 (s, 1H), 4.84-4.79 (m, 2H), 4.63 (Abq, 2H),
4.49 (t, J=4.8 Hz, 2H), 4.34 (s, 2H), 3.87-3.74 (m, 2H), 3.29-3.22
(m, 1H), 2.18-1.67 (m, 12H); LCMS m/z 500.2 [M+H].sup.+.
Example 53
9-(5-(4-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00088##
[0870] The titled compound was synthesized according to the
procedure described in Example 49 (50 mg, yield 34%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.56 (d, J=8.4 Hz, 2H), 7.36
(d, J=8.4 Hz, 2H), 6.59 (s, 1H), 4.85 (s, 2H), 4.63 (ABq, 2H), 4.50
(t, J=4.8 Hz, 2H), 4.40 (s, 2H), 3.88-3.76 (m, 2H), 3.36-3.27 (m,
1H), 2.16-1.65 (m, 12H); LCMS m/z 534.2 [M+H].sup.+.
Example 54
9-(5-(3-Chloro-5-fluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00089##
[0872] The titled compound was synthesized according to the
procedure described in Example 49 (26 mg, yield 18%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.1 (s, 1H), 7.22 (d, J=6 Hz, 2H),
7.05 (s, 1H), 7.36 (d, J=9.6 Hz, 1H), 6.53 (s, 1H), 4.94 (s, 1H),
4.74 (s, 1H), 4.69 (s, 2H), 4.42 (t, J=4 Hz, 2H), 4.20 (s, J=5.6
Hz, 2H), 3.70 (s, 2H), 3.18-3.26 (m, 1H), 1.99-1.54 (m, 12H); LCMS
m/z 518.2 [M+H].sup.+.
Example 55
9-(5-(3,5-Difluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00090##
[0874] The titled compound was synthesized according to the
procedure described in Example 49 (42 mg, yield 30%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 6.80-6.72 (m, 3H), 6.59 (s,
1H), 4.84 (br. s, 2H), 4.68 (s, 2H), 4.50 (t, J=5.2 Hz, 2H), 4.31
(s, 2H), 3.87-3.78 (m, 2H), 3.40-3.34 (m, 1H), 2.17-1.66 (m, 12H);
LCMS m/z 502.2 [M+H].sup.+.
Example 56
9-(5-((3,5-Dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00091##
[0876] To a solution of (3,5-dichlorophenyl)methanol (138 mg, 0.76
mmol) in DMF (2 mL) was added CDI (124 mg, 0.76 mmol). The reaction
mixture was stirred at room temperature for 2 h. Ethyl
9-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-azab-
icyclo[3.3.1]nonane-3-carboxylate (138 mg, 0.38 mmol) was added,
and the mixture was stirred at room temperature for 12 h. The
reaction mixture was purified by prep-HPLC (MeCN in water from 5%
to 95%) to give 3,5-dichlorobenzyl
2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate. To a mixture of
above ester in THF (5 mL) and H.sub.2O (5 mL) was added LiOH (36
mg, 1.52 mmol). The mixture was stirred at room temperature for 12
h. The organic solvent was removed under reduced pressure. The
resulting mixture was acidified to pH=5 with HCl (1 N). The mixture
was extracted with EA (20 mL.times.2). The combined organic layers
were washed with brine (10 mL), dried over sodium sulfate and
concentrated in vacuo to give
9-(5-((3,5-dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid as a yellow oil (50 mg, yield 24%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.37 (s, 1H), 7.30-7.27 (m, 2H),
6.53-6.52 (m, 1H), 5.09-5.07 (m, 2H), 4.83-4.78 (m, 2H), 4.67-4.62
(m, 2H), 4.50-4.48 (m, 2H), 3.91-3.78 (m, 2H), 3.29-3.25 (m, 1H),
2.15-1.65 (m, 12H); LCMS m/z 535.1 [M+H].sup.+.
Example 57
9-(5-((3-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00092##
[0878] The titled compound was synthesized according to the
procedure described in Example 56 (73 mg, yield 38%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.35-7.29 (m, 3H), 7.25 (t,
J=5.6 Hz, 1H), 6.53 (s, 0.44H), 6.47 (s, 0.56H), 5.08 (s, 2H),
4.82-4.81 (m, 2H), 4.64-4.61 (m, 2H), 4.49 (t, J=4.8 Hz, 2H),
3.85-3.81 (m, 2H), 3.28-3.22 (m, 1H), 2.17-2.09 (m, 1H), 2.04-1.90
(m, 8H), 1.86-1.64 (m, 3H); LCMS m/z 501.2 [M+H].sup.+.
Example 58
9-(5-((3-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazo-
lo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxyli-
c acid
##STR00093##
[0880] The titled compound was synthesized according to the
procedure described in Example 56 (47 mg, yield 23%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.63-7.53 (m, 4H), 6.54 (s,
0.45H), 6.47 (s, 0.55H), 5.18 (s, 2H), 4.83-4.78 (m, 2H), 4.65-4.62
(m, 2H), 4.50 (t, J=4.8 Hz, 2H), 3.87-3.83 (m, 2H), 3.35-3.26 (m,
1H), 2.16-1.65 (m, 12H); LCMS m/z 535.2 [M+H].sup.+.
Example 59
9-(5-((4-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00094##
[0882] The titled compound was synthesized according to the
procedure described in Example 56 (42 mg, yield 22%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.36-7.28 (m, 4H), 6.54 (s,
0.44H), 6.45 (s, 0.56H), 5.07 (s, 2H), 4.86-4.85 (m, 2H), 4.62-4.61
(m, 2H), 4.49 (t, J=4.8 Hz, 2H), 3.83-3.82 (m, 2H), 3.40-3.34 (m,
1H), 2.14-1.67 (m, 12H); LCMS m/z 501.1 [M+H].sup.+.
Example 60
[0883]
9-(54(4-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H--
pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-car-
boxylic acid
##STR00095##
[0884] The titled compound was synthesized according to the
procedure described in Example 56 (98 mg, yield 48%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.54 (d, J=8 Hz, 2H), 7.39 (t,
J=9.6 Hz, 2H), 6.43-6.40 (m, 1H), 5.07 (s, 2H), 4.80-4.79 (m, 2H),
4.56-4.51 (m, 2H), 4.39 (t, J=4.8 Hz, 2H), 3.77-3.71 (m, 2H),
3.31-3.23 (m, 1H), 2.01-1.67 (m, 12H); LCMS m/z 535.2
[M+H].sup.+.
Example 61
9-(5-((3-Chloro-5-fluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo-
[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00096##
[0886] The titled compound was synthesized according to the
procedure described in Example 56 (101 mg, yield 51%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.09-7.12 (m, 2H), 6.96-6.89
(m, 1H), 6.44-6.41 (m, 1H), 5.00 (s, 2H), 4.84 (s, 2H), 4.57-4.50
(m, 2H), 4.40-4.38 (m, 2H), 3.78-3.72 (m, 2H), 3.32-3.24 (m, 1H),
2.00-1.59 (m, 12H); LCMS m/z 519.2 [M+H].sup.+.
Example 62
9-(5-((3,5-Trifluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00097##
[0888] The titled compound was synthesized according to the
procedure described in Example 56 (96 mg, yield 50%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 6.83-6.71 (m, 3H), 6.45-6.41
(m, 1H), 4.99 (s, 2H), 4.82 (s, 2H), 4.56 (s, 1H), 4.51 (s, 1H),
4.38 (t, J=4.8 Hz, 2H), 3.77-3.71 (m, 2H), 3.31-3.23 (m, 1H),
2.00-1.55 (m, 12H); LCMS m/z 502.2, 503.2 [M+H].sup.+.
Example 63
9-(5-((3,5-Bis(trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carb-
oxylic acid
##STR00098##
[0890] The titled compound was synthesized according to the
procedure described in Example 56 (118 mg, yield 51%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.84-7.81 (m, 3H), 6.44-6.40
(m, 1H), 5.16-5.15 (m, 2H), 4.84 (s, 2H), 4.57-4.51 (m, 2H),
4.40-4.38 (m, 2H), 3.79-3.72 (m, 2H), 3.31-3.23 (m, 1H), 2.01-1.76
(m, 9H), 1.72-1.55 (m, 3H); LCMS m/z 603.2 [M+H].sup.+.
Example 64
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00099##
[0892] To a solution of
(3-fluoro-5-(trifluoromethyl)phenyl)methanol (178 mg, 0.92 mmol) in
DMF (2 mL), CDI (198 mg, 0.92 mmol) was added. The mixture was
stirred at room temperature for 2 h. Ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
hydrochloride (150 mg, 0.61 mmol) was added, and the resulted
mixture was stirred at room temperature for 12 h. The resulting
solution was diluted with ethyl acetate (30 ml) and washed with
H.sub.2O (20 ml.times.2). The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified by pre-TLC (MeOH/DCM=1/20) to give 2-ethyl
5-(3-fluoro-5-(trifluoromethyl)benzyl)
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate.
To a solution of above ester in THF (10 mL) and H.sub.2O (5 mL) was
added NaOH (50 mg, 1.2 mmol). The reaction mixture was stirred at
room temperature for 12 h. After removed THF under reduced
pressure, the resulting solution was adjusted to pH=4-5 with
aqueous HCl (1 N) solution and extracted with ethyl acetate (30
mL.times.2). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacyi to give
5-(((3-fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrah-
ydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid as a white
solid (74 mg, yield 30%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.37-7.35 (m, 1H), 7.29-7.24 (m, 1H), 7.21-7.17 (m, 1H), 6.86-6.72
(m, 1H), 5.15 (s, 2H), 4.59-4.56 (m, 4H), 3.90-3.79 (m, 2H),
2.06-1.94 (m, 2H); LCMS m/z 402.0 [M+H].sup.+.
Example 65
5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00100##
[0894] Using ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
and (3-chloro-5-(trifluoromethyl)phenyl)methanol as starting
material, following the procedure described in Example 64 (81 mg,
yield 31%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83-7.58 (m,
3H), 6.58 (s, 1H), 5.15 (s, 2H), 4.65-4.49 (m, 4H), 3.78-3.72 (m,
2H), 1.80-1.78 (m, 2H); LCMS m/z 418.0 [M+H].sup.+.
Example 66
5-(((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00101##
[0896] The titled compound was synthesized according to the
procedure described in Example 64 (69 mg, yield 23%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.57-7.48 (m, 2H), 7.22-7.17 (m, 1H),
6.85-6.68 (m, 1H), 5.10 (s, 2H), 4.58-4.54 (m, 4H), 3.87-3.77 (m,
2H), 2.05-1.93 (m, 2H); LCMS m/z 402.0 [M+H].sup.+.
Example 67
5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazol-
o[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00102##
[0898] The titled compound was synthesized according to the
procedure described in Example 64 (58 mg, yield 24%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.69-7.60 (m, 4H), 6.36 (s, 1H),
5.14 (s, 2H), 4.58-4.51 (m, 2H), 4.42-4.41 (m, 2H), 3.75-3.71 (m,
2H), 1.85-1.72 (m, 2H); LCMS m/z 384.1 [M+H].sup.+.
Example 68
5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-2-carboxylic acid
##STR00103##
[0900] The titled compound was synthesized according to the
procedure described in Example 64 (124 mg, yield 55%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.09-7.03 (m, 2H), 6.93-6.87 (m, 1H),
6.85-6.73 (m, 1H), 5.06 (s, 2H), 4.58-4.54 (m, 4H), 3.84-3.82 (m,
2H), 2.00 (m, 2H); LCMS m/z 368.0 [M+H].sup.+.
Example 69
5-(((3,5-Difluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-2-carboxylic acid
##STR00104##
[0902] The titled compound was synthesized according to the
procedure described in Example 64 (93 mg, yield 44%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.19-7.00 (m, 3H), 6.42 (s, 1H),
5.06-5.05 (m, 2H), 4.61-4.43 (m, 4H), 3.77-3.71 (m, 2H), 1.79 (m,
2H); LCMS m/z 352.1 [M+H].sup.+.
Example 70
5-(((3,4,5-Trifluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxylic acid
##STR00105##
[0904] The titled compound was synthesized according to the
procedure described in Example 64 (103 mg, yield 45%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.58 (s, 1H), 7.34-7.20 (m, 2H),
6.60-6.56 (m, 1H), 5.03-5.00 (m, 2H), 4.63-4.47 (m, 4H), 3.77-3.71
(m, 2H), 1.84-1.79 (m, 2H); LCMS m/z 370.1 [M+H].sup.+.
Example 71
5-(((3-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00106##
[0906] The titled compound was synthesized according to the
procedure described in Example 64 (130 mg, yield 53%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.58 (s, 1H), 7.79-7.72 (m, 1H),
7.48-7.31 (m, 2H), 6.62-6.61 (m, 1H), 5.16-5.14 (m, 2H), 4.66-4.48
(m, 4H), 3.80-3.73 (m, 2H), 1.87-1.81 (m, 2H); LCMS m/z 402.1
[M+H].sup.+.
Example 72
5-(((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00107##
[0908] The titled compound was synthesized according to the
procedure described in Example 64 (78 mg, yield 31%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.72-7.56 (m, 3H), 6.57-6.51 (m,
1H), 5.17 (s, 2H), 4.60-4.46 (m, 4H), 3.75-3.72 (m, 2H), 1.81 (m,
2H); LCMS m/z 402.1 [M+H].sup.+.
Example 73
5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazol-
o[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00108##
[0910] The titled compound was synthesized according to the
procedure described in Example 64 (78 mg, yield 33%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.63-7.61 (m, 2H), 7.44-7.40 (m, 2H),
6.85-6.70 (m, 1H), 5.16 (s, 2H), 4.59-4.55 (m, 4H), 3.84-3.82 (m,
2H), 2.05-1.93 (m, 2H); LCMS m/z 384.1 [M+H].sup.+.
Example 74
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carboxylic acid
##STR00109##
[0912] The titled compound was synthesized according to the
procedure described in Example 64 (56 mg, yield 28%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.28 (s, 1H), 7.19 (s, 2H),
6.61-6.48 (m, 1H), 4.53-4.45 (m, 4H), 4.28-4.22 (m, 2H), 3.74 (bs,
2H), 2.95-2.90 (m, 2H), 1.87-1.89 (m, 2H); LCMS m/z 398.1
[M+H].sup.+.
Example 75
5-(((3-Bromo-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carb oxylic acid
##STR00110##
[0914] The titled compound was synthesized according to the
procedure described in Example 64 (30 mg, yield 53%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.25-7.19 (m, 2H), 6.98-6.92 (m, 1H),
6.85-6.74 (m, 1H), 5.25 (s, 2H), 4.57 (bs, 4H), 3.83 (s, 2H), 2.02
(bs, 2H); LCMS m/z 412.0, 414.0 [M+H].sup.+.
Example 76
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00111##
[0916] To a solution of ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
hydrochloride (150 mg, 0.61 mmol) in dichloromethane (5 mL) was
added triphosgene (71 mg, 0.24 mmol) and Et.sub.3N (74 mg, 0.73
mmol). After stirred at room temperature for 30 min,
(3,5-bis(trifluoromethyl)phenyl)methanamine (224 mg, 0.92 mmol) and
Et.sub.3N (123 mg, 1.22 mmol, 2.0 eq) were added. The reaction
mixture was stirred at room temperature for 12 h. After removed
solvents under reduced pressure, the residue was purified by
pre-TLC (MeOH/DCM=1/20) to ethyl
5-((3,5-bis(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate. To a solution of
above ester in THF (10 mL) and H.sub.2O (5 mL) was added NaOH (50
mg, 1.2 mmol). The mixture was stirred at room temperature for 12
h. After removed THF under reduced pressure, the resulting solution
was adjusted to pH=4-5 with aqueous HCl (1 N) solution and
extracted with ethyl acetate (30 mL.times.2). The combined organic
layers were dried over anhydrous sodium sulfate and concentrated in
vacuo to give
5-(((3-fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid as a white solid
(109 mg, yield 39%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.49 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.37-7.34 (m, 1H), 6.65
(s, 1H), 4.58 (s, 2H), 4.48-4.46 (m, 2H), 4.37-4.35 (m, 2H), 3.70
(m, 2H), 1.76 (m, 2H); LCMS m/z 451.1 [M+H].sup.+.
Example 77
5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,-
4]diazepine-2-carboxylic acid
##STR00112##
[0918] The titled compound was synthesized according to the
procedure described in Example 76 (84 mg, yield 36%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.54 (s, 1H), 7.43-7.41 (m, 1H),
7.31-7.24 (m, 2H), 6.98 (s, 1H), 6.68 (s, 1H), 4.61 (s, 2H),
4.50-4.47 (m, 2H), 4.25-4.23 (m, 2H), 3.77 (m, 2H), 1.78 (m, 2H);
LCMS m/z 383.0 [M+H].sup.+.
Example 78
5-(7-Chloro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00113##
[0920] The titled compound was synthesized according to the
procedure described in Example 76 (50 mg, yield 32%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.51 (s, 1H), 7.28-7.17 (m, 3H),
6.61 (s, 1H), 4.44 (s, 4H), 4.32 (s, 2H), 3.58-3.55 (m, 2H), 3.36
(t, J=5.6 Hz, 2H), 2.83 (t, J=5.6 Hz, 2H), 1.95 (bs, 2H); LCMS m/z
376.1 [M+H].sup.+.
Example 79
5-(7-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8--
tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00114##
[0922] The titled compound was synthesized according to the
procedure described in Example 76 (50 mg, yield 32%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.46-7.43 (m, 2H), 7.35 (d, J=7.8
Hz, 1H), 6.67 (s, 1H), 4.51-4.49 (m, 6H), 3.68 (bs, 2H), 3.52 (t,
J=6.0 Hz, 2H), 2.99 (bs, 2H), 2.04 (bs, 2H); LCMS m/z 409.1
[M+H].sup.+.
Example 80
5-(5-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8--
tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00115##
[0924] The titled compound was synthesized according to the
procedure described in Example 76 (40 mg, yield 23%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.53 (d, J=7.2 Hz, 1H), 7.30-7.22
(m, 2H), 6.77 (s, 1H), 4.53-4.50 (m, 2H), 4.46 (s, 4H), 3.70-3.65
(m, 2H), 3.51 (t, J=6.0 Hz, 2H), 3.08 (t, J=6.0 Hz, 2H), 2.11 (bs,
2H); LCMS m/z 409.1 [M+H].sup.+.
Example 81
5-(5-Chloro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00116##
[0926] The titled compound was synthesized according to the
procedure described in Example 76 (8 mg, yield 5%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.24 (d, J=7.6 Hz, 1H), 7.14 (t,
J=7.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.48 (s, 4H),
4.41 (s, 2H), 3.69 (t, J=5.2 Hz, 2H), 3.53 (t, J=6.0 Hz, 2H), 2.93
(t, J=6.0 Hz, 2H), 2.08 (bs, 2H); LCMS m/z 75.1 [M+H].sup.+.
Example 82
5-(3-(3,5-bis(Trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyra-
zolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00117##
[0928] To a mixture of ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
hydrochloride (150 mg, 0.61 mmol) and
3-(3,5-bis(trifluoromethyl)phenyl)propanoic acid (263 mg, 0.92
mmol) in dichloromethane (10 mL), DIPEA (197 mg, 1.53 mmol) and
HATU (350 mg, 0.92 mmol) were added. The mixture was stirred at
room temperature for 12 h. After removed solvents under reduced
pressure, the residue was purified by pre-TLC (MeOH/DCM=1/20) to
give ethyl 5-(3-(3,5-bis(trifluoromethyl)phenyl)
propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxyl-
ate. To a solution of above ester in THF (10 mL) and H.sub.2O (5
mL) was added NaOH (50 mg, 1.2 mmol). The mixture was stirred at
room temperature for 12 h. After removed THF under reduced
pressure, the resulting solution was adjusted to pH=4-5 with
aqueous HCl (1 N) solution and extracted with ethyl acetate (30
mL.times.2). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacuo to give
5-(3-(3,5-bis(trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid as a white solid
(111 mg, yield 40%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.74-7.64 (m, 3H), 6.80-6.71 (m, 1H), 4.66-4.54 (m, 4H), 3.91-3.78
(m, 2H), 3.12-3.07 (m, 2H), 2.79-2.67 (m, 2H), 2.00 (m, 2H); LCMS
m/z 450.1 [M+H].sup.+.
Example 83
5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-2-carboxylic acid
##STR00118##
[0930] The titled compound was synthesized according to the
procedure described in Example 82 (68 mg, yield 29%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.38-7.30 (m, 3H), 6.49-6.36 (m,
1H), 4.66-4.56 (m, 2H), 4.43-4.35 (m, 2H), 3.80-3.71 (m, 2H),
2.79-2.64 (m, 4H), 1.84-1.73 (m, 2H); LCMS m/z 382.0
[M+H].sup.+.
Example 84
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxamido)propanoic acid
##STR00119##
[0931] Step 1
3,5-Dichlorobenzyl
2-((3-ethoxy-3-oxopropyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]di-
azepine-5(6H)-carboxylate
##STR00120##
[0933] The titled compound was synthesized according to the
procedure described in Example 12 (70 mg, yield 62%). LCMS m/z
483.1 [M+H].sup.+.
Step 2
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carboxamido)propanoic acid
##STR00121##
[0935] To a solution of above ester (70 mg, 0.14 mmol) in THF (2
mL) was added sodium hydroxide (12 mg, 0.29 mmol) and H.sub.2O (0.5
mL). The reaction mixture was stirred at rt for 15 h, and was
adjusted to pH=5 with HCl (1 N). The resulted solution was purified
by prep-HPLC (MeCN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as mobile
phase; from 5% to 95%) to afford
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-2-carboxamido)propanoic acid as a white solid
(35 mg, yield 53%) as white solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.39-7.17 (m, 3H), 6.66-6.63 (m, 1H),
5.10-5.07 (m, 2H), 4.66-4.60 (m, 2H), 4.52-4.50 (m, 2H), 3.87-3.81
(m, 2H), 3.60 (t, J=6.8 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H), 1.92-1.91
(m, 2H); LCMS m/z 455.1 [M+H].sup.+.
Example 85
(cis)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyraz-
olo[1,5-a][1,4]diazepine-2-carboxamido)cyclohexanecarboxylic
acid
##STR00122##
[0937] The titled compound was synthesized according to the
procedure described in Example 84 (73 mg, yield 62% over two
steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.38-7.16 (m,
3H), 6.67-6.65 (m, 1H), 5.11-5.07 (m, 2H), 4.66-4.60 (m, 2H),
4.53-4.50 (m, 2H), 3.98 (bs, 1H), 3.87-3.82 (m, 2H), 2.52 (m, 1H),
2.06-1.97 (m, 2H), 1.92 (bs, 2H), 1.78-1.64 (m, 6H); LCMS m/z 509.1
[M+H].sup.+.
Example 86
(trans)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyr-
azolo[1,5-a][1,4]diazepine-2-carboxamido)cyclohexanecarboxylic
acid
##STR00123##
[0939] The titled compound was synthesized according to the
procedure described in Example 84 (44 mg, yield 37% over two
steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39-7.34 (m,
1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.67-6.65 (m, 1H), 5.11-5.08 (m,
2H), 4.67-4.61 (m, 2H), 4.52 (t, J=5.2 Hz, 2H), 3.87-3.81 (m, 3H),
2.27-2.23 (m, 1H), 2.07-2.01 (m, 4H), 1.92 (bs, 2H), 1.58-1.55 (m,
2H), 1.42-1.40 (m, 2H); LCMS m/z 509.1 [M+H].sup.+.
Example 87
1-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carbonyl)piperidine-4-carboxylic acid
##STR00124##
[0941] The titled compound was synthesized according to the
procedure described in Example 84 (40 mg, yield 34% over two
steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39-7.37 (m,
1H), 7.31-7.26 (m, 2H), 6.64-6.52 (m, 1H), 5.10-5.08 (m, 2H),
4.67-4.44 (m, 6H), 3.88-3.83 (m, 2H), 3.32-3.31 (m, 1H), 3.06-3.00
(m, 1H), 2.68-1.60 (m, 1H), 2.03-1.93 (m, 4H), 1.73-1.64 (m, 2H);
LCMS m/z 495.1 [M+H].sup.+.
Example 88
1-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carbonyl)piperidine-3-carboxylic acid
##STR00125##
[0943] The titled compound was synthesized according to the
procedure described in Example 84 (55 mg, yield 42% over two
steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.37-7.26 (m,
3H), 6.54-6.53 (m, 1H), 5.09-5.07 (m, 2H), 4.67-4.62 (m, 3H),
4.52-4.49 (m, 3H), 3.88-3.82 (m, 2H), 3.29-3.28 (m, 1H), 3.15-3.13
(m, 1H), 2.55-2.53 (m, 1H), 2.15-2.12 (m, 1H), 1.80-1.74 (m, 4H),
1.58-1.55 (m, 1H); LCMS m/z 495.1 [M+H].sup.+.
Example 89
9-(5,6,7,8-Tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-azabi-
cyclo[3.3.1]nonane-3-carboxylic acid
##STR00126##
[0945] To
9-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid (11 mg, 0.025 mmol) was added a solution of TFA (0.1 mL) in
dichloromethane (1 mL). The reaction mixture was stirred at rt for
1 h. It was concentrated to get
9-(5,6,7,8-Tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-9-azab-
icyclo[3.3.1]nonane-3-carboxylic acid TFA salt as a white solid.
(14 mg, yield 100%). .sup.1H NMR (300 MHz, METHANOL-d.sub.4)
.delta. 6.77 (s, 1H), 4.86-4.94 (m, 2H), 4.56-4.64 (m, 2H), 4.54
(s, 2H), 3.53-3.64 (m, 2H), 3.36-3.47 (m, 1H), 1.24-2.26 (m, 12H);
LCMS m/z 333.1 [M+H].sup.+.
Example 90
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5--
a][1,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00127##
[0947] The titled compound was synthesized according to the
procedure described in Example 82 (26 mg, yield 70% over two
steps). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.01-7.16
(m, 3H), 6.42-6.51 (m, 1H), 4.86-4.92 (m, 2H), 4.63, 4.59 (s, s,
2H), 4.31-4.41 (m, 2H), 3.70-3.82 (m, 2H), 3.24-3.33 (m, 1H),
2.73-2.82 (m, 2H), 2.58-2.71 (m, 2H), 1.50-2.13 (m, 12H); LCMS m/z
532.9.2 [M+H].sup.+.
Example 91
5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz-
ine-2-carboxylic acid
##STR00128##
[0949] The titled compound was synthesized according to the
procedure described in Example 82 (98 mg, yield 89% over two
steps). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) .delta. 7.08-7.35
(m, 3H), 6.52-6.71 (m, 1H), 4.83, 4.79 (s, s, 2H), 3.94-4.29 (m,
4H), 2.73-3.04 (m, 4H); LCMS m/z 368.0 [M+H].sup.+.
Example 92
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]py-
razine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
##STR00129##
[0951] The titled compound was synthesized according to the
procedure described in Example 84 (33 mg, yield 79%, two steps).
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 6.99-7.22 (m, 3H),
6.21-6.38 (m, 1H), 4.78-4.87 (m, 2H), 4.72, 4.66 (s, s, 2H),
3.83-4.14 (m, 4H), 3.26-3.34 (m, 1H), 2.59-2.92 (m, 4H), 1.49-2.10
(m, 10H); LCMS m/z 519.2 [M+H].sup.+.
Example 93
8-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]py-
razine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid
##STR00130##
[0953] The titled compound was synthesized according to the
procedure described in Example 84 (20 mg, yield 79% over two
steps). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.05-7.31
(m, 3H), 6.44-6.61 (m, 1H), 5.14-5.43 (m, 1H), 4.81, 4.76 (s, s,
2H), 4.41-4.67 (m, 1H), 3.91-4.26 (m, 4H), 3.26-3.36 (m, 1H),
2.75-2.99 (m, 4H), 1.62-2.18 (m, 8H); LCMS m/z 504.9
[M+H].sup.+.
Example 94
1-(2-(9-Azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyra-
zin-5(4H)-yl)-3-(3,5-dichlorophenyl)propan-1-one
##STR00131##
[0955] The titled compound was synthesized according to the
procedure described in Example 12 (18 mg, yield 77%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.05-7.36 (m, 3H), 6.27-6.44
(m, 1H), 4.53-4.82 (m, 4H), 3.89-4.24 (m, 4H), 2.69-3.06 (m, 4H),
1.53-2.29 (m, 12H); LCMS m/z 475.0 [M+H].sup.+.
Example 95
3,5-Dichlorobenzyl
2-(3-(methoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro--
4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00132##
[0957] The titled compound was synthesized according to the
procedure described in Example 1 (14 mg, yield 17%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.19-7.47 (m, 3H), 6.45-6.58
(m, 1H), 5.03-5.13 (m, 2H), 4.75-4.95 (m, 2H), 4.55-4.71 (m, 2H),
4.42-4.52 (m, 2H), 3.76-3.93 (m, 2H), 3.67 (s, 3H), 3.35-3.49 (m,
1H), 1.59-2.21 (m, 12H); LCMS m/z 549.0 [M+H].sup.+.
Example 96
3-(3,5-Dichlorophenyl)-1-(2-(morpholine-4-carbonyl)-6,7-dihydropyrazolo[1,-
5-a]pyrazin-5(4H)-yl)propan-1-one
##STR00133##
[0959] The titled compound was synthesized according to the
procedure described in Example 12 (12 mg, yield 92%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.09-7.33 (m, 3H), 6.38-6.52
(m, 1H), 4.81, 4.76 (s, s, 2H), 3.91-4.22 (m, 6H), 3.57-3.81 (m,
6H), 2.73-3.00 (m, 4H); LCMS m/z 436.9 [M+H].sup.+.
Example 97
8-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,-
5-a][1,4]diazepine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic
acid
##STR00134##
[0961] The titled compound was synthesized according to the
procedure described in Example 84 (22 mg, yield 57%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.14-7.44 (m, 3H), 6.56-6.69
(m, 1H), 5.22-5.41 (m, 1H), 5.02-5.13 (m, 2H), 4.79-4.82 (m, 1H),
4.58-4.72 (m, 2H), 4.40-4.54 (m, 2H), 3.73-3.97 (m, 2H), 2.88-3.06
(m, 1H), 1.74-2.09 (m, 10H); LCMS m/z 520.9 [M+H].sup.+.
Example 98
2-(3,5-Dichlorobenzyl) 7-ethyl
3,4-dihydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate
##STR00135##
[0963] The titled compound was synthesized according to the
procedure described in Example 1 (195 mg, yield 49%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.24-7.45 (m, 3H), 6.32 (s,
1H), 5.15 (s, 2H), 4.51-4.74 (m, 2H), 4.22 (q, J=7.03 Hz, 2H),
3.98-4.10 (m, 2H), 3.86 (br. s., 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS
m/z 396.9 [M+H].sup.+.
Example 99
2-(3,5-Dichlorobenzyl) 8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate
##STR00136##
[0965] The titled compound was synthesized according to the
procedure described in Example 1 (315 mg, yield 77%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.09-7.43 (m, 3H), 6.32-6.49
(m, 1H), 4.99-5.15 (m, 2H), 4.39-4.57 (m, 2H), 4.10-4.27 (m, 4H),
3.68-3.72 (m, 2H), 1.78-1.90 (m, 2H), 1.30 (t, J=7.15 Hz, 3H); LCMS
m/z 410.9 [M+H].sup.+.
Example 100
2-(((3,5-Dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a]-
[1,4]diazepine-8-carboxylic acid
##STR00137##
[0967] The titled compound was synthesized according to the
procedure described in Example 7 (28 mg, yield 34%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.23-7.60 (m, 4H), 6.21-6.32 (m,
1H), 4.96-5.13 (m, 2H), 4.33-4.55 (m, 2H), 4.15-4.21 (m, 2H),
3.57-3.76 (m, 2H), 1.66-1.79 (m, 2H); LCMS m/z 382.9
[M+H].sup.+.
Example 101
3,5-Dichlorobenzyl
2-(4-hydroxypiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate
##STR00138##
[0969] The titled compound was synthesized according to the
procedure described in Example 12 (46 mg, yield 100%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.18-7.43 (m, 3H), 6.44-6.58
(m, 1H), 5.02-5.14 (m, 2H), 4.57-4.70 (m, 2H), 4.43-4.53 (m, 2H),
4.04-4.41 (m, 4H), 3.74-3.95 (m, 3H), 3.43-3.63 (m, 1H), 1.77-2.00
(m, 4H), 1.45-1.58 (m, 2H); LCMS m/z 466.9 [M+H].sup.+.
Example 102
3,5-Dichlorobenzyl
2-carbamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e
##STR00139##
[0971] The titled compound was synthesized according to the
procedure described in Example 12 (41 mg, yield 100%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.10-7.45 (m, 3H), 6.53-6.72
(m, 1H), 5.00-5.14 (m, 2H), 4.57-4.73 (m, 2H), 4.41-4.54 (m, 2H),
3.62-3.93 (m, 2H), 1.78-2.01 (m, 2H); LCMS m/z 382.9
[M+H].sup.+.
Example 103
9-(2-4(3,5-dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2--
a][1,4]diazepine-8-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic
acid
##STR00140##
[0973] The titled compound was synthesized according to the
procedure described in Example 84 (17 mg, yield 72%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.21-7.47 (m, 3H), 7.08 (s,
1H), 6.18-6.31 (m, 2H), 5.07-5.09 (m, 2H), 4.38-4.79 (m, 4H),
4.09-4.29 (m, 2H), 3.65-3.88 (m, 2H), 3.28-3.40 (m, 1H), 1.57-2.18
(m, 12H); LCMS m/z 533.9 [M+H].sup.+.
Example 104
3,5-Bis(trifluoromethyl)benzyl
2-carbamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e
##STR00141##
[0975] The titled compound was synthesized according to the
procedure described in Example 12 (63 mg, yield 93%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.76-7.98 (m, 3H), 6.50-6.74
(m, 1H), 5.17-5.34 (m, 2H), 4.58-4.73 (m, 2H), 4.40-4.55 (m, 2H),
3.70-3.96 (m, 2H), 1.81-2.00 (m, 2H); LCMS m/z 450.9
[M+H].sup.+.
Example 105
2-Ethyl 5-(3-methyl-5-(trifluoromethyl)benzyl)
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00142##
[0977] The titled compound was synthesized according to the
procedure described in Example 1 (((3 mg, yield 20%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.20-7.48 (m, 3H), 6.57-6.78
(m, 1H), 5.06-5.18 (m, 2H), 4.57-4.70 (m, 2H), 4.46-4.55 (m, 2H),
4.32 (q, J=7.11 Hz, 2H), 3.75-3.91 (m, 2H), 2.38 (s, 3H), 1.91 (br.
s., 2H), 1.35 (t, J=7.15 Hz, 3H); LCMS m/z 426.0 [M+H].sup.+.
Example 106
2-(3,5-Bis(trifluoromethyl)benzyl) 8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate
##STR00143##
[0979] The titled compound was synthesized according to the
procedure described in Example 1 (141 mg, yield 59%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.76-7.95 (m, 3H), 7.32 (br.
s., 1H), 6.30-6.50 (m, 1H), 5.16-5.40 (m, 2H), 4.40-4.62 (m, 2H),
4.12-4.29 (m, 4H), 3.63-3.93 (m, 2H), 1.84 (br. s., 2H), 1.29 (t,
J=7.15 Hz, 6H); LCMS m/z 496.0 [M+H].sup.+.
Example 107
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
7-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxyla-
te
##STR00144##
[0981] The titled compound was synthesized according to the
procedure described in Example 1 (54 mg, yield 55%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.76-8.01 (m, 3H), 6.55-6.79
(m, 1H), 5.34 (s, 2H), 4.78-4.94 (m, 2H), 4.50 (s, 2H), 4.34 (q,
J=7.11 Hz, 2H), 3.85-3.94 (m, 2H), 1.68 (s, 3H), 1.36 (t, J=7.03
Hz, 3H); LCMS m/z 493.9 [M+H].sup.+.
Example 108
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1.4]diazepine-2,5(6H)-dicarboxyla-
te
##STR00145##
[0983] The titled compound was synthesized according to the
procedure described in Example 1 (77 mg, yield 75%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.76-8.02 (m, 3H), 5.24-5.29
(m, 2H), 4.64-4.71 (m, 2H), 4.49-4.56 (m, 2H), 4.34 (q, J=7.19 Hz,
2H), 3.77-3.94 (m, 2H), 1.88-1.97 (m, 2H), 1.36 (t, J=7.15 Hz, 3H);
LCMS m/z 513.9 [M+H].sup.+.
Example 109
5-(((3-Methyl-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4-
H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00146##
[0985] The titled compound was synthesized according to the
procedure described in Example 8 (32 mg, yield 80%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.20-7.51 (m, 3H), 6.57-6.75
(m, 1H), 5.03-5.22 (m, 2H), 4.57-4.69 (m, 2H), 4.45-4.56 (m, 2H),
3.74-3.93 (m, 2H), 2.38 (s, 3H), 1.81-1.96 (m, 2H); LCMS m/z 398.0
[M+H].sup.+.
Example 110
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-5,6,7,8-tetrahy-
dro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00147##
[0987] The titled compound was synthesized according to the
procedure described in Example 8 (69 mg, yield 99%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.74-8.14 (m, 3H), 5.22-5.31
(m, 2H), 4.62-4.73 (m, 2H), 4.45-4.58 (m, 2H), 3.74-3.93 (m, 2H),
1.86-1.99 (m, 2H); LCMS m/z 486.1 [M+H].sup.+.
Example 111
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-7-methyl-5,6,7,8-tetrahy-
dro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00148##
[0989] The titled compound was synthesized according to the
procedure described in Example 7 (18 mg, yield 40%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.78-8.04 (m, 3H), 6.52-6.77
(m, 1H), 5.34 (br. s., 2H), 4.90 (br. s., 2H), 4.50 (s, 2H),
3.89-3.96 (m, 2H), 1.68 (br. s., 3H); LCMS m/z 466.2
[M+H].sup.+.
Example 112
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-chloro-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxylate
##STR00149##
[0991] The titled compound was synthesized according to the
procedure described in Example 1 (68 mg, yield 68%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.04 (s, 2H), 7.95 (s, 1H),
5.36 (s, 2H), 4.68-4.75 (m, 2H), 4.36 (q, J=7.03 Hz, 2H), 4.16-4.27
(m, 2H), 4.02 (br. s., 2H), 1.37 (t, J=7.15 Hz, 3H); LCMS m/z 500.1
[M+H].sup.+.
Example 113
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-4,5,6,7-tetrahy-
dropyrazolo[1,5-a]pyrazine-2-carboxylic acid
##STR00150##
[0993] The titled compound was synthesized according to the
procedure described in Example 7 (36 mg, yield 60%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.04 (s, 2H), 7.95 (s, 1H),
5.36 (s, 2H), 4.65-4.77 (m, 2H), 4.17-4.28 (m, 2H), 4.02 (br. s.,
2H); LCMS m/z 472.0 [M+H].sup.+.
Example 114
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl
3-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylat-
e
##STR00151##
[0995] The titled compound was synthesized according to the
procedure described in Example 1 (77 mg, yield 69%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.74-8.01 (m, 3H), 5.21-5.34
(m, 2H), 4.70 (s, 2H), 4.49-4.62 (m, 2H), 4.34 (q, J=7.03 Hz, 2H),
3.71-3.97 (m, 2H), 1.81-2.07 (m, 2H), 1.37 (t, J=7.15 Hz, 3H); LCMS
m/z 558, 560.0 [M+H].sup.+.
Example 115
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-bromo-5,6,7,8-tetrahyd-
ro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00152##
[0997] The titled compound was synthesized according to the
procedure described in Example 8 (66 mg, yield 96%). .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 7.74-8.01 (m, 3H), 5.22-5.32
(m, 2H), 4.70 (s, 2H), 4.47-4.60 (m, 2H), 3.76-3.95 (m, 2H),
1.83-2.03 (m, 2H); LCMS m/z 530.0, 532.0 [M+H].sup.+.
Example 116
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H--
pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00153##
[0998] Step 1
Ethyl
5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-2-carboxylate
##STR00154##
[1000] 2-Bromoacetyl chloride (70 mg, 0.45 mmol) was added dropwise
to a stirred solution of ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
hydrochloride (100 mg, 0.41 mmol) in dichloromethane (5 mL) at
0.degree. C. The reaction mixture was stirred for 15 min, diluted
with dichloromethane (10 mL), washed with water (3 mL), brine (3
mL), dried over sodium sulfate and evaporated in vacuo to give the
crude product ethyl
5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepi-
ne-2-carboxylate (130 mg) as a black oil, which was used in the
next step without further purification. LCMS m/z 330.0, 332.0
[M+H].sup.+.
Step 2
Ethyl
5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahyd-
ro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
##STR00155##
[1002] A mixture of ethyl
5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-c-
arboxylate (160 mg, 0.49 mmol), 3,5-bis(trifluoromethyl)aniline
(224 mg, 0.98 mmol), K.sub.2CO.sub.3 (203 mg, 1.47 mmol) and KI (81
mg, 0.49 mmol) in DMF (2 mL) was stirred at 100.degree. C. for 16 h
in a sealed tube. The mixture was diluted with EtOAc (10 mL),
washed with water (3 mL.times.2) and brine (3 mL). The organic
phase was dried over sodium sulfate and evaporated in vacuo. The
residue was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 0.05%
TFA as mobile phase; from 20% to 95%) to furnish the target
compound ethyl
5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate as a colorless oil (56
mg, putity 65%-70%) as a colorless oil. LCMS m/z 479.1
[M+H].sup.+.
Step 3
5-(24(3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00156##
[1004] To a solution of ethyl
5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (56 mg, 0.12 mmol) in
THF (2.0 mL) and H.sub.2O (0.5 mL) was added NaOH (19 mg, 0.48
mmol). The reaction mixture was stirred at rt for 16 h, and was
adjusted to pH=6 with HCl (1 N). The reaction mixture was
concentrated under reduced pressure, the residue was purified by
prep-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from
20% to 95%) to give
5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid as a white solid
(21 mg, yield 39%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.19-7.17 (m, 1H), 6.91-6.88 (m, 3H), 4.76-4.58 (m, 4H), 4.00-3.84
(m, 4H), 2.13-2.12 (m, 2H). LCMS m/z 451.1 [M+H].sup.+.
Example 117
5-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazo-
lo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00157##
[1005] Step 1
Ethyl
5-(2-(3,5-bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H--
pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
##STR00158##
[1007] The titled compound was synthesized according to the
procedure described in Example 116, step 2 (103 mg, yield 54%).
LCMS m/z 480.1 [M+H].sup.+.
Step 2
5-(3-(3,5-Bis(trifluoromethyl)phenyl)propyl)-5,6,7,8-tetrahydro-4H-pyrazol-
o[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00159##
[1009] The titled compound was synthesized according to the
procedure described in Example 7 (10 mg, yield 10%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.49-7.32 (m, 3H), 6.80 (bs, 1H),
4.85-4.80 (m, 2H), 4.68-4.57 (m, 4H), 3.93-3.87 (m, 2H), 2.09-2.02
(m, 2H); LCMS m/z 452.0 [M+H].sup.+.
Example 118
3,5-Bis(trifluoromethyl)benzyl
2-(3-methyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00160##
[1010] Step 1
3,5-Bis(trifluoromethyl)benzyl
2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00161##
[1012] To
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrah-
ydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (200 mg,
0.44 mmol) in dichloromethane (6 mL) was added SOCl.sub.2 (208 mg,
1.76 mmol) and DMF (0.1 mL). The mixture was refluxed for 16 h. The
solvent was removed under reduced pressure to provide
3,5-bis(trifluoromethyl)benzyl
2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate as a yellow solid, which was used in next step without
further purification.
Step 2
3,5-Dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate
##STR00162##
[1014] 3,5-bis(trifluoromethyl)benzyl
2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate from previous step was mixed with N'-hydroxyacetimidamide
(33 mg, 0.44 mmol) and diisoproylethylamine (68 mg, 0.53 mmol) in
CH.sub.3CN (3 mL) in a microwave vial. The mixture was heated with
microwave irritation at 150.degree. C. for 25 min. The solvent was
removed under reduced pressure, the residue was purified by
prep-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from
20% to 95%) to furnish the target compound 3,5-dichlorobenzyl
2-(4-aminopiperidine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate as a white solid (71 mg, yield 30%). .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.93-7.84 (m, 3H),
6.90-6.79 (m, 1H), 5.30-5.26 (m, 2H), 4.73-4.68 (m, 2H), 4.62-4.59
(m, 2H), 3.92-3.86 (m, 2H), 2.42 (s, 3H), 1.95 (bs, 2H); LCMS m/z
490.1 [M+H].sup.+.
Example 119
3,5-Bis(trifluoromethyl)benzyl
2-(5-methyl-1,3,4-oxadiazol-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00163##
[1015] Step 1
3,5-Bis(trifluoromethyl)benzyl
2-(2-acetylhydrazinecarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5(6H)-carboxylate
##STR00164##
[1017] To a solution of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (300 mg, 0.67 mmol)
in DMF (4 mL) was added HATU (304 mg, 0.80 mmol) and Et.sub.3N (203
mg, 2.01 mmol). After stirring at rt for 1 h, acetohydrazide (59
mg, 0.80 mmol) was added to the reaction solution. The mixture was
stirred at rt for 16 h, and was purified by prep-HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 20% to
95%) to furnish 3,5-bis(trifluoromethyl)benzyl
2-(2-acetylhydrazinecarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5(6H)-carboxylate as a white solid (194 mg, yield 57%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (bs, 1H), 8.68-8.65 (m, 1H),
7.83 (s, 1H), 7.77-7.73 (m, 2H), 6.78-6.66 (m, 1H), 5.20 (s, 2H),
4.56 (s, 2H), 4.46 (bs, 2H), 3.82 (s, 2H), 2.10 (s, 3H), 1.99 (s,
2H); LCMS m/z 508.1 [M+H].sup.+.
Step 2
3,5-Bis(trifluoromethyl)benzyl
2-(5-methyl-1,3,4-oxadiazol-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00165##
[1019] A mixture of 3,5-bis(trifluoromethyl)benzyl
2-(2-acetylhydrazinecarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5(6H)-carboxylate (140 mg, 0.28 mmol) in POCl.sub.3 (2 mL) was
heated at 100.degree. C. for 6 h. After POCl.sub.3 was removed
under reduced pressure, EtOAc (10 mL) was added. The mixture was
washed with 1 N NaOH (3 mL) and brine (3 mL), and the organic layer
was then dried over Na.sub.2SO.sub.4 and concentrated in vaccuo.
The residue was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with
0.05% TFA as mobile phase; from 20% to 95%) to furnish
3,5-bis(trifluoromethyl)benzyl
2-(5-methyl-1,3,4-oxadiazol-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate as a white solid (111 mg, yield 79%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.93-7.84 (m, 3H),
6.82-6.74 (m, 1H), 5.26-5.26 (m, 2H), 4.72-4.66 (m, 2H), 4.59-4.56
(m, 2H), 3.91-3.85 (m, 2H), 2.60 (s, 3H), 1.95-1.93 (m, 2H); LCMS
m/z 490.1 [M+H].sup.+.
Example 120
5-(((5-Fluoro-[1,1'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00166##
[1020] Step 1
2-Ethyl 5-((5-fluoro-[1,1'-biphenyl]-3-yl)methyl)
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00167##
[1022] Under an argon atmosphere, 5-(3-bromo-5-fluorobenzyl)
2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(120 mg, 0.27 mmol), phenylboronic acid (40 mg, 0.32 mmol),
K.sub.2CO.sub.3 (112 mg, 0.81 mmol) and Pd(PPh.sub.3).sub.4 (31 mg,
0.027 mmol) were dissolved in dioxane (3 mL) and H.sub.2O (1 mL).
After stirring at 110.degree. C. for 4 h, the reaction mixture was
diluted with EtOAc (10 mL). The mixture was washed with water (3
mL), brine (5 mL), dried over sodium sulfate and evaporated in
vacuo. The residue was purified by prep-HPLC (CH.sub.3CN/H.sub.2O
with 0.05% TFA as mobile phase; from 20% to 95%) to get 2-ethyl
5-((5-fluoro-[1,1'-biphenyl]-3-yl)methyl)
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
as a white solid (102 mg, yield 56%). LCMS m/z 438.2
[M+H].sup.+.
Step 2
5-(((5-Fluoro-[1,1'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00168##
[1024] The titled compound was synthesized according to the
procedure described in Example 7 (48 mg, yield 50%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.76 (bs, 1H), 7.54-7.53 (m, 2H),
7.46-7.43 (m, 2H), 7.38-7.22 (m, 3H), 7.01-6.97 (m, 1H), 6.85-6.72
(m, 1H), 5.15 (s, 2H), 4.59-4.57 (m, 4H), 3.83 (s, 2H), 2.00 (bs,
2H); LCMS m/z 410.2 [M+H].sup.+.
Example 121
3,5-Dichlorobenzyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00169##
[1026] To a mixture of (3,5-bis-trifluoromethyl-phenyl)-methanol
(87 mg, 0.36 mmol) and N,N-carbonyldiimidazole (58 mg, 0.36 mmol)
in THF (4.0 mL) was added 1.0 M of chlorotrimethylsilane in
tetrahydrofuran (0.02 mL, 0.02 mmol). The mixture was stirred at RT
for 1 h. The above mixture was added to a stirring mixture of
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (50 mg, 0.24
mmol) and N,N-diisopropylethylamine (0.08 mL, 0.48 mmol). The
reaction mixture was stirred at rt for 3 days. The reaction was
diluted with EtOAc, washed with brine. The organic phase was dried
and concentrated. The crude was purified by prep-HPLC
(MeCN/H.sub.2O with 0.1% TFA) to give the desired product as a
white powder (22 mg, TFA salt). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.81-7.98 (m, 3H), 7.23-7.37 (m, 1H),
6.13-6.31 (m, 1H), 5.19-5.31 (m, 2H), 4.57-4.72 (m, 2H), 4.38-4.51
(m, 2H), 3.74-3.94 (m, 2H), 1.89 (d, J=4.52 Hz, 2H); LCMS m/z 408.1
[M+H].sup.+.
Example 122
3,5-Dichlorobenzyl
2-cyano-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00170##
[1028] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (57 mg, yield
62%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.34-7.44 (m,
1H), 7.16-7.32 (m, 2H), 6.64-6.76 (m, 1H), 5.03-5.15 (m, 2H),
4.59-4.71 (m, 2H), 4.49-4.57 (m, 2H), 3.77-3.92 (m, 2H), 1.84-1.98
(m, 2H); LCMS m/z 365.1 [M+H].sup.+.
Example 123
3,5-Dichlorobenzyl
2-(1H-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-c-
arboxylate
##STR00171##
[1030] To a solution of
2-cyano-7,8-dihydro-4H,6H-1,5,8a-triaza-azulene-5-carboxylic acid
3,5-dichloro-benzyl ester (15 mg, 0.04 mmol) in
N,N-dimethylformamide (0.5 mL) was added zinc dibromide (20 mg,
0.09 mmol), followed by sodium azide (11.7 mg, 0.18 mmol). The
mixture was heated in microwave vial at 175.degree. C. for 20 min.
The reaction was then diluted with ethyl acetate, washed with
water, the organic phase was then dried and purified by HPLC
(acetonitrile/water with 0.1% TFA) to give desired product as a
white powder (6 mg). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.22-7.42 (m, 2H), 7.15 (s, 1H), 6.77-6.89 (m, 1H),
5.04-5.17 (m, 2H), 4.65-4.76 (m, 2H), 4.54-4.63 (m, 2H), 3.79-3.96
(m, 2H), 1.88-2.01 (m, 2H); LCMS m/z 408.1 [M+H].sup.+.
Example 124
3,5-Bis(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00172##
[1032] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (67 mg, yield
30%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.79-8.00 (m,
3H), 5.91-6.12 (m, 1H), 5.19-5.32 (m, 2H), 4.48-4.65 (m, 2H),
4.29-4.43 (m, 2H), 3.71-3.91 (m, 2H), 2.08-2.23 (m, 3H), 1.88 (d,
J=4.52 Hz, 2H); LCMS m/z 422.1 [M+H].sup.+.
Example 125
3,5-Bis(trifluoromethyl)benzyl
2-cyano-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00173##
[1034] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (97 mg, yield
90%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.79-7.99 (m,
3H), 6.57-6.79 (m, 1H), 5.19-5.34 (m, 2H), 4.59-4.72 (m, 2H),
4.49-4.57 (m, 2H), 3.76-3.94 (m, 2H), 1.91 (d, J=4.52 Hz, 2H); LCMS
m/z 433.1 [M+H].sup.+.
Example 126
3-Fluoro-5-(trifluoromethyl)benzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate
##STR00174##
[1036] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (83 mg, yield
77%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.53-7.63 (m,
2H), 7.39-7.51 (m, 2H), 5.28 (s, 2H), 4.68-4.81 (m, 2H), 4.10-4.19
(m, 2H), 3.97 (br. s., 2H); LCMS m/z 412.1 [M+H].sup.+.
Example 127
3,5-Bis(trifluoromethyl)benzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate
##STR00175##
[1038] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (86 mg, yield
71%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.04 (br. s.,
2H), 7.95 (br. s., 1H), 7.58 (s, 1H), 5.35 (s, 2H), 4.79 (d, J=7.53
Hz, 2H), 4.13 (d, J=5.02 Hz, 2H), 3.97 (br. s., 2H); LCMS m/z 462.1
[M+H].sup.+.
Example 128
3-Fluoro-5-(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00176##
[1040] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (67 mg, yield
81%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.18-7.53 (m,
3H), 5.94-6.13 (m, 1H), 5.12-5.25 (m, 2H), 4.51-4.64 (m, 2H),
4.28-4.42 (m, 2H), 3.71-3.92 (m, 2H), 2.17 (s, 3H), 1.88 (d, J=4.02
Hz, 2H); LCMS m/z 372.1 [M+H].sup.+.
Example 129
3-Fluoro-5-(trifluoromethyl)benzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00177##
[1042] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (82 mg, yield
85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.35-7.76 (m,
3H), 6.77-6.98 (m, 1H), 5.15 (d, J=10.79 Hz, 2H), 4.48-4.73 (m,
4H), 3.64-3.86 (m, 2H), 1.72-1.93 (m, 2H); LCMS m/z 383.1
[M+H].sup.+.
Example 130
3,5-Dichlorobenzyl
2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00178##
[1044] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (53 mg, yield
67%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.37 (br. s.,
1H), 7.17-7.32 (m, 2H), 5.99-6.12 (m, 1H), 5.02-5.13 (m, 2H),
4.49-4.63 (m, 2H), 4.30-4.41 (m, 2H), 3.72-3.90 (m, 2H), 2.20 (s,
3H), 1.88 (d, J=4.77 Hz, 2H); LCMS m/z 354.1 [M+H].sup.+.
Example 131
3,5-Dichlorobenzyl
2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate
##STR00179##
[1046] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (77 mg, yield
80%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.60 (d,
J=1.00 Hz, 1H), 7.33-7.44 (m, 3H), 5.17 (s, 2H), 4.77 (br. s., 2H),
4.10-4.19 (m, 2H), 3.96 (br. s., 2H); LCMS m/z 394.0
[M+H].sup.+.
Example 132
3,5-Bis(trifluoromethyl)benzyl
6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxylate
##STR00180##
[1048] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (23 mg, yield
24%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.88 (d,
J=9.04 Hz, 1H), 7.85-8.00 (m, 3H), 7.50 (d, J=10.04 Hz, 1H), 5.28
(d, J=11.80 Hz, 2H), 4.62-4.79 (m, 2H), 4.48-4.61 (m, 2H),
3.73-3.98 (m, 2H), 2.00 (d, J=3.26 Hz, 2H); LCMS m/z 408.1
[M+H].sup.+.
Example 133
3,5-Dichlorobenzyl
6,7-dihydro-5H-imidazo[1,5-a][1,4]diazepine-8(9H)-carboxylate
##STR00181##
[1050] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (15 mg, yield
18%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.87 (d,
J=8.53 Hz, 1H), 7.50 (d, J=10.79 Hz, 1H), 7.40 (t, J=1.63 Hz, 1H),
7.28 (d, J=17.82 Hz, 2H), 5.10 (d, J=14.05 Hz, 2H), 4.61-4.78 (m,
2H), 4.47-4.59 (m, 2H), 3.87 (d, J=16.31 Hz, 2H), 2.00 (br. s.,
2H); LCMS m/z 340.0 [M+H].sup.+.
Example 134
3,5-Bis(trifluoromethyl)benzyl
3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carb-
oxylate
##STR00182##
[1052] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (17 mg, TFA
salt, yield 17%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.87-8.14 (m, 3H), 5.36 (s, 2H), 4.96 (d, J=3.51 Hz, 2H), 4.26 (t,
J=5.40 Hz, 2H), 4.01 (br. s., 2H); .sup.19F NMR (376 MHz,
METHANOL-d.sub.4) 8 ppm 77.72 (br. s., 3F, TFA), 64.67 (s, 3F),
64.40 (s, 6F); LCMS m/z 463.1 [M+H].sup.+.
Example 135
3-Chloro-5-(trifluoromethyl)benzyl
3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carb-
oxylate
##STR00183##
[1054] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (25 mg, TFA
salt, yield 27%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.75 (s, 1H), 7.68 (s, 2H), 5.27 (s, 2H), 4.96 (br. s., 2H), 4.26
(t, J=5.40 Hz, 2H), 4.01 (br. s., 2H); .sup.19F NMR (376 MHz,
METHANOL-d.sub.4) 8 ppm 77.75 (br. s., 3F, TFA), 64.66 (s, 3F),
64.36 (s, 3F); LCMS m/z 429.0 [M+H].sup.+.
Example 136
3,5-Bis(trifluoromethyl)benzyl
2-(1H-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-c-
arboxylate
##STR00184##
[1056] The titled compound was synthesized according to the
procedure described in Example 123 as a white powder (25 mg, yield
32%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.86-7.96 (m,
1H), 7.80 (br. s., 2H), 6.74-6.90 (m, 1H), 5.21-5.34 (m, 2H),
4.64-4.78 (m, 2H), 4.54-4.63 (m, 2H), 3.79-3.98 (m, 2H), 1.94 (d,
J=5.27 Hz, 2H); LCMS m/z 476.1 [M+H].sup.+.
Example 137
3-Chloro-5-(trifluoromethyl)benzyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00185##
[1058] The titled compound was synthesized according to the
procedure described in Example 1 as a white powder (21 mg). .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.46-7.71 (m, 3H), 7.29 (d,
J=1.76 Hz, 1H), 6.12-6.29 (m, 1H), 5.11-5.23 (m, 2H), 4.55-4.70 (m,
2H), 4.38-4.51 (m, 2H), 3.73-3.94 (m, 2H), 1.89 (d, J=4.77 Hz, 2H);
LCMS m/z 374.1 [M+H].sup.+.
Example 138
3-(3,5-Bis(trifluoromethyl)phenyl)-1-(7,8-dihydro-4H-pyrazolo[1,5-a][1,4]d-
iazepin-5(6H)-yl)propan-1-one
##STR00186##
[1060] To a mixture of 3-(3,5-bis-trifluoromethyl-phenyl)-propionic
acid (133 mg, 0.46 mmol) in DMF (4 mL) was added HATU (194 mg, 0.51
mmol) and N,N-diisopropylethylamine (0.16 mL, 0.93 mmol). The
mixture was stirred at rt for 10 min.
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (65 mg, 0.31
mmol) was then added. The reaction mixture was stirred at rt
overnight. The reaction was diluted with ethyl acetate, washed with
brine. The organic phase was dried and concentrated. The crude
product was purified by HPLC (MeCN/H.sub.2O with 0.1% TFA) to give
3-(3,5-bis(trifluoromethyl)phenyl)-1-(7,8-dihydro-4H-pyrazolo[1,5-a][1,4]-
diazepin-5(6H)-yl)propan-1-one as a white powder (108 mg, TFA
salt). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.83 (s,
1H), 7.68-7.79 (m, 2H), 7.28 (dd, J=1.88, 14.43 Hz, 1H), 6.19-6.29
(m, 1H), 4.69 (d, J=11.04 Hz, 2H), 4.35-4.49 (m, 2H), 3.79-3.94 (m,
2H), 3.06 (t, J=7.03 Hz, 2H), 2.72-2.92 (m, 2H), 1.78-1.97 (m, 2H);
LCMS m/z 406.1 [M+H].sup.+.
Example 139
5-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00187##
[1062] The titled compound was synthesized according to the
procedure described in Example 1 as a white solid (100 mg, yield
50%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.89-7.80 (m,
3H), 6.75, 6.67 (s, s, 1H), 5.85-5.80 (m, 1H), 4.61-4.47 (m, 4H),
4.37-4.31 (m, 2H), 4.00-3.55 (m, 2H), 2.01-1.73 (m, 2H), 1.60-1.56
(m, 3H), 1.38-1.24 (m, 3H); LCMS m/z 494.1 [M+H].sup.+.
Example 140
5-((1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00188##
[1064] The titled compound was synthesized according to the
procedure described in Example 8 as a white solid (50 mg, yield
53%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.92-7.84 (m,
3H), 6.71, 6.63 (s, s, 1H), 5.87-5.79 (m, 1H), 4.79-4.50 (m, 4H),
3.99-3.68 (m, 2H), 1.95-1.82 (m, 2H), 1.61-1.56 (m, 3H); LCMS m/z
466.1 [M+H].sup.+.
Example 141
5-(3,5-Bis(trifluoromethyl)phenethyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00189##
[1066] The titled compound was synthesized according to the
procedure described in Example 1 as a white solid (((3 mg, yield
12%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.80-7.77 (m, 1H),
7.67-7.66 (m, 2H), 6.77, 6.49 (s, s, 1H), 4.53-4.50 (m, 3H),
4.42-4.30 (m, 5H), 3.78-3.70 (m, 2H), 3.09 (q, J=6.4 Hz, 2H),
2.01-1.85 (m, 2H), 1.41-1.35 (m, 3H); LCMS m/z 494.1
[M+H].sup.+.
Example 142
5-((3,5-Bis(trifluoromethyl)phenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyr-
azolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00190##
[1068] The titled compound was synthesized according to the
procedure described in Example 8 as a white solid (35 mg, yield
85%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.87-7.84 (m,
3H), 6.68, 6.30 (s, s, 1H), 4.55-4.49 (m, 4H), 4.40-4.33 (m, 2H),
3.75-3.73 (m, 2H), 3.18-3.13 (m, 2H), 1.88-1.78 (m, 2H); LCMS m/z
466.2 [M+H].sup.+.
Example 143
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-2-carboxylic acid
##STR00191##
[1070] The titled compound was synthesized according to the
procedure described in Example 64 as a white solid (56 mg, yield
28% over two steps). .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.28 (s, 1H), 7.19 (s, 2H), 6.61-6.48 (m, 1H), 4.53-4.45
(m, 4H), 4.28-4.22 (m, 2H), 3.74 (bs, 2H), 2.95-2.90 (m, 2H),
1.87-1.89 (m, 2H); LCMS m/z 398.0 [M+H].sup.+.
Example 144
3,5-Bis(trifluoromethyl)benzyl
2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-
-5(6H)-carboxylate
##STR00192##
[1072] A mixture of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.0 g, 2.2 mmol),
DIPEA (567 mg, 4.4 mmol), HATU (1.25 g, 3.3 mmol) and
N,O-dimethylhydroxylamine hydrochloride (256 mg, 2.64 mmol) in DMF
(10 mL) was stirred at rt for 3 h, the reaction mixture was diluted
with EtOAc (80 mL) and washed with brine (50 mL.times.2). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc) to give
3,5-bis(trifluoromethyl)benzyl
2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-
-5(6H)-carboxylate as a yellow solid (1.1 g, yield 100%) as a
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83 (s,
1H), 7.77-7.76 (m, 2H), 6.74, 6.62 (s, s, 1H), 5.19 (s, 2H),
4.56-4.52 (m, 4H), 3.82-3.81 (m, 2H), 3.70, 3.66 (s, s, 3H), 3.41,
4.40 (s, s, 3H), 1.99-1.98 (m, 2H); LCMS m/z 494.8 [M+H].sup.+.
Example 145
3,5-Bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00193##
[1074] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-
-5(6H)-carboxylate (1.0 g, 2.0 mmol) in THF (15 mL) was added
CH.sub.3MgBr (3 mL, 6.0 mol) at 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 2.5 h, quenched with water and
concentrated in vacuo. The residue was diluted with EtOAc (50 mL),
washed with H.sub.2O (50 mL) and brine (50 mL), dried over sodium
sulfate, and concentrated to give 3,5-bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
as a yellow solid (700 mg, yield 77%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.82 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 6.75,
6.63 (s, s, 1H), 5.20 (s, 2H), 4.56-4.55 (m, 2H), 4.51 (d, J=4.8
Hz, 2H), 3.84 (d, J=4.8 Hz, 2H), 2.53 (s, 3H), 2.00-1.99 (m, 2H);
LCMS m/z 450.1 [M+H].sup.+.
Example 146
3,5-Bis(trifluoromethyl)benzyl
2-(1-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00194##
[1076] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(100 mg, 0.22 mmol) in methanol (10 mL) was added NaBH.sub.4 (25
mg, 0.66 mol, 3.0 eq). The reaction mixture was stirred at rt for 4
h. It was quenched with water and adjusted to pH=7. The mixture was
concentrated in vacuo and the residue was purified by prep-HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to
95%) to furnish the target compound as a yellow oil (86 mg, yield
86%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.94 (s, 3H),
6.25, 6.17 (s, s, 1H), 5.25 (s, 2H), 4.79-4.76 (m, 1H), 4.64-4.58
(m, 2H), 4.41-4.40 (m, 2H), 3.87-3.78 (m, 2H), 1.91-1.90 (m, 2H),
1.43-1.41 (m, 3H); LCMS m/z 451.8 [M+H].sup.+.
Example 147
3,5-Bis(trifluoromethyl)benzyl
2-(1-aminoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbo-
xylate
##STR00195##
[1078] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(180 mg, 0.40 mmol) in methanol (3 mL) was added ammonium acetate
(308 mg, 4.00 mmol). The mixture was heated at 65.degree. C. for 2
h, followed by adding NaBH.sub.3CN (76 mg, 1.20 mmol) and heated at
65.degree. C. for 4 h. The reaction mixture was concentrated and
purified by prep-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 20% to 95%) to furnish the target compound as a pale
yellow oil (36 mg, yield 24%) as a pale yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.95 (bs, 3H), 6.31, 6.23 (s, s, 1H),
5.25 (s, 2H), 4.68-4.65 (m, 2H), 4.48-4.39 (m, 3H), 3.90-3.84 (m,
2H), 1.91 (s, 2H), 1.58 (t, J=6.0 Hz, 3H); LCMS m/z 451.2
[M+H].sup.+.
Example 148
3,5-Bis(trifluoromethyl)benzyl
2-(1-(piperidin-1-yl)ethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine--
5(6H)-carboxylate
##STR00196##
[1080] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(110 mg, 0.24 mmol) in THF (2 mL) were added piperidine (41 mg,
0.48 mmol) and Ti(i-OPr).sub.4 (136 mg, 0.48 mmol). The mixture was
stirred under reflux for 16 h, followed by adding NaBH.sub.4 (102
mg, 0.48 mmol). The reaction mixture was stirred under reflux for
additional 5 h, diluted with water (3 mL) and methanol (3 mL),
filtered and concentrated, the residue was purified by prep-HPLC
(MeOH/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as mobile phase; from
5% to 95%) to furnish the target compound as a yellow oil (33 mg,
yield 26%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.93
(s, 3H), 6.40, 6.34 (s, s, 1H), 5.27 (s, 2H), 4.69-4.61 (m, 2H),
4.50-4.42 (m, 3H), 3.90-3.79 (m, 2H), 3.52-3.40 (m, 2H), 2.96-2.70
(m, 2H), 1.93-1.72 (m, 8H), 1.67 (t, J=6.8 Hz, 3H); LCMS m/z 519.2
[M+H].sup.+.
Example 149
1-(1-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-
-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic
acid
##STR00197##
[1082] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-acetyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(300 mg, 0.67 mmol) in THF (2 mL) were added Ti (i-OPr).sub.4 (951
mg, 3.35 mmol) and ethyl piperidine-4-carboxylate (210 mg, 1.34
mmol). The mixture was stirred under reflux for 4 h, followed by
adding NaBH.sub.4 (284 mg, 1.34 mmol). The reaction mixture was
stirred under reflux for additional 16 h, diluted with water (3 mL)
and methanol (3 mL), filtered and concentrated. The residue was
purified by prep-HPLC (MeOH/H.sub.2O with 0.05% TFA as mobile
phase; from 5% to 95%) to provide a mixture of ethyl ester and
isopropyl ester as an oil (110 mg).
[1083] To a solution of above ester (100 mg, 0.16 mmol) in methanol
(10 mL) was added LiOH monohydrate (20 mg, 0.48 mmol). The reaction
mixture was stirred at 40.degree. C. for 4 h. It was adjusted to
pH=6 with 1N HCl, concentrated in vacuo. The residue was purified
by prep-HPLC (CH.sub.3CN/H.sub.2O with 0.05% NH.sub.4HCO.sub.3 as
mobile phase; from 5% to 95%) to get
1-(1-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydr-
o-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic
acid as a yellow oil (44 mg, yield 47%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.82 (s, 3H), 6.26, 6.18 (s, s, 1H), 5.16
(s, 2H), 4.62-4.45 (m, 2H), 4.37-4.36 (m, 2H), 4.21-4.15 (m, 1H),
3.78-3.70 (m, 2H), 3.27-3.24 (m, 1H), 3.20-3.11 (m, 1H), 2.72-2.59
(m, 2H), 2.12-2.06 (m, 1H), 1.92-1.81 (m, 6H), 1.52-1.47 (m, 3H);
LCMS m/z 563.3 [M+H].sup.+.
Example 150
5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
##STR00198##
[1085] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol
(15.1 g, 72.0 mmol) and CDI (11.7 g, 72.0 mmol) in DMF (100 mL) was
stirred at rt for 3 h. Then ethyl
5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate
(14.7 g, 60.0 mmol) and TEA (7.9 g, 78.0 mmol) were added. The
mixture was stirred at rt for 16 h. After the reaction completed,
the mixture was diluted with water (300 mL) and extracted with
EtOAc (200 mL.times.2). The combined organic layers were washed
with water (300 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc=4:1) to give the title compound
as a white solid (22.2 g, 83% yield); ESI-MS m/z 446.1
[M+H].sup.+.
Example 151
3-chloro-5-(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate
##STR00199##
[1087] To a solution of 5-(3-chloro-5-(trifluoromethyl)benzyl)
2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(20 g, 44.8 mmol) in THF (200 mL) was added 2N lithium borohydride
in THF (45 mL, 89.6 mmol) at 0.degree. C. The reaction was stirred
for 6 h at rt and quenched with sat. aq. NH.sub.4Cl (200 mL). The
mixture was extracted with ethyl acetate (200 mL.times.2). The
combined organic phase was washed with brine (200 mL.times.2),
dried over sodium sulfate and evaporated in vacuum to give the
title compound as white solid (17.1 g, 95% yield), which was used
for the next step without further purification; ESI-MS m/z 404.1
[M+H].sup.+.
Example 152
[1088] 3-chloro-5-(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00200##
[1089] A mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate (16 g, 40 mmol) and IBX (33 g, 120 mmol) in EtOAc (200 mL)
was stirred at reflux for 3 h. After cooled to rt, the mixture was
filtered and the filtrate was concentrated. The residue was
purified by column chromatography on silica gel (petroleum
ether/EtOAc=4:1) to give the title compound as a white solid (13.6
g, 85% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.89 (s,
1H), 7.55 (s, 1H), 7.49-7.39 (m, 2H), 6.77-6.65 (m, 1H), 5.13 (s,
2H), 4.59-4.53 (m, 4H), 3.84 (t, J=5.2 Hz, 2H), 2.04-2.02 (m, 2H);
ESI-MS m/z 402.0 [M+H].sup.+.
Example 153
3-chloro-5-(trifluoromethyl)benzyl
2-(((4,5-dihydrothiazol-2-yl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a]-
[1,4]diazepine-5(6H)-carboxylate
##STR00201##
[1091] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(150 mg, 0.36 mmol) and 4,5-dihydrothiazol-2-amine (51 mg, 0.48
mmol) in THF (4 mL) was added Ti(OiPr).sub.4 (213 mg, 0.72 mmol).
The mixture was stirred at 100.degree. C. for 2 h under microwave,
then NaBH.sub.3CN (48 mg, 0.75 mmol) was added. The mixture was
stirred at 100.degree. C. for 16 h. After cooling to rt, the
mixture was filtered and the filtrate was purified by reversed
phase HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase;
from 5% to 95%) to give the title compound as a white solid. (50
mg, 20% yield).sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.65-7.63
(m, 1H), 7.59-7.57 (m, 2H), 6.21-6.17 (m, 1H), 5.17-5.16 (m, 2H),
4.62-4.56 (m, 2H), 4.40-4.39 (m, 2H), 4.33 (s, 2H), 3.93-3.79 (m,
4H), 3.33-3.28 (m, 2H), 1.90-1.87 (m, 2H), ESI-MS m/z 488.1
[M+H].sup.+
Example 154
3-chloro-5-(trifluoromethyl)benzyl
2-(((4,5-dihydro-1H-imidazol-2-yl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1-
,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00202##
[1093] Following the same condition as in Example 153, the title
compound is obtained as a white solid (21 mg, 9% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.60 (br s, 1H), 7.82 (s, 1H),
7.74-7.65 (m, 2H), 6.16-6.12 (m, 1H), 5.14-5.12 (m, 2H), 4.62-4.53
(m, 2H), 4.39-4.35 (m, 2H), 4.24 (d, J=5.6 Hz, 2H), 3.77-3.72 (m,
2H), 3.60-3.58 (m, 4H), 1.80-1.75 (m, 2H); ESI-MS m/z 471.1
[M+H].sup.+
Example 155
3-chloro-5-(trifluoromethyl)benzyl
2-(1-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00203##
[1095] To a solution of 3-chloro-5-(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(481 mg, 1.2 mmol) in THF (15 mL) was added CH.sub.3MgBr (3 M, 0.8
mL, 2.4 mmol) at 0.degree. C. The mixture was stirred at rt for 4 h
and quenched with sat. aq. NH.sub.4Cl (20 mL). The mixture was
extracted with EtOAc (3.times.40 mL). The organic phase was dried
over sodium sulfate and evaporated in vacuum, the residue was
purified by prep-TLC on silica gel (petroleum ether/EtOAc=2/1) to
afford the title compound as a white solid (350 mg, 70% yield).
ESI-MS m/z 418.1 [M+H].sup.+.
Example 156
3-chloro-5-(trifluoromethyl)benzyl
2-(1-((4,5-dihydrothiazol-2-yl)amino)ethyl)-7,8-dihydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-5(6H)-carboxylate
##STR00204##
[1097] To a solution of 3-chloro-5-(trifluoromethyl)benzyl
2-(1-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate (136 mg, 0.33 mmol) in DCM (5 mL) was added SOCl.sub.2
(196 mg, 1.65 mmol) at 0.degree. C. After stirring at rt for 6 h,
the reaction mixture was evaporated in vacuum. The residue was
mixed with 4,5-dihydrothiazol-2-amine (44 mg, 0.43 mmol),
Cs.sub.2CO.sub.3 (645 mg, 1.98 mmol) and KI (84 mg, 0.5 mmol) in
acetonitrile (5 mL). The mixture was stirred at 85.degree. C. for
16 h. After cooled to rt, the reaction mixture was filtered, the
filtrate was purified by reversed phase HPLC (CH.sub.3CN/H.sub.2O
with 0.05% TFA as mobile phase; from 5% to 95%) to give the title
compound as a brown solid (46 mg, 19% yield): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.70-7.66 (m, 1H), 7.65-7.57 (m, 2H),
6.31-6.26 (m, 1H), 5.25 (q, J=6.8 Hz, 1H), 5.18-5.17 (m, 2H),
4.69-4.57 (m, 2H), 4.46 (t, J=4.8 Hz, 2H), 4.12-3.99 (m, 1H),
3.92-3.70 (m, 3H), 3.52-3.37 (m, 2H), 1.95-1.91 (m, 2H), 1.67-1.64
(m, 3H). ESI-MS m/z 502.1 [M+H].sup.+.
Example 157
3-chloro-5-(trifluoromethyl)benzyl
2-(1-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00205##
[1099] Following the same condition as Example 156 the title
compound was obtained as a white solid (8 mg, 4% yield): .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.67 (s, 1H), 7.65-7.57 (m, 2H),
6.22-6.17 (m, 1H), 5.22-5.13 (m, 2H), 4.70-4.55 (m, 3H), 4.47-4.40
(m, 2H), 3.92-3.75 (m, 2H), 3.71-3.68 (m, 1H), 3.70 (s, 3H),
1.94-1.86 (m, 2H), 1.53 (d, J=6.8 Hz, 3H). ESI-MS m/z 485.1
[M+H].sup.+.
Example 158
3-chloro-5-(trifluoromethyl)benzyl
2-(piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00206##
[1101] A mixture of
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (150 mg, 0.36
mmol), DIEPA (93 mg, 0.72 mmol), HATU (138 mg, 0.36 mmol) and
tert-butyl piperazine-1-carboxylate (67 mg, 0.36 mmol) in DMF (2
mL) was stirred at rt for 2 h, the reaction mixture was diluted
with EtOAc (30 mL) and washed with brine (2.times.5 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuum. The residue was purified by prep-TLC
(petroleum ether/ethyl acetate=1/2) to give the Boc-protected
intermediate as a yellow solid (160 mg, 76% yield): ESI-MS m/z
586.2 [M+H].sup.+.
[1102] To a solution of the above intermediate (160 mg, 0.27 mmol)
in dioxane (4 mL) was added hydrochloric acid (12 M, 1 mL). The
reaction mixture was stirred at rt for 4 h and was evaporated in
vacuum, the residue was dissolved in methanol (4 mL) and was
adjusted pH=8-9 with NaOH (4 N). The resulted solution was purified
by prep-HPLC (CH.sub.3CN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as
mobile phase; from 10% to 95%) to give the title compound as a
white solid (100 mg, 76% yield): .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 7.82-7.80 (m, 1H), 7.74-7.68 (m, 1H),
7.66-7.62 (m, 1H), 6.45, 6.43 (s, s, 1H), 5.16, 5.13 (s, s, 2H),
4.64, 4.56 (s, s, 2H), 4.45-4.44 (m, 2H), 3.79-3.72 (m, 4H), 3.50
(bs, 2H), 3.39-3.36 (m, 1H), 2.73-2.59 (m, 4H), 1.88-1.74 (m, 2H);
ESI-MS m/z 486.2 [M+H].sup.+.
Example 159
3-chloro-5-(trifluoromethyl)benzyl
2-(5-methyl-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-7,8-dihydro-4H-pyra-
zolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00207##
[1104] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-(2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5--
a][1,4]diazepine-5(6H)-carboxylate (130 mg, 0.247 mmol) in
CH.sub.3OH (5 mL) were added aqueous formalin solution (12 M, 0.103
mL, 1.235 mmol) and NaBH.sub.3CN (78 mg, 1.235 mmol). The mixture
was stirred at rt for 3 h, diluted with EtOAc (20 mL), washed with
saturated aqueous NaHCO.sub.3 (2.times.5 mL), dried over sodium
sulfate anhydrate and concentrated in vacuum. The residue was
purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%) to give the
title compound as a white solid (70 mg, 52% yield): .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 7.81 (d, J=9.6 Hz, 1H), 7.73-7.56
(m, 2H), 6.54, 6.46 (s, s, 1H), 5.16, 5.13 (s, s, 2H), 4.74-4.33
(m, 5H), 3.82-3.63 (m, 3H), 3.41-3.28 (m, 1H), 2.90-2.65 (m, 3H),
2.29, 2.28 (s, s, 3H), 2.04-1.89 (m, 1H), 1.89-1.63 (m, 4H),
1.60-1.47 (m, 1H); ESI-MS m/z 526.0 [M+H].sup.+.
Example 162
3-chloro-5-(trifluoromethyl)benzyl
2-(2,6-dimethylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine--
5(4H)-carboxylate
##STR00208##
[1105] Step 1
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrazine-2-carboxylic acid
##STR00209##
[1107] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol
(484 mg, 2.30 mmol, 1.5 eq) and CDI (376 mg, 2.30 mmol, 1.5 eq) in
DMF (2 mL) was stirred at rt for 3 h, then ethyl
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (300 mg,
1.54 mmol) and Et.sub.3N (155 mg, 1.54 mmol) were added. The
mixture was stirred at rt for 16 h, quenched with brine (50 mL),
and extracted with ethyl acetate (3.times.50 mL). The combined
organic phase was washed with brine (2.times.50 mL), dried over
sodium sulfate and evaporated in vacuum to give the crude product
which was purified by column chromatography on silica gel
(petroleum ether/EtOAc=5:1) to give the ester intermediate (400 mg,
60% yield) as a white solid. ESI-MS (M+H).sup.+: 432.1.
[1108] To a solution of above intermediate (400 mg, 0.93 mmol) in
THF (6 mL) and H.sub.2O (1 mL) was added NaOH (74 mg, 1.86 mmol).
The reaction mixture was stirred at rt for 16 h and acidified pH=6
with 1N HCl. The mixture was partitioned between EtOAc (50 mL) and
water (50 mL). The aqueous layer was extracted with EtOAc (50
mL.times.2). The combined organics were dried and concentrated to
give the title intermediate as yellow solid (300 mg, 80% yield).
ESI-MS (M+H).sup.+: 404.1.
Step 2
3-chloro-5-(trifluoromethyl)benzyl
2-(2,6-dimethylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine--
5 (4H)-carboxylate
##STR00210##
[1110] To a mixture of
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydrop-
yrazolo[1,5-a]pyrazine-2-carboxylic acid (140 mg, 0.35 mmol),
tert-butyl 3,5-dimethylpiperazine-1-carboxylate (97 mg, 0.45 mmol)
and HATU (198 mg, 0.52 mmol) in DMF (3 mL) was added DIPEA (90 mg,
0.69 mmol). The mixture was stirred at rt for 2 h and then
concentrated. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc=1:2) to give the Boc-protected
intermediate as yellow oil (120 mg, 57% yield). ESI-MS (M+H).sup.+:
600.2.
[1111] To a solution of the above Boc-protected intermediate (120
mg, 0.2 mmol) in dioxane (2 mL) was added conc. HCl (1 mL). The
reaction mixture was stirred at rt for 2 h and concentrated. The
residue was purified by reversed phase HPLC (0.05% TFA/H.sub.2O:
CH.sub.3CN=65%: 35%) to give the title compound as a white solid
(87 mg, 87% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.74
(s, 1H), 7.69 (s, 2H), 6.54 (s, 1H), 5.27 (s, 2H), 5.26-5.15 (m,
2H), 4.84-4.78 (m, 2H), 4.25-4.22 (m, 2H), 4.05-4.01 (m, 2H),
3.40-3.30 (m, 4H), 1.48 (d, J=7.2 Hz, 6H); ESI-MS (M+H).sup.+:
500.2.
Example 176
3-chloro-5-(trifluoromethyl)benzyl
2-(2,2,4-trimethylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1-
,4]diazepine-5(6H)-carboxylate
##STR00211##
[1113] Using
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid and
1,3,3-trimethylpiperazine as starting materials, and following the
same condition as described in example 158, the title compound was
obtained as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.67-7.51 (m, 3H), 6.58, 6.56 (s, s, 1H), 5.19, 5.16 (s s,
2H), 4.72-4.59 (m, 2H), 4.50 (t, J=4.8 Hz, 2H), 3.99-3.34 (m, 6H),
3.30-3.09 (m, 2H), 2.97 (s, 3H), 1.98-1.87 (m, 2H), 1.63 (s, 6H);
ESI-MS m/z 528.2 [M+H].sup.+.
Example 207
3-chloro-5-(trifluoromethyl)benzyl
2-(2,2-dimethylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]-
diazepine-5(6H)-carboxylate
##STR00212##
[1115] Using
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid and tert-butyl
3,3-dimethylpiperazine-1-carboxylate as starting materials, and
following the same condition as described in example 158, the title
compound was obtained as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 7.82-7.79 (m, 1H), 7.74-7.62 (m, 2H),
6.46-6.38 (m, 1H), 5.15, 5.13 (s, s, 2H), 4.65, 4.56 (s, s, 2H),
4.44-4.43 (m, 2H), 3.80-3.73 (m, 3H), 3.55-3.44 (m, 2H), 3.30-3.29
(m, 1H), 2.71 (s, 2H), 1.96-1.94 (m, 1H), 1.86-1.74 (m, 2H),
1.00-0.86 (m, 6H); MS m/z 514.0 [M+H].sup.+.
[1116] The following compounds were synthesized using the same
conditions as in Examples 158 or 159
TABLE-US-00002 ESI-MS Example Structure [M + H].sup.+ 1H-NMR 160
##STR00213## 514.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.65-7.52 (m, 3H), 6.69- 6.67 (m, 1H), 5.23-5.15 (m, 2H), 4.94-4.90
(m, 2H), 4.76- 4.61 (m, 2H), 4.54-4.51 (m, 2H), 3.91-3.74 (m, 2H),
3.69- 3.65 (m, 2H), 3.39-3.32 (m, 2H), 1.94-1.91 (m, 2H), 1.48 (d,
J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H); 161 ##STR00214## 514.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.67-7.53 (m, 3H), 6.70-
6.68 (m, 1H), 5.24-5.16 (m, 2H), 5.02-4.94 (m, 1H), 4.92- 4.85 (m,
1H), 4.78-4.63 (m, 2H), 4.55-4.53 (m, 2H), 3.92- 3.79 (m, 2H),
3.70-3.67 (m, 2H), 3.40-3.36 (m, 2H), 1.95- 1.92 (m, 2H), 1.50 (d,
J = 6.8 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H); 163 ##STR00215## 548.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.94-7.89 (m, 3H), 6.66-
6.63 (m, 1H), 5.30-5.23 (m, 4H), 4.70-4.63 (m, 2H), 4.54- 4.51 (m,
2H), 3.91-3.84 (m, 2H), 3.42-3.37 (m, 2H), 3.30- 3.26 (m, 2H),
1.94-1.92 (m, 2H), 1.49 (d, J = 1.2 Hz, 6H). 164 ##STR00216## 514.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.65-7.54 (m, 3H), 6.66-
6.64 (m, 1H), 5.31-5.17 (m, 4H), 4.69-4.63 (m, 2H), 4.53- 4.51 (m,
2H), 3.90-3.84 (m, 2H), 3.41-3.38 (m, 2H), 3.30- 3.27 (m, 2H),
1.94-1.92 (m, 2H), 1.49 (d, J = 7.2 Hz, 6H). 165 ##STR00217## 512.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.62-7.59 (m, 1H), 7.53-
7.50 (m, 2H), 6.71-6.68 (m, 1H), 5.21-5.16 (m, 2H), 4.68- 4.63 (m,
2H), 4.55-4.38 (m, 4H), 3.91-3.85 (m, 3H) 3.40- 3.35 (m, 1H),
3.33-3.30 (m, 2H), 2.32-1.92 (m, 6H); 166 ##STR00218## 512.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.63 (m, 1H),
7.57-7.50 (m, 2H), 6.71-6.68 (m, 1H), 5.22-5.17 (m, 2H), 4.70-4.38
(m, 7H), 4.00-3.87 (m, 3H), 3.42 (m, 1H), 2.32-1.89 (m, 7H); 167
##STR00219## 512.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.64
(s, 1H), 7.57-7.53 (m, 2H), 6.71-6.68 (m, 1H), 5.16 (s, 2H),
4.69-4.56 (m, 6H), 4.37-4.20 (m, 2H), 4.09-3.89 (m, 4H), 3.40-3.31
(m, 2H), 2.35-2.30 (m, 1H), 2.04-1.92 (m, 3H); 168 ##STR00220##
526.1 1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.64-7.62 (m, 1H),
7.57- 7.52 (m, 2H), 6.68-6.66 (m, 1H), 5.18-5.15 (m, 2H), 4.68-
4.61 (m, 2H), 4.53-4.51 (m, 2H), 3.99-3.40 (m, 10H), 3.32-3.30 (m,
1H), 2.96-2.93 (m, 4H), 2.04-1.92 (m, 2H); 169 ##STR00221## 540.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.62-7.59 (m, 1H), 7.56-
7.48 (m, 2H), 6.67 (s, 1H), 5.18-5.14 (m, 2H), 4.91-4.53 (m, 4H),
4.04-3.89 (m, 4H), 3.82-3.71 (m, 2H), 3.23-3.20 (m, 5H), 2.09-1.85
(m, 7H); 170 ##STR00222## 512.2 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.64-7.61 (m, 1H), 7.57- 7.51 (m, 2H), 6.69-6.66 (m, 1H),
5.18-5.15 (m, 2H), 4.68- 4.51 (m, 4H), 4.18-4.15 (m, 2H), 3.89-3.83
(m, 3H), 3.71- 3.60 (m, 3H), 3.23-3.19 (m, 4H), 1.95-1.90 (m, 2H);
171 ##STR00223## 511.1 .sup.1H NMR (400 MHz, DMSO- d.sub.6)
.delta.: 7.82-7.80 (m, 1H), 7.76-7.70 (m, 1H), 7.67-7.64 (m, 1H),
6.53, 6.52 (s, s, 1H), 5.17, 5.15 (s, s, 2H), 4.85- 4.48 (m, 6H),
4.23-4.17 (m, 1H), 3.79-3.67 (m, 2H), 3.52- 3.45 (m, 1H), 3.28-3.06
(m, 1H), 2.88-2.77 (m, 2H), 1.92- 1.78 (m, 2H); 172 ##STR00224##
542.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.64-7.54 (m, 3H),
6.58, 6.56 (s, s, 1H), 5.19, 5.16 (s s, 2H), 4.68-4.61 (m, 2H),
4.50 (t, J = 5.2 Hz, 2H), 4.10-3.32 (m, 6H), 3.26-3.07 (m, 4H),
1.93-1.91 (m, 2H), 1.64 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H). 173
##STR00225## 536.4 .sup.1H NMR (400 MHz, DMSO- d.sub.6) .delta. ppm
8.09-7.99 (m, 2H), 7.92 (s, 1H), 6.83-6.70 (m, 1H), 5.24 (d, J =
12.30 Hz, 2H), 4.77- 4.48 (m, 4H), 3.96-3.70 (m, 4H), 3.42 (m, 2H),
1.83 (br. s., 2H) 174 ##STR00226## 540.1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.57 (s, 1H), 7.50-7.38 (m, 2H), 6.67, 6.59
(s, s, 1H), 5.22-5.03 (m, 2H), 4.97-4.81 (m, 1H), 4.68-4.57 (m,
1H), 4.54-4.38 (m, 3H), 3.96-3.85 (m, 1H), 3.79-3.69 (m, 2H),
3.65-3.54 (m, 2H), 3.20-3.13 (m, 1H), 2.82 (s, 3H), 2.72- 2.48 (m,
3H), 2.29-2.11 (m, 2H), 2.04-1.93 (m, 2H), 1.88- 1.77 (m, 2H). 175
##STR00227## 526.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.68-7.54 (m, 3H), 6.62, 6.59 (s, s, 1H), 5.18, 5.16 (s, s, 2H),
4.68, 4.62 (s, s, 2H), 4.51 (t, J = 5.2 Hz, 2H), 4.19- 4.08 (m,
2H), 3.93-3.80 (m, 2H), 3.52 (s, 2H), 3.06 (t, J = 5.2 Hz, 2H),
2.47-2.28 (m, 4H), 1.97-1.80 (m, 4H). 178 ##STR00228## 568.0
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.64-7.51 (m, 3H),
6.93-6.72 (m, 1H), 5.86-5.47 (m, 1H), 5.28-5.10 (m, 2H), 4.81-4.59
(m, 2H), 4.54 (t, J = 4.8 Hz, 2H), 4.13-3.99 (m, 1H), 3.98-3.34 (m,
5H), 3.30-3.10 (m, 2H), 2.99 (s, 3H), 1.94 (bs, 2H); 179
##STR00229## 540.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.65-7.58 (m, 3H), 6.52- 6.48 (m, 1H), 5.18-5.17 (m, 2H), 4.68-4.48
(m, 6H), 3.89- 3.83 (m, 2H), 2.65-2.35 (m, 5H), 1.92 (bs, 2H),
1.36-0.52 (m, 8H). 180 ##STR00230## 526.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.65-7.58 (m, 3H), 6.52- 6.46 (m, 1H), 5.18,
5.16 (s, s, 2H), 4.67-4.59 (m, 4H), 4.49 (t, J = 4.8 Hz, 2H),
3.89-3.83 (m, 2H), 2.59-2.38 (m, 2H), 2.30 (s, 3H), 1.91 (bs, 2H),
1.41-1.23 (m, 6H); 181 ##STR00231## 554.0 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.65-7.52 (m, 3H), 6.85- 6.72 (m, 1H),
5.70-5.41 (m, 1H), 5.16 (s, 2H), 4.76-4.63 (m, 2H), 4.55-4.53 (m,
2H), 3.89-3.80 (m, 3H), 3.70-3.42 (m, 3H), 3.26-3.21 (m, 2H),
1.93-1.92 (m, 2H); 182 ##STR00232## 522.2 .sup.1H NMR (400 MHz,
DMSO) .delta.: 8.06-8.04 (m, 3H), 7.95 (s, 1H), 6.54, 6.49 (s, s,
1H), 5.25, 5.23 (s, s, 2H), 4.66, 4.57 (s, s, 2H), 4.47-4.46 (m,
2H), 3.79-3.74 (m, 2H), 3.19- 3.18 (m, 2H), 2.59 (t, J = 7.2 Hz,
2H), 1.85-1.80 (m, 2H), 1.51-1.36 (m, 4H); 183 ##STR00233## 525.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.72-7.48 (m, 3H), 6.74-
6.63 (m, 1H), 5.28-5.13 (m, 2H), 5.13-4.94 (m, 1H), 4.70- 4.50 (m,
5H), 3.89-3.78 (m, 2H), 3.17-2.83 (m, 3H), 2.35 (s, 3H), 2.29-2.26
(m, 1H), 2.18-2.02 (m, 1H), 1.99-1.86 (m, 2H); 184 ##STR00234##
544.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.70-7.52 (m, 3H),
6.77- 6.68 (m, 1H), 6.68-6.54 (m, 0.5H), 5.70-5.59 (m, 0.5H),
5.26-5.11 (m, 2H), 4.82-4.57 (m, 2.5H), 4.57-4.45 (m, 2H),
4.17-4.03 (m, 1H), 3.99-3.70 (m, 2H), 3.66-3.34 (m, 2.5H),
3.28-3.07 (m, 2H), 2.96 (s, 3H), 1.94 (bs, 2H); 185 ##STR00235##
544.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.71-7.51 (m, 3H),
6.70, 6.67 (s, s, 1H), 5.62-5.03 (m, 3H), 4.87-4.44 (m, 5H), 4.17-
4.03 (m, 1H), 4.01-3.71 (m, 3H), 3.74-3.38 (m, 2H), 3.31- 3.18 (m,
1H), 3.03 (s, 3H), 1.93 (bs, 2H). 186 ##STR00236## 568.0 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.69-7.49 (m, 3H), 6.60, 6.57
(s, s, 1H), 5.18, 5.16 (s, s, 2H), 4.68, 4.62 (s, s, 2H), 4.54-4.47
(m, 2H), 4.26-3.97 (m, 2H), 3.97-3.53 (m, 4H), 3.20 (bs, 1H), 3.01
(bs, 1H), 2.71-2.60 (m, 1H), 2.58 (s, 3H), 1.99-1.87 (m, 2H); 187
##STR00237## 512.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.68-7.48 (m, 3H), 6.67, 6.65 (s, s, 1H), 5.19, 5.17 (s s, 2H),
4.74-4.59 (m, 2H), 4.59- 4.43 (m, 3H), 4.43-4.25 (m, 1H), 4.13-3.98
(m, 1H), 3.95- 3.73 (m, 3H), 3.42 (t, J = 5.6 Hz, 2H), 1.92 (bs,
2H), 1.11 (bs, 4H). 188 ##STR00238## 512.0 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.71-7.54 (m, 3H), 6.63, 6.60 (s, s, 1H), 5.16
(s, 2H), 4.83-4.412 (m, 6H), 4.14 (bs, 1H), 4.00-3.73 (m, 2H),
3.66- 3.36 (m, 2H), 3.31-2.97 (m, 2H), 2.77 (bs, 1H), 2.25-2.02 (m,
2H), 2.01-1.85 (m, 2H). 189 ##STR00239## 544.0 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 7.64-7.54 (m, 3H), 6.61, 6.58 (s, s, 1H),
5.19, 5.17 (s, s, 2H), 4.68, 4.63 (s, s, 2H), 4.60-4.50 (m, 3H),
3.90-3.84 (m, 2H), 3.43-3.42 (m, 2H), 3.18-3.05 (m, 2H), 2.84-2.77
(m, 2H), 1.95-1.93 (m, 2H); 190 ##STR00240## 531.1 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.83-7.81 (m, 1H), 7.76- 7.70 (m, 2H),
6.84-6.82 (m, 1H), 6.76, 6.67 (s, s, 1H), 5.20 (s, 2H), 4.56 (s,
2H), 4.45 (t, J = 4.4 Hz, 2H), 3.81 (s, 2H), 3.46-3.43 (m, 2H),
2.38-2.37 (m, 1H), 2.26-2.22 (m, 2H), 1.98-1.96 (m, 3H), 1.76-1.69
(m, 2H), 1.65-1.60 (m, 2H). 191 ##STR00241## 564.0 .sup.1H NMR (400
MHz, DMSO- d.sub.6) .delta.: 8.10-8.03 (m, 2H), 8.00 (s, 1H),
6.52-6.45 (m, 1H), 5.57- 5.40 (m, 0.5H), 5.31-5.15 (m, 2H),
4.90-4.52 (m, 3H), 4.52-4.37 (m, 2H), 4.29-4.18 (m, 0.5H),
3.88-3.44 (m, 4H), 3.24-2.77 (m, 3H), 2.76-2.63 (m, 1H), 1.93-1.68
(m, 2H). 192 ##STR00242## 564.0 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 8.01-7.84 (m, 3H), 6.69, 6.65 (s, s, 1H), 5.63-5.20 (m,
3H), 5.20-4.97 (m, 1H), 4.70, 4.64 (s, s, 2H), 4.54 (bs, 2H),
4.22-4.08 (m, 1H), 3.98-3.79 (m, 2H), 3.78-3.63 (m, 1H), 3.58-3.36
(m, 2H), 3.27-3.15 (m, 1H), 1.94 (bs, 2H). 193 ##STR00243## 500.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.51 (m, 3H), 6.67-
6.60 (m, 1H), 5.18, 5.16 (s, s, 2H), 4.68, 4.62 (s, s, 2H),
4.53-4.48 (m, 2H), 4.25-4.09 (m, 2H), 3.95-3.78 (m, 4H), 3.55-3.53
(m, 1H), 3.40-3.35 (m, 3H), 2.17 (bs, 2H), 1.92 (bs, 2H); 195
##STR00244## 500.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.68-7.49 (m, 3H), 6.75-6.65 (m, 1H), 5.24-5.11 (m, 2H), 4.76-4.58
(m, 2H), 4.58-4.47 (m, 2H), 4.40-4.27 (m, 1H), 4.26-4.03 (m, 1H),
4.03-3.67 (m, 5H), 2.79 (d, J = 6.4 Hz, 3H), 2.53-2.35 (m, 1H),
2.29- 2.09 (m, 1H), 1.93 (bs, 2H). 196 ##STR00245## 511.1 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.69-7.49 (m, 3H), 6.74- 6.58
(m, 1H), 5.28-5.12 (m, 2H), 5.09-4.94 (m, 1H), 4.81- 4.60 (m, 3H),
4.60-4.40 (m, 3H), 3.97-3.74 (m, 2H), 3.22- 2.92 (m, 3H), 2.83-2.71
(m, 1H), 1.95 (bs, 2H); 197 ##STR00246## 512.0 .sup.1H NMR (400
MHz, DMSO- d.sub.6) .delta.: 7.88-7.76 (m, 1H), 7.76-7.57 (m, 2H),
6.60-6.42 (m, 1H), 5.16, 5.13 (s, s, 2H), 4.84-4.34 (m, 5H),
3.82-3.69 (m, 2H), 3.53-3.44 (m, 4H), 3.08-2.91 (m, 2H), 1.95-1.58
(m, 6H); 198 ##STR00247## 514.0 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.68-7.50 (m, 3H), 6.67, 6.65 (s, s, 1H), 5.46-5.08 (m,
3H), 4.88-4.75 (m, 1H), 4.69, 4.63 (s, s, 2H), 4.58-4.48 (m, 2H),
3.96-3.76 (m, 2H), 3.51- 3.35 (m, 2H), 3.23-3.00 (m, 1H), 2.90-2.69
(m, 1H), 2.01- 1.86 (m, 2H), 1.37 (s, 6H). 199 ##STR00248## 514.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.69-7.53 (m, 3H), 6.53,
6.51 (s, s, 1H), 5.18, 5.17 (s, s, 2H), 4.80-4.57 (m, 4H), 4.49 (t,
J = 4.8 Hz, 2H), 3.95- 3.77 (m, 2H), 2.88 (bs, 4H), 1.98-1.86 (m,
2H), 1.41-1.35 (m, 6H); 200 ##STR00249## 514.0 .sup.1H NMR (400
MHz, DMSO- d.sub.6) .delta.: 7.82-7.79 (m, 1H), 7.74-7.62 (m, 2H),
6.46-6.38 (m, 1H), 5.15, 5.13 (s, s, 2H), 4.65, 4.56 (s, s, 2H),
4.44- 4.43 (m, 2H), 3.80-3.73 (m, 3H), 3.55-3.44 (m, 2H), 3.30-
3.29 (m, 1H), 2.71 (s, 2H), 1.96-1.94 (m, 1H), 1.86-1.74 (m, 2H),
1.00-0.86 (m, 6H); 201 ##STR00250## 526.0 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.71-7.50 (m, 3H), 6.63, 6.61 (s, s, 1H),
5.19, 5.17 (s, s, 2H), 5.04-4.80 (m, 1H), 4.68, 4.62 (s, s, 2H),
4.58- 4.40 (m, 3H), 3.98-3.80 (m, 2H), 3.80-3.62 (m, 2H), 3.61-
3.47 (m, 1H), 3.25-3.14 (m, 1H), 2.67 (s, 3H), 2.20 (bs, 2H),
2.03-1.77 (m, 4H). 202 ##STR00251## 486.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.69-7.42 (m, 3H), 6.66, 6.62 (s, s, 1H),
5.23-5.12 (m, 2H), 4.78-4.57 (m, 3H), 4.56- 4.46 (m, 2H), 4.37-4.24
(m, 2H), 3.95-3.73 (m, 3H), 3.71- 3.57 (m, 1H), 2.37 (s, 3H), 1.90
(bs, 2H); 203 ##STR00252## 512.0 .sup.1H NMR (400 MHz, DMSO-
d.sub.6) .delta.: 7.85-7.76 (m, 1H), 7.76- 7.66 (m, 1H), 7.65-7.57
(m, 1H), 6.53 (s, 1H), 5.16, 5.13 (s, s, 2H), 5.09-4.99 (m, 1H),
4.71-4.54 (m, 2H), 4.51-4.38 (m, 3H), 3.83-3.65 (m, 2H), 2.83-2.70
(m, 2H), 2.65-2.55 (m, 2H), 1.92-1.62 (m, 6H); 204 ##STR00253##
498.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.68-7.49 (m, 3H),
6.75- 6.67 (m, 1H), 5.87-5.80 (m, 0.6H), 5.28-5.22 (m, 0.4H),
5.21-5.07 (m, 2H), 4.80-4.59 (m, 2H), 4.58-4.49 (m, 3H), 4.26-3.86
(m, 2H), 3.85-3.64 (m, 2H), 3.57-3.38 (m, 2H), 2.25-2.15 (m, 1H),
2.09-1.99 (m, 1H), 1.99-1.85 (m, 2H). 205 ##STR00254## 514.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.54 (m, 3H), 6.66,
6.64 (s, s, 1H), 5.19-5.16 (m, 3H), 4.71-4.63 (m, 2H), 4.54- 4.51
(m, 2H), 3.90-3.82 (m, 2H), 3.42-3.32 (m, 3H), 3.29- 3.14 (m, 3H),
2.00-1.90 (m, 3H), 1.87-1.71 (m, 1H), 0.95 (bs, 3H). 206
##STR00255## 514.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.65-7.54 (m, 3H), 6.58, 6.55 (s, s, 1H), 5.18, 5.16 (s s, 2H),
4.86-4.60 (m, 3H), 4.60-4.42 (m, 3H), 3.95-3.76 (m, 2H), 3.28-3.07
(m, 1H), 3.05-2.51 (m, 4H), 1.92 (bs, 2H), 1.58- 1.32 (m, 2H),
1.09-0.85 (m, 3H). 208 ##STR00256## 500.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.67-7.53 (m, 3H), 6.67, 6.65 (s, s, 1H),
5.27-5.00 (m, 3H), 4.75-4.56 (m, 3H), 4.56- 4.45 (m, 2H), 3.95-3.75
(m, 2H), 3.72-3.35 (m, 3H), 3.27- 2.93 (m, 2H), 1.99-1.83 (m, 2H),
1.45-1.26 (m, 3H). 209 ##STR00257## 512.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.706-7.49 (m, 3H), 6.67, 6.65 (s, s, 1H),
5.25-5.01 (m, 3H), 4.74-4.46 (m, 5H), 4.23- 4.03 (m, 2H), 3.95-3.77
(m, 2H), 3.69-3.54 (m, 1H), 3.29- 3.17 (m, 1H), 2.17-1.86 (m, 6H).
210 ##STR00258## 512.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.70-7.48 (m, 3H), 6.70- 6.54 (m, 1H), 5.19-5.17 (m, 2H), 4.73-4.58
(m, 2H), 4.57- 3.99 (m, 4H), 3.94-3.78 (m, 2H), 3.42 (t, J = 4.8
Hz, 2H),
3.30-3.18 (m, 2H), 1.92 (bs, 2H), 1.22-0.80 (m, 4H). 211
##STR00259## 526.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.56-7.44 (m, 3H), 6.60, 6.55 (s, s, 1H), 5.13 (s, 2H), 4.86-4.66
(m, 2H), 4.57-4.46 (m, 4H), 3.82-3.81 (m, 2H), 3.30 (bs, 0.5H),
3.12-2.97 (m, 3H), 2.59 (bs, 0.5H), 2.21- 1.45 (m, 9H). 212
##STR00260## 500.1 .sup.1H NMR (400 MHz, DMSO- d.sub.6) .delta.:
8.19-8.06 (m, 1H), 7.86-7.54 (m, 3H), 6.60-6.50 (m, 1H), 5.16, 5.13
(s, s, 2H), 4.66-4.54 (m, 3H), 4.48 (bs, 2H), 4.20-4.00 (m, 2H),
3.83- 3.65 (m, 3H), 3.24 (bs, 2H), 1.92-1.72 (m, 2H); 213
##STR00261## 500.2 .sup.1H NMR (400 MHz, DMSO- d.sub.6) .delta.:
8.81 (bs, 1H), 7.87-7.77 (m, 1H), 7.77-7.56 (m, 2H), 6.56, 6.54 (s,
s, 1H), 5.25- 4.96 (m, 3H), 4.86-4.33 (m, 6H), 3.86-3.64 (m, 2H),
3.35- 3.19 (m, 2H), 3.19-2.89 (m, 2H), 1.89-1.73 (m, 2H), 1.38-
1.23 (m, 3H); 214 ##STR00262## 526.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.62-7.54 (m, 3H), 6.56, 6.53 (s, s, 1H),
5.17, 5.15 (s, s, 2H), 4.81-4.61 (m, 4H), 4.51-4.48 (m, 2H),
3.88-3.82 (m, 2H), 3.30 (bs, 0.5H), 3.15-2.94 (m, 3H), 2.66-2.60
(m, 0.5H), 2.26-2.19 (m, 2H), 2.07 (bs, 1H), 1.51-1.33 (m, 5H),
1.13-0.89 (m, 1H). 215 ##STR00263## 534.2 .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta.: 7.81-7.97 (m, 3H), 6.55-6.73 (m, 1H),
5.25 (br. s., 2H), 4.57-4.76 (m, 2H), 4.45-4.55 (m, 2H), 3.77-3.96
(m, 2H), 3.40-3.75 (m, 4H), 3.02-3.36 (m, 4H), 2.95 (s, 3H),
1.85-1.96 (m, 2H) 216 ##STR00264## 500.2 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 7.43-7.68 (m, 3H), 6.57-6.69 (m, 1H), 5.15
(br. s., 2H), 4.57-4.72 (m, 2H), 4.43-4.55 (m, 2H), 3.76- 3.95 (m,
2H), 3.38-3.72 (m, 4H), 3.02-3.25 (m, 4H), 2.95 (s, 3H), 1.85-1.98
(m, 2H) 217 ##STR00265## 540.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.68-7.55 (m, 3H), 6.56, 6.52 (s, s, 1H), 5.19, 5.17 (s,
s, 2H), 4.71-4.58 (m, 3H), 4.54-4.42 (m, 3H), 3.93-3.77 (m, 2H),
3.75-3.66 (m, 1H), 3.41-3.33 (m, 1H), 2.93 (bs, 1H), 2.80 (bs, 1H),
2.62 (s, 3H), 2.16-2.04 (m, 2H), 2.01- 1.89 (m, 3H), 1.70-1.62 (m,
2H), 1.58-1.49 (m, 1H). 218 ##STR00266## 562.1 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 8.05-7.87 (m, 3H), 6.58, 6.55 (s, s, 1H),
5.26 (bs, 2H), 4.88-4.87 (m, 1H), 4.79-4.44 (m, 5H), 3.99-3.33 (m,
6H), 2.98 (s, 3H), 1.93 (s, 2H), 1.63 (s, 6H) 219 ##STR00267##
546.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.98-7.88 (m, 3H),
6.60, 6.56 (s, s, 1H), 5.27, 5.26 (s, s, 2H), 4.69, 4.62 (s, s,
2H), 4.51 (t, J = 4.8 Hz, 2H), 4.47- 4.03 (m, 2H), 3.96-3.77 (m,
2H), 3.29-3.12 (m, 4H), 1.92 (s, 2H), 1.15-0.79 (m, 4H). 220
##STR00268## 560.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.94-7.91 (m, 3H), 6.61, 6.56 (s, s, 1H), 5.34-5.19 (m, 2H),
5.08-4.95 (m, 1H), 4.76-4.59 (m, 2H), 4.56-4.48 (m, 2H), 3.95-3.51
(m, 5H), 3.20-3.04 (m, 2H), 2.92 (s, 3H), 1.92 (bs, 2H), 1.26-0.77
(m, 4H). 221 ##STR00269## 546.0 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.98-7.84 (m, 3H), 6.67, 6.64 (s, s, 1H), 5.28, 5.26 (s,
s, 2H), 5.25-5.02 (m, 1H), 4.77-4.56 (m, 3H), 4.56-4.47 (m, 2H),
4.24-4.03 (m, 2H), 3.98-3.77 (m, 2H), 3.66-3.54 (m, 1H), 3.28-3.17
(m, 1H), 2.19-1.85 (m, 6H). 222 ##STR00270## 560.0 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 8.01-7.82 (m, 3H), 6.78- 6.62 (m, 1H),
5.58-5.40 (m, 1H), 5.37-5.18 (m, 2H), 4.87- 4.43 (m, 5H), 4.41-3.68
(m, 6H), 3.03 (s, 3H), 2.47-1.81 (m, 6H). 223 ##STR00271## 548.0
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.95-7.88 (m, 3H), 6.56,
6.52 (s, s, 1H), 5.28, 5.26 (s, s, 2H), 4.75-4.61 (m, 3H),
4.53-4.48 (m, 3H), 3.92-3.81 (m, 2H), 2.88-2.76 (m, 2H), 2.72-2.65
(m, 1H), 2.44-2.35 (m, 1H), 1.99-1.88 (m, 2H), 1.15 (d, J = 6.0 Hz,
3H), 1.05 (d, J = 5.6 Hz, 3H). 224 ##STR00272## 546.1 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.98-7.85 (m, 3H), 6.70-6.55 (m,
1H), 5.32-5.22 (m, 2H), 5.09-4.93 (m, 1H), 4.71-4.57 (m, 2H),
4.56-4.45 (m, 2H), 4.20-3.59 (m, 4H), 3.28-3.03 (m, 3H), 214-1.75
(m, 6H). 225 ##STR00273## 560.0 .sup.1H NMR (400 MHz, DMSO-
d.sub.6) .delta.: 8.11-8.00 (m, 2H), 7.97 (s, 1H), 6.45, 6.39 (s,
s, 1H), 5.24, 5.22 (s, s, 2H), 4.64, 4.56 (s, s, 2H), 4.50-4.38 (m,
2H), 4.36-4.22 (m, 1H), 4.16- 4.05 (m, 1H), 3.84-3.66 (m, 2H),
3.27-3.10 (m, 2H), 3.09- 2.99 (m, 1H), 2.90-2.77 (m, 1H), 2.17 (s,
3H), 1.95-1.74 (m, 4H), 1.54-1.38 (m, 2H). 226 ##STR00274## 530.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.70-7.56 (m, 3H), 6.71-
6.64 (m, 1H), 5.99-5.88 (m, 0.5H), 5.31-5.23 (m, 0.5H), 5.21-5.07
(m, 2H), 4.85-4.43 (m, 5H), 4.00-3.66 (m, 3H), 3.44-3.35 (m, 1H),
3.28-2.99 (m, 3H), 2.00-1.82 (m, 2H); 227 ##STR00275## 530.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.53 (m, 3H), 6.69,
6.66 (s, s, 1H), 5.61-5.02 (m, 3H), 4.70-4.53 (m, 5H), 4.17- 4.15
(m, 1H), 3.90-3.84 (m, 2H), 3.63-3.49 (m, 2H), 3.25- 3.23 (m, 2H),
1.94 (bs, 2H). 228 ##STR00276## 492.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.39-7.37 (m, 1H), 7.30-7.25 (m, 2H), 6.57,
6.55 (s, s, 1H), 5.10, 5.08 (s, s, 2H), 4.88-4.59 (m, 4H),
4.52-4.49 (m, 2H), 3.88-3.83 (m, 2H), 3.30 (bs, 0.5H), 3.16-2.95
(m, 3H), 2.66- 2.61 (m, 0.5H), 2.28-1.40 (m, 8H), 1.13-0.89 (m,
1H). 229 ##STR00277## 556.2 .sup.1H NMR (400 MHz, DMSO- d.sub.6)
.delta.: 7.80 (s, 1H), 7.74-7.65 (m, 2H), 6.33, 6.27 (s, s, 1H),
5.15, 5.13 (s, s, 2H), 4.63, 4.54 (s, s, 2H), 4.43-4.41 (m, 2H),
3.77-3.73 (m, 2H), 3.62-3.56 (m, 2H), 2.28-2.13 (m, 9H), 1.82-1.79
(m, 2H), 1.67-1.61 (m, 2H), 0.80-0.76 (m, 6H). 230 ##STR00278##
574.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.97-7.90 (m, 3H),
6.56, 6.51 (s, s, 1H), 5.28, 5.26 (s, s, 2H), 4.72-4.57 (m, 3H),
4.55-4.48 (m, 2H), 4.47-4.40 (m, 1H), 3.94-3.78 (m, 2H), 3.74-3.64
(m, 1H), 3.40-3.34 (m, 1H), 2.90 (bs, 1H), 2.77 (bs, 1H), 2.60 (s,
3H) 2.15-2.03 (m, 2H), 2.00-1.87 (m, 3H), 1.68-1.60 (m, 2H),
1.57-1.48 (m, 1H). 231 ##STR00279## 542.1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.55 (s, 1H), 7.49-7.41 (m, 2H), 6.60, 6.54
(s, s, 1H), 5.14, 5.12 (s, s, 2H), 4.55 (s, 2H), 4.43 (t, J = 4.8
Hz, 2H), 4.18-4.14 (m, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.34 (bs,
2H), 3.20 (s, 2H), 2.35 (q, J = 7.2 Hz, 2H), 2.01-1.96 (m, 4H),
0.92 (t, J = 7.2 Hz, 6H). 232 ##STR00280## 554.2 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 7.67-7.56 (m, 3H), 6.45, 6.41 (s, s, 1H),
5.18, 5.17 (s, s, 2H), 4.66, 4.61 (s, s, 2H), 4.48 (t, J = 5.2 Hz,
2H), 3.91- 3.79 (m, 2H), 3.73-3.67 (m, 2H), 2.47-2.40 (m, 2H), 2.38
(s, 2H), 2.29 (s, 3H), 2.24- 2.13 (m, 2H), 2.03-1.84 (m, 6H),
1.67-1.56 (m, 2H). 233 ##STR00281## 574.0 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.83 (s, 1H), 7.76-7.72 (m, 2H), 6.68, 6.58
(s, s, 1H), 5.34- 5.10 (m, 2H), 4.98-4.82 (m, 1H), 4.70-4.59 (m,
2H), 4.55-4.38 (m, 3H), 3.98-3.87 (m, 1H), 3.82-3.70 (m, 2H),
3.67-3.55 (m, 1H), 3.19-3.16 (m, 1H), 2.82 (s, 3H), 2.73-2.48 (m,
3H), 2.33-2.12 (m, 2H), 2.05- 1.96 (m, 2H), 1.89-1.79 (m, 2H). 234
##STR00282## 540.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.65-7.54 (m, 3H), 6.58, 6.56 (s, s, 1H), 5.19, 5.16 (s, s, 2H),
4.68, 4.61 (s, s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.17- 4.08 (m,
2H), 3.89-3.83 (m, 2H), 3.36-3.31 (m, 4H), 2.41- 2.36 (m, 2H),
2.12-2.00 (m, 2H), 1.97-1.80 (m, 4H), 1.75- 1.64 (m, 2H). 235
##STR00283## 560.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.99-7.89 (m, 3H), 6.62, 6.57 (s, s, 1H), 5.27 (s, 2H), 4.69, 4.62
(s, s, 2H), 4.51 (t, J = 4.8 Hz, 2H), 4.18-4.09 (m, 2H), 3.94-3.80
(m, 2H), 3.52 (s, 2H), 3.06 (t, J = 4.8 Hz, 2H), 2.47- 2.29 (m,
4H), 1.98-1.80 (m, 4H) 236 ##STR00284## 556.2 .sup.1H NMR (400 MHz,
DMSO- d.sub.6) .delta.: 7.80 (s, 1H), 7.74-7.65 (m, 2H), 6.33, 6.27
(s, s, 1H), 5.15, 5.13 (s, s, 2H), 4.63, 4.54 (s, s, 2H), 4.43-4.41
(m, 2H), 3.77-3.73 (m, 2H), 3.62-3.56 (m, 2H), 2.28-2.13 (m, 9H),
1.82-1.79 (m, 2H), 1.67-1.61 (m, 2H), 0.80-0.76 (m, 6H). 237
##STR00285## 574.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.99-7.87 (m, 3H), 6.62, 6.57 (s, s, 1H), 5.34-5.21 (m, 2H),
5.13-4.92 (m, 1H), 4.76- 4.59 (m, 2H), 4.56-4.46 (m, 2H), 4.02-3.77
(m, 2H), 3.75- 3.42 (m, 3H), 3.24 (q, J = 7.2 Hz, 2H), 3.18-3.02
(m, 2H), 1.93 (bs, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.28-0.76 (m,
4H). 238 ##STR00286## 588.1 .sup.1H NMR (400 MHz, DMSO- d.sub.6)
.delta.: 8.06-8.03 (m, 2H), 7.95 (s, 1H), 6.51, 6.45 (s, s, 1H),
5.34-5.17 (m, 2H), 4.71-4.38 (m, 5H), 3.89-3.61 (m, 3H), 3.44-3.41
(m, 2H), 3.18-3.05 (m, 2H), 2.84 (s, 3H), 2.46- 2.36 (m, 1H),
2.26-2.12 (m, 1H), 2.01-1.72 (m, 5H), 1.65- 1.42 (m, 3H). 239
##STR00287## 548.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.94-7.89 (m, 3H), 6.57, 6.54 (s, s, 1H), 5.28, 5.26 (s, s, 2H),
4.69, 4.62 (s, s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.13- 4.05 (m,
2H), 3.91-3.82 (m, 2H), 3.40 (t, J = 5.2 Hz, 2H), 3.26 (s, 2H),
1.93-1.92 (m, 2H), 1.65 (s, 6H). 240 ##STR00288## 574.1 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.94-7.89 (m, 3H), 6.58, 6.55 (s, s,
1H), 5.28, 5.26 (s, s, 2H), 4.69, 4.62 (s, s, 2H), 4.51 (t, J = 5.2
Hz, 2H), 4.17- 4.08 (m, 2H), 3.91-3.82 (m, 2H), 3.34-3.31 (m, 4H),
2.42- 2.35 (m, 2H), 2.06 (bs, 2H), 1.94-1.91 (m, 2H), 1.85-1.81 (m,
2H), 1.72-1.64 (m, 2H). 241 ##STR00289## 576.1 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 7.94-7.90 (m, 3H), 6.56, 6.53 (s, s, 1H),
5.28, 5.26 (s, s, 2H), 4.69, 4.62 (s, s, 2H), 4.51 (t, J = 4.8 Hz,
2H), 4.16- 4.09 (m, 2H), 3.92-3.82 (m, 2H), 3.39-3.33 (m, 4H),
2.32- 2.23 (m, 2H), 2.05-1.99 (m, 2H), 1.94-1.92 (m, 2H), 0.95 (t,
J = 7.2 Hz, 6H). 242 ##STR00290## 520.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.96-7.88 (m, 2H), 7.85 (s, 1H), 6.66, 6.60
(s, s, 1H), 5.32-5.22 (m, 2H), 4.76-4.58 (m, 3H), 4.52 (t, J = 4.0
Hz, 2H), 4.35-4.24 (m, 2H), 3.93- 3.74 (m, 3H), 3.68-3.59 (m, 1H),
2.36 (s, 3H), 1.92 (bs, 2H). 243 ##STR00291## 534.1 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 8.00-7.83 (m, 3H), 6.76- 6.64 (m,
1H), 5.35-5.21 (m, 2H), 4.77-4.60 (m, 2H), 4.59- 4.49 (m, 2H),
4.38-4.04 (m, 2H), 4.02-3.68 (m, 5H), 2.78 (d, J = 6.0 Hz, 3H),
2.55-2.32 (m, 1H), 2.28-2.09 (m, 1H), 1.93 (bs, 2H). 244
##STR00292## 576.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.99-7.85 (m, 3H), 6.58, 6.55 (s, s, 1H), 5..26 (bs, 2H), 4.78-4.41
(m, 5H), 4.00-3.38 (m, 5H), 3.29-3.04 (m, 4H), 1.93 (bs, 2H), 1.65
(s, 6H), 1.40 (t, J = 1.2 Hz, 3H). 245 ##STR00293## 545.2 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 8.04-7.83 (m, 3H), 6.79- 6.61
(m, 1H), 5.76-5.57 (m, 0.5H), 5.36-5.21 (m, 2H), 5.12-4.96 (m,
0.5H), 4.84- 4.32 (m, 5H), 3.94-3.61 (m, 2H), 3.43-3.280 (m, 1H),
3.27-2.90 (m, 3H), 2.84-2.68 (m, 1H), 2.01-1.85 (m, 2H). 246
##STR00294## 545.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
8.03-7.86 (m, 3H), 6.71- 6.53 (m, 1H), 5.26 (s, 2H), 4.81-4.58 (m,
3H), 4.57-4.29 (m, 3H), 4.24-4.07 (m, 1H), 4.00-3.64 (m, 3H),
3.55-3.35 (m, 1H), 3.12-2.84 (m, 2H), 1.94 (bs, 2H). 247
##STR00295## 548.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.93-7.86 (m, 3H), 6.69- 6.66 (m, 1H), 5.29-5.26 (m, 2H), 4.93-4.90
(m, 2H), 4.74- 4.61 (m, 2H), 4.54-4.52 (m, 2H), 3.90-3.75 (m, 2H),
3.69- 3.64 (m, 2H), 3.39-3.34 (m, 2H), 1.95-1.90 (m, 2H), 1.50-
1.47 (m, 6H); 248 ##STR00296## 548.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.94-7.88 (m, 3H), 6.70-6.67 (m, 1H),
5.34-5.25 (m, 2H), 5.02-4.94 (m, 1H), 4.91-4.85 (m, 1H), 4.80-4.63
(m, 2H), 4.55-4.53 (m, 2H), 3.94-3.75 (m, 2H), 3.70-3.67 (m, 2H),
3.44-3.37 (m, 2H), 1.94-1.89 (m, 2H), 1.51-1.48 (m, 6H); 249
##STR00297## 548.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.94-7.89 (m, 3H), 6.66- 6.63 (m, 1H), 5.29-5.24 (m, 4H), 4.70-4.63
(m, 2H), 4.54- 4.51 (m, 2H), 3.91-3.84 (m, 2H), 3.42-3.37 (m, 2H),
3.30- 3.26 (m, 2H), 1.95-1.92 (m, 2H), 1.49 (d, J = 7.2 Hz, 6H) 502
##STR00298## 505.2 .sup.1H NMR (400 MHz, DMSO) .delta.: 8.07-8.01
(m, 3H), 7.95 (s, 1H), 6.55-6.50 (m, 1H), 5.25- 5.23 (m, 2H),
4.66-4.58 (m, 2H), 4.49-4.47 (m, 2H), 3.79-3.74 (m, 2H), 3.06 (t, J
= 5.6 Hz, 2H), 1.86- 1.81 (m, 2H), 1.01-0.98 (m, 1H), 0.40-0.36 (m,
2H), 0.22-0.18 (m, 2H) 503 ##STR00299## 491.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.93-7.83 (m, 3H), 6.66- 6.60 (m, 1H), 5.28,
5.23 (s, s, 2H), 4.67-4.60 (m, 2H), 4.51- 4.49 (m, 2H), 3.88-3.82
(m, 2H), 2.80-2.77 (m, 1H), 1.90 (bs, 2H), 0.80-0.77 (m, 2H),
0.64-0.60 (m, 2H) 504 ##STR00300## 521.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.93-7.83 (m, 3H), 6.66- 6.60 (m, 1H), 5.28,
5.25 (s, s, 2H), 4.67-4.61 (m, 2H), 4.54- 4.51 (m, 2H), 4.04-3.96
(m, 1.5H), 3.89-3.83 (m, 2H), 2.76- 2.69 (m, 1.5H), 2.39-2.33 (m,
1H), 1.98-1.91 (m, 4H) 505 ##STR00301## 507.2 .sup.1H NMR (400 MHz,
DMSO- d.sub.6) .delta.: 8.80-8.75 (m, 1H), 8.07-8.03 (m, 2H), 7.93
(s, 1H), 6.57-6.52 (m, 1H), 5.25- 5.22 (m, 2H), 4.98-4.92 (m, 1H),
4.69-4.66 (m, 3H), 4.61- 4.57 (m, 3H), 4.50-4.49 (m, 2H), 3.79-3.74
(m, 2H), 1.85- 1.81 (m, 2H) 506 ##STR00302## 535.2 .sup.1H NMR (400
MHz, DMSO- d.sub.6) .delta.: 8.06-8.03 (m, 2H), 7.93-7.86 (m, 2H),
6.56-6.52 (m, 1H), 5.25-5.23 (m, 2H), 4.66-4.57 (m, 2H), 4.48 (s,
2H), 3.94 (bs, 1H), 3.86-3.84 (m, 2H), 3.79-3.74 (m, 2H), 3.38-3.30
(m, 2H), 1.81 (bs, 2H), 1.64-1.59 (m, 4H) 514 ##STR00303## 534.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.00-7.83 (m, 3H), 6.76-
6.64 (m, 1H), 5.35-5.21 (m, 2H), 4.77-4.60 (m, 2H), 4.59- 4.49 (m,
2H), 4.38-4.04 (m, 2H), 4.02-3.68 (m, 5H), 2.78 (d, J = 6.0 Hz,
3H), 2.55-2.32 (m, 1H), 2.28-2.09 (m, 1H), 1.93 (bs, 2H).
515 ##STR00304## 518.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.67-7.57 (m, 3H), 5.18 (s, 2H), 4.66, 4.62 (s, s, 2H), 4.47 (t, J
= 4.8 Hz, 2H), 3.92-3.81 (m, 2H), 3.81-3.71 (m, 4H), 2.56-2.42 (m,
4H), 2.36-2.32 (m, 3H), 1.98-1.88 (m, 2H).
Example 250
3-Chloro-5-(trifluoromethyl)benzyl
2-(2-chloroacetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00305##
[1118]
5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-
hydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (10 g,
23.4 mmol) was added to thionyl chloride (60 mL) at rt under
N.sub.2 atmosphere and was heated to reflux for 4 h. Excess thionyl
chloride was removed under vacuum and traces were removed by
co-evaporation of the residue with toluene under vacuum. The crude
acid chloride was then dissolved in anhydrous acetonitrile and
cooled to 0.degree. C. under N.sub.2 atmosphere. TMSCHN.sub.2 (2 M,
24 mL, 48 mmol) was added slowly. The reaction mixture was allowed
to warm to rt and stirred for 18 h. The reaction mixture was then
cooled again to 0.degree. C. and HCl (6 M, 25 mL) was added and
stirring was continued for additional 3 h. The reaction mixture was
then neutralized with 1.0 M NaOH solution and extracted with ethyl
acetate (3.times.150 mL). The combined organic phase was washed
with brine (2.times.100 mL), dried over sodium sulfate and
evaporated under vacuum to give the crude product which was
purified by silica gel column chromatography (Petroleum
ether/EtOAc=2/1) to yield the titled compound (7 g) which was
further purified by crystallization from EtOAc (20 mL) to give the
title compound as a white solid (5 g, 48% yield). .sup.1H NMR (400
MHz, DMSO) .delta.: 7.80-7.54 (m, 3H), 6.73, 6.70 (s, s, 1H), 5.14,
5.11 (s, s, 2H), 4.92 (s, 2H), 4.68, 4.60 (s, s, 2H), 4.55-4.52 (m,
2H), 3.80-3.73 (m, 2H), 1.83-1.80 (m, 2H). ESI-MS m/z 450
[M+H].sup.+.
Example 251
3-Chloro-5-(trifluoromethyl)benzyl
2-((8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)-7,8-dihydro-4H-pyra-
zolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00306##
[1120] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-(2-chloroacetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate (100 mg, 0.2 mmol) and (S)-pyrrolidin-2-ylmethanol (20 mg,
0.2 mmol) in DCM (5 mL) was added DIPEA (52 mg, 0.4 mmol). The
reaction was stirred at rt for 16 h, then triethylsilane (70 mg,
0.6 mmol) and TFA (680 mg, 6.0 mmol, 30.0 eq) were added. The
mixture was stirred at 40.degree. C. for 16 h. After cooling to rt,
the mixture was concentrated and the residue was purified by
reversed phase HPLC (0.05% ammonia/H.sub.2O: CH.sub.3CN=40%: 60%)
to give the title compound (53 mg, 40% yield) as a yellow solid as
a mixture of diastereomers. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.67-7.58 (m, 3H), 6.30-6.18 (m, 1H), 5.16 (s, 2H),
4.67-4.53 (m, 3H), 4.43-4.41 (m, 2H), 4.08-3.95 (m, 1H), 3.87-3.77
(m, 3H), 3.47-3.08 (m, 1H), 2.98-2.89 (m, 1H), 2.69-2.62 (m, 2H),
2.40-2.19 (m, 1H), 1.98-1.73 (m, 6H); ESI-MS m/z 499.1;
[M+H].sup.+.
Example 252A and 252B
3-Chloro-5-(trifluoromethyl)benzyl
2-((8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)-7,8-dihydro-4H-pyra-
zolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00307##
[1122] Using (R)-pyrrolidin-2-ylmethanol and following the same
condition as in Example 251, the title compound was obtain and
purified by reversed phase HPLC (0.05% ammonia/H.sub.2O:
CH.sub.3CN=40%: 60%) to give the title compound as two
diastereomers as yellow solids. A (22 mg, 33% yield).sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.67-7.59 (m, 3H), 6.26-6.18 (m,
1H), 5.17 (s, 2H), 4.62-4.52 (m, 3H), 4.43-4.41 (m, 2H), 4.09-4.06
(m, 1H), 3.87-3.81 (m, 2H), 3.47-2.32 (m, 1H), 3.20-3.10 (m, 2H),
2.43-2.35 (m, 1H), 2.28-2.17 (m, 2H), 1.91-1.81 (m, 5H), 1.41-1.34
(m, 1H); ESI-MS m/z 499.2[M+H].sup.+. B (60 mg, 72% yield) .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.59 (m, 3H), 6.30-6.21 (m,
1H), 5.16 (s, 2H), 4.63-4.57 (m, 3H), 4.43-4.41 (m, 2H), 3.97-3.93
(m, 1H), 3.87-3.80 (m, 3H), 2.95-2.88 (m, 2H), 2.68-2.60 (m, 3H),
1.95-1.89 (m, 3H), 1.78-1.74 (m, 3H); ESI-MS m/z 499.2
[M+H].sup.+.
Example 253
3-chloro-5-(trifluoromethyl)benzyl
2-((9aS)-octahydropyrido[2,1-c][1,4]oxazin-3-yl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00308##
[1124] Using (S)-piperidin-2-ylmethanol and following the same
condition as in Example 251, the title compound was obtain as a
white solid (55 mg, 48% yield) as a mixture of diastereomers.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.51 (m, 3H),
6.86-6.81 (m, 1H), 5.18-5.16 (m, 2H), 5.04-4.99 (m, 1H), 4.85-4.72
(m, 2H), 4.65-4.60 (m, 3H), 4.10-3.60 (m, 6H), 3.40-3.35 (m, 1H),
3.30-3.25 (m, 1H), 1.96-1.91 (m, 2H), 1.38-1.18 (m, 6H); ESI-MS m/z
513.2 [M+H].sup.+.
Example 254
3-chloro-5-(trifluoromethyl)benzyl
2-((9aR)-octahydropyrido[2,1-c][1,4]oxazin-3-yl)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00309##
[1126] Using (R)-piperidin-2-ylmethanol and following the same
condition as in Example 251, the title compound was obtained as a
white solid (20 mg, 40% yield) as a mixture of diastereomers.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.67-7.56 (m, 3H),
6.39-6.26 (m, 1H), 5.37-4.99 (m, 3H), 4.86-4.43 (m, 4H), 4.11-3.36
(m, 8H), 3.30-3.05 (m, 1H), 2.36-1.39 (m, 8H); ESI-MS m/z 513.2
[M+H].sup.+.
Example 255
3,5-bis(trifluoromethyl)benzyl
2-((8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)-6,7-dihydropyrazolo-
[1,5-a]pyrazine-5(4H)-carboxylate
##STR00310##
[1127] Step 1
3,5-bis(trifluoromethyl)benzyl
2-(2-chloroacetyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5
(4H)-carboxylate
##STR00311##
[1129] A solution of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyraz-
olo[1,5-a]pyrazine-2-carboxylic acid (400 mg, 0.91 mmol) in thionyl
chloride (8 mL) was heated at reflux for 4 h. Excess thionyl
chloride was removed under reduced pressure. The crude acid
chloride was then dissolved in anhydrous acetonitrile (10 mL) and
cooled to 0.degree. C. under N.sub.2 atmosphere. TMSCHN.sub.2 (2 M,
0.91 mL, 1.83 mmol) was added slowly. The reaction mixture was
allowed to warm to rt and stirred for 18 h. The reaction mixture
was then cooled again to 0.degree. C. and HCl (6 M, 2 mL) was added
and stirring was continued for additional 3 h. The reaction mixture
was then neutralized with 1.0 M NaOH solution and extracted with
ethyl acetate (3.times.15 mL). The combined organic phase was
washed with brine (2.times.20 mL), dried over sodium sulfate and
evaporated in vacuum to give the crude product which was purified
by column chromatography on silica gel (petroleum ether/EtOAc=2/1)
to give the title compound as yellow solid (300 mg, 69% yield).
ESI-MS m/z 470.1 [M+H].sup.+.
Step 2
(S)-3,5-bis(trifluoromethyl)benzyl
2-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)acetyl)-6,7-dihydropyrazolo[1,5-a]-
pyrazine-5(4H)-carboxylate
##STR00312##
[1131] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-(2-chloroacetyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
(100 mg, 0.21 mmol) and (S)-pyrrolidin-2-ylmethanol (24 mg, 0.23
mmol) in DCM (3 mL) was added DIPEA (55 mg, 0.42 mmol, 2.0 eq). The
reaction mixture was stirred at rt for 16 h. Then the mixture was
concentrated and the residue was purified by column chromatography
on silica gel (petroleum ether/EtOAc=1:2) to give the title
compound as a yellow solid (70 mg, 60% yield). ESI-MS 535.2
[M+H].sup.+.
Step 3
3,5-bis(trifluoromethyl)benzyl
2((8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)-6,7-dihydropyrazolo[-
1,5-a]pyrazine-5(4H)-carboxylate
##STR00313##
[1133] To a solution of (S)-3,5-bis(trifluoromethyl)benzyl
2-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)acetyl)-6,7-dihydropyrazolo[1,5-a]-
pyrazine-5 (4H)-carboxylate
(70 mg, 0.13 mmol, 1.0 eq) in DCM (2 mL) was added triethylsilane
(46 mg, 0.39 mmol, 3.0 eq) and TFA (445 mg, 3.90 mmol, 30.0 eq).
The reaction mixture was stirred at 40.degree. C. for 16 h. After
cooling to rt, the mixture was concentrated and the residue was
purified by reversed phase HPLC (0.05% TFA/H.sub.2O:
CH.sub.3CN=65%: 35%) to give the title compound (50 mg, 74% yield)
as a yellow solid: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.03
(s, 2H), 7.96 (s, 1H), 6.27-6.25 (m, 1H), 5.35 (s, 2H), 4.80-4.73
(m, 3H), 4.18-4.12 (m, 3H), 4.14-4.08 (m, 2H), 3.90-3.48 (m, 5H),
3.28-3.25 (m, 1H), 2.38-2.25 (m, 4H); ESI-MS m/z 519.2
[M+H].sup.+.
Example 256
3,5-bis(trifluoromethyl)benzyl
2-((8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)-6,7-dihydropyrazolo-
[1,5-a]pyrazine-5(4H)-carboxylate
##STR00314##
[1135] Using (R)-pyrrolidin-2-ylmethanol and
3,5-bis(trifluoromethyl)benzyl
2-(2-chloroacetyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
as starting material and following the same condition as in Example
255, the title compound was obtained as a yellow solid (16 mg, 23%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.02 (s, 2H),
7.95 (s, 1H), 6.26-6.24 (m, 1H), 5.34 (s, 2H), 4.89-4.73 (m, 3H),
4.18-4.15 (m, 3H), 4.05-3.95 (m, 2H), 3.75-3.36 (m, 5H), 3.27-3.24
(m, 1H), 2.32-2.23 (m, 4H); ESI-MS m/z 519.1 [M+H].sup.+.
Example 257
3-chloro-5-(trifluoromethyl)benzyl
2-(2-(3-methylmorpholino)acetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaze-
pine-5(6H)-carboxylate
##STR00315##
[1137] To a solution of
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro--
4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (50 mg, 0.1
mmol) in acetonitrile (3 mL) were added 3-methylmorpholine (20 mg,
0.2 mmol) and TEA (23 mg, 0.22 mmol). The mixture was stirred at
50.degree. C. for 3 h. After cooling to rt, the mixture was
purified by reversed phase HPLC (MeCN and H.sub.2O with 0.05% TFA
as mobile phase) to give the title compound as a white solid (33
mg, 55% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.66-7.64 (m, 1H), 7.55-7.51 (m, 2H), 6.84-6.80 (m, 1H), 5.18-5.15
(m, 2H), 4.82-4.59 (m, 5H), 4.03-4.00 (m, 2H), 3.91-3.88 (m, 2H),
3.68-3.59 (m, 2H), 3.35 (s, 4H), 1.96-1.90 (m, 2H), 1.34 (br, 3H);
ESI-MS m/z 515.1 [M+H].sup.+.
[1138] The following compounds were synthesized using the same
conditions as in Example 257
TABLE-US-00003 ESI- MS Example Structure [M+H].sup.+ 1H-NMR 258
##STR00316## 517.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.31
(s, 2H), 7.96 (s, 1H), 6.74 (s, 1H), 5.35 (s, 2H), 4.86-4.80 (m,
4H), 4.30-4.28 (m, 2H), 4.05-4.03 (m, 2H), 3.89- 3.86 (m, 2H),
3.49-3.46 (m, 2H), 1.92-1.89 (m, 2H), 0.93-0.90 (m, 1H), 0.72- 0.70
(m, 1H); 259 ##STR00317## 521.2 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.93 (s, 2H), 7.85 (s, 1H), 6.66 (s, 1H), 5.25 (s, 2H),
4.75-4.70 (m, 4H), 4.20-4.18 (m, 2H), 3.98-3.90 (m, 6H), 3.45- 3.25
(m, 4H); 260 ##STR00318## 549.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 8.04 (s, 2H), 7.97 (s, 1H), 6.79 (s, 1H), 5.36 (s, 2H),
4.86-4.73 (m, 4H), 4.33-4.31 (m, 2H), 4.04-3.78 (m, 6H), 3.50- 3.48
(m, 2H), 1.56 (s, 3H), 1.40 (s, 3H); 261 ##STR00319## 529.2 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.65-7.51 (m, 3H), 6.86-6.84 (m,
1H), 5.19-5.16 (m, 2H), 4.98- 4.90 (m, 2H), 4.86-4.62 (m, 5H),
4.01-3.86 (m, 4H), 3.73-3.67 (m, 3H), 1.97- 1.94 (m, 2H), 1.17 (d,
J = 6.8 Hz, 6H); 262 ##STR00320## 499.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.66-7.51 (m, 3H), 6.84-6.79 (m, 1H),
5.18-5.16 (m, 2H), 4.95- 4.58 (m, 6H), 4.08-3.59 (m, 4H), 3.23-3.16
(m, 1H), 2.38-2.31 (m, 1H), 2.18- 2.08 (m, 2H), 1.95-1.93 (m, 2H),
1.82-1.74 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H); 263 ##STR00321## 497.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.51 (m, 3H),
6.82-6.77 (m, 1H), 5.18-5.16 (m, 2H), 4.87- 4.57 (m, 6H), 3.89-3.85
(m, 4H), 3.47-3.45 (m, 2H), 2.00-1.92 (m, 4H), , 0.96- 0.69 (m,
2H); 264 ##STR00322## 501.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.66-7.51 (m, 3H), 6.83-6.78 (m, 1H), 5.18-5.16 (m, 2H),
4.97- 4.90 (m, 2H), 4.71-4.59 (m, 5H), 3.96-3.72 (m, 4H), 3.47-3.42
(m, 1H), 3.25- 3.20 (m, 1H), 2.40-1.94 (m, 4H); 265 ##STR00323##
499.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.50 (m, 3H),
6.84-6.79 (m, 1H), 5.18-5.16 (m, 2H), 4.86- 4.58 (m, 6H), 3.98-3.59
(m, 4H), 3.29-3.16 (m, 1H), 2.39-2.02 (m, 3H), 1.94- 1.59 (m, 3H),
1.39 (d, J = 6.4 Hz, 3H); 266 ##STR00324## 529.3 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 7.67-7.56 (m, 3H), 6.39-6.26 (m, 1H),
5.18-5.16 (m, 2H), 4.84- 4.43 (m, 5H), 4.12-3.30 (m, 8H), 3.10-3.04
(m, 1H), 1.99-1.65 (m, 8H); 267 ##STR00325## 529.2 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.: 7.66-7.53 (m, 3H), 6.86-6.81 (m, 1H),
5.18-5.17 (m, 2H), 4.86- 4.60 (m, 6H), 4.01-3.77 (m, 6H),
3.50-3.3.45 (m, 2H), 1.96-1.92 (m, 2H), 1.55 (s, 3H), 1.35 (s, 3H);
268 ##STR00326## 515.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.66-7.51 (m, 3H), 6.85-6.80 (m, 1H), 5.18-5.16 (m, 2H), 4.82- 4.60
(m, 6H), 4.10-3.84 (m, 5H), 3.54-3.51 (m, 2H), 3.16-2.93 (m, 2H),
1.95- 1.90 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H); 269 ##STR00327##
529.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.50 (m, 3H),
6.85-6.80 (m, 1H), 5.20-5.18 (m, 2H), 4.79- 4.59 (m, 6H), 3.99-3.85
(m, 4H), 3.51-3.49 (m, 2H), 2.85-2.81 (m, 2H), 1.95- 1.90 (m, 2H),
1.24 (d, J = 6.4 Hz, 6H) 270 ##STR00328## 500.1 .sup.1H NMR (400
MHz, DMSO-d.sub.6) d ppm 7.89-7.55 (m, 3 H), 6.88-6.75 (m, 1 H),
5.22-5.08 (m, 2 H), 4.85-4.51(m, 6 H), 3.88- 3.71 (m, 2 H), 3.43
(m, 2 H), 3.04 (br. s., 2 H), 1.94- 1.64 (m, 8 H) 271 ##STR00329##
501.4 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) d ppm 7.71-7.48 (m,
3H), 6.90- 6.76 (m, 1H), 5.18 (d, J = 8.28 Hz, 2H), 4.85 (m, 4H),
4.78-4.55 (m, 4H), 3.98- 3.81(m, 2H), 3.38 (m., 6H), 1.96 (br. s.,
2H) 272 ##STR00330## 515.2 .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
d ppm 7.72-7.48 (m, 3 H), 6.90- 6.74 (m, 1 H), 5.18 (d, J = 8.03
Hz, 2 H), 4.85 (m, 4H), 4.55-4.77 (m, 4 H), 3.79-3.96 (m, 2 H),
3.32 (m, 3H), 1.96 (br. s., 2 H) 273 ##STR00331## 485.5 .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) d ppm 7.71-7.47(m, 3 H), 6.89- 6.74(m,
1 H), 5.24-5.12(m, 2 H), 4.78-4.53(m, 4 H), 3.97-3.72 (m, 4 H),
3.25- 3.10(m, 2 H), 2.28-1.88(m, 6 H)
Example 274
3-chloro-5-(trifluoromethyl)benzyl
2-(piperidin-4-ylamino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxyl-
ate
##STR00332##
[1140] A mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (190
mg, 0.5 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (150 mg,
0.75 mmol) and Ti(OEt).sub.4 (290 mg, 1.0 mmol) in THF (3 mL) was
heated at 100.degree. C. for 2 h under microwave condition. The
mixture was cooled down and NaBH.sub.3CN (67 mg, 1.0 mmol) was
added. The reaction was heated at 100.degree. C. for 1 h and
diluted with water (50 mL). The mixture was extracted with EtOAc
(50 mL.times.2). The combined organic layer was concentrated and
the residue was purified by prep. TLC on silica gel (petroleum
ether/EtOAc=1:1) to give the Boc-protected intermediate as a yellow
solid (120 mg, 40% yield): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.59 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 5.40 (s, 1H),
5.19 (s, 2H), 4.68-4.64 (m, 2H), 4.01-3.94 (m, 5H), 3.51-3.39 (m,
4H), 2.93-2.88 (m, 2H), 2.04-2.00 (m, 2H), 1.46 (s, 9H); ESI-MS m/z
558.2 [M+H].
[1141] To a solution of the above intermediate (120 mg, 0.2 mmol)
in dioxane (2 mL) was added conc. HCl (1 mL). The reaction mixture
was stirred at rt for 3 h and concentrated.
[1142] The residue was purified by reversed phase HPLC (MeCN and
H.sub.2O with 0.05% TFA as mobile phase) to give the title compound
as a yellow solid (62 mg, 50% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.73 (s, 1H), 7.71-7.69 (m, 2H), 5.25 (s, 2H),
4.91 (s, 1H), 4.74-4.69 (m, 2H), 4.04-4.00 (m, 4H), 3.60-3.55 (m,
1H), 3.47-3.43 (m, 2H), 3.15-3.08 (m, 2H), 2.25-2.21 (m, 2H),
1.78-1.68 (m, 2H); ESI-MS m/z 458.2 [M+H].
Example 275
2-(3-chloro-5-(trifluoromethyl)benzyl) 8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate
##STR00333##
[1144] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol
(305 mg, 1.5 mmol), CDI (243 mg, 1.5 mmol) in DMF (5 mL) was
stirred at rt for 2 h, followed by adding DMAP (122 mg, 1.0 mmol),
TEA (202 mg, 2.0 mmol) and ethyl
2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate
(305 mg, 1.0 mmol). The mixture was stirred at rt for 16 h,
quenched with brine (10 mL), and extracted with EtOAc (3.times.20
mL). The combined organic phase was washed with brine (2.times.15
mL), dried over sodium sulfate and evaporated in vacuum to give a
crude product which was purified by prep-TLC (petroleum ether/ethyl
acetate=3/1) to give the title compound as a white solid. (354 mg,
66% yield); ESI-MS m/z 445.1 [M+H].
Example 276
2-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylic acid
##STR00334##
[1146] To a mixture of 2-(3-chloro-5-(trifluoromethyl)benzyl)
8-ethyl
4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxylate
(222 mg, 0.5 mmol) in EtOH (10 mL) and water (2 mL) was added NaOH
(160 mg, 4.0 mmol). Then the mixture was stirred at 80.degree. C.
for 8 h and was adjusted to pH=4 with HCl (1 N). The solid was
collected and was washed with water (5 mL), dried in vacuum to give
the title compound as white solid (150 mg, 72% yield).
Example 277
3-chloro-5-(trifluoromethyl)benzyl
8-(4-methylpiperazine-1-carbonyl)-4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diaze-
pine-2(3H)-carboxylate
##STR00335##
[1148] To a solution of
2-4(3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylic acid (100 mg, 0.24
mmol) in DMF (3 mL) were added 1-methylpiperazine (48 mg, 0.48
mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). The
mixture was stirred at rt for 3 h, quenched with brine (15 mL), and
extracted with ethyl acetate (3.times.30 mL). The combined organic
phase was washed with brine (2.times.10 mL), dried over sodium
sulfate and evaporated in vacuum to give the crude product which
was purified by prep-HPLC (ACN/H.sub.2O with 0.05% TFA as mobile
phase; from 5% to 95%) to yield the title compound as white solid
(41 mg, 34% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.65-7.58 (m, 3H), 7.11-7.09 (m, 1H), 6.26, 6.21 (s, s, 1H), 5.18,
5.13 (s, s, 2H), 4.55-4.48 (m, 2H), 4.23-4.21 (m, 2H), 3.75-3.73
(m, 6H), 2.47-2.43 (m, 4H), 2.33, 2.32 (s, s, 3H), 1.87 (bs, 2H);
ESI-MS m/z 499.0 [M+H].
Example 278
3-chloro-5-(trifluoromethyl)benzyl
8-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-4,5-dihydro-1H-pyrr-
olo[1,2-a][1,4]diazepine-2(3H)-carboxylate
##STR00336##
[1150] Following the same condition as in Example 277, the titled
compound was obtained as a white solid (36 mg, 29% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.: 7.65-7.59 (m, 3H), 7.11-7.09 (m,
1H), 6.27, 6.21 (s, s, 1H), 5.18, 5.13 (s, s, 2H), 4.54-4.48 (m,
2H), 4.35-4.21 (m, 4H), 3.81-3.67 (m, 2H), 3.49-3.37 (m, 1H),
3.20-2.96 (m, 3H), 2.32, 2.31 (s, s, 3H), 2.05-1.97 (m, 2H),
1.94-1.82 (m, 2H), 1.74-1.44 (m, 2H); ESI-MS m/z 525.1 [M+H].
Example 279
3,5-Bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
Step 1
3,5-Bis(trifluoromethyl)benzyl
2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepi-
ne-5(6H)-carboxylate
##STR00337##
[1152] To a solution of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (15.0 g, 33 mmol) in
t-BuOH (60 mL)/dry toluene (60 mL) were added triethylamine (6.6 g,
66 mmol) and DPPA (11 g, 39.6 mmol). The reaction mixture was
stirred at RT for 16 h and then heated at refluxed for 8 h. The
mixture was cooled down, concentrated, diluted with water (80 mL)
and extracted with ethyl acetate. The organic layer was separated,
dried, and concentrated. The crude was purified by column
chromatography on silica gel (PE/EA 2:1-1/1) to give the title
compound as a yellow solid (7.75 g, 45% yield); ESI-MS m/z 523.1
[M+H].sup.+.
Step 2
3,5-Bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00338##
[1154] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepi-
ne-5(6H)-carboxylate (5.9 g, 11.3 mmol) in dioxane (20 mL) were
added conc. HCl (6 mL). The mixture was stirred at RT for 8 h. The
reaction mixture was then diluted with water (30 mL). The mixture
was extracted with ethyl acetate/petroleum ether (50 mL.times.2,
20:1). The aqueous phase was adjusted to pH=8 and extracted with
ethyl acetate (100 mL.times.2). The combined organics was dried and
concentrated to give the title compound as a white solid (4.54 g,
95% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 8.06-2.03 (m,
3H), 5.35-5.31 (m, 1H), 5.23 (s, 2H), 4.45-4.37 (m, 4H), 4.09-4.08
(m, 2H), 3.70-3.65 (m, 2H), 1.73-1.72 (m, 2H); ESI-MS m/z 423.0
[M+H].sup.+.
Example 280
3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00339##
[1156] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(5.0 g, 11.8 mmol, 1.0 eq) in CH.sub.3CN (25 mL) was added TsOH
(2.45 g, 14.2 mmol) and CuBr.sub.2 (26 mg, 0.12 mmol). The reaction
mixture was cooled to 0.degree. C., tert-Butyl nitrite (1.82 g,
17.7 mmol) and TBAB (7.6 g, 23.6 mmol) were then added. The
reaction mixture was stirred at RT for 1 h. After concentrated, the
residue was purified by silica gel column (PE/EA=2/1) to give the
title compound as a white solid (3.21 g, 59% yield). .sup.1H NMR
(400 MHz, DMSO-d6) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.32-6.20
(m, 1H), 5.25 (s, 2H), 4.60-4.53 (m, 2H), 4.40-4.37 (m, 2H),
3.75-3.70 (m, 2H), 1.82-1.77 (m, 2H); ESI-MS m/z 485.9
[M+H].sup.+.
Example 282
3,5-bis(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate
##STR00340##
[1158] Methanol (76 uL, 1.87 mmol) was added to a mixture of 2.0 M
of lithium tetrahydroborate in tetrahydrofuran (1 mL) in
tetrahydrofuran (4.8 mL, 59 mmol) at RT.
5-(3,5-bis(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(0.6 g, 1.2 mmol) was then added. The mixture was then stirred at
RT for 4 h. The reaction was queched with 1N HCl to pH=1, stirred
at RT for 1 h. Solid K.sub.2CO.sub.3 was then added to adjust the
pH to 8. The mixture was extracted with ethyl acetate. The organic
layer was then separated, dried and concentrated. The crude was
purified by HPLC to give the title compound as a light yellow oil
(536 mg) which was used in the next step without further
purifications. ESI-MS m/z 438.1 [M+H].sup.+.
Example 283
3,5-bis(trifluoromethyl)benzyl
2-(bromomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbox-
ylate
##STR00341##
[1160] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate, 3,5-bis-trifluoromethyl-benzyl ester (0.53 g, 1.2 mmol) in
tetrahydrofuran (10 mL) under nitrogen was dropwise added 1 M of
phosphorus tribromide in methylene chloride (2.4 mL, 2.42 mmol) at
0.degree. C. The reaction mixture was stirred at RT for 30 min. The
reaction mixture was quenched with water, washed with water. The
organic phase was separated, dried, filtered and concentrated to
give the title compound as a light yellow oil (0.66 g) which was
immediately in next step without further purifications.
Example 284
3,5-bis(trifluoromethyl)benzyl
2-(aminomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbox-
ylate
##STR00342##
[1162] To a stirred solution of 2,4,6-Trimethoxybenzylamine
hydrochloride (117 mg, 0.50 mmol) in N,N-dimethylformamide (2.0 mL)
was added N,N-diisopropylethylamine (87 uL, 0.50 mmol). The mixture
was stirred at RT for 10 min. Potassium carbonate (28 mg, 0.20
mmol) was then added. The mixture was stirred at RT for 20 min. A
solution of 3,5-bis(trifluoromethyl)benzyl
2-(bromomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbox-
ylate (50 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was then
added. The reaction mixture was then stirred at RT overnight.
Diluted with ethyl acetate, washed with water (3.times.). The
organic phase was dried, and concentrated. The crude was stirred in
a solution of methylene chloride (5 mL) and trifluoroacetic acid
(0.1 mL, 1 mmol) at RT overnight. The reaction was then neutralized
with 3N NaOH, the organic phase was dried and concentrated. The
crude was then purified by HPLC to give the title compound as a
white powder (15 mg): .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.85-8.01 (m, 3H), 6.19-6.38 (m, 1H), 5.25 (d, J=2.76 Hz, 2H),
4.56-4.70 (m, 2H), 4.39-4.52 (m, 2H), 4.02 (s, 2H), 3.74-3.95 (m,
2H), 1.81-1.96 (m, 2H); ESI-MS m/z 437.1 [M+H].sup.+.
Example 285
3,5-bis(trifluoromethyl)benzyl
2-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate
##STR00343##
[1164] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate 3,5-bis-trifluoromethyl-benzyl ester (90 mg, 0.21 mmol) and
methyl iodide (64 uL, 1.03 mmol) in N,N-dimethylformamide (2.0 mL)
was added sodium hydride (10 mg, 0.25 mmol). The mixture was then
stirred at RT for 2 h. The mixture was extracted with ethyl
acetate. The organic layer was then separated, dried and
concentrated. The crude was purified by HPLC to give the title
compound as a light yellow oil (38 mg). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.85 (s, 1H), 7.77 (d, J=5.77 Hz, 2H),
6.14-6.39 (m, 1H), 5.21 (s, 2H), 4.39-4.63 (m, 6H), 3.78-3.88 (m,
2H), 3.41 (s, 3H), 2.02 (br. s., 2H); ESI-MS m/z 452.1
[M+H].sup.+.
Example 286
3-chloro-5-(trifluoromethyl)benzyl
2-(2,2,2-trifluoro-1-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate
##STR00344##
[1166] To a solution of 3-chloro-5-(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo-[1,5-a][1,4]diazepine-5(6H)-carboxylate
(175 mg, 0.44 mmol) in THF (5 mL) were added
(trifluoromethyl)trimethylsilane (125 mg, 0.88 mmol) and
tetrabutylamonium fluoride (44 uL, 1 N in THF, 0.044 mmol) at RT
under nitrogen atmosphere and the resulting mixture was stirred for
16 h. A solution of HCl (6N, 1 mL) was added and the reaction
mixture was stirred for another hour, diluted with water (10 mL),
extracted with ethyl acetate (3.times.20 mL). The combined organic
phase was washed with brine (10 mL), dried over sodium sulfate and
concentrated. The crude product was purified by HPLC (ACN/H.sub.2O
with 0.05% NH.sub.3H.sub.2O as mobile phase) to give the title
compound as a white solid (70 mg, 34% yield): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.64-7.58 (m, 3H), 6.37, 6.30 (s, s, 1H),
5.16-5.15 (m, 2H), 4.50-4.93 (m, 1H), 4.64-4.57 (m, 2H), 4.45 (t,
J=5.2 Hz, 2H), 3.90-3.81 (m, 2H), 1.91 (s, 2H); ESI-MS m/z 472.0
[M+H].sup.+.
Example 287
3-(((5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-hydro-
-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)amino)-2,2-dimethylcyclo-buta-
necarboxylic acid
##STR00345##
[1168] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(160 mg, 0.37 mmol) and 3-Amino-2,2-dimethyl-cyclobutanecarboxylic
acid (105 mg, 0.74 mmol) in methanol (2 mL) was heated in microwave
at 100.degree. C. for 10 min, 1.0 M of sodium cyanoborohydride in
tetrahydrofuran (0.74 mL, 0.74 mmol) was then added. The reaction
was stirred ar RT for 16 h. The reaction was quenched with water,
worked up with ethyl acetate and brine. Dried over MgSO4 and
concentrated. The crude was purified by HPLC to give the title
compound as a white powder (161 mg, TFA salt): .sup.1H NMR (400
MHz, METHANOL-d4) .delta. 7.93 (br. s., 3H), 6.26-6.42 (m, 1H),
5.25 (d, J=6.27 Hz, 2H), 4.56-4.72 (m, 2H), 4.43-4.53 (m, 2H), 4.07
(t, J=6.27 Hz, 2H), 3.77-3.95 (m, 2H), 3.44-3.57 (m, 1H), 2.73 (t,
J=9.04 Hz, 1H), 2.25 (t, J=8.91 Hz, 2H), 1.90 (br. s., 2H), 1.31
(s, 3H), 1.17 (s, 3H); ESI-MS m/z 563.2 [M+H].sup.+.
[1169] The following compounds were synthesized using the same
conditions as in Example 287
TABLE-US-00004 ESI- MS Example Structure (M+H)+ H-NMR 288
##STR00346## 563.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.85-7.99 (m, 3H), 6.22-6.40 (m, 1H), 5.25 (br. s., 2H), 4.55- 4.72
(m, 2H), 4.41- 4.52 (m, 2H), 4.12 (d, J = 4.02 Hz, 2H), 3.76- 3.96
(m, 2H), 3.15 (d, J = 9.79 Hz, 1H), 2.67 (d, J = 6.27 Hz, 1H), 2.21
(br. s., 2H), 1.81-2.09 (m, 4H), 1.54-1.72 (m, 4H) 289 ##STR00347##
563.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.83-8.00 (m, 3H),
6.26-6.42 (m, 1H), 5.25 (d, J = 3.01 Hz, 2H), 4.57-4.73 (m, 2H),
4.41-4.54 (m, 2H), 4.14 (d, J = 3.26 Hz, 2H), 3.76-3.95 (m, 2H),
3.13 (d, J = 3.76 Hz, 1H), 2.05-2.41 (m, 5H), 1.82-1.98 (m, 2H),
1.35-1.60 (m, 4H)
Example 290
3,5-bis(trifluoromethyl)benzyl
2-((4-methylpiperazin-1-yl)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate
##STR00348##
[1171] To a stirred solution of piperazine, 1-methyl-(50 mg, 0.50
mmol) in N,N-dimethylformamide (2.0 mL) was added potassium
carbonate (28 mg, 0.20 mmol). The mixture was stirred at rt for 10
min. A solution of 3,5-bis(trifluoromethyl)benzyl
2-(bromomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbox-
ylate (50 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was then
added. The reaction mixture was then stirred at RT for 16 h.
Diluted with ethyl acetate, washed with water (3.times.). The
organic phase was dried, and concentrated. The crude was purified
by HPLC to give the title compound (7 mg). .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.85-8.00 (m, 3H), 6.14-6.32 (m, 1H), 5.26 (s,
2H), 4.54-4.68 (m, 2H), 4.37-4.48 (m, 2H), 3.77-3.96 (m, 2H),
3.63-3.75 (m, 2H), 3.26 (td, J=1.63, 3.26 Hz, 4H), 2.67-3.04 (m,
7H), 1.83-1.96 (m, 2H); ESI-MS m/z 520.2 [M+H].sup.+.
[1172] The following compounds were synthesized using the same
conditions as in Examples 290
TABLE-US-00005 ESI- MS Example Structure (M+H)+ H-NMR 291
##STR00349## 505.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.82-
7.97 (m, 3H), 6.29-6.45 (m, 1H), 5.26 (s, 2H), 4.55- 4.73 (m, 2H),
4.43-4.54 (m, 2H), 4.17 (d, J = 5.52 Hz, 2H), 3.77-3.99 (m, 2H),
3.50 (d, J = 11.80 Hz, 2H), 2.83-3.03 (m, 2H), 1.60-2.04 (m, 7H),
1.39- 1.57 (m, 1H) 292 ##STR00350## 531.2 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.88- 8.01 (m, 3H), 6.31-6.49 (m, 1H), 5 28
(s, 2H), 4 57- 4.75 (m, 2H), 4.44-4.56 (m, 2H), 3.75-4.15 (m, 6H),
2.36 (br. s., 2H), 2.07 (d, J = 8.78 Hz, 2H), 1.52- 1.99 (m, 8H)
293 ##STR00351## 545.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.93 (br. s., 3H), 6.31-6.46 (m, 1H), 5.26 (s, 2H), 4.56- 4.72 (m,
2H), 4.35-4.53 (m, 4H), 3.72-3.96 (m, 2H), 3.54 (br. s., 2H), 2.32-
2.54 (m, 2H), 1.98-2.26 (m, 6H), 1.65-1.97 (m, 6H) 294 ##STR00352##
451 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.85- 7.98 (m, 3H),
6.21-6.38 (m, 1H), 5.26 (br. s., 2H), 4.56-4.73 (m, 2H), 4.42- 4.53
(m, 2H), 4.03-4.27 (m, 2H), 3.71-3.96 (m, 2H), 2.62-2.75 (m, 3H),
1.83-1.98 (m, 2H) 295 ##STR00353## 465.2 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.82- 8.00 (m, 3H), 6.29-6.44 (m, 1H), 5.26
(br. s., 2H), 4.57-4.74 (m, 2H), 4.45- 4.55 (m, 2H), 4.21 (d, J =
3.26 Hz, 2H), 3.77-3.96 (m, 2H), 2.85 (s, 6H), 1.84- 2.00 (m, 2H)
296 ##STR00354## 575.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.88- 8.01 (m, 3H), 6.31-6.44 (m, 1H), 5.26 (s, 2H), 4.56- 4.74 (m,
2H), 4.49 (d, J = 4.77 Hz, 2H), 4.09 (d, J = 5.27 Hz, 3H),
3.79-3.94 (m, 2H), 3.26 (dd, J = 1.63, 3.39 Hz, 2H), 2.89-3.04 (m,
1H), 2.38 (br. s., 2H), 1.81-2.19 (m, 7H) 297 ##STR00355## 589.2
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.93 (br. s., 3H),
6.30-6.47 (m, 1H), 5.26 (s, 2H), 4.55- 4.73 (m, 2H), 4.34-4.54 (m,
4H), 3.77-3.98 (m, 2H), 3.66 (d, J = 14.56 Hz, 2H), 3.25-3.28 (m,
2H), 2.00-2.58 (m, 7H), 1.65- 1.97 (m, 4H) 511 ##STR00356## 493.2
1H NMR (400 MHz, CD3OD) .delta.: 7.93-7.91 (m, 3H), 6.23, 6.16 (s,
s, 1H), 5.27, 5.25 (s, s, 2H), 4.70- 4.63 (m, 4H), 4.42-4.36 (m,
4H), 3.98-3.94 (m, 1H), 3.87-3.80 (m, 2H), 3.62 (bs, 2H), 1.89-1.87
(m, 2H) 513 ##STR00357## 477.1 1H NMR (400 MHz, CDCl3) .delta.:
7.95-7.93 (m, 3H), 6.37, 6.31 (s, s, 1H), 5.28, 5.26 (s, s, 2H),
4.68, 4.61 (s, s, 2H), 4.51-4.48 (m, 2H), 4.23-4.22 (m, 2H),
3.92-3.83 (m, 2H), 2.81-2.79 (m, 1H), 1.92- 1.90 (m, 2H), 0.92-0.85
(m, 4H) 510 ##STR00358## 523.2 1H NMR (400 MHz, CDCl3) .delta.:
7.94-7.90 (m, 3H), 6.42, 6.37 (s, s, 1H), 5.27 (s, 2H), 4.69-4.62
(m, 2H), 4.52-4.50 (m, 2H), 4.26-4.25 (m, 2H), 3.91- 3.84 (m, 2H),
3.61-3.46 (m, 2H), 3.35-3.32 (m, 1H), 3.30-3.09 (m, 2H), 2.33-2.22
(m, 2H), 2.10- 1.92 (m, 4H)
Example 298
3,5-bis(trifluoromethyl)benzyl
2-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-5(6H)-carboxylate
##STR00359##
[1174] To a solution of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (110 mg, 0.24 mmol)
in N,N-dimethylformamide (3.3 mL, 43 mmol) was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (158 mg, 0.41 mmol) and
N,N-diisopropylethylamine (0.13 mL, 0.73 mmol). Stirred at RT for
10 min, 1-piperazineethanol (63 mg, 0.49 mmol) was then added. The
reaction was stirred at RT for 2 h. Diluted with ethyl acetate,
washed with water (3.times.). The organic phase was then dried and
concentrated. The crude was purified by HPLC to give the title
compound as a white powder (114 mg). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.92-7.92 (m, OH), 7.91-8.10 (m, 3H), 6.55 (d, J=17.57 Hz,
1H), 5.23 (br. s., 2H), 4.37-4.77 (m, 6H), 3.65-3.88 (m, 4H), 3.55
(br. s., 3H), 2.96-3.29 (m, 5H), 1.72-1.93 (m, 2H); ESI-MS m/z
564.2 [M+H].sup.+.
Example 299
3,5-bis(trifluoromethyl)benzyl
2-((methylsulfonyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5(6H)-carboxylate
##STR00360##
[1176] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate (151 mg, 0.32 mmol) in dichloromethane (5 mL) was added
methanesulfonamide (61 mg, 0.64 mmol), diisopropylethylamine (83
mg, 0.64 mmol) and DMAP (10 mg). The mixture was stirred at RT for
5 h, and then diluted with dichloromethane (60 mL), washed with
aqueous NH.sub.4Cl (30 mL.times.2) and brine (15 mL). The organic
phase was dried over sodium sulfate and concentrated under reduced
pressure. The crude was purified by HPLC (CH.sub.3CN/H.sub.2O with
10 mM NH.sub.4HCO.sub.3 as mobile phase) to give the title compound
as a white solid (62 mg, 37% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 11.61 (s, 1H), 8.07-8.04 (m, 2H), 7.94 (s,
1H), 6.82, 6.74 (s, s, 1H), 5.25, 5.22 (s, s, 2H), 4.69, 4.59 (s,
s, 2H), 4.54-4.53 (m, 2H), 3.80-3.74 (m, 2H), 3.28 (s, 3H),
1.86-1.81 (m, 2H); ESI-MS m/z 529.1 [M+H].sup.+.
Example 300
3,5-bis(trifluoromethyl)benzyl
2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00361##
[1178] A solution of sodium nitrite (258 mg, 3.73 mmol) in water (3
mL) was added to a stirred solution of
3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]-diazepine-5(6H)-carboxylate
(1.5 g, 3.55 mmol) in acetic acid/concentrated hydrochloric
acid/water (2:1:1, 20 mL) at -10.degree. C. and stirred for 30
minutes. The solution was added to a stirred suspension of copper
sulfate (97 mg, 0.60 mmol) in acetic acid saturated with sulphur
dioxide (16 mL) at -10.degree. C. for 1 h. The mixture was allowed
to warm to RT for another hour and adjusted to PH=7 with LiOH,
diluted with ethyl acetate (60 mL), washed with water (10
mL.times.2) and brine (15 mL). The organic phase was dried over
sodium sulfate and concentrated. The crude was purified by column
chromatography (PE/EA=1/2) to give the title compound as a yellow
solid (900 mg, 50% yield); ESI-MS m/z 506.0 [M+H].sup.+.
Example 301
3,5-bis(trifluoromethyl)benzyl
2-sulfamoyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e
##STR00362##
[1180] A mixture of 3,5-bis(trifluoromethyl)benzyl
2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate (80 mg, 0.16 mmol), ammonia (1 mL, 37% in water) in THF (4
mL) was stirred at RT for 16 h. The mixture was concentrated, the
residue was purified by HPLC (CH.sub.3CN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase) to give the title compound as a
yellow solid (26 mg, 34% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 8.08 (s, 3H), 7.39-7.36 (m, 2H), 6.53, 6.46
(s, s, 1H), 5.24, 5.22 (s, s, 2H), 4.69, 4.59 (s, s, 2H), 4.49-4.48
(m, 2H), 3.79-3.74 (m, 2H), 1.86 (bs, 2H); ESI-MS m/z 487.1
[M+H].sup.+.
Example 302
3,5-bis(trifluoromethyl)benzyl
2-(N,N-dimethylsulfamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(-
6H)-carboxylate
##STR00363##
[1182] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate (80 mg, 0.16 mmol) in THF (4 mL) were added triethylamine
(32 mg, 0.32 mmol) and dimethylamine hydrochloride (26 mg, 0.32
mmol). The reaction was stirred at RT for 16 h. The reaction
mixture was then concentrated under reduced pressure. The crude was
purified by HPLC (CH.sub.3CN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3
as mobile phase) to give the title compound as a yellow solid (40
mg, 49% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.85 (s,
1H), 7.78 (s, 2H), 6.63, 6.51 (s, s, 1H), 5.22, 5.20 (s, s, 2H),
4.58, 4.54 (s, s, 2H), 4.53-4.52 (m, 2H), 3.86-3.83 (m, 2H), 2.80
(s, 6H), 2.03-2.01 (m, 2H); ESI-MS m/z 515.1 [M+H].sup.+.
[1183] The following compounds were synthesized using the same
conditions as in Example 302
TABLE-US-00006 ESI-MS Example Structure (M+H)+ H-NMR 304
##STR00364## 555.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.95-
7.93 (m, 3H), 6.60, 6.51 (s, s, 1H), 5.26 (s, 2H), 4.70, 4.63 (s,
s, 2H), 4.55- 4.53 (m, 2H), 3.90-3.84 (m, 2H), 3.05-3.02 (m, 4H),
1.96-1.95 (m, 2H), 1.61-1.60 (m, 4H), 1.45 (bs, 2H) 305
##STR00365## 581.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.99-
7.89 (m, 3H), 6.62, 6.53 (s, s, 1H), 5.28, 5.25 (s, s, 2H), 4.70,
4.61 (s, s, 2H), 4.55-4.52 (m, 2H), 4.40- 4.11 (m, 2H), 3.91-3.79
(m, 2H), 1.93-1.37 (m, 12H) 306 ##STR00366## 595.2 .sup.1H NMR (400
MHz, METHANOL-d4) .delta. 7.98- 7.94 (m, 3H), 6.62, 6.54 (s, s,
1H), 5.25 (s, 2H), 4.71, 4.63 (s, s, 2H), 4.55- 4.53 (m, 2H), 4.03
(bs, 2H), 3.91-3.84 (m, 2H), 2.08-2.02 (m, 2H), 1.93 (bs, 2H),
1.85-1.77 (m, 4H), 1.62-1.58 (m, 4H), 1.50-1.49 (m, 2H) 308
##STR00367## 570.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.97-
7.95 (m, 3H), 6.65, 6.56 (s, s, 1H), 5.27, 5.26 (s, s, 2H), 4.72,
4.65 (s, s, 2H), 4.57-4.55 (m, 2H), 3.91- 3.85 (m, 2H), 3.13-3.09
(m, 4H), 2.50-2.49 (m, 4H), 2.28 (s, 3H), 1.95 (bs, 2H)
Example 313
3,5-bis(trifluoromethyl)benzyl
2-(piperidin-4-ylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00368##
[1185] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(500 mg, 1.18 mmol) in THF (10 mL) were added tert-butyl
4-oxopiperidine-1-carboxylate (235 mg, 1.18 mmol) and Ti
(OiPr).sub.4 (1.67 g, 5.90 mmol). The mixture was stirred at
30.degree. C. for 16 h, followed by the addition of NaBH.sub.3CN
(148 mg, 2.36 mmol), and the reaction mixture was stirred at
70.degree. C. for 5 h. The mixture was diluted with ethyl acetate,
washed with water, and the organic layer was dried and
concentrated. The crude was purified by column chromatography on
silica gel (PE/EA=1/1) to give the Boc-protected intermediate as a
yellow oil (390 mg, 54% yield): ESI-MS m/z 606.1 [M+H].sup.+.
[1186] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-7,8-dihydro-4H-pyrazolo[-
1,5-a][1,4]diazepine-5(6H)-carboxylate (90 mg, 0.15 mmol) in
dichloromethane (4 mL) was added TFA (0.5 mL). The mixture was
stirred at RT for 4 h. The reaction mixture was concentrated under
reduced pressure. The crude was purified by HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase) to give the
title compound as a yellow solid (60 mg, 71% yield): .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 8.56-8.55 (m, 1H), 8.39-8.38 (m,
1H), 8.05-8.00 (m, 3H), 5.49, 5.39 (s, s, 1H), 5.22 (s, 2H),
4.49-4.40 (m, 2H), 4.13-4.07 (m, 2H), 3.71-3.65 (m, 2H), 3.40-3.37
(m, 1H), 3.25-3.22 (m, 2H), 2.93-2.92 (m, 2H), 1.99-1.97 (m, 2H),
1.74-1.73 (m, 2H), 1.56-1.49 (m, 2H); ESI-MS m/z 506.0
[M+H].sup.+.
Example 352
3,5-bis(trifluoromethyl)benzyl
2-((1-methylpiperidin-4-yl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00369##
[1188] Using 3,5-bis(trifluoromethyl)benzyl
2-(piperidin-4-ylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate as starting material and following the same condition
as in example 159, the title compound was obtained as a white
powder: .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.84-7.78 (m,
3H), 5.17 (s, 2H), 4.49-4.43 (m, 2H), 4.17-4.16 (m, 2H), 3.74-3.66
(m, 2H), 3.48-3.38 (m, 2.5H), 3.28-3.13 (m, 1H), 3.02-2.96 (m,
1.5H), 2.77 (s, 3H), 2.18-2.15 (m, 1.5H), 2.02-1.91 (m, 1H),
1.83-1.82 (m, 2H), 1.66-1.55 (m, 1.5H); ESI-MS m/z 520.1
[M+H].sup.+.
[1189] The following compounds were synthesized using the same
conditions as in Example 313:
TABLE-US-00007 ESI-MS Example Structure (M+H)+ H-NMR 314
##STR00370## 548.1 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.52-
8.49 (m, 1H), 8.23- 8.17 (m, 1H), 8.07- 8.00 (m, 3H), 5.47, 5.38
(s, s, 1H), 5.26- 5.21 (m, 2H), 4.50, 4.41 (s, s, 2H), 4.19- 4.11
(m, 2H), 3.75- 3.62 (m, 2H), 3.44- 2.91 (m, 4H), 2.15- 1.68 (m,
5H), 1.51- 1.37 (m, 1H), 1.27- 1.11 (m, 1H), 0.98- 0.81 (m, 6H) 315
##STR00371## 520.1 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.71-
8.62 (m, 1H), 8.24- 8.21 (m, 1H), 8.07- 8.01 (m, 3H), 5.44- 5.34
(m, 1H), 5.23 (s, 2H), 4.48, 4.40 (s, s, 2H), 4.14-4.12 (m, 2H),
3.72-3.66 (m, 2H), 3.27-3.05 (m, 3H), 2.99-2.87 (m, 1H), 2.11-2.05
(m, 1H), 1.88-1.84 (m, 1H), 1.74-1.56 (m, 3H), 1.40-1.30 (m, 1H),
1.22-1.17 (m, 3H) 316 ##STR00372## 546 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta.: 7.95-7.91 (m, 3H), 5.67-5.53 (m, 1H), 5.28
(s, 2H), 4.56, 4.50 (s, s, 2H), 4.30-4.19 (m, 2H), 3.89-3.70 (m,
4H), 3.69-3.56 (m, 1H), 2.59-2.34 (m, 2H), 2.22-1.96 (m, 2H),
1.95-1.66 (m, 6H), 1.65-1.44 (m, 2H) 317 ##STR00373## 506.2 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.53 (bs, 1H), 8.08-8.02 (m, 3H),
5.46, 5.38 (s, s, 1H), 5.25 (s, 2H), 4.51, 4.47 (s, s, 2H),
4.16-4.15 (m, 2H), 3.74-3.69 (m, 2H), 3.51 (bs, 1H), 3.36- 3.13 (m,
2H), 2.85- 2.74 (m, 2H), 1.92- 1.85 (m, 4H), 1.53- 1.46 (m, 2H) 318
##STR00374## 532.2 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.76-
8.44 (m, 2H), 8.10- 8.00 (m, 3H), 5.49- 5.37 (m, 1H), 5.24 (s, 2H),
4.50, 4.42 (s, s, 2H), 4.20-4.11 (m, 2H), 4.02-3.86 (m, 2H),
3.76-3.41 (m, 3H), 2.32-2.23 (m, 1H), 2.14-1.83 (m, 6H), 1.83-1.52
(m, 3H) 319 ##STR00375## 562.1 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.95-7.89 (m, 3H), 5.67, 5.60 (s, s, 1H), 5.28 (s, 2H),
4.61- 4.48 (m, 2H), 4.30- 4.22 (m, 2H), 3.89- 3.75 (m, 2H), 3.57-
3.33 (m, 2H), 3.29- 2.98 (m, 2H), 2.40- 2.06 (m, 2H), 2.00- 1.66
(m, 3H), 1.64- 1.30 (m, 1H), 1.11- 0.96 (m, 9H). 320 ##STR00376##
534.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.95-7.90 (m, 3H),
5.68, 5.60 (s, s, 1H), 5.28 (s, 2H), 4.57, 4.51 (s, s, 2H),
4.28-4.25 (m, 2H), 3.85-3.77 (m, 2H), 3.69-3.66 (m, 1H), 3.31-3.26
(m, 2H), 2.31-2.08 (m, 2H), 1.91 (bs, 2H), 1.54-1.43 (m, 8H) 322
##STR00377## 534.2 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.81-
8.46 (m, 2H), 8.08- 7.99 (m, 3H), 5.50- 5.40 (m, 1H), 5.24 (s, 2H),
4.50, 4.42 (s, s, 2H), 4.18-4.11 (m, 2H), 3.79-3.17 (m, 5H),
2.15-2.06 (m, 1H), 1.94-1.70 (m, 3H), 1.63-1.49 (m, 1H), 1.34-1.15
(m, 7H). 323 ##STR00378## 534.1 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.95-7.90 (m, 3H), 5.65, 5.57 (s, s, 1H), 5.28 (s, 2H),
4.57, 4.51 (s, s, 2H), 4.26-4.24 (m, 2H), 3.87-3.73 (m, 2H),
3.55-3.35 (m, 2H), 3.27-3.02 (m, 2H), 2.41-2.04 (m, 2H), 1.91 (bs,
2H), 1.79-1.48 (m, 3H), 1.34-1.22 (m, 1H), 1.08-0.98 (m, 3H) 326
##STR00379## 520.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.95-7.91 (m, 3H), 5.48, 5.40 (s, s, 1H), 5.32-5.24 (m, 2H),
4.56-4.49 (m, 2H), 4.27-4.24 (m, 2H), 3.99-3.84 (m, 3H), 3.37-3.17
(m, 4H), 2.06-1.70 (m, 8H).
Example 328
3,5-bis(trifluoromethyl)benzyl
2-(2-oxopiperidin-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
Step 1
3,5-bis(trifluoromethyl)benzyl
2-(5-bromopentanamido)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate
##STR00380##
[1191] A mixture of 3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(200 mg, 0.47 mmol), 5-bromopentanoyl chloride (279 mg, 1.41 mmol)
and DIEA (182 mg, 1.41 mmol) in THF (3 mL) was stirred at RT for 16
h. Then the mixture was diluted with ethyl acetate (15 mL), washed
with water (2.times.) and brine. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The residue
was concentrated to give the title compound as a brown oil (220 mg,
Y: 79%) which was used in next step without further purification.
ESI-MS m/z 585.1 [M+H].sup.+.
Step 2
3,5-bis(trifluoromethyl)benzyl
2-(2-oxopiperidin-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00381##
[1193] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(5-bromopentanamido)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate (220 mg, 0.38 mmol) in dry THF (5 mL) was added sodium
hydride (46 mg, 60%, 1.14 mmol) at 0.degree. C. The mixture was
stirred at RT for 4 h. Cooled to 0.degree. C., the reaction was
quenched with methanol (5 mL). The reaction mixture was then
concentrated under reduced pressure. The crude was purified by HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase) to give the
title compound as a white solid (68 mg, 35% yield): .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.95-7.85 (m, 3H), 6.57-6.50 (m,
1H), 5.28, 5.26 (s, s, 2H), 4.62, 4.57 (s, s, 2H), 4.39 (t, J=5.2
Hz, 2H), 3.93-3.74 (m, 4H), 2.51 (t, J=6.4 Hz, 2H), 1.99-1.82 (m,
6H); ESI-MS m/z 505.0 [M+H].sup.+.
Example 337
3,5-bis(trifluoromethyl)benzyl
2-acetamido-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylat-
e
##STR00382##
[1195] Using 3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
and acetyl chloride as stating material and following the same
condition as in example 328, step 1, the title compound was
prepared as a white solid: .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.95-7.84 (m, 3H), 6.48, 6.45 (s, s, 1H), 5.28, 5.26 (s, s,
2H), 4.60, 4.55 (s, s, 2H), 4.36-4.30 (m, 2H), 3.88-3.76 (m, 2H),
2.08 (s, 3H), 1.88-1.85 (m, 2H).; ESI-MS m/z 465.1 [M+H].sup.+.
Example 338
Synthesis of 3,5-bis(trifluoromethyl)benzyl
2-(4-methylpiperazin-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate
##STR00383##
[1197] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(280 mg, 0.78 mmol), 1-methylpiperazine (312 mg, 3.12 mmol) and
t-BuONa (83 mg, 0.86 mmol) in THF (4 mL) were added
Pd.sub.2(dba).sub.3 (71 mg, 0.078 mmol) and
2-(di-tert-butyl-phosphino)biphenyl (93 mg, 0.3 mmol) under
nitrogen atmosphere. The reaction mixture was heated in microwave
at 80.degree. C. for 3 h. After cooled to RT, the reaction mixture
was filtered, concentrated and purified by HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase) to give the
title compound as a white solid (50 mg, 16% yield): .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.95-7.92 (m, 3H), 5.75, 5.64 (s, s,
1H), 5.26 (s, 2H), 4.55, 4.50 (s, s, 2H), 4.25 (t, J=5.2 Hz, 2H),
3.82-3.75 (m, 2H), 3.14-3.11 (m, 4H), 2.54 (bs, 4H), 2.32 (s, 3H),
1.89-1.85 (m, 2H); ESI-MS m/z 506.0 [M+H].sup.+.
[1198] The following compounds were synthesized using the same
conditions as in Example 338
TABLE-US-00008 ESI-MS Example Structure (M+H)+ H-NMR 339
##STR00384## 492 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.94-7.91 (m, 3H), 5.82, 5.74 (s, s, 1H), 5.27 (s, 2H), 4.58, 4.52
(s, s, 2H), 4.29 (t, J = 5.2 Hz, 2H), 3.87-3.76 (m, 2H), 3.40-3.34
(m, 4H), 3.31- 3.27 (m, 4H), 1.92-1.84 (m, 2H). 340 ##STR00385##
520.1 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.09-7.96 (m, 3H),
5.76, 5.65 (s, s, 1H), 5.24, 5.22 (s, s, 2H), 4.52, 4.44 (s, s,
2H), 4.24-4.16 (m, 2H), 3.77-3.65 (m, 2H), 3.26- 3.13 (m, 4H),
3.04, 2.99 (s, s, 2H), 1.81-1.70 (m, 2H), 1.36-1.29 (m, 6H). 341
##STR00386## 520 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.98-7.90 (m, 3H), 5.83, 5.75 (s, s, 1H), 5.28 (s, 2H), 4.58, 4.52
(s, s, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.89-3.69 (m, 4H), 3.43-3.38
(m, 1H), 3.28- 3.19 (m, 2H), 3.02-2.92 (m, 1H), 2.76-2.67 (m, 1H),
1.88 (bs, 2H), 1.76-1.67 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H). 342
##STR00387## 506 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.95-7.92 (m, 3H), 5.70, 5.63 (s, s, 1H), 5.28 (s, 2H), 4.57, 4.51
(s, s, 2H), 4.26 (t, J = 5.2 Hz, 2H), 3.85-3.77 (m, 2H), 3.69-3.66
(m, 2H), 3.49- 3.42 (m, 2H), 3.32-3.26 (m, 4H), 2.13-2.10 (m, 2H),
1.89-1.87 (m, 2H). 343 ##STR00388## 506 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.95-7.93 (m, 3H), 5.75, 5.65 (s, s, 1H), 5.27
(s, 2H), 4.55, 4.51 (s, s, 2H), 4.26 (t, J = 5.2 Hz, 2H), 3.84-3.76
(m, 2H), 3.51-3.44 (m, 2H), 3.05- 2.85 (m, 3H), 2.71-2.60 (m, 1H),
2.37-2.27 (m, 1H), 1.88 (bs, 2H), 1.12 (d, J = 6.4, 3H). 344
##STR00389## 518 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.69 (bs,
1H), 8.06-8.00 (m, 3H), 5.46, 5.38 (s, s, 1H), 5.24 (s, 2H),
4.54-4.41 (m, 3H), 4.20-4.09 (m, 2H), 3.77-3.62 (m, 2H), 3.55-3.46
(m, 1H), 3.38- 3.29 (m, 1H), 3.18-3.09 (m, 1H), 2.90-2.65 (m, 2H),
2.03-1.38 (m, 6H). 345 ##STR00390## 520 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.97-7.90 (m, 3H), 5.82, 5.74 (s, s, 1H), 5.27
(s, 2H), 4.57, 4.52 (s, s, 2H), 4.28 (t, J = 5.2 Hz, 2H), 3.88-3.75
(m, 4H), 3.49-3.39 (m, 2H), 2.71- 2.60 (m, 2H), 1.88 (bs, 2H), 1.36
(d, J = 6.4, 6H). 346 ##STR00391## 532.3 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.97-7.91 (m, 3H), 5.83, 5.75 (s, s, 1H), 5.27
(s, 2H), 4.58, 4.52 (s, s, 2H), 4.31-4.26 (m, 2H), 4.14-3.64 (m,
5H), 3.58- 3.34 (m, 3H), 3.27-2.79 (m, 3H), 2.38-1.68 (m, 6H). 347
##STR00392## 532.1 .sup.1H NMR (400 MHz, CDCl3) .delta. 7.84 (s,
1H), 7.79-7.77 (m, 2H), 5.69, 5.56 (s, s, 1H), 5.19 (s, 2H), 4.46,
4.44 (s, s, 2H), 4.28-4.25 (m, 2H), 3.79-3.71 (m, 3H), 3.59- 3.53
(m, 1H), 3.16-3.06 (m, 2H), 2.93-2.84 (m, 1H), 2.57-2.48 (m, 1H),
2.38-2.28 (m, 1H), 2.23- 2.05 (m, 2H), 1.99-1.72 (m, 5H), 1.54-1.46
(m, 1H). 348 ##STR00393## 518.1 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.93-7.90 (m, 3H), 5.80, 5.73 (s, s, 1H), 5.27 (s, 2H),
4.57, 4.51 (s, s, 2H), 4.28 (t, J = 5.2 Hz, 2H), 3.86-3.77 (m, 2H),
3.43 (s, 4H), 3.28, 3.26 (s, s, 2H), 1.92-1.83 (m, 2H), 1.11-0.98
(m, 4H). 349 ##STR00394## 532.1 .sup.1H NMR (400 MHz, CDCl3)
.delta.: 7.84 (s, 1H), 7.80-7.77 (m, 2H), 5.61, 5.49 (s, s, 1H),
5.19 (s, 2H), 4.45-4.43 (m, 2H), 4.27 (t, J = 4.8 Hz, 2H),
3.77-3.74 (m, 2H), 3.14- 3.13 (m, 4H), 2.89-2.88 (m, 4H), 3.32 (s,
3H), 2.27-2.24 (m, 2H), 1.95- 1.91 (m, 2H). 350 ##STR00395## 546.1
.sup.1H NMR (400 MHz, CDCl3) .delta. 7.84 (s, 1H), 7.80-7.76 (m,
2H), 5.61, 5.50 (s, s, 1H), 5.19 (s, 2H), 4.47-4.44 (m, 2H), 4.27
(t, J = 4.8 Hz, 2H), 3.79-3.72 (m, 2H), 3.20- 3.08 (m, 4H),
3.07-2.96 (m, 2H), 2.88 (bs, 2H), 2.46 (q, J = 7.2 Hz, 2H),
2.21-2.11 (m, 2H), 1.99- 1.87 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H) 351
##STR00396## 518.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.93
(s, 3H), 5.72, 5.64 (s, s, 1H), 5.27 (s, 2H), 4.58, 4.52 (s, s,
2H), 4.28 (t, J = 5.2 Hz, 2H), 3.87-3.76 (m, 2H), 3.62- 3.55 (m,
2H), 3.39-3.32 (m, 2H), 3.19-3.06 (m, 6H), 1.89 (bs, 2H). 353
##STR00397## 532.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.98-7.87 (m, 3H), 5.81, 5.75 (s, s, 1H), 5.27 (s, 2H), 4.57, 4.51
(s, s, 2H), 4.31-4.26 (m, 2H), 3.88-3.75 (m, 2H), 3.72- 3.36 (m,
5H), 3.10-3.29 (m, 1H), 2.99 (s, 3H), 1.93-1.82 (m, 2H), 1.28 (bs,
2H), 1.12-0.97 (m, 2H). 354 ##STR00398## 520.1 .sup.1H NMR (400
MHz, METHANOL-d4) .delta. 7.93-7.91 (m, 3H), 5.82, 5.74 (s, s, 1H),
5.28 (s, 2H), 4.58, 4.52 (s, s, 2H), 4.30-4.27 (m, 2H), 3.88-3.74
(m, 4H), 3.65- 3.55 (m, 2H), 3.25 (q, J = 7.6 Hz, 2H), 3.20- 3.09
(m, 2H), 3.08-2.97 (m, 2H), 1.88 (bs, 2H), 1.38 (t, J = 7.6 Hz,
3H). 355 ##STR00399## 520.1 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.98-7.88 (m, 3H), 5.80, 5.71 (s, s, 1H), 5.28 (s, 2H),
4.60, 4.55 (s, s, 2H), 4.33-4.26 (m, 2H), 3.89-3.66 (m, 4H), 3.65-
3.40 (m, 4H), 3.36-3.18 (m, 2H), 2.94 (s, 3H), 2.28-2.19 (m, 2H),
1.97- 1.87 (m, 2H). 356 ##STR00400## 534.1 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.94-7.90 (m, 3H), 5.82, 5.75 (s, s, 1H),
5.30- 5.24 (m, 2H), 4.58, 4.52 (s, s, 2H), 4.29 (t, J = 5.2 Hz,
2H), 3.88-3.74 (m, 4H), 3.61-3.48 (m, 3H), 3.27-3.15 (m, 2H),
3.09-2.97 (m, 2H), 1.93- 1.84 (m, 2H), 1.40 (d, J = 6.4 Hz, 6H).
357 ##STR00401## 534.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.96-7.89 (m, 3H), 5.82, 5.75 (s, s, 1H), 5.27 (s, 2H), 4.58, 4.52
(s, s, 2H), 4.29 (t, J = 5.2 Hz, 2H), 3.88-3.72 (m, 4H), 3.65-3.56
(m, 2H), 3.22- 3.10 (m, 4H), 3.09-2.99 (m, 2H), 1.92-1.85 (m, 2H),
1.84-1.74 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H). 358 ##STR00402## 536.2
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.84 (s, 1H), 7.77 (s,
2H), 5.70, 5.57 (s, s, 1H), 5.21 (s, 2H), 4.50- 4.42 (m, 2H),
4.28-4.26 (m, 2H), 3.90-3.51 (m, 7H), 3.50-2.77 (m, 7H), 2.01-1.85
(m, 2H). 359 ##STR00403## 518.2 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.96-7.90 (m, 3H), 5.70- 5.61 (m, 1H), 5.33-5.24 (m, 2H),
4.64-4.50 (m, 2H), 4.42-4.35 (m, 1H), 4.29 (t, J = 5.2 Hz, 2H),
4.22-4.14 (m, 1H), 3.88- 3.72 (m, 2H), 3.61-3.51 (m, 1H), 3.44-3.36
(m, 1H), 3.30-3.14 (m, 2H), 2.48-2.37 (m, 1H), 2.34- 2.24 (m, 1H),
2.20-2.02 (m, 2H), 1.93-1.85 (m, 2H). 360 ##STR00404## 532.2
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.97-7.90 (m, 3H), 5.68-
5.60 (m, 1H), 5.28 (s, 2H), 4.58-4.52 (m, 2H), 4.32-4.26 (m, 3H),
4.16- 4.09 (m, 1H), 3.88-3.82 (m, 1H), 3.81-3.72 (m, 1H), 3.74-3.51
(m, 2H), 3.31-3.20 (m, 2H), 2.96 (s, 3H), 2.60-2.00 (m, 4H),
1.93-1.83 (m, 2H).
Example 361
2-((5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-hydro--
4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)propanoic acid
##STR00405##
[1200] To a solution of 2 3,5-bis(trifluoromethyl)benzyl
2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
3,5-bis-trifluoromethyl-benzyl ester (110 mg, 0.26 mmol) in acetone
(2 mL) was added sodium carbonate (138 mg, 1.3 mmol) and 3.0 M of
aqueous sodium hydroxide solution (1 mL, 3 mmol). Water (0.5 mL)
was also added. 2-Bromopropionic acid (0.3 mL, 3 mmol) was then
added. When gas formation stopped, the mixture was heated in
microwave at 100.degree. C. for 10 min. Another portion of
2-bromopropionic acid (0.3 mL, 3 mmol) was added. The mixture was
then heated in microwave at 100.degree. C. for another 10 min. The
mixture was then diluted with ethyl acetate, neutralized with 2N
HCl. The organic layer was separated, dried and concentrated. The
crude was purified by HPLC to give the title compound as a white
powder (51 mg). .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.86-8.04 (m, 3H), 5.62-5.81 (m, 1H), 5.29 (s, 2H), 4.58 (d,
J=19.07 Hz, 2H), 4.28 (d, J=4.77 Hz, 2H), 4.09 (dd, J=7.15, 17.69
Hz, 1H), 3.72-3.91 (m, 2H), 1.96 (br. s. 2H), 1.41-1.51 (m, 3H);
ESI-MS m/z 495.1 [M+H].sup.+.
[1201] The following compounds were synthesized using the same
conditions as in Example 361
TABLE-US-00009 ESI-MS Example Structure (M + H)+ H-NMR 362
##STR00406## 509.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.89-
8.04 (m, 3H), 5.61- 5.79 (m, 1H), 5.29 (s, 2H), 4.57 (d, J = 19.33
Hz, 2H), 4.17-4.33 (m, 2H), 3.91-4.03 (m, 1H), 3.71-3.89 (m, 2H),
1.71- 2.04 (m, 4H), 0.95- 1.12 (m, 3H) 363 ##STR00407## 523.2
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.90- 8.02 (m, 3H),
5.60- 5.80 (m, 1H), 5.29 (s, 2H), 4.57 (d, J = 18.32 Hz, 2H),
4.18-4.33 (m, 2H), 3.82 (dt, J = 5.27, 13.93 Hz, 3H), 2.18 (d, J =
6.27 Hz, 1H), 1.96 (br. s., 2H), 1.03 (d, J = 6.78 Hz, 6H)
Example 369
3-chloro-5-(trifluoromethyl)benzyl
2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbo-
xylate
##STR00408##
[1203] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl
2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(100 mg, 0.22 mmol), pyridin-4-ylboronic acid (30 mg, 0.24 mmol)
and K.sub.2CO.sub.3 (60 mg, 0.44 mmol) in dioxane (5 mL) and
H.sub.2O (1 mL) was added Pd(PPh.sub.3).sub.4 (25 mg, 0.022 mmol).
The mixture was stirred at 90.degree. C. for 16 h under N.sub.2.
After cooling to rt, the mixture was filtered and the filtrate was
purified by reversed phase HPLC (0.05% TFA/H.sub.2O:
CH.sub.3CN=65%: 35%) to give the title compound (60 mg, 50% yield)
as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
8.76-8.73 (m, 2H), 8.38-8.33 (m, 2H), 7.63-7.49 (m, 3H), 7.07-7.01
(m, 1H), 5.21-5.17 (m, 2H), 4.74-4.69 (m, 2H), 4.64-4.62 (m, 2H),
3.92-3.87 (m, 2H), 1.99-1.95 (m, 2H); ESI-MS m/z
451.1[M+H].sup.+.
[1204] The following compounds were synthesized using the same
conditions as in Example 369
TABLE-US-00010 ESI-MS Example Structure (M + H)+ H-NMR 367
##STR00409## 485.1 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 8.40
(d, J = 5.6 Hz, 2H), 7.96-7.70 (m, 5H), 6.79, 6.69 (s, s, 1H),
5.29, 5.26 (s, s, 2H), 4.70, 4.65 (s, s, 2H), 4.55 (t, J = 5.2 Hz,
2H), 3.94- 3.82 (m, 2H), 1.99-1.91 (m, 2H). 368 ##STR00410## 499.2
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 8.59 (t, J = 6.8 Hz,
1H), 8.23-8.l4 (m, 2H), 7.95- 7.83 (m, 3H), 7.05-6.98 (m, 1H),
5.30-5.27 (m, 2H), 4.75-4.69 (m, 2H), 4.66-4.60 (m, 2H), 3.97- 3.83
(m, 2H), 2.78 (s, 3H), 2.02-1.93 (m, 2H). 370 ##STR00411## 465
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 8.60-8.57 (m, 1H), 8.23-
8.15 (m, 2H), 7.63-7.50 (m, 3H), 7.05-6.97 (m, 1H), 5.21-5.17 (m,
2H), 4.73-4.68 (m, 2H), 4.64- 4.61 (m, 2H), 3.93-3.87 (m, 2H), 2.78
(s, 3H), 1.99-1.96 (m, 2H).
Example 371
3,5-bis(trifluoromethyl)benzyl
2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-5(6H)-carboxylate
##STR00412##
[1206] A solution of
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahyd-
ro-pyridine hydrochloride (96 mg, 0.37 mmol) and
3,5-bis(trifluoromethyl)benzyl
2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(120 mg, 0.25 mmol) in 1,4-dioxane (2.4 mL, 31 mmol) and dimethyl
sulfoxide (0.6 mL) was degassed for 10 min.
Bis(tricyclohexylphosphine)palladium (0) (16 mg, 0.024 mmol) and
1.2 M of saturated aqueous NaHCO.sub.3 solution (0.6 mL, 0.74 mmol)
were then added. The reaction was heated in microwave at
120.degree. C. for 30 min. The reaction mixture was diluted with
ethyl acetate, washed with water. The organic layer was then dried,
concentrated. The crude was then purified by HPLC to give the title
compound as a white powder (86 mg): .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.90-8.13 (m, 3H), 6.25-6.48 (m, 1H), 5.94-6.18 (m, 1H),
5.23 (d, J=7.28 Hz, 2H), 4.48-4.70 (m, 2H), 4.38 (d, J=4.52 Hz,
2H), 3.93 (d, J=17.07 Hz, 1H), 3.63-3.83 (m, 3H), 3.54 (br. s.,
1H), 3.19 (br. s., 1H), 2.87 (d, J=4.02 Hz, 3H), 2.55-2.80 (m, 2H),
1.78 (br. s., 2H); ESI-MS m/z 503.2 [M+H].sup.+.
Example 372
3,5-bis(trifluoromethyl)benzyl
2-(1-methylpiperidin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate
##STR00413##
[1208] To a dry, nitrogen filled flask was added 10% palladium on
carbon (16 mg, 0.015 mmol). A mixture of
3,5-bis(trifluoromethyl)benzyl
2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a-
][1,4]diazepine-5(6H)-carboxylate (60 mg, 0.1 mmol) in ethanol (4.0
mL) was then added to the flask under nitrogen. The flask was then
applied vacuum, followed by flashing with hydrogen. The degas
process repeated for three times. The reaction mixture was then
stirred under hydrogen bolloon overnight. Filter off the catalyst,
the solution was concentrated. The crude was then purified by HPLC
to give the title compound as a white powder (18 mg): .sup.1H NMR
(300 MHz, DMSO-d6) .delta. 7.92-8.13 (m, 3H), 5.88-6.10 (m, 1H),
5.23 (br. s., 2H), 4.46-4.64 (m, 2H), 4.34 (br. s., 2H), 3.71 (br.
s., 2H), 3.46 (d, J=11.33 Hz, 2H), 2.89-3.14 (m, 2H), 2.60-2.86 (m,
4H), 1.92-2.16 (m, 2H), 1.57-1.88 (m, 4H). ESI-MS m/z 505.3
[M+H].sup.+.
Example 373
3,5-bis(trifluoromethyl)benzyl
2-(1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]dia-
zepine-5(6H)-carboxylate
##STR00414##
[1210] A solution of tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (134 mg, 0.43 mmol) and 3,5-bis(trifluoromethyl)benzyl
2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(140 mg, 0.29 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) was degassed
with nitrogen for 10 min. Bis(tricyclohexylphosphine)palladium (0)
(19 mg, 0.03 mmol) and 1.2 M of saturated aqueous NaHCO.sub.3
solution (0.5 mL, 0.6 mmol) were then added. The reaction was
heated in microwave at 120.degree. C. for 30 min. The reaction
mixture was diluted with ethyl acetate, washed with water. The
organic layer was then dried, concentrated. The crude was then
purified by ISCO (EtOAc/hexanes gradient 5% to 100%, silica gel 12
g column) to give the Boc-protected intermediate as a white powder
(120 mg). ESI-MS m/z 589.2 [M+H].sup.+.
[1211] 3,5-bis(trifluoromethyl)benzyl
2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (50 mg) was
dissolved in methylene chloride (2.0 mL), and trifluoroacetic acid
(0.2 mL) was then added. The mixture was stirred at RT for 2 h.
Remove the solvent. The crude was purified by HPLC to give the
title compound as a white powder (35 mg): .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.75 (br. s., 1H), 7.93-8.13 (m, 3H), 6.23-6.49
(m, 1H), 5.95-6.20 (m, 1H), 5.23 (d, J=8.53 Hz, 2H), 4.49-4.66 (m,
2H), 4.39 (br. s., 2H), 3.64-3.84 (m, 4H), 3.26 (br. s., 2H), 2.59
(br. s., 2H), 1.78 (br. s., 2H); ESI-MS m/z 489.3 [M+H].sup.+.
Example 374
3,5-bis(trifluoromethyl)benzyl
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-5(6H)-carboxylate
##STR00415##
[1213] To a dry, nitrogen filled flask was added 10% palladium on
carbon (13 mg, 0.012 mmol). A mixture of
3,5-bis(trifluoromethyl)benzyl
2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H-
-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (70.0 mg, 0.119
mmol) in ethanol (5.0 mL) was then added to the flask under
nitrogen. The flask was then applied vacuum, followed by flashing
with hydrogen (3.times.). The reaction mixture was then stirred
under hydrogen bolloon overnight. Filter off the catalyst, the
solution was concentrated. The crude was then purified by HPLC to
give the title compound as a white powder (46 mg): ESI-MS m/z 591.3
[M+H].sup.+.
Example 375
3,5-bis(trifluoromethyl)benzyl
2-(piperidin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-car-
boxylate
##STR00416##
[1215] A solution of 3,5-bis(trifluoromethyl)benzyl
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][-
1,4]diazepine-5(6H)-carboxylate (36 mg) in methylene chloride (2.0
mL) and trifluoroacetic acid (0.2 mL) was stirred at RT for 2 h.
Remove the solvent. The crude was purified by HPLC to give the
title compound as a white powder (16 mg). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.20-8.64 (m, 1H), 7.91-8.12 (m, 3H), 5.89-6.10
(m, 1H), 5.23 (d, J=4.02 Hz, 2H), 4.45-4.64 (m, 2H), 4.33 (br. s.,
2H), 3.73 (d, J=19.07 Hz, 2H), 3.29 (d, J=11.80 Hz, 2H), 2.90-3.07
(m, 2H), 2.78 (d, J=10.79 Hz, 1H), 1.97 (d, J=11.80 Hz, 2H),
1.57-1.88 (m, 4H); ESI-MS m/z 491.3 [M+H].sup.+.
[1216] The following compounds were synthesized using the same
conditions as in Examples 371-375
TABLE-US-00011 ESI-MS Example Structure (M + H)+ H-NMR 376
##STR00417## 515.2 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.64-
8.89 (m, 2H), 7.91- 8.13 (m, 3H), 6.19- 6.46 (m, 2H), 5.12- 5.34
(m, 2H), 4.11- 4.75 (m, 6H), 3.54- 3.90 (m, 2H), 2.93 (d, J = 15.31
Hz, 1H), 1.93- 2.26 (m, 3H), 1.63- 1.89 (m, 3H) 377 ##STR00418##
517.3 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.39- 8.68 (m, 1H),
7.90- 8.13 (m, 3H), 5.84- 6.26 (m, 1H), 5.23 (s, 2H), 4.45-4.65 (m,
2H), 4.34 (br. s., 2H), 3.85-4.07 (m, 2H), 3.73 (d, J = 19.07 Hz,
2H), 2.91-3.10 (m, 1H), 2.28-2.45 (m, 1H), 2.11-2.25 (m, 1H),
1.49-2.07 (m, 8H) 378 ##STR00419## 517.2 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.96- 8.17 (m, 3H), 6.26- 6.51 (m, 1H), 5.23 (d, J
= 9.04 Hz, 2H), 4.49- 4.73 (m, 2H), 4.39 (br. s., 2H), 4.08 (br.
s., 1H), 3.78 (br. s., 1H), 2.77 (d, J = 16.82 Hz, 1H), 2.19-2.36
(m, 1H), 1.78 (d, J = 12.80 Hz, 2H), 1.10-1.49 (m, 9H) 379
##STR00420## 529.3 .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
7.80-7.99 (m, 3H), 6.19-6.52 (m, 2H), 5.16-5.39 (m, 2H), 4.36-4.78
(m, 4H), 4.01-4.29 (m, 2H), 3.63-3.97 (m, 2H), 3.00-3.25 (m, 1H),
2.80-2.96 (m, 3H), 2.62-2.78 (m, 1H), 2.19-2.60 (m, 3H), 1.79-2.09
(m, 3H) 380 ##STR00421## 491.2 .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. 7.91 (d, J = 5.27 Hz, 3H), 6.05-6.23 (m, 1H), 5.26 (s, 2H),
4.51- 4.73 (m, 2H), 4.32- 4.46 (m, 2H), 3.68- 3.97 (m, 2H), 3.34-
3.52 (m, 2H), 2.94- 3.19 (m, 3H), 1.58- 2.17 (m, 6H) 381
##STR00422## 531.3 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.94
(br. s., 3H), 6.15- 6.36 (m, 1H), 5.28 (s, 2H), 4.55-4.70 (m, 2H),
4.39-4.49 (m, 2H), 3.75-3.95 (m, 4H), 3.12 (d, J = 6.53 Hz, 1H),
2.63-2.82 (m, 5H), 2.32-2.46 (m, 2H), 1.84-2.09 (m, 6H); 382
##STR00423## 519.2 .sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.92
(br. s., 3H), 5.99- 6.21 (m, 1H), 5.26 (s, 2H), 4.50-4.69 (m, 2H),
4.32-4.48 (m, 2H), 3.73-3.94 (m, 2H), 3.35-3.39 (m, 1H), 2.86-3.05
(m, 1H), 2.08-2.40 (m, 2H), 1.69-2.05 (m, 3H), 1.42-1.58 (m, 3H),
1.24-1.40 (m, 5H) 383 ##STR00424## 577.3 .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. 7.91 (d, J = 9.79 Hz, 3H), 6.01-6.17 (m, 1H),
5.26 (d, J = 3.51 Hz, 2H), 4.51-4.68 (m, 2H), 4.34-4.47 (m, 2H),
3.75-3.91 (m, 2H), 3.60-3.73 (m, 1H), 3.48 (br. s., 1H), 3.35 (br.
s., 3H), 1.81- 2.34 (m, 4H), 1.46 (s, 9H) 384 ##STR00425## 477.3
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. 7.86-7.99 (m, 3H),
6.09-6.24 (m, 1H), 5.26 (s, 2H), 4.52-4.72 (m, 2H), 4.35-4.47 (m,
2H), 3.73-3.93 (m, 2H), 3.35-3.63 (m, 5H), 2.28-2.45 (m, 1H),
2.03-2.20 (m, 1H), 1.82-1.97 (m, 2H) 385 ##STR00426## 491.2 .sup.1H
NMR (400 MHz, METHANOL-d4) .delta. 7.84-7.99 (m, 3H), 6.04-6.28 (m,
1H), 5.26 (s, 2H), 4.51-4.70 (m, 2H), 4.34-4.47 (m, 2H), 3.65-3.97
(m, 5H), 3.39-3.62 (m, 1H), 3.15-3.26 (m, 1H), 2.99 (d, J = 12.80
Hz, 3H), 2.33-2.62 (m, 1H), 2.06-2.31 (m, 1H), 1.89 (br. s.,
2H)
Example 386
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid
##STR00427##
[1217] Step 1
3,5-bis(Trifluoromethyl)benzyl
2-(2-diazoacetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate
##STR00428##
[1219] To a solution of
5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-p-
yrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.0 g, 2.2 mmol,
1.0 eq) in DCM (5 mL) were added SOCl.sub.2 (2.64 g, 22 mg, 10.0
eq). The reaction mixture was stirred at rt for 3 h, concentrated
in vacuum. DCM (5 mL) was added to the residue, followed by adding
2 M of Trimethylsilyldiazomethane in THF (5.5 mL, 11 mmol, 5 eq) at
0.degree. C. The mixture was stirred at rt for 16 h, quenched with
brine (5 mL), and extracted with DCM (3.times.10 mL). The combined
organic phase was washed with brine (2.times.5 mL), dried over
sodium sulfate and evaporated in vacuum to give the crude product
which was purified by column chromatography on silica gel
(PE/EA=10/1) to yield 3,5-bis(trifluoromethyl)benzyl
2-(2-diazoacetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate (0.6 g, 57% yield) as a white solid; ESI-MS m/z 476.1
[M+H].sup.+.
Step 2
3,5-bis(Trifluoromethyl)benzyl
2-(2-ethoxy-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate
##STR00429##
[1221] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(2-diazoacetyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate (600 mg, 1.26 mmol, 1.0 eq) in EtOH (2 mL) were added
pyridine (1 mL). The reaction mixture was heated in a microwave
reactor at 170.degree. C. for 20 mins. The resulted solution was
purified by column chromatography on silica gel (PE/EA=5/1) to
afford 3,5-bis(trifluoromethyl)benzyl
2-(2-ethoxy-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate (350 mg, 56% yield) as white solid: ESI-MS m/z 494.1
[M+H].sup.+.
Step 3
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid
##STR00430##
[1223] A mixture of 3,5-bis(trifluoromethyl)benzyl
2-(2-ethoxy-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate (100 mg, 0.2 mmol, 1.0 eq), lithium hydroxide
monohydrate (17 mg, 0.4 mmol, 2.0 eq) in THF (4 mL) and water (1
ml) was stirred at rt for 16 h, adjusted to pH 3-4 with 1 N HCl,
concentrated and the residue was purified by prep-HPLC
(ACN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to 95%) to
give the title compound as a white solid (30 mg, 28% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.94-7.89 (m, 3H), 6.20,
6.14 (s, s, 1H), 5.26 (s, 2H), 4.61, 4.56 (s, s, 2H), 4.39 (t,
J=4.4 Hz, 2H), 3.87-3.79 (m, 2H), 3.53 (s, 2H), 1.90-1.87 (m, 2H);
ESI-MS m/z 466.2 [M+H].sup.+.
Example 387
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid
##STR00431##
[1224] Step 1
3,5-bis(Trifluoromethyl)benzyl
2-(1-ethoxy-1-oxopropan-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5 (6H)-carboxylate
##STR00432##
[1226] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(2-ethoxy-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H-
)-carboxylate (150 mg, 0.30 mmol, 1.0 eq) in dry THF (5 mL) was
added Lithium diisopropylamide (0.18 mL, 2M in THF, 0.36 mmol, 1.2
eq) at -70.degree. C. under a nitrogen atmosphere, the reaction
mixture was stirred at -70.degree. C. for 15 min, followed by
adding CH.sub.3I (37 uL, 0.6 mmol, 2.0 eq). The reaction mixture
was slowly warmed to rt and stirred for 16 h, quenched with
saturated ammonium chloride aqueous solution (10 mL), extracted
with ethyl acetate (3.times.15 mL). The combined organic phase was
washed with water (5 mL), dried over MgSO.sub.4 and concentrated,
the residue was purified by prep-HPLC (ACN/H.sub.2O with 0.05% TFA
as mobile phase; from 5% to 95%) to give the product as a white
solid (100 mg, 65% yield). ESI-MS m/z 508.1 [M+H].sup.+.
Step 2
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid
##STR00433##
[1228] The title compound was synthesized according to the
procedure described in Example 7 (26 mg, yield 28%). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.95-7.93 (m, 3H), 6.20, 6.13 (s, s,
1H), 5.26 (s, 2H), 4.63-4.57 (m, 2H), 4.42-4.39 (m, 2H), 3.87-3.80
(m, 2H), 3.72-3.69 (m, 1H), 1.91 (bs, 2H), 1.44 (m, 3H); ESI-MS m/z
480.1 [M+H].sup.+.
Example 388
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid
##STR00434##
[1229] Step 1
3,5-bis(Trifluoromethyl)benzyl
2-(1-ethoxy-1-oxopropan-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-
e-5(6H)-carboxylate
##STR00435##
[1231] To a solution of T15-63-E (150 mg, 0.30 mmol, 1.0 eq) in dry
DMF (5 mL) was added NaH (48 mg, 60%, 1.2 mmol, 4.0 eq) at
0.degree. C. under a nitrogen atmosphere, the reaction mixture was
stirred at 0.degree. C. for 15 min, followed by adding CH.sub.3I
(75 uL, 1.2 mmol, 4.0 eq). The mixture was stirred at rt 16 h,
quenched with water (15 mL), extracted with ethyl acetate
(3.times.20 mL). The combined organic phase was washed with water
(10 mL), dried over MgSO4 and concentrated, the residue was
purified by prep-HPLC (ACN/H.sub.2O with 0.05% TFA as mobile phase;
from 5% to 95%) to give the product as a white solid (105 mg, 66%
yield). ESI-MS m/z 522.1 [M+H].sup.+.
Step 2
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-
-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid
##STR00436##
[1233] The titled compound was synthesized according to the
procedure described in Example 7 (19 mg, 19% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.96-7.95 (m, 3H), 6.20, 6.12 (s, s,
1H), 5.25 (s, 2H), 4.61, 4.56 (s, s, 2H), 4.40 (t, J=4.8 Hz, 2H),
3.86-3.80 (m, 2H), 1.91 (bs, 2H), 1.50, 1.48 (s, s, 6H); ESI-MS m/z
494.1 [M+H].sup.+.
Example 389
3,5-bis(Trifluoromethyl)benzyl
2-(1,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate
##STR00437##
[1234] Step 1
3,5-bis(Trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate
##STR00438##
[1236] To a mixture of 5-(3,5-bis(trifluoromethyl)benzyl) 2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(479 mg, 1 mmol, 1.0 eq) in anhydrous THF (10 mL) was added
LiBH.sub.4 (109 mg, 5 mmol, 5.0 eq). The mixture was stirred at rt
for 16 h, quenched with saturated aqueous NH.sub.4Cl solution (20
mL), extracted with ethyl acetate (3.times.40 mL). The combined
organic phase was washed with brine (2.times.10 mL), dried over
sodium sulfate and evaporated in vacuum to give the crude product
3,5-bis(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate (328 mg, Y: 75%), which was used in the next step reaction
without purification. ESI-MS m/z 438.1 [M+H].sup.+.
Step 2
3,5-bis(Trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
##STR00439##
[1238] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carb-
oxylate (800 mg, 1.83 mmol, 1.0 eq) in EA (30 mL) was added IBX
(1.54 g, 5.49 mmol, 3.0 eq). The reaction mixture was stirred under
reflux for 3 h. The mixture was washed with saturated aqueous
sodium bicarbonate (2.times.20 mL) and H.sub.2O (20 mL). The
organic layer was dried and concentrated off to give
3,5-bis(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(716 mg, 90% yield) as a yellow oil. ESI-MS m/z 436.1
[M+H].sup.+.
Step 3
3,5-bis(Trifluoromethyl)benzyl
2-(amino(cyano)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate
##STR00440##
[1240] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(660 mg, 1.52 mmol, 1.0 eq) in CH.sub.3OH (2 mL) were added TMSCN
(165 mg, 1.67 mmol, 1.1 eq), ZnI.sub.2 (48 mg, 0.152 mmol, 0.1 eq)
and NH.sub.3 (7 M CH.sub.3OH, 2.2 mL, 15.4 mmol, 10 eq). The
reaction mixture was stirred at rt for 16 h, concentrated and the
residue was purified by prep-HPLC (ACN/H.sub.2O with 0.05% TFA as
mobile phase; from 5% to 95%) to give
3,5-bis(trifluoromethyl)benzyl
2-(amino(cyano)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate (300 mg, 42% yield) as a yellow oil. ESI-MS m/z 462.1
[M+H].sup.+.
Step 4
3,5-bis(Trifluoromethyl)benzyl
2-(1,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate
##STR00441##
[1242] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(amino(cyano)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-
-carboxylate (150 mg, 0.325 mmol, 1.0 eq) in CH.sub.3OH (8 mL) and
DMSO (4 mL) were added NaOH (26 mg, 0.65 mmol, 2.0 eq) and
H.sub.2O.sub.2 (35% in water, 159 mg, 1.625 mmol, 5.0 eq). The
mixture was stirred at rt for 30 min, concentrated and the residue
was purified by prep-HPLC (ACN/H.sub.2O with 0.05% TFA as mobile
phase, from 5% to 95%) to give 3,5-bis(trifluoromethyl)benzyl
2-(1,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate (100 mg, 64% yield) as a yellow solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 8.47 (s, 2H), 8.09-8.07 (m, 3H),
7.86-7.82 (m, 1H), 7.62-7.59 (m, 1H), 6.32, 6.25 (s, s, 1H), 5.21
(s, 2H), 4.79-4.78 (m, 1H), 4.72-4.56 (m, 2H), 4.43-4.42 (m, 2H),
3.79-3.78 (m, 2H), 1.83-1.82 (m, 2H); ESI-MS m/z 480.1
[M+H].sup.+.
Example 390
2-Amino-2-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-
hydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid
##STR00442##
[1244] To a solution of 3,5-bis(trifluoromethyl)benzyl
2-(1,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-
(6H)-carboxylate (70 mg, 0.146 mmol, 1.0 eq) in CH.sub.3OH (1 mL)
were added H.sub.2O (1 mL) and TFA (1 mL). The reaction mixture was
stirred at 100.degree. C. for 16 h. The mixture was concentrated
off and the residue was purified by prep-HPLC (ACN/H.sub.2O with 10
mM NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%) to give
2-amino-2-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetr-
ahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid (10.5 mg,
15% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 8.07 (s, 3H), 6.08, 6.03 (s, s, 1H), 5.26-5.18 (m, 2H),
4.65-4.46 (m, 2H), 4.33-4.32 (m, 2H), 4.05-4.04 (m, 1H), 3.75-3.61
(m, 2H), 1.79-1.78 (m, 2H); ESI-MS m/z 481.1 [M+H].sup.+.
Example 391
3,5-bis(Trifluoromethyl)benzyl
2-(N'-hydroxycarbamimidoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine--
5(6H)-carboxylate
##STR00443##
[1246] To a mixture of compound 3,5-bis(trifluoromethyl)benzyl
2-cyano-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate
(100 mg, 0.23 mmol, 1.0 eq) in ethanol (3 mL) and CH.sub.2Cl.sub.2
(0.3 mL) were added hydroxylamine hydrochloride (24 mg, 0.35 mmol,
1.5 eq) and triethylamine (40 mg, 0.39 mmol, 1.7 eq). The mixture
was stirred at rt for 16 h, diluted with EtOAc (10 mL), washed with
brine (10 mL), filtered and concentrated to give the crude product
which was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 10 mM
NH.sub.4HCO.sub.3 as mobile phase; from 20% to 95%) to furnish
compound 3,5-bis(trifluoromethyl)benzyl
2-(N'-hydroxycarbamimidoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine--
5(6H)-carboxylate (93 mg, Y: 87%) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.: 7.95-7.88 (m, 3H), 6.49, 6.43 (s, s,
1H), 5.27, 5.25 (s, s, 2H), 4.65, 4.59 (s, s, 2H), 4.49-4.47 (m,
2H), 3.88-3.82 (m, 2H), 1.91 (s, 2H). ESI-MS m/z 466.1
[M+H].sup.+.
Example 392
3,5-bis(Trifluoromethyl)benzyl
2-(5-methyl-1,2,4-oxadiazol-3-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5(6H)-carboxylate
##STR00444##
[1248] To a mixture of 3,5-bis(trifluoromethyl)benzyl
2-(N'-hydroxycarbamimidoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine--
5(6H)-carboxylate (73 mg, 0.16 mmol, 1.0 eq) with CH.sub.3CN (1.5
mL) in a microwave vial were added acetyl chloride (25 mg, 0.31
mmol, 2.0 eq) and N,N-diisopropylethylamine (59 mg, 0.46 mmol, 2.9
eq). The mixture was heated with microwave irritation at
150.degree. C. for 45 min and then diluted with EtOAc (10 mL),
washed with brine (5 mL), dried over sodium sulfate, filtered, and
concentrated in vacuum to give the crude product which was purified
by prep-HPLC (CH.sub.3CN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as
mobile phase; from 20% to 95%) to furnish the compound
3,5-bis(trifluoromethyl)benzyl
2-(5-methyl-1,2,4-oxadiazol-3-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diaz-
epine-5 (6H)-carboxylate (55 mg, 72% yield) as a white solid.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.94-7.91 (m, 1H), 7.86
(s, 2H), 6.77, 6.67 (s, s, 1H), 5.29, 5.26 (s, s, 2H), 4.71, 4.66
(s, s, 2H), 4.57-4.55 (m, 2H), 3.91-3.85 (m, 2H), 2.64 (s, 3H),
1.94-1.93 (m, 2H). ESI-MS m/z 490.1 [M+H].sup.+.
Example 393
3,5-bis(Trifluoromethyl)benzyl
2-(4-methylpiperazin-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbo-
xylate
##STR00445##
[1250] Using 3,5-bis(trifluoromethyl)benzyl
2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and
1-methylpiperazine as starting materials, the title compound was
synthesized according to the coupling conditions described in
Example 338. .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.: 8.01 (br,
3H), 5.60 (s, 1H), 5.28 (s, 2H), 4.66-4.61 (m, 2H), 3.96-3.92 (m,
4H), 3.55-3.47 (m, 4H), 3.25-3.18 (m, 4H), 2.74 (s, 3H). ESI-MS m/z
492.2 [M+H].sup.+.
Example 394
3,5-bis(trifluoromethyl)benzyl
2-(piperazin-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00446##
[1252] Using 3,5-bis(trifluoromethyl)benzyl
2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and
tert-butyl piperazine-1-carboxylate as starting materials, the
title compound was synthesized according to the coupling conditions
described in Example 338 followed by standard Boc-deprotection step
as in example 158. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
7.89-8.05 (m, 3H), 5.70 (s, 1H), 5.33 (s, 2H), 4.62-4.74 (m, 2H),
3.90-4.05 (m, 4H), 3.35-3.45 (m, 4H), 3.25-3.33 (m, 4H); ESI-MS m/z
478.2 [M+H].sup.+.
Example 395
3,5-bis(Trifluoromethyl)benzyl
2-(1-aminoethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00447##
[1254] The titled compound was synthesized according to the
procedure described in Example 147. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.04 (s, 2H), 7.97 (s, 1H), 6.23 (s, 1H),
5.36 (s, 2H), 4.88-4.76 (m, 2H), 4.46 (q, J=6.8 Hz, 1H), 4.19 (t,
J=5.6 Hz, 2H), 4.02 (brs, 2H), 1.62 (d, J=6.8 Hz, 3H). ESI-MS m/z
437.1 [M+H].sup.+.
Example 396
3,5-bis(Trifluoromethyl)benzyl
2-(1-hydroxyethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00448##
[1256] The titled compound was synthesized according to the
procedure described in Example 146. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.38 (s, 1H),
5.37 (s, 2H), 4.97-4.84 (m, 3H), 4.28 (t, J=5.2 Hz, 2H), 4.06 (brs,
2H), 1.51 (t, J=6.8 Hz, 3H). LCMS m/z 438.1 [M+H].sup.+
Example 398
3,5-bis(trifluoromethyl)benzyl
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyraz-
ine-5(4H)-carboxylate
##STR00449##
[1258] The titled compound was synthesized according to the
procedure described in Example 371. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) d 7.88-8.07 (m, 3H), 6.03 (s, 1H), 5.33 (s, 2H),
4.53-4.81 (m, 2H), 4.06-4.20 (m, 4H), 3.98 (br. s., 2H), 2.71-2.95
(m, 3H), 1.78-1.96 (m, 2H), 1.55 (dd, J=3.89, 12.67 Hz, 2H), 1.46
(s, 9H); LCMS m/z 577.2 [M+H].sup.+.
Example 399
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-3-fluoro-5,6,7,8-tet-
rahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00450##
[1260] To a mixture of 5-(3-chloro-5-(trifluoromethyl)benzyl)
2-ethyl
7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate
(250 mg, 0.56 mmol) in acetonitrile (6 mL) was added Selectfluor
(994 mg, 2.8 mmol). The reaction mixture was heated in a microwave
reactor at 100.degree. C. for 3 h. After cooled to rt, the mixture
was filtered and concentrated, the residue was purified by prep-TLC
(PE/EA=1/1) to afford the ester intermediate (30 mg, 11% yield) as
a colourless oil. LCMS m/z 464.1 [M+H].sup.+.
[1261] To a solution of the ester intermediate (120 mg, 0.26 mmol)
in THF (4 mL) were added LiOH.H.sub.2O (22 mg, 0.52 mmol) and
H.sub.2O (1 mL). The reaction mixture was stirred at rt for 16 h
and was adjusted to pH=4-5 with HCl (1 N). The precipitate was
collected and dissolved in EtOAc (100 mL), washed with water (10
mL.times.2), dried over sodium sulfate and evaporated in vacuum to
give the crude product which was purified by prep-HPLC
(CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to
95%) to give the title compound as a white solid (80 mg, 71%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.66-7.60 (m,
2H), 7.54 (d, J=6.4 Hz, 1H), 5.20, 5.18 (s, s, 2H), 4.66, 4.62 (s,
s, 2H), 4.49 (t, J=4.8 Hz, 2H), 3.90-3.80 (m, 2H), 1.96-1.87 (m,
2H); LCMS m/z 436.0 [M+H].sup.+.
Example 507
5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-3-fluoro-5,6,7,8-tetrahy-
dro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid
##STR00451##
[1263] The titled compound was synthesized according to the
procedure described in Example 399. .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.75-8.04 (m, 3H), 5.13-5.36 (m, 2H),
4.56-4.73 (m, 2H), 4.34-4.55 (m, 2H), 3.67-3.97 (m, 2H), 1.86-1.95
(m, 2H); LCMS m/z 470.0 [M+H].sup.+.
Example 400
3,5-bis(trifluoromethyl)benzyl
2-(methoxy(methyl)carbamoyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-car-
boxylate
##STR00452##
[1265] The titled compound was synthesized according to the
procedure described in Example 144. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.96 (s, 1H), 6.64 (s, 1H),
5.37 (s, 2H), 4.85-4.79 (m, 2H), 4.27 (t, J=5.2 Hz, 2H), 4.05 (brs,
2H), 3.78 (s, 3H), 3.44 (s, 3H). LCMS m/z 481.0 [M+H].sup.+.
Example 401
3,5-bis(trifluoromethyl)benzyl
2-acetyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00453##
[1267] The titled compound was synthesized according to the
procedure described in Example 145. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.64 (s, 1H),
5.37 (s, 2H), 4.85-4.62 (m, 2H), 4.29 (t, J=5.2 Hz, 2H), 4.05 (brs,
2H), 2.53 (s, 3H). LCMS m/z 436.0 [M+H].sup.+
Example 402
5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl
6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxylate
##STR00454##
[1269] The title compound was synthesized according to the
procedure described in Example 1. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta.: 7.59 (s, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 6.64 (s, 1H),
5.20 (s, 2H), 4.77 (s, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.31-4.29 (m,
2H), 4.01-3.98 (m, 2H), 1.39 (t, J=7.2 Hz, 3H). LCMS m/z 453.9
[M+Na].sup.+
[1270] The procedure for Example 402 was used for all of the
compounds shown in the table below:
TABLE-US-00012 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
403 ##STR00455## 466.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.67 (s, 1H), 5.36 (s, 2H), 4.84-4.81
(m, 2H), 4.38 (q, J = 6.8 Hz, 2H), 4.27 (t, J = 5.2 Hz, 2H), 4.05
(brs, 2H), 1.38 (t, J = 7.2 Hz, 3H) 404 ##STR00456## 446.1 1H NMR
(400 MHz, Methanol-d4) .delta.: 7.64-7.57 (m, 2H), 7.52-7.49 (m,
1H), 6.73, 6.66 (s, s, 1H), 5.19, 5.16 (s, s, 2H), 4.67, 4.61 (s,
s, 2H), 4.54- 4.52 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.88-3.83 (m,
2H), 1.92-1.91 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H) 405 ##STR00457##
466.3 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.04-7.95 (m,
3H), 7.60 (d, J = 2.0 Hz, 1H), 6.27 7.60 (d, J = 2.0 Hz, 1H),
5.39-5.15 (m, 4H), 4.78- 4.75 (m, 1H), 4.57-4.46 (m, 1H), 4.13-4.76
(m, 3H), 1.21-1.07 (m, 3H) 406 ##STR00458## 466.1 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.85 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H),
7.36 (s, 1H), 6.14-6.27 (m, 1H), 5.29-5.17 (m, 2H), 4.95-4.84 (m,
2H), 4.50-4.23 (m, 3H), 3.74 (d, J = 6.4 Hz, 3H), 3.56-3.52 (m,
1H), 3.00-2.91 (m, 1H) 407 ##STR00459## 474 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.04 (s, 2H), 7.97 (s, 1H), 6.22 (s, 1H),
5.36 (s, 2H), 4.79-4.74 (m, 2H), 4.17-4.14 (m, 2H), 4.03-3.95 (m,
2H) 408 ##STR00460## 466 .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.06 (s, 2H), 7.97 (s, 1H), 7.89 (s, 1H), 5.38 (s, 2H),
5.02-4.97 (m, 2H), 4.31-4.22 (m, 4H), 4.03 (brs, 2H), 1.34 (brs,
3H) 409 ##STR00461## 496.1 .sup.1H NMR (400 MHz, Methanol-d4) d
7.75-8.04 (m, 3H), 6.58-6.78 (m, 1H), 5.13-5.37 (m, 2H), 3.67-4.79
(m, 10H), 1.34 (t, J = 7.15 Hz, 3H)
Example 410
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrazine-2-carboxylic acid
##STR00462##
[1272] The title compound was synthesized according to the
procedure described in Example 7. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 7.74 (s, 1H), 7.69 (s, 2H), 6.66 (s, 1H),
5.27 (s, 2H), 4.77-4.75 (m, 2H), 4.28-4.26 (m, 2H), 4.05-4.03 (m,
2H). LCMS m/z 403.8 [M+H].sup.+ The procedure for Example 410 was
used for all of the compounds shown in the table below:
TABLE-US-00013 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
412 ##STR00463## 532.1 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.85-8.12 (m, 4H), 7.57-7.73 (m, 1H), 6.14-6.42 (m, 1H), 5.25, 5.23
(s, s, 2H), 4.95 (s, 2H), 4.50-4.72 (m, 2H), 4.35-4.42 (m, 2H),
3.73- 3.85 (m, 2H), 1.72-1.92 (m, 2H) 413 ##STR00464## 438 .sup.1H
NMR (400 MHz, Methanol-d4) .delta.: 8.04 (s, 2H), 7.96 (s, 1H),
7.58 (s, 1H), 6.25 (s, 1H), 5.40-4.10 (m, 4H), 4.83-4.79 (m, 1H),
4.47-4.43 (m, 1H), 3.86-3.74 (m, 1H) 415 ##STR00465## 452.1 .sup.1H
NMR (400 MHz, DMSO-d6) .delta.: 8.02 (s, 1H), 7.98 (s, 1H), 7.92
(s, 1H), 7.16 (s, 1H), 6.10-6.03 (m, 1H), 5.30-5.11 (m, 2H), 4.90-
4.70 (m, 2H), 4.44-4.30 (m, 1H), 4.26-4.16 (m, 2H), 3.26-3.13 (m,
1H), 2.20-2.09 (m, 1H) 417 ##STR00466## 438 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.96 (s, 1H), 7.88 (s, 1H),
5.38 (s, 2H), 5.03-4.97 (m, 2H), 4.26-4.22 (m, 2H), 4.03 (brs, 2H)
418 ##STR00467## 549.3 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.45 (s, 1H), 5.37 (s, 2H), 4.84-4.79
(m, 2H), 4.49-4.47 (m, 2H), 4.24 (t, J = 5.6 Hz, 2H), 4.04 (brs,
2H), 3.08- 3.06 (m, 1H), 2.68-2.64 (m, 1H), 2.05-1.92 (m, 2H),
1.74-1.67 (m, 2H) 419 ##STR00468## 436.1 .sup.1H NMR (400 MHz,
DMSO-d6) .delta.: 8.12 (s, 2H), 8.08 (s, 1H), 6.55 (s, 1H), 5.30
(s, 2H), 4.73-4.67 (m, 2H), 4.18 (t, J = 4.8 Hz, 2H), 3.91 (brs,
2H) 420 ##STR00469## 396.1 .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.13-7.35 (m, 3H), 6.65-6.74 (m, 1H), 5.44 (q, J = 6.53 Hz,
1H), 3.77- 4.49 (m, 4H), 2.58-3.05 (m, 4H), 1.78-1.99 (m, 2H),
1.41-1.65 (m, 2H) 421 ##STR00470## 468.1 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.86-8.13 (m, 3H), 6.53, 6.58 (s, s, 1H),
5.13-5.33 (m, 2H), 4.33-4.73 (m, 4H), 3.55-3.94 (m, 4H)
Example 422
3,5-bis(trifluoromethyl)benzyl
2-(4-aminopiperidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-
-carboxylate hydrochloride
##STR00471##
[1274] A mixture of compound 3,5-bis(trifluoromethyl)benzyl
2-(4-((tert-butoxycarbonyl)amino)piperidine-1-carbonyl)-6,7-dihydropyrazo-
lo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.20 mmol, 1.0 eq.) in
HCl/EA (2 mL) was stirred at room temperature for 1 h. TLC
(PE/EA=1/1) showed the starting material was consumed completely.
The solvent was removed in vacuum and the crude was purified by
prep-HPLC to give 3,5-bis(trifluoromethyl)benzyl
2-(4-aminopiperidine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-
-carboxylate hydrochloride (75 mg, 90% yield) as a white solid.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.05 (s, 2H), 7.97 (s,
1H), 6.50 (s, 1H), 5.37 (s, 2H), 4.89-4.71 (m, 4H), 4.25 (t, J=5.2
Hz, 2H), 4.05 (brs, 2H), 3.48-3.44 (m, 1H), 3.33-3.26 (m, 1H),
2.97-2.94 (m, 1H), 2.17-2.06 (m, 2H), 1.62-1.60 (m, 2H). LCMS m/z
520.1 [M+H].sup.+
[1275] The procedure for Example 422 was used for all of the
compounds shown in the table below:
TABLE-US-00014 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
423 ##STR00472## 520.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.46 (s, 1H), 5.37 (s, 2H), 4.85-4.79
(m, 2H), 4.58-4.52 (m, 2H), 4.25 (t, J = 5.6 Hz, 2H), 4.04 (brs,
2H), 2.85- 2.73 (m, 3H), 2.44-2.41 (m, 1H), 1.46 (t, J = 7.2 Hz,
3H). 424 ##STR00473## 492 .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.63 (s, 1H), 5.37 (s, 2H),
4.85-4.83 (m, 3H), 4.63-4.42 (m, 2H), 4.27-4.04 (m, 6H). 425
##STR00474## 480 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05
(s, 2H), 7.97 (s, 1H), 6.63 (s, 1H), 5.37 (s, 2H), 5.04 (brs, 1H),
4.85-4.79 (m, 2H), 4.26 (t, J = 5.2 Hz, 2H), 3.65 (t, J = 5.6 Hz,
2H), 3.16 (t, J = 5.6 Hz, 2H). 426 ##STR00475## 532 .sup.1H NMR
(400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.65
(s, 1H), 5.63 (brs, 1H), 5.37 (s, 2H), 4.98-4.81 (m, 3H), 4.26 (t,
J = 5.6 Hz, 2H), 4.04 (brs, 2H), 3.47-3.32 (m, 4H), 2.28-2.07 (m,
4H) 427 ##STR00476## 532.3 .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.06 (s, 2H), 7.98 (s, 1H), 6.44 (s, 1H), 5.37 (s, 2H),
4.86-4.79 (m, 2H), 4.62-4.59 (m, 1H), 4.30-4.25 (m, 4H), 4.05 (brs,
2H), 3.64-3.60 (m, 4H), 2.55-2.54 (m, 1H), 2.33- 2.67 (m, 3H),
1.80-1.78 (m, 3H) 428 ##STR00477## 532 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.56 (s, 1H),
5.37 (s, 2H), 4.85-4.79 (m, 2H), 4.61-4.40 (m, 2H), 4.23-3.44 (m,
9H), 2.63-2.25 (m, 4H), 1.83 (d, J = 6.8 Hz, 3H) 429 ##STR00478##
498 .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 8.23 (s, 1H), 7.84 (s,
2H), 7.77 (s, 1H), 6.47 (s, 1H), 5.23 (s, 2H), 4.75- 4.69 (m, 2H),
4.49-4.46 (m, 1H), 4.29-4.26 (m, 1H), 4.18-4.16 (m, 2H), 3.93-3.91
(m, 3H), 3.80-3.77 (m, 1H), 3.50-3.45 (m, 1H), 3.04- 3.01 (m, 1H),
1.80-1.77 (m, 2H), 1.68-1.61 (m, 2H) 430 ##STR00479## 534 .sup.1H
NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H),
6.56 (s, 1H), 5.37 (s, 2H), 5.23 (brs, 2H), 4.86-4.83 (m, 2H), 4.25
(t, J = 5.6 Hz, 2H), 4.05 (brs, 2H), 3.42-3.34 (m, 4H), 1.51 (d, J
= 7.6 Hz, 6H) 431 ##STR00480## 458 .sup.1H NMR (400 MHz, DMSO-d6)
.delta.: 8.20 (s, 1H), 7.82 (s, 2H), 7.75 (s, 1H), 6.50 (s, 1H),
5.21 (s, 2H), 4.73- 4.57 (m, 3H), 4.18-4.16 (m, 4H), 3.89-3.87 (m,
4H) 432 ##STR00481## 500 .sup.1HNMR (400 MHz, DMSO-d6) .delta.:
9.38 (br, 2H), 7.81 (s, 2H), 7.74 (s, 1H), 6.40 (s, 1H), 5.20 (s,
2H), 4.71- 4.65 (m, 2H), 4.14-4.12 (m, 2H), 3.89-3.86 (m, 4H),
3.19-3.17 (m, 2H), 3.10 (s, 2H), 1.50 (s, 6H) 433 ##STR00482##
534.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H),
7.97 (s, 1H), 6.56 (s, 1H), 5.37 (s, 2H), 5.24 (brs, 1H), 4.86-4.83
(m, 2H), 4.25 (t, J = 5.2 Hz, 2H), 4.05 (brs, 2H), 3.45-3.32 (m,
5H), 3.19-3.16 (m, 1H), 1.16 (d, J = 6.0 Hz, 3H), 1.06 (d, J = 6.0
Hz, 3H) 434 ##STR00483## 472 .sup.1HNMR (400 MHz, DMSO-d6) .delta.:
9.18 (br, 2H), 7.83 (s, 2H), 7.76 (s, 1H), 6.52 (s, 1H), 5.23 (s,
2H), 4.75- 4.70 (m, 2H), 4.19-4.17 (m, 4H), 3.92-3.82 (m, 4H),
3.15-3.13 (m, 4H) 435 ##STR00484## 506.4 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.44 (s, 1H),
5.37 (s, 2H), 4.80-4.71 (m, 3H), 4.25 (t, J = 5.2 Hz, 2H), 4.04
(brs, 1H), 3.64 (brs, 8H), 1.81 (d, J = 7.2 Hz, 3H) 436
##STR00485## 534 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05
(s, 2H), 7.97 (s, 1H), 6.59 (s, 1H), 5.37 (s, 2H), 4.87-4.80 (m,
2H), 4.35-4.25 (m, 4H), 4.04-3.81 (m, 4H), 3.39-3.36 (m, 2H), 1.44
(s, 6H) 437 ##STR00486## 532 .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.58 (s, 1H), 5.37 (s, 2H),
5.03-5.00 (m, 1H), 4.85-4.80 (m, 2H), 4.66-4.59 (m, 1H), 4.27-4.05
(m, 6H), 3.67- 3.62 (m, 1H), 3.32-3.30 (m, 1H), 2.12-1.96 (m, 4H)
438 ##STR00487## 506 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.02 (s, 2H), 7.94 (s, 1H), 6.60 (s, 1H), 5.34 (s, 2H), 4.93-4.82
(m, 3H), 4.63-4.59 (m, 1H), 4.63-4.59 (m, 1H), 4.47-4.40 (m, 1H),
4.24- 4.01 (m, 6H), 2.73 (s, 3H) 439 ##STR00488## 520.1 .sup.1H NMR
(400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.58
(s, 1H), 5.37 (s, 2H), 5.04 (brs, 1H), 4.86-4.65 (m, 3H), 4.26 (t,
J = 5.6 Hz, 2H), 4.05 (brs, 2H), 3.70-3.45 (m, 3H), 3.26-3.08 (m,
2H), 1.45- 1.38 (m, 3H) 440 ##STR00489## 506.1 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.87 (s, 1H), 7.84 (s, 2H), 6.58 (s, 1H),
5.29 (s, 2H), 4.78 (s, 2H), 4.49 (brs, 2H), 4.23-4.00 (m, 6H),
3.30-3.28 (m, 4H) 441 ##STR00490## 534.1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.87 (s, 1H), 7.83 (s, 2H), 6.47 (s, 1H), 5.29
(s, 2H), 4.76 (s, 2H), 4.21-3.99 (m, 6H), 3.40 (s, 2H), 3.13 (s,
2H), 1.70 (s, 6H) 442 ##STR00491## 498.2 .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 7.50-7.78 (m, 3H), 6.59 (s, 1H), 5.25 (s, 2H),
4.80 (br. s., 2H), 3.50- 4.34 (m, 10H), 3.12-3.25 (m, 4H) 443
##STR00492## 477.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.
7.87-8.10 (m, 3H), 6.05 (s, 1H), 5.34 (s, 2H), 4.57-4.81 (m, 2H),
4.08-4.17 (m, 2H), 3.99 (br. s., 2H), 3.38-3.53 (m, 2H), 3.04-3.20
(m, 2H), 2.97 (tt, J = 3.76, 11.29 Hz, 1H), 2.16 (dd, J = 2.64,
14.43 Hz, 2H), 1.76-1.96 (m, 2H) 444 ##STR00493## 475.1 .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 7.82-8.09 (m, 3H), 6.45 (br. s.,
1H), 6.36 (s, 1H), 5.34 (s, 2H), 4.73- 4.81 (m, 2H), 4.09-4.20 (m,
2H), 3.89-4.04 (m, 4H), 3.36 (t, J = 6.15 Hz, 2H), 2.48-2.64 (m,
2H) 516 ##STR00494## 475.2 .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.87-8.13 (m, 3H), 6.03-6.41 (m, 2H), 5.34 (s, 2H), 4.76
(d, J = 17.32 Hz, 2H), 4.11-4.23 (m, 2H), 4.00 (br. s., 2H), 3.82
(d, J = 2.76 Hz, 2H), 3.42 (t, J = 6.27 Hz, 2H), 2.71- 2.90 (m,
1H)
Example 445
8-(1-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo-
[1,5-a][1,4]diazepin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic
acid
##STR00495##
[1277] The titled compound was synthesized according to the
procedure described in Example 149. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.40 (s, 1H), 7.30-7.27 (m, 2H), 6.38, 6.31
(s, s, 1H), 5.14-5.03 (m, 2H), 4.74-4.70 (m, 1H), 4.61-4.54 (m,
1H), 4.45 (t, J=5.2 Hz, 2H), 4.13-4.11 (m, 1H), 3.93-3.69 (m, 3H),
3.58-3.52 (m, 1H), 2.62-2.57 (m, 1H), 2.16-2.09 (m, 3H), 1.80-1.55
(m, 7H), 1.56 (t, J=9.6 Hz, 3H); LCMS m/z 521.1 [M+H].sup.+
[1278] The procedure described in Example 445 was used for all of
the compounds shown in the table below:
TABLE-US-00015 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
446 ##STR00496## 451.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.38 (d, J = 1.6 Hz 1H), 7.29-7.27 (m, 2H), 6.20, 6.13 (s, s, 1H),
5.12- 5.04 (m, 2H), 4.69-4.52 (m, 2H), 4.42 (t, J = 4.4 Hz, 2H),
3.88-3.74 (m, 2H), 3.67 (q, J = 6.8 Hz, 1H), 2.45-2.44 (m, 4H),
1.90-1.89 (m, 2H), 1.58-1.51 (m, 4H), 1.41-1.38 (m, 5H) 447
##STR00497## 495.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.29
(s, 1H), 7.21-7.16 (m, 2H), 6.27, 6.21 (s, s, 1H), 5.02-4.95 (m,
2H), 4.60-4.49 (m, 2H), 4.38 (t, J = 4.8 Hz, 2H), 4.27-4.21 (m,
1H), 3.78-3.65 (m, 2H), 3.24-3.23 (m, 1H), 2.97-2.59 (m, 3H),
2.15-2.14 (m, 1H), 1.92-1.80 (m, 6H), 1.53- 1.51 (m, 3H) 448
##STR00498## 628 (+Na) .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.04 (s, 2H), 7.96 (s, 1H), 6.12 (s, 1H), 5.36 (s, 2H), 4.89-4.74
(m, 2H), 4.16 (t, J = 7.6 Hz, 2H), 4.01 (brs, 2H), 3.69 (t, J = 6.8
Hz, 1H), 3.41 (brs, 4H), 2.45-2.42 (m, 4H), 1.45 (s, 9H), 1.42 (d,
J = 7.2 Hz, 3H) 449 ##STR00499## 654 (+Na) .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.08 (s, 1H),
5.36 (s, 2H), 4.80-4.73 (m, 2H), 4.15-4.11 (m, 6H), 3.60 (t, J =
6.8 Hz, 1H), 2.68-2.60 (m, 2H), 2.36-2.25 (m, 2H), 1.92-1.80 (m,
4H), 1.42 (s, 9H), 1.35 (d, J = 7.2 Hz, 3H) 450 ##STR00500## 654
(+Na) .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.04 (s, 2H),
7.97 (s, 1H), 6.21 (s, 1H), 5.36 (s, 2H), 4.86-4.75 (m, 2H),
4.15-4.13 (m, 2H), 4.02 (brs, 2H), 3.66-3.54 (m, 4H), 3.2-2.94 (m,
3H), 1.98 (brs, 2H), 1.66-1.55 (m, 2H), 1.46 (s, 9H), 1.36 (d, J =
7.2 Hz, 3H) 451 ##STR00501## 467.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.32 (s, 1H), 7.22-7.19 (m, 2H), 6.13, 6.06
(s, s, 1H), 5.04-4.82 (m, 2H), 4.60-4.48 (m, 2H), 4.35 (t, J = 4.8
Hz, 2H), 3.79-3.58 (m, 3H), 3.44-3.42 (m, 1H), 2.74-2.73 (m, 2H),
2.15-2.05 (m, 2H), 1.83-1.73 (m, 4H), 1.52-1.41 (m, 2H), 1.33 (d, J
= 7.2 Hz, 3H) 452 ##STR00502## 477.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.40-7.39 (m, 1H), 7.29-7.28 (m, 2H), 6.42,
6.34 (s, s, 1H), 5.14-5.03 (m, 2H), 4.75-4.57 (m, 2H), 4.51- 4.48
(m, 2H), 4.33-4.32 (m, 1H), 4.19-4.10 (m, 1H), 3.91-3.72 (m, 2H),
3.58-3.45 (m, 1H), 2.40-2.18 (m, 2H), 2.09-1.78 (m, 8H), 1.70- 1.65
(m, 5H) 453 ##STR00503## 491.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 7.42-7.41 (m, 1H), 7.30-7.29 (m, 2H), 6.42, 6.35 (s, s,
1H), 5.14-5.03 (m, 2H), 4.99-4.96 (m, 1H), 4.74- 4.57 (m, 2H),
4.50-4.47 (m, 2H), 3.93-3.73 (m, 3H), 3.16 (bs, 1H), 2.39-2.25 (m,
3H), 2.19-2.09 (m, 3H), 1.95-1.64 (m, 11H) 454 ##STR00504## 437.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.37 (s, 1H), 7.27-7.25
(m, 2H), 6.23, 6.16 (s, s, 1H), 5.11-5.02 (m, 2H), 4.67-4.53 (m,
2H), 4.40-4.37 (m, 2H), 3.89-3.70 (m, 2H), 3.45 (q, J = 6.8 Hz,
1H), 2.62-2.60 (m, 2H), 2.45-2.42 (m, 2H), 1.89-1.84 (m, 2H),
1.76-1.74 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H) 455 ##STR00505## 466.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.41 (s, 1H), 7.30-7.38
(m, 2H), 6.34, 6.28 (s, s, 1H), 5.08 (s, 2H), 4.69-4.59 (m, 2H),
4.47 (t, J = 5.6 Hz, 2H), 4.27-4.24 (m, 1H), 3.87- 3.76 (m, 2H),
3.55-3.53 (m, 1H), 3.38-3.37 (m, 3H), 3.19-3.18 (m, 4H), 2.87 (s,
3H), 1.91-1.90 (m, 2H), 1.60 (t, J = 5.6 Hz, 3H) 456 ##STR00506##
549.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H),
7.98 (s, 1H), 6.36 (s, 1H), 5.37 (s, 2H), 4.84-4.78 (m, 2H),
4.57-4.55 (m, 1H), 4.23 (t, J = 4.8 Hz, 2H), 4.04 (brs, 2H), 3.65-
3.52 (m, 2H), 3.04-2.88 (m, 2H), 2.55-2.51 (m, 1H), 2.26-2.22 (m,
2H), 1.94-1.70 (m, 5H) 457 ##STR00507## 521.1 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.40- 6.37 (m,
1H), 5.37 (s, 2H), 4.87-4.79 (m, 2H), 4.57-4.54 (m, 1H), 4.24- 4.06
(m, 4H), 3.78-2.85 (m, 5H), 2.12-1.72 (m, 7H) 458 ##STR00508##
505.5 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H),
7.98 (s, 1H), 6.35 (s, 1H), 5.37 (s, 2H), 4.85-4.79 (m, 2H),
4.52-4.50 (m, 1H), 4.23 (t, J = 5.6 Hz, 2H), 4.04 (brs, 2H), 3.57-
3.44 (m, 2H), 2.95-2.80 (m, 2H), 1.96-1.71 (m, 8H), 1.43-1.40 (m,
1H) 459 ##STR00509## 535.2 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.28-7.26 (m, 1H), 7.19-7.15 (m, 2H), 6.47 (s, 1H),
5.11-4.99 (m, 2H), 4.92-4.77 (m, 1H), 4.44-4.23 (m, 4H), 4.13-4.06
(m, 1H), 3.75- 3.73 (m, 1H), 3.47-3.45 (m, 1H), 3.06-3.04 (m, 1H),
2.85-2.81 (m, 1H), 2.59-2.52 (m, 1H), 2.36-2.24 (m, 1H), 2.12-1.84
(m, 6H), 1.75- 1.70 (m, 1H), 1.62-1.59 (m, 1H), 1.54 (d, J = 6.4
Hz, 3H), 1.39-1.36 (m, 1H), 1.19-1.16 (m, 1H) 508 ##STR00510##
491.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.84-7.77 (m, 3H),
6.14, 6.02 (s, s, 1H), 5.19 (s, 2H), 4.52-4.50 (m, 2H), 4.39-4.37
(m, 2H), 3.90 (q, J = 6.8 Hz, 1H), 3.79-3.78 (m, 2H), 2.10-2.06 (m,
1H), 1.96-1.93 (m, 2H), 1.39-1.36 (m, 3H), 0.46-0.33 (m, 4H) 509
##STR00511## 507.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.:
7.84-7.77 (m, 3H), 6.12, 6.00 (s, s, 1H), 5.20 (s, 2H), 4.78 (t, J
= 6.8 Hz, 1H), 4.62-4.37 (m, 6H), 4.23 (t, J = 6.4 Hz, 1H),
4.04-4.00 (m, 1H), 3.82-3.76 (m, 3H), 1.97-1.84 (m, 2H); 1.35 (t, J
= 6.8 Hz, 3H) 512 ##STR00512## 537.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.: 7.93 (s, 3H), 6.43-6.34 (m, 1H), 5.26 (s, 2H),
4.99-4.87 (m, 1H), 4.74- 4.61 (m, 2H), 4.56-4.50 (m, 3H), 3.90-3.79
(m, 2H), 3.65-3.36 (m, 2H), 3.21-2.91 (m, 2H), 2.30-2.18 (m, 2H),
2.13-1.93 (m, 4H), 1.91- 1.67 (m, 3H)
Example 460
3,5-bis(trifluoromethyl)benzyl
2-((2-hydroxyethyl)carbamoyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-ca-
rboxylate
##STR00513##
[1280] The titled compound was synthesized according to the
procedure described in Example 12. .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.59 (s, 1H),
5.36 (s, 2H), 4.85-4.83 (m, 2H), 4.25 (t, J=5.6 Hz, 2H), 4.03 (brs,
2H), 3.69 (t, J=6.0 Hz, 2H), 3.49 (t, J=6.0 Hz, 2H). LCMS m/z
481.1.1 [M+H].sup.+
[1281] The procedure for Example 460 was used for all of the
compounds shown in the table below:
TABLE-US-00016 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
462 ##STR00514## 634.3 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.89 (s, 1H), 7.85 (s, 2H), 6.44 (s, 1H), 5.31 (s, 2H), 4.78 (s,
2H), 4.24 (brs, 2H), 4.02-3.99 (m, 4H), 3.53- 3.47 (m, 4H), 1.64
(s, 6H), 1.49 (s, 9H) 464 ##STR00515## 620.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.89 (s, 1H), 7.86 (s, 2H), 6.50 (s, 1H), 5.31
(s, 2H), 4.92 (brs, 1H), 4.79 (s, 2H), 4.54 (brs, 1H), 4.27- 3.86
(m, 6H), 3.41-2.84 (m, 3H), 1.50 (s, 9H), 1.29 (d, J = 6.4 Hz, 3H)
466 ##STR00516## 634.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.54 (d, J = 12.8 Hz, 1H), 4.86-4.84
(m, 2H), 4.27-4.03 (m, 6H), 3.83-3.66 (m, 4H), 1.50 (s, 9H), 1.47
(s, 3H), 1.38 (s, 3H) 467 ##STR00517## 620 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.51 (s, 1H),
5.37 (s, 2H), 4.84-4.80 (m, 2H), 4.61-4.25 (m, 4H), 4.05-3.87 (m,
3H), 3.51-3.49 (m, 1H), 3.23- 3.15 (m, 2H), 1.49 (s, 9H), 1.19-
1.12 (m, 3H) 469 ##STR00518## 634 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.55 (s, 1H),
5.37 (s, 2H), 4.84-4.82 (m, 2H), 4.52-4.49 (m, 1H), 4.31-4.05 (m,
6H), 3.41-3.39 (m, 1H), 3.05- 3.03 (m, 1H), 1.50 (s, 9H), 1.25 (d,
J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H) 470 ##STR00519## 632
.sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s,
1H), 6.48 (s, 1H), 5.37 (s, 2H), 4.85-4.81 (m, 2H), 4.50-4.21 (m,
6H), 4.04 (brs, 2H), 3.41-3.38 (m, 1H), 3.04-3.01 (m, 1H),
1.94-1.74 (m, 4H), 1.51 (s, 9H) 471 ##STR00520## 571.9 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.58 (s, 1H), 7.55 (s, 1H), 7.50 (s,
1H), 6.50 (s, 1H), 5.20 (s, 2H), 4.76 (s, 2H), 4.23-4.21 (m, 2H),
4.00- 3.97 (m, 4H), 3.77-3.72 (m, 2H), 3.49-3.46 (m, 4H), 1.47 (s,
9H) 472 ##STR00521## 494.9 .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.59 (s, 1H), 5.36 (s, 2H),
4.84-4.78 (m, 2H), 4.25 (t, J = 5.2 Hz, 2H), 4.18- 4.16 (m, 1H),
4.14 (brs, 2H), 3.60- 3.55 (m, 2H), 1.24 (d, J = 6.8 Hz, 3H) 474
##STR00522## 632 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05
(s, 2H), 7.97 (s, 1H), 6.59 (s, 1H), 5.37 (s, 2H), 4.86-4.79 (m,
3H), 4.26 (t, J = 5.6 Hz, 2H), 4.04- 3.91 (m, 4H), 3.22-3.10 (m,
2H), 2.01-1.79 (m, 4H), 1.49 (s, 9H) 475 ##STR00523## 600 .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.58 (s, 1H), 7.55 (s, 1H), 7.50
(s, 1H), 6.40 (s, 1H), 5.19 (s, 2H), 4.74 (s, 2H), 4.20 (s, 2H),
3.98-3.96 (m, 4H), 3.50-3.44 (m, 4H), 1.55 (s, 6H), 1.46 (s, 9H)
476 ##STR00524## 634.2 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.45 (s, 1H), 5.37 (s, 2H), 4.86-4.79
(m, 4H), 4.24 (t, J = 5.2 Hz, 2H), 4.05- 3.98 (m, 4H), 3.18-3.08
(m, 2H), 1.51 (s, 9H), 1.33 (d, J = 6.4 Hz, 6H) 478 ##STR00525##
598 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.58 (s, 1H), 7.55
(s, 1H), 7.50 (s, 1H), 6.46 (s, 1H), 5.19 (s, 2H), 4.75 (s, 2H),
4.47-4.44 (m, 2H), 4.24- 4.20 (m, 4H), 3.99-3.98 (m, 2H), 3.40-3.38
(m, 1H), 3.02-3.00 (m, 1H), 1.90-1.89 (m, 2H), 1.77-1.75 (m, 2H),
1.47 (s, 9H) 479 ##STR00526## 487 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 7.74 (s, 1H), 7.69-7.67 (m, 2H), 6.44 (s,
1H), 5.27 (s, 2H), 4.79-4.77 (m, 2H), 4.24-4.18 (m, 4H), 4.03- 3.90
(m, 3H), 3.53-3.48 (m, 1H), 3.32-3.29 (m, 1H), 1.92-1.87 (m, 2H),
1.54-1.52 (m, 2H) 480 ##STR00527## 486.9 (+Na) .sup.1H NMR (400
MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.47 (s,
1H), 5.37 (s, 2H), 4.85-4.79 (m, 2H), 4.24 (t, J = 5.2 Hz, 2H),
4.04 (brs, 2H), 3.31 (s, 3H), 3.10 (s, 3H) 481 ##STR00528## 479.1
.sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s,
1H), 6.58 (s, 1H), 5.36 (s, 2H), 4.86-4.78 (m, 2H), 4.25 (t, J =
5.6 Hz, 2H), 4.03 (brs, 2H), 3.32-3.30 (m, 2H), 1.67- 1.58 (m, 2H),
0.97 (t, J = 7.6 Hz, 3H) 482 ##STR00529## 451.1 .sup.1H NMR (400
MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.57 (s,
1H), 5.36 (s, 2H), 4.85-4.78 (m, 2H), 4.24 (t, J = 5.2 Hz, 2H),
4.03 (brs, 2H), 2.90 (s, 3H) 483 ##STR00530## 493.1 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.87 (s, 1H), 7.83 (s, 2H), 6.59 (s,
1H), 5.29 (s, 2H), 4.76-4.72 (m, 4H), 4.44-4.37 (m, 2H), 4.22-4.21
(m, 2H), 4.03-3.98 (m, 3H), 2.57 (d, J = 4.4 Hz, 1H) 485
##STR00531## 477.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05
(s, 2H), 7.97 (s, 1H), 6.57 (s, 1H), 5.36 (s, 2H), 4.84-4.82 (m,
2H), 4.61 (t, J = 7.2 Hz, 2H), 4.25- 4.16 (m, 4H), 4.03 (brs, 2H),
2.43- 2.35 (m, 2H) 486 ##STR00532## 606.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.89 (s, 1H), 7.86 (s, 2H), 6.53 (s, 1H), 5.31
(s, 2H), 4.79 (s, 2H), 4.26 (brs, 2H), 4.04-4.01 (m, 4H), 3.75
(brs, 2H), 3.52-3.48 (m, 4H), 1.50 (s, 9H) 487 ##STR00533## 545.1
.sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s,
1H), 6.42 (s, 1H), 5.37 (s, 2H), 4.86-4.78 (m, 4H), 4.23 (t, J =
5.6 Hz, 2H), 4.04 (brs, 2H), 2.21-1.96 (m, 2H), 1.94- 1.65 (m, 10H)
488 ##STR00534## 519.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.04 (s, 2H), 7.95 (s, 1H), 6.42 (s, 1H), 5.36 (s, 2H), 4.82-4.78
(m, 2H), 4.60-4.50 (m, 2H), 4.23 (t, J = 5.2 Hz, 2H), 4.04 (brs,
2H), 3.15- 3.08 (m, 1H), 2.83-2.78 (m, 1H), 1.79-1.66 (m, 3H),
1.18-1.12 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H) 489 ##STR00535## 520.1
.sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.96 (s,
1H), 6.51 (s, 1H), 5.36 (s, 2H), 4.78 (brs, 2H), 4.17-3.88 (m, 8H),
2.87 (brs, 4H), 2.59 (s, 3H) 490 ##STR00536## 521 .sup.1H NMR (400
MHz, Methanol-d4) .delta.: 8.05 (s, 2H), 7.97 (s, 1H), 6.45 (s,
1H), 5.37 (s, 2H), 4.80-4.77 (m, 2H), 4.27-3.89 (m, 7H), 3.53-3.50
(m, 1H), 3.33-3.32 (m, 1H), 1.96- 1.87 (m, 2H), 1.57-1.48 (m, 2H)
491 ##STR00537## 437 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
8.05 (s, 2H), 7.97 (s, 1H), 6.60 (s, 1H), 5.37 (s, 2H), 4.87-4.78
(m, 2H), 4.26 (t, J = 5.2 Hz, 2H), 4.04 (brs, 2H) 492 ##STR00538##
519.1 .sup.1H NMR (400 MHz, Methanol-d4) .delta.: 8.05 (s, 2H),
7.97 (s, 1H), 6.58 (s, 1H), 5.36 (s, 2H), 4.82-4.78 (m, 2H), 4.25
(t, J = 5.2 Hz, 2H), 4.12- 3.80 (m, 3H), 1.95-1.67 (m, 5H),
1.44-1.20 (m, 5H) 493 ##STR00539## 505.1 .sup.1H NMR (400 MHz,
Methanol-d4) .delta.: 8.05 (s, 2H), 7.96 (s, 1H), 6.42 (s, 1H),
5.36 (s, 2H), 4.82-4.77 (m, 2H), 4.23 (t, J = 5.2 Hz, 2H), 4.04
(brs, 2H), 3.81-3.79 (m, 2H), 3.71- 3.68 (m, 2H), 1.74-1.59 (m, 6H)
494 ##STR00540## 585 (+Na) .sup.1H NMR (400 MHz, Methanol-d4)
.delta.: 8.05 (s, 2H), 7.96 (s, 1H), 6.45 (s, 1H), 5.37 (s, 2H),
4.78-4.48 (m, 2H), 4.55-4.45 (m, 2H), 4.24 (t, J = 5.2 Hz, 2H),
4.04 (brs, 2H), 3.70 (s, 3H), 3.34-3.32 (m, 1H), 3.05- 3.01 (m,
1H), 2.75-2.69 (m, 1H), 2.03-1.92 (m, 2H), 1.71-1.66 (m, 2H) 495
##STR00541## 514.2 .sup.1H NMR (400 MHz, Methanol-d4) .delta.:
7.56-7.83 (m, 3H), 6.47 (s, 1H), 5.25 (s, 2H), 4.71-4.87 (m, 2H),
4.14-4.27 (m, 2H), 4.02 (br. s., 2H), 3.20-3.35 (m, 6H), 2.96 (s,
3H), 1.62 (br. s., 6H)
Example 496
3,5-bis(trifluoromethyl)benzyl
2-(pyridin-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00542##
[1283] The titled compound was synthesized according to the
procedure described in Example X (7-member analog, suzuki
coupling). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.12 (s,
1H), 8.56-8.76 (m, 2H), 7.80-8.10 (m, 4H), 6.75 (s, 1H), 5.36 (s,
2H), 4.78-4.88 (m, 2H), 4.22-4.38 (m, 2H), 4.06 (br. s., 2H); LCMS
m/z 471.1 [M+H].sup.+
[1284] The above general procedure was used for all of the
compounds shown in the table below:
TABLE-US-00017 ESI-MS Example Structure [M + H].sup.+ .sup.1H-NMR
497 ##STR00543## 575.2 .sup.1H NMR (400 MHz, Methanol-d4) d
7.89-8.08 (m, 3H), 6.26 (s, 1H), 6.20 (br. s., 1H), 5.34 (s, 2H),
4.64-4.80 (m, 2H), 4.09-4.21 (m, 2H), 3.91-4.09 (m, 4H), 3.53- 3.69
(m, 2H), 2.42-2.53 (m, 2H), 1.48 (s, 9H) 498 ##STR00544## 575.2
.sup.1H NMR (400 MHz, Methanol-d4) d 7.84-8.11 (m, 3H), 6.17-6.41
(m, 2H), 5.34 (s, 2H), 3.86-4.78 (m, 6H), 3.50- 3.58 (m, 2H), 2.28
(br. s., 2H), 1.48 (s, 9H) 499 ##STR00545## 471.1 .sup.1H NMR (400
MHz, Methanol-d4) .delta. 8.73 (d, J = 6.78 Hz, 2H), 8.32 (d, J =
6.78 Hz, 2H), 7.97- 8.08 (m, 2H), 7.95 (s, 1H), 6.95 (s, 1H), 5.36
(s, 2H), 4.90 (br. s., 2H), 4.33 (t, J = 5.52 Hz, 2H), 4.07 (br.
s., 2H) 500 ##STR00546## 460.1 .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 7.77-8.09 (m, 5H), 6.32 (s, 1H), 5.35 (s, 2H), 4.76 (br.
s., 2H), 4.14-4.23 (m, 2H), 4.03 (br. s., 2H)
[1285] The following compounds were synthesized by the methods
described above, and have an IC.sub.50 value of greater than 10
.mu.M for the Autotaxin (ATX) assay described in Example 514:
##STR00547##
Example 517
Activity Measurements
S1P Receptor Activity Assays
[1286] Agonist percentage activation determinations were obtained
by assaying sample compounds and referencing the Emax control for
each receptor profiled. Antagonist percentage inhibition
determinations were obtained by assaying sample compounds and
referencing the control EC80 wells for each receptor profiled. The
samples were run using a "Single Addition" assay protocol for the
agonist and antagonist assay run. The protocol design was as
follows:
Compound Preparation
[1287] Master stock solution: Unless specified otherwise, all
sample compounds were diluted in 100% anhydrous DMSO including all
serial dilutions. All control wells contained identical solvent
final concentrations as did the sample compound wells.
[1288] Compound plate for assay: The sample compounds were
transferred from a master stock solution into a daughter plate that
was used in the assay. Each sample compound was diluted into assay
buffer (1.times.HBSS with 20 mM HEPES and 2.5 mM Probenecid) at an
appropriate concentration to obtain final concentrations.
Calcium Flux Assay: Agonist Assay Format
[1289] Sample compounds were plated in an eight-point, four-fold
dilution series in duplicate with a top concentration of 10 .mu.M.
The concentrations described here reflect the final concentration
of the compounds during the antagonist assay. During the agonist
assay the compound concentrations were 1.25 fold higher to allow
for the final desired concentration to be achieved with further
dilution by EC.sub.80 of reference agonists during the antagonist
assay.
[1290] Reference agonists were handled as mentioned above serving
as assay control. The reference agonists were handled as described
above for Emax.
[1291] Assay was read for 180 seconds using the FLIPRTETRA (This
assay run added sample compounds and reference agonist to
respective wells). At the completion of the first "Single Addition"
assay run, assay plate was removed from the FLIPRTETRA and placed
at 25.degree. C. for seven (7) minutes.
Calcium Flux Assay: Antagonist Assay Format
[1292] Using the EC.sub.80 values determined during the agonist
assay, stimulated all pre-incubated sample compound and reference
antagonist (if applicable) wells with EC.sub.80 of reference
agonist. Read for 180 seconds using the FLIPRTETRA (This assay
added reference agonist to respective wells--then fluorescence
measurements were collected to calculate percentage inhibition
values).
Data Processing
[1293] All plates were subjected to appropriate baseline
corrections. Once baseline corrections were processed, maximum
fluorescence values were exported and data manipulated to calculate
percentage activation, percentage inhibition and Z'.
Autotaxin (ATX) Assay
[1294] ATX (Autotaxin) is a 125 KDa glycoprotein with
lysophospholipase D (LPLD) activity that generates the bioactive
lipid lysophosphatidic acid (LPA) from lysophosphatidylcholine
(LPC). The ATX biochemical assay utilizes a FRET (fluorescence
resonance energy transfer) technology platform. The fluorescence
signal of FRET substrate FS-3 is quenched due to intra-molecular
FRET of a fluorophore to a non-fluorescing quencher (Ferguson, C.
G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, which is
incorporated by reference in its entirety). ATX catalyzes the
hydrolysis of the substrate which separates the dabsyl quencher
from the fluorescein reporter, which becomes fluorescent. The
reaction is monitored by a SpectraMax M5 (Molecular Devices,
Sunnyvale, Calif.) with at excitation wavelength 485 nm and
emission wavelength 535 nm.
Reagents
[1295] Fatty acid free-BSA (Sigma A8806): 10 mg/mL in H.sub.2O,
stored at 4.degree. C.
[1296] 2.times.ATX assay buffer: 100 mM Tris, 280 mM NaCl, 10 mM
KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2, pH 7.4.
[1297] Human ATX protein: expressed and purified in house. Stored
at -80.degree. C.
[1298] Substrate FS-3 (Echelon, L-2000): 100 .mu.g in 77.74 .mu.L
H.sub.2O (1 mM stock), stored at -20.degree. C.
[1299] 384-well flat bottom plates--Corning #3575.
Assay
[1300] Compound dilution--All compounds were provided at 10 mM in
100% DMSO. In the first well, 2 .mu.L of 10 mM compound was added
to 78 .mu.L of DMSO (1:40 dilution). In subsequent wells 3-fold
dilution (total 10 dilutions) were performed.
[1301] 1.times.ATX assay buffer was made up with a final
concentration of 1 mg/mL fatty acid free-BSA using 2.times.ATX
assay buffer, 10 mg/ml fatty acid free-BSA and ddH.sub.2O.
[1302] ATX protein was diluted with 1.times.ATX assay buffer to a
concentration of 1.32 .mu.g/mL (1.32.times.). 38 .mu.L was added
per well to the assay plate. The final concentration of ATX in the
reaction as 1.0 .mu.g/mL.
[1303] 2 .mu.L per well of compounds was transferred to provide the
desired concentration. The plate was centrifuged, then incubated at
room temperature for 30 minutes on the shaker.
[1304] FS-3 was diluted with 1.times.ATX assay buffer to a
concentration of FS-3 of 10 .mu.M (5.times.). Then, 10 .mu.L was
added per well to the assay plate. The final concentration of FS-3
in the reaction was 2 .mu.M. The plate was centrifuged. The plate
was kept shaking at room temperature for 2 hours. Because FS-3
substrate is light sensitive, plates were kept covered and
protected from light.
[1305] Fluorescence was measured using SpectraMax M5 (excitation at
485 nm/emission at 538 nm, top read).
[1306] The compounds of examples 2-4, 7-8, 12, 15-32, 41, 43, 46,
48-49, 58-65, 82-83, 85, 87, 90, 92, 94-95, 97, 100-103, 105-106,
108-111, 114-115, 118-119, 124-125, 127, 132-133, 136, 144-146,
148, 153, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,
168, 169, 170, 171, 172, 173, 174, 175, 176, 178, 179, 180, 181,
182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 195,
196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 229 230, 231, 232, 233, 234,
235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247,
248, 249, 250, 251, 252A, 252B, 253, 254, 255, 256, 257, 258, 259,
260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272,
273, 274, 277, 278, 280, 285, 286, 293, 298, 299, 302, 304, 305,
306, 308, 314, 315, 316, 318, 319, 320, 322, 323, 326, 328, 337,
338, 340, 341, 342, 343, 345, 346, 347, 348, 349, 350, 351, 353,
354, 355, 356, 357, 358, 359, 360, 362, 363, 367, 368, 369, 370,
371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383,
386, 387, 388, 390, 392, 393, 394, 395, 396, 398, 399, 400, 402,
403, 404, 409, 412, 418, 422, 423, 424, 425, 426, 427, 428, 429,
430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442,
443, 444, 448, 449, 450, 458, 460, 462, 464, 466,467, 469, 470,
471, 472, 474, 475, 476, 478, 479, 481, 482, 483, 485, 486, 487,
488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500,
502, 503, 504, 505, 506, 507, 508, 510, 512, 514, 515, and 516 had
an IC.sub.50 of no greater than 100 nM. The compounds of examples
14, 45, 57, 86, 88, 112, 113, 122, 123, 128, 154, 157, 289, 291,
292, 296, 297, 301, 313, 317, 339, 344, 352, 361, 384, 385, 410,
415, 419, 446, 453, 456, 457, 480, 509, 511, and 513 had an
IC.sub.50 of no greater than 250 nM. The compounds of examples 1,
10, 42, 67, 68, 75, 93, 99, 116, 117, 126, 129-131, 134, 135, 141,
147, 149, 287, 288, 290, 294, 401, 420, 421, and 454 had an
IC.sub.50 of no greater than 500 nM. The compounds of examples 9,
11, 34, 36, 38, 39, 40, 44, 47, 50-55, 66, 69-74, 76, 78-81, 84,
91, 96, 98, 140, 141, 284, 295, 408, 413, 417, 445, 447, 451, 452,
455, and 459 had an IC.sub.50 between 500 nM and 10 .mu.M. The
compounds of examples 405 and 406 had an IC.sub.50 greater than 10
.mu.M. The compound of example 407 had 50% inhibition at 10 uM. The
compounds of examples 279 and 282 had 60% inhibition at 10 uM.
OPC Differentiation Assay
[1307] Enriched populations of oligodendrocytes were grown from
post-natal day 2 (P2) female Sprague Dawley rats. The forebrain was
dissected out and placed in Hank's buffered saline solution (HBSS;
Invitrogen, Grand Island, N.Y.). The tissue was cut into 1 mm
fragments and incubated at 37.degree. C. for 15 minutes in 0.01%
trypsin and 10 .mu.g/mL DNase. Dissociated cells were plated on
poly-L-lysine-coated T75 tissue culture flasks and grown at
37.degree. C. for 10 days in Dulbecco's modified Eagle's medium
(DMEM) with 20% fetal calf serum (Invitrogen). A2B5+ OPCs were
collected by shaking the flask overnight at 200 rpm and 37.degree.
C., resulting in a 95% pure population.
[1308] For the differentiation assay, 2 .mu.M and 20 .mu.M
antagonist or the same concentrations of vehicle (DMSO) were
applied to OPCs cultured in CNTF/T3 containing media. After a 3-day
incubation, after a 3-day incubation, cell were lysed and then
subjected to MSD (Meso Scale Discovery-R) analysis. EC.sub.50 was
calculated by Prism using a nonlinear sigmoidal dose-response
curvecells. Alternatively, cells were lysed in 80 .mu.L lysis
buffer (50 mM HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic
acid], pH 7.5, 150 mM NaCl, 1.5 mM MgCl.sub.2, 1 mM ethylene glycol
tetraacetic acid (EGTA), 1% Triton X-100 and 10% glycerol) for 30
minutes at 4.degree. C. After centrifugation at 14,000 g for 15
minutes, the supernatants were boiled in Laemmli sample buffer,
subjected to 4-20% SDS-PAGE, and analyzed by Western blotting with
anti-MBP, anti-myelin-associated glycoprotein (MAG), or anti-beta
actin antibodies. The secondary antibodies used were anti-mouse
IgG-HRP (horseradish peroxidase) and anti-rabbit IgG-HRP
respectively.
LPA Plasma Assay and IC.sub.50 Assay by LC-MS/MS
[1309] 20:4 LPA (Lysophosphatidic acid) and 18:1 LPA were purchased
from Avanti Polar Lipids, INC at a concentration of 10 mg/mL in
chloroform, respectively. Stock solutions for 20:4 LPA and 18:1 LPA
were separately prepared at 1.00 mg/mL in Methanol and were stored
in a -20.degree. C. freezer. 18:3 LPA, the internal standard, was
purchased from Eschelon Bioscience, Inc. as 1 mg in powder form. A
stock solution was prepared at 1 mg/mL in chloroform and then
diluted to 100 .mu.g/mL in Methanol and was stored in a -20.degree.
C. freezer. The internal standard solution of 125 ng/mL in
acetonitrile was prepared and stored in a 4.degree. C.
refrigerator.
Plasma LPA Assays
[1310] 2% BSA (Bovine serum albumin) was used as a surrogate matrix
for preparation of standards and QC samples due to the presence of
endogenous LPAs in rat plasma samples. 20:4 LPA and 18:1 LPA
calibration standards were prepared fresh with each batch at
concentrations ranging from 0.5 ng/mL to 1000 ng/mL in 2% BSA. 20:4
LPA and 18:1 LPA QC samples were prepared fresh with each batch at
concentrations of 1, 5, 20, 50, 250, and 1000 ng/mL in 2% BSA.
Study samples were thawed on ice and processed within 2 hours on
ice. The protein precipitation method was applied for sample
preparation. The injection plate was loaded onto a CTC PAL
autosampler for injection to determine the concentration of 20:4
LPA and 18:1 LPA by LC/MS/MS. Reverse phase HPLC using a C8 column
was used for the separation.
IC.sub.50 Assay
[1311] The stock solution (10 mM) for each compound was made in
DMSO. For each compound, the stock solution (10 mM in DMSO) was
diluted in 60% DMSO to make ten intermediate stock solutions. The
ten intermediate stocks were then diluted in rat K.sub.2 EDTA
plasma to make ten samples at concentrations ranging from 30 .mu.M
to 0.00152 .mu.M. One control sample was made by spiking DMSO into
rat K.sub.2 EDTA plasma. All eleven samples were placed in
37.degree. C. incubator for 18 hours, extracted right after 18 hr
incubation and transferred to an autosampler tray for injection
onto the LC-MS/MS system. The quantitation of IC.sub.50 assay was
performed by determining the peak area ratio of 20:4 LPA (or 18:1
LPA) over internal standard (18:3 LPA). The IC.sub.50 value for
each compound was calculated by using GraphPad Prism software.
[1312] The compounds of examples 7, 8, 12, 18, 20, 25, 49, 60, 65,
82, 90, 101, 158, 159, 168, 169, 170, 173, 176, 181, 189, 195, 196,
197, 198, 199, 200, 201, 203, 204, 205, 206, 207, 208, 209, 210,
212, 213, 214, 215, 216, 222, 223, 224, 225, 227, 271, 272, 277,
298, 299, 302, 304, 305, 306, 308, 319, 338, 346, 347, 349, 367,
368, 376, 386, 387, 388, 429, 432, 436, 437, 442, 503, 504, 506,
507, 514 and 515 had an IC.sub.50 of no greater than 500 nM. The
compounds of examples 41, 100, 270, 280, 390, 392, 394, 421, 424,
430, 434, 440, 441, 444, 479, 488, 490, 500, 502, 505, 508 and 516
had an IC.sub.50 between 500 nM and 10 .mu.M. The compounds of
examples 472 and 499 had an IC.sub.50 greater than 10 .mu.M.
OPC Oligodendrocyte Myelination Assay
[1313] Embryonic neocortical neurons are dissected from embryonic
day 18 (E18) Sprague Dawley rats, and then plated on poly-D-lysine
(100 .mu.g/mL)-coated cover slips and grown in neurobasal medium
supplemented with B27 (Invitrogen) for one week. A2B5.sup.+ OPCs
are prepared as described above and then added into the cultured
neocortical neurons. One day later, different concentrations of a
compound or salt as described herein and control reagents are
applied into the co-cultures. Fresh media containing the different
concentrations of a compound or salt as described herein or control
compounds are supplied every three days. After ten days,
co-cultures are subjected to sodium dodecyl sulfate polyacrylamide
gel electrophoresis (SDS-PAGE)/Western blot analyses to quantify
MAG, MBP, and MOG.
Remyelination Assay in Brain Slice Culture
[1314] Approximately three to four consecutive 300 .mu.m slices are
taken from the junction of the corpus callosum to the hippocampus
in post-natal, day 17 Sprague Dawley rats (Charles River,
Willmington, Mass.). Slices are cultured in basal DMEM supplemented
with 25% horse serum for three days, before being treated with 6
mg/mL LPC (Sigma L-4129) for a further three days. The medium is
then changed, and slices incubated with medium containing a
compound or salt as described herein or vehicle control for a final
period of three days, after which myelination is visualized by
black gold staining (Millipore, Bedford, Mass.) following the
manufacture's protocol. Images are acquired using a Leica M420
microscope (Bannockburn, Ill.) and the staining intensity of corpus
callosum is analyzed using Metamorph software (Molecular Devices,
Downingtown, Pa.). Three or four brain slices are used for each
treatment group.
Lysolecithin Demyelination Model
[1315] Adult Sprague Dawley rats (220-260 g) are anesthetized by
intraperitoneal injection of a cocktail, consisting of Ketamine (35
mg/kg), Xylazine (6 mg/kg) and Acepromazine (1 mg/kg). The back of
the animal is shaved from the lower thoracic to the lumbar region,
subsequently sanitized with 70% isopropanol, Betadine Scrub
solution, and 70% isopropanol again. The animal is then placed onto
stereotaxic frame.
[1316] After ensuring an adequate anesthetic level, the skin is
incised along the midline over the thoracic region. The dorsal
fascia is incised and the paraspinal muscles separated from the
spinous processes of the thoracic vertebrae T-9 through T-11. The
T-10 vertebra is demolished, and the lamina removed with
micro-rongeurs. Once the dorsal spinal cord region is exposed, a
microcapillary glass needle is inserted into the dorsal column to a
depth of 0.6 mm. The demyelinating reagent, 1.5 .mu.L of 1%
Lysolecithin (LPC, Sigma# L1381) in saline is injected with the
infusion rate of 2 nL/sec controlled by a micro-pump (World
Precision Instrument #micro4). Once the injection is completed, the
needle is placed for additional 1 min before removal. The
paraspinal muscles and the lumbar fascia are closed with suture
(#5, silk). The skin incision is closed with wound clips. Animals
are allowed to recover from the anesthesia and are observed in the
humidified incubator.
[1317] Buprenorphine (0.05 mg/kg) is administrated subcutaneously
(s.c.) twice a day for additional two days following operation.
[1318] Three days following the primary surgery, treatments with a
compound or salt as described herein (30 pmol), LPA (30 pmol) or
control (0.1% DMSO in saline) are injected at the primary injection
region in a volume of 1.5 .mu.L with the same infusion speed as
indicated above. Nine days following the primary surgery, the
animals are anesthetized and perfused trans-cardially with heparin
(10 iu/mL) in saline followed by 4% PFA in PBS. The spinal cords
are removed and post fixed in PFA overnight. Then the cords are cut
into 100 .mu.M thickness longitudinally and then 1% loxuol fast
blue is stained and histological evaluation for remyelination and
repair is assessed under microscope.
[1319] For systemic treatment, the animals are administered once
daily intraperitoneally with either a compound or salt as described
herein (10 mg/kg) or control (15% HPCD
(hydroxypropyl-.beta.-cyclodextrin)) 2 days following the primary
surgery. Nine days after the primary surgery, animals are
sacrificed and the spinal cords were processed as indicated
above.
CFA Inflammatory Pain Model
[1320] In the CFA (complete Freund's adjuvant) model, adult male SD
(250-300 g) rats are anesthetized with isoflurane inhalation (4.5%
induction/2.0% maintenance). Heat-killed M. Tuberculosis H37 RA
(non-viable) suspended at a concentration of 1.0 mg/ml in
incomplete Freund's adjuvant is used (Chondrex Inc., catalog#7008).
At day 0, intradermal injection (i.d.) of 100 .mu.l of CFA (1:1
oil/saline) is slowly perfused into the right footpad of the rats.
At day 1, baseline tactile allodynia test are conducted: rats that
develop sensitive painful response are enrolled to the study. At
day 2, rats are orally dosed once with either vehicle or ATX
inhibitor, then at 2 hrs, 4 hrs, 6 hrs and 24 hrs after dosage, all
rats are tested for mechanical allodynia response.
[1321] Tactile allodynia is tested as follows. A rat is placed in
an elevated Plexiglas observation chamber (approximately
4''.times.6''.times.10'') having a wire grid (1 cm.sup.2 spacing)
mesh floor under polycarbonate cages. The rat is left to acclimate
to the experimental conditions for 20 minutes before testing
begins. After the rat is calm, tactile allodynia is assessed using
a series of von Frey filaments ranging from 2.04-28.84 g
(Stoelting, Wood Dale, Ill.). Graded pressure is presented to a
localized area on the plantar surface of the paw via the use of Von
Frey hairs (monofilaments which are calibrated to bend at a known
pressure). A response to the VonFrey hair is recorded as the rat
withdrawing the tested paw and is usually followed by lifting and
licking. A series of filaments are used to determine the threshold
response using the established "Up-Down" method. Each paw is tested
4-6 times repeatedly with 1-2 seconds (modified from Seltzer et
al., 1991) in between each probe to accurately assess the behavior.
A sharp lifting of the paw is scored as a positive response.
Rat Model of Neuropathic Pain
[1322] Chronic Constriction Injury (CCI) Surgery: In the CCI model
(Bennett and Xie, Pain, 1989, which is incorporated by reference in
its entirety), adult male SD (250-275 g) rats are anesthetized with
isoflurane inhalation (4.5% induction/2.0% maintenance). The
surgery is performed under aseptic conditions and involves exposing
the sciatic nerve at the mid-thigh level. Ocular lubricant is used
as needed to prevent corneal drying. After shaving and disinfecting
the skin (betadine followed by 70% ethanol), a small incision is
made just caudal to the biceps femoris. Care is taken to not
disturb the sciatic nerve. The nerve is slightly elevated, and 4
loose ligatures of 4-0 chromic gut suture are inserted under the
nerve, and then are loosely tied around it. The sutures constrict
the nerve but do not strangle it. Prior to inserting the chromic
gut, it is rinsed twice in sterile saline. The incision is closed
with wound clips, and rats are allowed to recover from anesthesia
on a circulating water heating pad before being returned to their
home cages. In the sham controls the skin is opened, and the
sciatic nerve is identified and elevated, but no sutures are tied
around the nerve. All rats are screened for pain response around
post-surgery day 7 and only rats with sensitive pain response are
enrolled to the study.
[1323] Animals are orally dosed twice/day for 3 times/week with
either vehicle or ATX inhibitor post-surgery at days 10, 12, 14,
17, 19 and 21, and animals are also tested at the same schedule for
three types of neuropathic pain: thermal hyperalgesia, tactile
allodynia and incapacitance.
[1324] (1) Plantar thermal hyperalgesia: Rats are tested for
hyperalgesia using a plantar device (Ugo Basile Inc., Cat.#37370).
After acclimation to the testing room, rats are placed on an
elevated glass floor beneath inverted clear plastic cages, and a
radiant heat source beneath the glass is aimed at the mid-plantar
surface of the hindpaw after they have ceased all exploratory
behavior. The onset of light activates a timer, which is terminated
by a hindpaw withdrawal response. A cutoff time of 30 seconds is
used to avoid tissue damage in the absence of a response. The
average withdrawal latency value of three trials from the
ipsilateral hindpaw is measured with at least 5-10 minutes between
each trial to avoid any tissue damage.
[1325] (2) Tactile allodynia is tested as described above.
[1326] (3) Incapacitance: The incapacitance test measures the
weight the rat places on each of its hindpaws. The rat is placed in
a small, clear Plexiglas box (6'' long.times.3'' wide.times.4''
tall). The box is tilted up and opens in the front. The rat is
placed in the box so that its hindpaws are at the back (lower)
portion of the box, and the forepaws are at the front (raised) part
of the box. The rat's head is at the opening in the front of the
box. The box is placed on a divided scale such that each of the
rat's hindpaws is on one of the two weighing pans of the scale. The
weight that the rat placed on each hindpaw is then measured. The
procedure is rapid (about 10 sec) and does not cause the animal any
pain.
Calcium Mobilization
[1327] Compounds that are not specific for a particular S1P
receptor can cause undesirable side effects. Accordingly, compounds
are tested to identify those that are specific. Accordingly, the
test compounds are tested in a calcium mobilization assay. The
procedure is essentially as described in Davis et al. (2005)
Journal of Biological Chemistry, vol. 280, pp. 9833-9841, which is
incorporated by reference in its entirety with the following
modifications. Calcium mobilization assays are performed in
recombinant CHEM cells expressing human S1P.sub.1, S1P.sub.2,
S1P.sub.3, S1P.sub.4, or S1P.sub.5 purchased from Millipore
(Billerica, Mass.). To detect free intracellular calcium,
S1P.sub.1, S1P.sub.2, S1P.sub.3, S1P.sub.4, or S1P.sub.5 cells are
loaded with FLIPR Calcium 4 dye from Molecular Devices (Sunnyvale,
Calif.). Cells are imaged for calcium mobilization using a
FLIPRTETRA equipped with a 96-well dispense head.
In Vivo Screening Assays
[1328] Measurement of circulating lymphocytes: Compounds are
dissolved in 30% HPCD. Mice (C57bl/6 male, 6-10 week-old) are
administered 0.5 and 5 mg/kg of a compound via oral gavage 30% HPCD
is included as a negative control.
[1329] Blood is collected from the retro-orbital sinus 5 and 24
hours after drug administration under short isoflurane anesthesia.
Whole blood samples are subjected to hematology analysis.
Peripheral lymphocyte counts are determined using an automated
analyzer (HEMAVET.TM. 3700). Subpopulations of peripheral blood
lymphocytes are stained by fluorochrome-conjugated specific
antibodies and analyzed using a fluorescent activating cell sorter
(FACSCALIBUR.TM.). Three mice are used to assess the lymphocyte
depletion activity of each compound screened.
[1330] Compounds of formula (I), or pharmaceutically acceptable
salts thereof, can induce full lymphopenia at times as short as 4
hours or less to as long as 48 hours or more; for example, 4 to 36
hours, or 5 to 24 hours. In some cases, a compound of formula can
induce full lymphopenia at 5 hours and partial lymphopenia at 24
hours. The dosage required to induce lymphopenia can be in the
range of, e.g., 0.001 mg/kg to 100 mg/kg; or 0.01 mg/kg to 10
mg/kg. The dosage can be 10 mg/kg or less, such as 5 mg/kg or less,
1 mg/kg or less, or 0.1 mg/kg or less.
[1331] Other embodiments are within the scope of the following
claims.
* * * * *