U.S. patent application number 17/484520 was filed with the patent office on 2022-04-14 for aminopyrimidine compound.
The applicant listed for this patent is Cardurion Pharmaceuticals, LLC. Invention is credited to Malcolm MACCOSS, Nobuyuki MATSUNAGA, Yasufumi MIYAMOTO, Takashi NAKAHATA, Tomohiro OKAWA, Akito SHIBUYA, Zenyu SHIOKAWA, Junya SHIRAI.
Application Number | 20220112184 17/484520 |
Document ID | / |
Family ID | 1000006048508 |
Filed Date | 2022-04-14 |
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United States Patent
Application |
20220112184 |
Kind Code |
A1 |
MATSUNAGA; Nobuyuki ; et
al. |
April 14, 2022 |
AMINOPYRIMIDINE COMPOUND
Abstract
The present invention provides a compound having a CaMKII
inhibitory action, which is expected to be useful as an agent for
the prophylaxis or treatment of cardiac diseases (particularly
catecholaminergic polymorphic ventricular tachycardia,
postoperative atrial fibrillation, heart failure, fatal arrhythmia)
and the like. The present invention relates to a compound
represented by the formula (I): ##STR00001## wherein each symbol is
as defined in the specification, or a salt thereof.
Inventors: |
MATSUNAGA; Nobuyuki;
(Kanagawa, JP) ; MIYAMOTO; Yasufumi; (Kanagawa,
JP) ; SHIRAI; Junya; (Kanagawa, JP) ;
NAKAHATA; Takashi; (Kanagawa, JP) ; SHIOKAWA;
Zenyu; (Kanagawa, JP) ; OKAWA; Tomohiro;
(Kanagawa, JP) ; SHIBUYA; Akito; (Kanagawa,
JP) ; MACCOSS; Malcolm; (Seabrook Island,
SC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cardurion Pharmaceuticals, LLC |
Cambridge |
MA |
US |
|
|
Family ID: |
1000006048508 |
Appl. No.: |
17/484520 |
Filed: |
September 24, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16580984 |
Sep 24, 2019 |
11130752 |
|
|
17484520 |
|
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62735897 |
Sep 25, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 498/08 20130101; C07D 413/14 20130101; A61P 9/00 20180101 |
International
Class: |
C07D 413/14 20060101
C07D413/14; A61P 9/00 20060101 A61P009/00; C07D 417/14 20060101
C07D417/14; C07D 498/08 20060101 C07D498/08 |
Claims
1-8. (canceled)
9. A method of inhibiting calcium/calmodulin-dependent protein
kinase II in a mammal, which comprises administering an effective
amount of a compound represented by the formula (I): ##STR00546##
wherein A is CH or N; R.sup.1 is a C.sub.1-3 alkyl group; R.sup.2
is (1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: wherein
X.sup.1 is a C.sub.1-6 alkylene group optionally substituted by 1
to 4 halogen atoms, X.sup.2 is (i) a bond, or (ii) a group
represented by the formula: ##STR00547## wherein n is an integer of
1 to 4, p is an integer of 0 to 7, and Y is (i) a hydrogen atom, or
(ii) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
halogen atoms, (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: wherein X.sup.3 is a C.sub.1-6 alkylene
group optionally substituted by 1 to 4 halogen atoms, and Z.sup.1
is (i) a cyano group, (ii) a C.sub.1-6 alkylsulfonyl group, or
(iii) a 3- to 8-membered monocyclic oxygen-containing non-aromatic
heterocyclic group, (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: wherein X.sup.4 is a bond or a C.sub.1-6
alkylene group optionally substituted by 1 to 4 halogen atoms, and
Z.sup.2 is a 5- or 6-membered monocyclic nitrogen containing
aromatic heterocyclic group optionally substituted by 1 to 3
C.sub.1-6 alkyl groups, or (4) a hydroxy group; R.sup.3 is a cyano
group or a halogen atom; and R.sup.4 is a morpholinyl group or a
bridged morpholinyl group, each optionally substituted by 1 to 3
C.sub.1-6 alkyl groups; or a pharmaceutically acceptable salt
thereof.
10. The method according to claim 9, wherein the compound is
selected from
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1-
R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1-
H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)--
4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxyprop-
oxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl-
)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cycloh-
exyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-
-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)--
1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile,
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexy-
l)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)p-
ropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-
-pyrazol-4-yl)pyrimidin-2-amine, or a pharmaceutically acceptable
salt thereof.
11. A method for the prophylaxis or treatment of cardiac diseases
in a mammal, which comprises administering an effective amount of a
compound represented by the formula (I): ##STR00548## wherein A is
CH or N; R.sup.1 is a C.sub.1-3 alkyl group; R.sup.2 is (1) a group
represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: wherein
X.sup.1 is a C.sub.1-6 alkylene group optionally substituted by 1
to 4 halogen atoms, X.sup.2 is (i) a bond, or (ii) a group
represented by the formula: ##STR00549## wherein n is an integer of
1 to 4, p is an integer of 0 to 7, and Y is (i) a hydrogen atom, or
(ii) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
halogen atoms, (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: wherein X.sup.3 is a C.sub.1-6 alkylene
group optionally substituted by 1 to 4 halogen atoms, and Z.sup.1
is (i) a cyano group, (ii) a C.sub.1-6 alkylsulfonyl group, or
(iii) a 3- to 8-membered monocyclic oxygen-containing non-aromatic
heterocyclic group, (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: wherein X.sup.4 is a bond or a C.sub.1-6
alkylene group optionally substituted by 1 to 4 halogen atoms, and
Z.sup.2 is a 5- or 6-membered monocyclic nitrogen containing
aromatic heterocyclic group optionally substituted by 1 to 3
C.sub.1-6 alkyl groups, or (4) a hydroxy group; R.sup.3 is a cyano
group or a halogen atom; and R.sup.4 is a morpholinyl group or a
bridged morpholinyl group, each optionally substituted by 1 to 3
C.sub.1-6 alkyl groups; or a pharmaceutically acceptable salt
thereof.
12. The method according to claim 11, wherein the compound is
selected from
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1-
R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1-
H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)--
4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxyprop-
oxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl-
)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cycloh-
exyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-
-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)--
1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile,
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexy-
l)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)p-
ropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-
-pyrazol-4-yl)pyrimidin-2-amine, or a pharmaceutically acceptable
salt thereof.
13. The method according to claim 11, wherein the cardiac disease
is selected from catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure, and
fatal arrhythmia.
14. The method according to claim 13, wherein the cardiac disease
is postoperative atrial fibrillation.
15. The method according to claim 13, wherein the cardiac disease
is catecholaminergic polymorphic ventricular tachycardia.
16. The method according to claim 13, wherein the cardiac disease
is heart failure.
17. The method according to claim 13, wherein the cardiac disease
is fatal arrhythmia.
18. The method according to claim 11, wherein the mammal is a
human.
19. A pharmaceutical composition comprising a compound represented
by the formula (I): ##STR00550## wherein A is CH or N; R.sup.1 is a
C.sub.1-3 alkyl group; R.sup.2 is (1) a group represented by the
formula: --O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y:
wherein X.sup.1 is a C.sub.1-6 alkylene group optionally
substituted by 1 to 4 halogen atoms, X.sup.2 is (i) a bond, or (ii)
a group represented by the formula: ##STR00551## wherein n is an
integer of 1 to 4, p is an integer of 0 to 7, and Y is (i) a
hydrogen atom, or (ii) a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 halogen atoms, (2) a group represented by the
formula: --O--X.sup.3--Z.sup.1: wherein X.sup.3 is a C.sub.1-6
alkylene group optionally substituted by 1 to 4 halogen atoms, and
Z.sup.1 is (i) a cyano group, (ii) a C.sub.1-6 alkylsulfonyl group,
or (iii) a 3- to 8-membered monocyclic oxygen-containing
non-aromatic heterocyclic group, (3) a group represented by the
formula: --O--X.sup.4--Z.sup.2: wherein X.sup.4 is a bond or a
C.sub.1-6 alkylene group optionally substituted by 1 to 4 halogen
atoms, and Z.sup.2 is a 5- or 6-membered monocyclic nitrogen
containing aromatic heterocyclic group optionally substituted by 1
to 3 C.sub.1-6 alkyl groups, or (4) a hydroxy group; R.sup.3 is a
cyano group or a halogen atom; and R.sup.4 is a morpholinyl group
or a bridged morpholinyl group, each optionally substituted by 1 to
3 C.sub.1-6 alkyl groups; or a pharmaceutically acceptable salt
thereof.
20. The pharmaceutical composition according to claim 19, wherein
the compound is selected from
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyr-
azol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)--
4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxyprop-
oxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl-
)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cycloh-
exyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-
-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)--
1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile,
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexy-
l)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)p-
ropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-
-pyrazol-4-yl)pyrimidin-2-amine, or a pharmaceutically acceptable
salt thereof.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/580,984, filed Sep. 24, 2019, which claims
the benefit of priority to U.S. Patent Application No. 62/735,897,
filed on Sep. 25, 2018, the entire contents of which are herein
incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to an aminopyrimidine compound
having a calcium/calmodulin-dependent protein kinase II (sometimes
to be abbreviated as "CaMKII" in the present specification)
inhibitory action, which is expected to be useful as an agent for
the prophylaxis or treatment of cardiac diseases (particularly
catecholaminergic polymorphic ventricular tachycardia,
postoperative atrial fibrillation, heart failure, fatal arrhythmia)
and the like.
BACKGROUND
[0003] Cardiac diseases include heart failure, arrhythmia,
myocardial infarction, angina, valvular heart disease and the like,
and they are high-mortality diseases. In treatment of cardiac
diseases with a drug, the symptoms are improved by control of each
risk factor and symptomatic therapy. However, the satisfaction with
treatment remains low level, and there is now no definitive
therapy.
[0004] Calcium-calmodulin complex binds to
Ca.sup.2+/calmodulin-dependent protein kinase (CaMK) included in
serine/threonine protein kinase, and activates the kinase. The CaMK
family includes CaMKII, and four isoforms (.alpha., .beta., .gamma.
and .delta.) exist as CaMKII. CaMKII .alpha. and CaMKII .beta. are
expressed mainly in cerebral tissue, and CaMKII .gamma. and CaMKII
.delta. are expressed in many tissues including heart. CaMKII is
activated by amino acid-modification due to oxidative stress or
hyperglycemia, in addition to the binding of calcium-calmodulin
complex. CaMKII regulates cell functions by phosphorylation of a
transcription factor which is a substrate, a protein that plays a
function in organelle uptake/excretion of Ca.sup.2+, a protein that
regulates contract and relax of muscles, a channel that regulates
an intracellular ion concentration, and the like, due to its kinase
activation.
[0005] Some documents suggest that CaMKII plays a harmful role in
progress of cardiac disease conditions. Expression and activity of
CaMKII are increased in heart of human patient or animal with heart
failure (Non-Patent Documents 1-4). In transgenic mouse
overexpressing CaMKII .delta. in heart, onsets of cardiac
hypertrophy and heart failure are reported (Non-Patent Document 4).
By studies using an inhibitor by a pharmacological method, and
studies using a gene deletion by genetic method, protecting effects
on heart failure, cardiac hypertrophy, myocardial infarction and
arrhythmia by an inhibition of CaMKII and an overexpression of
CaMKII inhibitory protein are reported in mouse (Non-Patent
Documents 5-7). For catecholaminergic polymorphic ventricular
tachycardia, improving effects on disease conditions by CaMKII
inhibitor in mutant ryanodine knock-in mouse (RyR2.sup.R4496C+/-
mouse) are reported (Non-Patent Document 8). These findings suggest
availabilities of CaMKII inhibitors in the prophylaxis and/or
treatment of cardiac diseases including heart failure, cardiac
hypertrophy, myocardial infarction and cardiac arrhythmia.
[0006] Recently, CaMKII exacerbating action on growth or metastasis
of a certain type of cancer is suggested (Non-Patent Document 9).
In addition, therapeutic effect on acute renal failure, intimal
hypertrophy, hepatic fibrosis, stroke, pain, rheumatoid arthritis
and the like by CaMKII inhibition are also indicated (Non-Patent
Documents 10-15).
[0007] However, genetic methods achieve only deficiency of protein
or overexpression of inhibitory protein, and they are different
from a mechanism which inhibits temporarily kinase activity, and
therefore, effects by kinase inhibitor cannot be always expected.
In addition, inhibitors which have been already reported are not
suitable for application as a medicament for a CaMKII selective
inhibitor, because they have a low kinase selectivity to CaMKII, or
they are not suitable for oral administration or chronic
administration.
[0008] As a heterocyclic compound, the following compounds are
known. Patent Document 1 describes that a compound represented by
the following formula (I):
##STR00002##
wherein each symbol is as defined in Patent Document 1, is a FLT3
inhibitor and useful for the treatment of acute myelogenous
leukemia and the like.
[0009] Patent Document 2 describes that a compound represented by
the following formula (I):
##STR00003##
wherein each symbol is as defined in Patent Document 2, is a Syk
(Spleen tyrosine kinase) inhibitor and useful for the treatment of
diseases or conditions mediated by Syk (e.g., rheumatism).
[0010] Patent Document 3 describes that a compound represented by
the following formula (I):
##STR00004##
wherein each symbol is as defined in Patent Document 3, is a mGluR
(metabotropic glutamate receptors)5 modulator and useful for the
treatment or prophylaxis of diseases or conditions in which mGluR5
is involved (e.g., pain disorder, anxiety, depression, Alzheimer's
disease, Parkinson's disease, etc.).
[0011] Patent Document 4 describes that a compound represented by
the following formula (I):
##STR00005##
wherein each symbol is as defined in Patent Document 4, is a kinase
inhibitor (particularly an inhibitor of kinase domain in VEGF
receptor (VEGF receptor tyrosine kinase inhibitor)) and useful for
the treatment of vascular abnormality, tumor, diabetic retinopathy,
rheumatism, endometriosis, psoriasis and the like.
[0012] Patent Document 5 describes that a compound represented by
the following formula (I):
##STR00006##
wherein each symbol is as defined in Patent Document 5, is a kinase
(p38 kinase, etc.) inhibitor and useful for reduction of ischemic
cell death (particularly reduction of traumatic neuronalcell
death).
[0013] Patent Document 6 describes that a compound represented by
the following formula (I):
##STR00007##
wherein each symbol is as defined in Patent Document 6, is a CaMKII
inhibitor and useful for treatment of cardiac diseases
(particularly catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure,
fatal arrhythmia) and the like.
DOCUMENT LIST
Patent Document
[0014] Patent Document 1: WO 2013/157540 [0015] Patent Document 2:
WO 2013/052394 [0016] Patent Document 3: WO 2005/021529 [0017]
Patent Document 4: WO 2002/024681 [0018] Patent Document 5: WO
2002/011724 [0019] Patent Document 6: WO 2018/183112
Non-Patent Document
[0019] [0020] Non-Patent Document 1: European Journal of Heart
Failure, vol. 16, p. 1292-1300 [0021] Non-Patent Document 2:
Circulation Research, vol. 84, p. 713-721 [0022] Non-Patent
Document 3: Molecular Endocrinology, vol. 17, p. 183-192 [0023]
Non-Patent Document 4: Circulation Research, vol. 92, p. 912-919
[0024] Non-Patent Document 5: Proceedings of the National Academy
of Sciences, vol. 106, p. 2342-2347 [0025] Non-Patent Document 6:
Circulation Research, vol. 112, p. 935-944 [0026] Non-Patent
Document 7: Nature, vol. 502, p. 372-376 [0027] Non-Patent Document
8: Journal of Molecular and Cellular Cardiology, vol. 50, p.
214-222 [0028] Non-Patent Document 9: Oncotarget, vol. 20, p.
11725-11734 [0029] Non-Patent Document 10: Arterioscler Thromb Vasc
Biol, vol. 28, p. 441-447 [0030] Non-Patent Document 11: Cell
Calcium, vol. 45, p. 284-292 [0031] Non-Patent Document 12: J Clin
Invest, vol. 119, p. 2925-2941 [0032] Non-Patent Document 13: J
Biol Chem, vol. 285, p. 20675-20682 [0033] Non-Patent Document 14:
J Pharmacol Exp Ther, vol. 325, p. 267-275 [0034] Non-Patent
Document 15: BMC Musculoskelet Disord, vol. 30, p. 61
SUMMARY
[0035] An object of the present invention is to provide a compound
having a CaMKII inhibitory action, which is expected to be useful
as an agent for the prophylaxis or treatment of cardiac diseases
(particularly catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure,
fatal arrhythmia) and the like.
[0036] The present inventors have conducted intensive studies in an
attempt to solve the above-mentioned problems and found that a
compound represented by the following formula (I) has a CaMKII
inhibitory action, and therefore, is expected to be useful as an
agent for the prophylaxis or treatment of cardiac diseases
(particularly catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure,
fatal arrhythmia) and the like, which resulted in the completion of
the present invention.
[0037] Accordingly, the present invention provides the
following.
[1] A compound represented by the formula (I):
##STR00008##
wherein
A is CH or N;
[0038] R.sup.1 is a C.sub.1-3 alkyl group;
R.sup.2 is
[0039] (1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0040]
wherein [0041] X.sup.1 is a C.sub.1-6 alkylene group optionally
substituted by 1 to 4 halogen atoms, [0042] X.sup.2 is [0043] (i) a
bond, or [0044] (ii) a group represented by the formula:
[0044] ##STR00009## [0045] wherein n is an integer of 1 to 4,
[0046] p is an integer of 0 to 7, and [0047] Y is [0048] (i) a
hydrogen atom, or [0049] (ii) a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 halogen atoms, (2) a group represented by the
formula: --O--X.sup.3--Z.sup.1: [0050] wherein [0051] X.sup.3 is a
C.sub.1-6 alkylene group optionally substituted by 1 to 4 halogen
atoms, and [0052] Z.sup.1 is [0053] (i) a cyano group, [0054] (ii)
a C.sub.1-6 alkylsulfonyl group, or [0055] (iii) a 3- to 8-membered
monocyclic non-aromatic heterocyclic group, (3) a group represented
by the formula: --O--X.sup.4--Z.sup.2: [0056] wherein [0057]
X.sup.4 is a bond or a C.sub.1-6 alkylene group optionally
substituted by 1 to 4 halogen atoms, and [0058] Z.sup.2 is a 5- or
6-membered monocyclic aromatic heterocyclic group optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups, or (4) a hydroxy
group; R.sup.3 is a cyano group or a halogen atom; and R.sup.4 is a
morpholinyl group or a bridged morpholinyl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups; or a salt thereof
(hereinafter sometimes to be referred to as "compound (I)"). [1a] A
compound represented by the formula (I):
##STR00010##
[0058] wherein
A is CH or N;
[0059] R.sup.1 is a C.sub.1-3 alkyl group;
R.sup.2 is
[0060] (1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0061] wherein [0062] each of
X.sup.1 is independently a C.sub.1-6 alkylene group optionally
substituted by 1 to 4 halogen atoms, each of X.sup.2 is
independently [0063] (i) a bond, or [0064] (ii) a group represented
by the formula:
[0064] ##STR00011## [0065] wherein n is an integer of 1 to 4,
[0066] m is an integer of 0 to 8, and [0067] Y is [0068] (i) a
hydrogen atom, or [0069] (ii) a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 halogen atoms, (2) a group represented by the
formula: --O--X.sup.3--Z.sup.1: [0070] wherein [0071] X.sup.3 is a
C.sub.1-6 alkylene group optionally substituted by 1 to 4 halogen
atoms, and [0072] Z.sup.1 is [0073] (i) a cyano group, [0074] (ii)
a C.sub.1-6 alkylsulfonyl group, or [0075] (iii) a 3- to 8-membered
monocyclic non-aromatic heterocyclic group, or (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0076] wherein
[0077] X.sup.4 is a bond or a C.sub.1-6 alkylene group optionally
substituted by 1 to 4 halogen atoms, and [0078] Z.sup.2 is a 5- or
6-membered monocyclic aromatic heterocyclic group optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups; R.sup.3 is a cyano
group or a halogen atom; and R.sup.4 is a morpholinyl group or a
bridged morpholinyl group, each optionally substituted by 1 to 3
C.sub.1-6 alkyl groups; provided that when m is 0, then Y is a
hydrogen atom, or a salt thereof. [2] The compound or salt of the
above-mentioned [1], wherein
[0079] R.sup.1 is a methyl group;
[0080] R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0081]
wherein [0082] X.sup.1 is a C.sub.1-6 alkylene group, [0083]
X.sup.2 is a bond, [0084] p is an integer of 0 or 1, and [0085] Y
is [0086] (i) a hydrogen atom, or [0087] (ii) a C.sub.1-3 alkyl
group optionally substituted by 1 to 3 halogen atoms, (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0088] wherein
[0089] X.sup.3 is a C.sub.1-3 alkylene group, and [0090] Z.sup.1 is
[0091] (i) a cyano group, [0092] (ii) a C.sub.1-3 alkylsulfonyl
group, or [0093] (iii) a 3- to 6-membered monocyclic non-aromatic
heterocyclic group, (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0094] wherein [0095] X.sup.4 is a C.sub.1-3
alkylene group, and [0096] Z.sup.2 is a 5- or 6-membered monocyclic
aromatic heterocyclic group optionally substituted by 1 to 3
C.sub.1-3 alkyl groups, or (4) a hydroxy group;
[0097] R.sup.3 is a cyano group or a chlorine atom; and
[0098] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups.
[3] The compound or salt of the above-mentioned [1], wherein
[0099] R.sup.1 is a methyl group;
[0100] R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0101]
wherein [0102] X.sup.1 is a C.sub.1-6 alkylene group, [0103]
X.sup.2 is a bond, [0104] p is an integer of 0 or 1, and [0105] Y
is [0106] (i) a hydrogen atom, or [0107] (ii) a C.sub.1-3 alkyl
group, or (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0108] wherein [0109] X.sup.3 is a C.sub.1-3
alkylene group, and [0110] Z.sup.1 is a 3- to 6-membered monocyclic
non-aromatic heterocyclic group;
[0111] R.sup.3 is a cyano group or a chlorine atom; and
[0112] R.sup.4 is a morpholino group, a morpholino group
substituted by 1 or 2 C.sub.1-6 alkyl groups, or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.
[4] The compound or salt of the above-mentioned [3], wherein
R.sup.2 is (1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0113]
wherein [0114] X.sup.1 is --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3-- or
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2, [0115] X.sup.2 is a bond, [0116] p is an integer of 0 or
1, and [0117] Y is a hydrogen atom, a methyl group or an ethyl
group, or (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0118] wherein [0119] X.sup.3 is
--CH.sub.2-- or --(CH.sub.2).sub.2--, and [0120] Z.sup.1 is an
oxetanyl group or a tetrahydropyranyl group. [5] A compound
selected from [0121]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-
-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethox-
y)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0122]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile, [0123]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0124]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile, [0125]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-py-
razol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0126]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile, [0127]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride, [0128]
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1--
ol, [0129]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)--
4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-
-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0130]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile, [0131]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)--
1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0132]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0133]
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexy-
l)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol, [0134]
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimid-
in-2-amine, [0135]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and [0136]
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine-
, or a salt thereof. [6] A medicament comprising the compound or
salt of the above-mentioned [1]. [7] The medicament of the
above-mentioned [6], which is a calcium/calmodulin-dependent
protein kinase II inhibitor. [8] The medicament of the
above-mentioned [6], which is an agent for the prophylaxis or
treatment of cardiac diseases. [9] The medicament of the
above-mentioned [8], wherein the cardiac disease is selected from
catecholaminergic polymorphic ventricular tachycardia,
postoperative atrial fibrillation, heart failure and fatal
arrhythmia. [10] The compound or salt of the above-mentioned [1]
for use in the prophylaxis or treatment of cardiac diseases. [11]
The compound or salt of the above-mentioned [10], wherein the
cardiac disease is selected from catecholaminergic polymorphic
ventricular tachycardia, postoperative atrial fibrillation, heart
failure and fatal arrhythmia. [12] A method of inhibiting
calcium/calmodulin-dependent protein kinase II in a mammal, which
comprises administering an effective amount of the compound or salt
of the above-mentioned [1] to the mammal. [13] A method for the
prophylaxis or treatment of cardiac diseases in a mammal, which
comprises administering an effective amount of the compound or salt
of the above-mentioned [1] to the mammal. [14] The method of the
above-mentioned [13], wherein the cardiac disease is selected from
catecholaminergic polymorphic ventricular tachycardia,
postoperative atrial fibrillation, heart failure and fatal
arrhythmia. [15] Use of the compound or salt of the above-mentioned
[1] for the production of an agent for the prophylaxis or treatment
of cardiac diseases. [16] The use of the above-mentioned [15],
wherein the cardiac disease is selected from catecholaminergic
polymorphic ventricular tachycardia, postoperative atrial
fibrillation, heart failure and fatal arrhythmia.
[0137] According to the present invention, a compound having a
superior CaMKII inhibitory action, which is expected to be useful
as an agent for the prophylaxis or treatment of cardiac diseases
(particularly catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure,
fatal arrhythmia) and the like can be provided.
DETAILED DESCRIPTION
[0138] The present invention is explained in detail in the
following.
[0139] The definition of each substituent used in the present
specification is described in detail in the following. Unless
otherwise specified, each substituent has the following
definition.
[0140] In the present specification, examples of the "halogen atom"
include fluorine, chlorine, bromine and iodine.
[0141] In the present specification, examples of the "C.sub.1-3
alkyl group" include methyl, ethyl, propyl and isopropyl.
[0142] In the present specification, examples of the "C.sub.1-6
alkyl group" include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Preferred is
a C.sub.1-3 alkyl group.
[0143] In the present specification, examples of the "C.sub.1-6
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,
isopentylsulfonyl, neopentylsulfanyl, 1-ethylpropylsulfonyl and
hexylsulfonyl. Preferred is a C.sub.1-3 alkylsulfonyl group.
[0144] In the present specification, examples of the "C.sub.1-3
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl,
propylsulfonyl and isopropylsulfonyl.
[0145] In the present specification, examples of the "C.sub.1-6
alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
Preferred is a C.sub.1-3 alkoxy group.
[0146] In the present specification, examples of the "C.sub.1-3
alkoxy group" include methoxy, ethoxy, propoxy and isopropoxy.
[0147] In the present specification, examples of the "5- or
6-membered monocyclic aromatic heterocyclic group" include thienyl,
furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like.
Preferred is a 5- or 6-membered monocyclic nitrogen-containing
aromatic heterocyclic group.
[0148] In the present specification, examples of the "5- or
6-membered monocyclic nitrogen-containing aromatic heterocyclic
group" include pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl,
triazinyl and the like.
[0149] In the present specification, examples of the "3- to
8-membered monocyclic non-aromatic heterocyclic group" include
aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,
tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,
imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl,
pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl,
tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl,
piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl,
dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl,
dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl,
morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl,
oxepanyl, azocanyl, diazocanyl and the like. Preferred is a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group.
[0150] In the present specification, examples of the "3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group" include oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl and the like.
[0151] In the present specification, examples of the "bridged
morpholinyl group" include 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.
[0152] In the present specification, examples of the "C.sub.1-6
alkylene group" include --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--(CH.sub.2).sub.6--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH(C.sub.2H.sub.5)--, --CH(C.sub.3H.sub.7)--,
--CH(CH(CH.sub.3).sub.2)--, --(CH(CH.sub.3)).sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--C(CH.sub.3).sub.2--,
--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--,
--C(CH.sub.3).sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2-- and
--C(CH.sub.3).sub.2--CH.sub.2--CH.sub.2--CH.sub.2--. In the present
specification, examples of the "C.sub.1-3 alkylene group" include
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH(C.sub.2H.sub.5)--,
--CH.sub.2--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2-- and
--CH.sub.2--C(CH.sub.3).sub.2--.
[0153] The definition of each symbol in the formula (I) is
explained in detail in the following.
[0154] A is CH or N.
[0155] R.sup.1 is a C.sub.1-3 alkyl group (e.g., methyl).
[0156] R.sup.1 is preferably a methyl group.
[0157] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0158] wherein [0159] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0160] each of X.sup.2 is independently [0161] (i)
a bond, or [0162] (ii) a group represented by the formula:
[0162] ##STR00012## [0163] wherein n is an integer of 1 to 4,
[0164] m is an integer of 0 to 8, and [0165] Y is [0166] (i) a
hydrogen atom, or [0167] (ii) a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0168] wherein [0169] X.sup.3
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0170] Z.sup.1
is [0171] (i) a cyano group, [0172] (ii) a C.sub.1-6 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0173] (iii) a 3-
to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,
oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0174] wherein
[0175] X.sup.4 is a bond or a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and [0176] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl,
pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-6 alkyl
groups (e.g., methyl).
[0177] R.sup.2 is preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0178] wherein [0179] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0180] each of X.sup.2 is independently [0181] (i)
a bond, or [0182] (ii) a group represented by the formula:
[0182] ##STR00013## [0183] wherein n is an integer of 1 or 2,
[0184] m is an integer of 0 to 8, and [0185] Y is [0186] (i) a
hydrogen atom, or [0187] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0188] wherein [0189] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0190] Z.sup.1
is [0191] (i) a cyano group, [0192] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0193] (iii) a 3-
to 6-membered monocyclic oxygen-containing non-aromatic
heterocyclic group (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), or (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0194] wherein [0195] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0196] Z.sup.2 is a 5- or
6-membered monocyclic nitrogen-containing aromatic heterocyclic
group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl).
[0197] As another embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0198] wherein [0199] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0200] X.sup.2 is a bond, [0201] m is an integer of 0 to 2, and
[0202] Y is [0203] (i) a hydrogen atom, or [0204] (ii) a C.sub.1-6
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0205] wherein
[0206] X.sup.3 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0207] Z.sup.1 is
a C.sub.1-6 alkylsulfonyl group (e.g., methylsulfonyl), or (3) a
group represented by the formula: --O--X.sup.4--Z.sup.2: [0208]
wherein [0209] X.sup.4 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--), and [0210] Z.sup.2 is a 5- or 6-membered monocyclic
aromatic heterocyclic group (e.g., pyridyl).
[0211] In this embodiment, R.sup.2 is more preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0212] wherein [0213] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0214] X.sup.2 is a bond, [0215] m is an integer of 0 to 2, and
[0216] Y is [0217] (i) a hydrogen atom, or [0218] (ii) a C.sub.1-3
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0219] wherein
[0220] X.sup.3 is a C.sub.1-3 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0221] Z.sup.1 is
a C.sub.1-3 alkylsulfonyl group (e.g., methylsulfonyl), or (3) a
group represented by the formula: --O--X.sup.4--Z.sup.2: [0222]
wherein [0223] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--), and [0224] Z.sup.2 is a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group (e.g.,
pyridyl).
[0225] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0226] wherein [0227] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), each of X.sup.2 is independently [0228] (i) a bond,
or [0229] (ii) a group represented by the formula:
[0229] ##STR00014## [0230] wherein n is an integer of 1 to 4,
[0231] m is an integer of 0 to 8 (preferably an integer of 1 to 8),
and [0232] Y is [0233] (i) a hydrogen atom, or [0234] (ii) a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0235] wherein [0236] X.sup.3 is a C.sub.1-6
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0237] Z.sup.1 is [0238] (i) a
cyano group, [0239] (ii) a C.sub.1-6 alkylsulfonyl group (e.g.,
methylsulfonyl, ethylsulfonyl), or [0240] (iii) a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydrofuryl, tetrahydropyranyl), or (3) a group represented by
the formula: --O--X.sup.4--Z.sup.2: [0241] wherein [0242] X.sup.4
is a bond or a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0243] Z.sup.2
is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl,
pyridyl, pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-6
alkyl groups (e.g., methyl).
[0244] R.sup.2 is preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0245] wherein [0246] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0247] each of X.sup.2 is independently [0248] (i)
a bond, or [0249] (ii) a group represented by the formula:
[0249] ##STR00015## [0250] wherein n is an integer of 1 or 2,
[0251] m is an integer of 0 to 8 (preferably an integer of 1 to 8),
and [0252] Y is [0253] (i) a hydrogen atom, or [0254] (ii) a
C.sub.1-3 alkyl group (the C.sub.1-3 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0255] wherein [0256] X.sup.3 is a C.sub.1-3
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0257] Z.sup.1 is [0258] (i) a
cyano group, [0259] (ii) a C.sub.1-3 alkylsulfonyl group (e.g.,
methylsulfonyl, ethylsulfonyl), or [0260] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0261]
wherein [0262] X.sup.4 is a bond or a C.sub.1-3 alkylene group
(e.g., --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and [0263] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl,
pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-3 alkyl
groups (e.g., methyl).
[0264] As another embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0265] wherein [0266] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0267] X.sup.2 is a bond, [0268] m is an integer of 0 to
2 (preferably an integer of 1 or 2), and [0269] Y is [0270] (i) a
hydrogen atom, or [0271] (ii) a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0272] wherein [0273] X.sup.3
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0274] Z.sup.1 is
[0275] (i) a cyano group, [0276] (ii) a C.sub.1-6 alkylsulfonyl
group (e.g., methylsulfonyl), or [0277] (iii) a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydrofuryl, tetrahydropyranyl), or (3) a group represented by
the formula: --O--X.sup.4--Z.sup.2: [0278] wherein [0279] X.sup.4
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0280] Z.sup.2 is
a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl,
pyridyl) optionally substituted by 1 to 3 C.sub.1-6 alkyl groups
(e.g., methyl).
[0281] In this embodiment, R.sup.2 is more preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0282] wherein [0283] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0284] X.sup.2 is a bond, [0285] m is an integer of 0 to
2 (preferably an integer of 1 or 2), and [0286] Y is [0287] (i) a
hydrogen atom, or [0288] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0289] wherein [0290] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0291] Z.sup.1 is
[0292] (i) a cyano group, [0293] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl), or [0294] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0295]
wherein [0296] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and
[0297] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl).
[0298] As another embodiment, R.sup.2 is more preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0299] wherein [0300] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0301] X.sup.2 is a bond, [0302] m is an integer of 1 or
2, and [0303] Y is [0304] (i) a hydrogen atom, or [0305] (ii) a
C.sub.1-6 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0306] wherein
[0307] X.sup.3 is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0308] Z.sup.1 is a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydropyranyl).
[0309] As another embodiment, R.sup.2 is further more
preferably
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0310] wherein [0311] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0312] X.sup.2 is a bond, [0313] m is an integer of 1 or
2, and [0314] Y is [0315] (i) a hydrogen atom, or [0316] (ii) a
C.sub.1-3 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0317] wherein
[0318] X.sup.3 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0319] Z.sup.1 is a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydropyranyl).
[0320] Furthermore, as another embodiment, R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0321]
wherein [0322] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0323] X.sup.2 is [0324] (i) a bond, or [0325] (ii)
a group represented by the formula:
[0325] ##STR00016## [0326] wherein n is an integer of 1 to 4,
[0327] p is an integer of 0 to 7, and [0328] Y is [0329] (i) a
hydrogen atom, or [0330] (ii) a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0331] wherein [0332] X.sup.3
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0333] Z.sup.1
is [0334] (i) a cyano group, [0335] (ii) a C.sub.1-6 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0336] (iii) a 3-
to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,
oxetanyl, tetrahydrofuryl, tetrahydropyranyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0337] wherein
[0338] X.sup.4 is a bond or a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and [0339] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl,
pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-6 alkyl
groups (e.g., methyl), or (4) a hydroxy group.
[0340] In this embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0341]
wherein [0342] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0343] X.sup.2 is [0344] (i) a bond, or [0345] (ii)
a group represented by the formula:
[0345] ##STR00017## [0346] wherein n is an integer of 1 or 2,
[0347] p is an integer of 0 to 7, and [0348] Y is [0349] (i) a
hydrogen atom, or [0350] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0351] wherein [0352] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0353] Z.sup.1
is [0354] (i) a cyano group, [0355] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0356] (iii) a 3-
to 6-membered monocyclic oxygen-containing non-aromatic
heterocyclic group (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0357] wherein [0358] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0359] Z.sup.2 is a 5- or
6-membered monocyclic nitrogen-containing aromatic heterocyclic
group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl), or (4) a hydroxy group.
[0360] Moreover, as another embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0361]
wherein [0362] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--)
[0363] X.sup.2 is a bond, [0364] p is an integer of 0 or 1, and
[0365] Y is [0366] (i) a hydrogen atom, or [0367] (ii) a C.sub.1-6
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0368] wherein
[0369] X.sup.3 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0370] Z.sup.1 is
a C.sub.1-6 alkylsulfonyl group (e.g., methylsulfonyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0371] wherein
[0372] X.sup.4 is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--),
and [0373] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (e.g., pyridyl), or (4) a hydroxy group.
[0374] In this embodiment, R.sup.2 is more preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0375]
wherein [0376] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0377] X.sup.2 is a bond, [0378] p is an integer of 0 or 1, and
[0379] Y is [0380] (i) a hydrogen atom, or [0381] (ii) a C.sub.1-3
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0382] wherein
[0383] X.sup.3 is a C.sub.1-3 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0384] Z.sup.1 is
a C.sub.1-3 alkylsulfonyl group (e.g., methylsulfonyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0385] wherein
[0386] X.sup.4 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--),
and [0387] Z.sup.2 is a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group (e.g., pyridyl), or
(4) a hydroxy group.
[0388] Furthermore, as another embodiment, R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0389]
wherein [0390] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0391] X.sup.2 is [0392] (i) a bond, or [0393] (ii)
a group represented by the formula:
[0393] ##STR00018## [0394] wherein n is an integer of 1 to 4,
[0395] p is an integer of 0 to 7, and [0396] Y is [0397] (i) a
hydrogen atom, or [0398] (ii) a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0399] wherein [0400] X.sup.3
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0401] Z.sup.1
is [0402] (i) a cyano group, [0403] (ii) a C.sub.1-6 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0404] (iii) a 3-
to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,
oxetanyl, tetrahydrofuryl, tetrahydropyranyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0405] wherein
[0406] X.sup.4 is a bond or a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and [0407] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (e.g., oxazolyl, thiazolyl, pyrazolyl,
triazolyl, imidazolyl, isoxazolyl, pyridyl, pyrimidinyl) optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl), or (4)
a hydroxy group.
[0408] In this embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0409]
wherein [0410] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0411] X.sup.2 is [0412] (i) a bond, or [0413] (ii)
a group represented by the formula:
[0413] ##STR00019## [0414] wherein n is an integer of 1 or 2,
[0415] p is an integer of 0 to 7, and [0416] Y is [0417] (i) a
hydrogen atom, or [0418] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0419] wherein [0420] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0421] Z.sup.1
is [0422] (i) a cyano group, [0423] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0424] (iii) a 3-
to 6-membered monocyclic non-aromatic heterocyclic group
(preferably a 3- to 6-membered monocyclic oxygen-containing
non-aromatic heterocyclic group) (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0425] wherein [0426] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0427] Z.sup.2 is a 5- or
6-membered monocyclic aromatic heterocyclic group (preferably a 5-
or 6-membered monocyclic nitrogen-containing aromatic heterocyclic
group) (e.g., oxazolyl, thiazolyl, pyrazolyl, triazolyl,
imidazolyl, isoxazolyl, pyridyl, pyrimidinyl) optionally
substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g., methyl), or (4)
a hydroxy group.
[0428] Moreover, as another embodiment, R.sup.2 is preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0429]
wherein [0430] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0431] X.sup.2 is a bond, [0432] p is an integer of 0 or
1, and [0433] Y is [0434] (i) a hydrogen atom, or [0435] (ii) a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0436] wherein [0437] X.sup.3 is a C.sub.1-6
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--), and [0438] Z.sup.1 is [0439] (i) a cyano
group, [0440] (ii) a C.sub.1-6 alkylsulfonyl group (e.g.,
methylsulfonyl), or [0441] (iii) a 3- to 8-membered monocyclic
non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0442] wherein [0443] X.sup.4 is a C.sub.1-6
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--), and [0444] Z.sup.2 is a 5- or 6-membered
monocyclic aromatic heterocyclic group (e.g., oxazolyl, thiazolyl,
pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl) optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl), or (4)
a hydroxy group.
[0445] In this embodiment, R.sup.2 is more preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0446]
wherein [0447] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0448] X.sup.2 is a bond, [0449] p is an integer of 0 or
1, and [0450] Y is [0451] (i) a hydrogen atom, or [0452] (ii) a
C.sub.1-3 alkyl group (the C.sub.1-3 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0453] wherein [0454] X.sup.3 is a C.sub.1-3
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--), and [0455] Z.sup.1 is [0456] (i) a cyano
group, [0457] (ii) a C.sub.1-3 alkylsulfonyl group (e.g.,
methylsulfonyl), or [0458] (iii) a 3- to 6-membered monocyclic
non-aromatic heterocyclic group (preferably a 3- to 6-membered
monocyclic oxygen-containing non-aromatic heterocyclic group)
(e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0459] wherein
[0460] X.sup.4 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0461] Z.sup.2 is
a 5- or 6-membered monocyclic aromatic heterocyclic group
(preferably a 5- or 6-membered monocyclic nitrogen-containing
aromatic heterocyclic group) (e.g., oxazolyl, thiazolyl, pyrazolyl,
triazolyl, imidazolyl, isoxazolyl, pyridyl) optionally substituted
by 1 to 3 C.sub.1-3 alkyl groups (e.g., methyl), or (4) a hydroxy
group.
[0462] Moreover, as another embodiment, R.sup.2 is more
preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: wherein
[0463] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0464] X.sup.2 is a bond, [0465] p is an integer of 0 or
1, and [0466] Y is [0467] (i) a hydrogen atom, or [0468] (ii) a
C.sub.1-6 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0469] wherein
[0470] X.sup.3 is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0471] Z.sup.1 is a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydropyranyl).
[0472] Moreover, as another embodiment, R.sup.2 is further more
preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0473]
wherein [0474] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0475] X.sup.2 is a bond, [0476] p is an integer of 0 or
1, and [0477] Y is [0478] (i) a hydrogen atom, or [0479] (ii) a
C.sub.1-3 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0480] wherein
[0481] X.sup.3 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0482] Z.sup.1 is a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydropyranyl).
[0483] Moreover, as another embodiment, R.sup.2 is still more
preferably
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0484]
wherein [0485] X.sup.1 is --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3-- or
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2, [0486] X.sup.2 is a bond, [0487] p is an integer of 0 or
1, and [0488] Y is a hydrogen atom, a methyl group or an ethyl
group, or (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0489] wherein [0490] X.sup.3 is
--CH.sub.2-- or --(CH.sub.2).sub.2--, and [0491] Z.sup.1 is an
oxetanyl group or a tetrahydropyranyl group.
[0492] R.sup.3 is a cyano group or a halogen atom (e.g., a chlorine
atom).
[0493] R.sup.3 is preferably a cyano group or a chlorine atom.
[0494] R.sup.4 is a morpholinyl group (e.g., morpholino) or a
bridged morpholinyl group (e.g.,
3-oxa-8-azabicyclo[3.2.1]octan-8-yl), each optionally substituted
by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0495] R.sup.4 is preferably a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0496] R.sup.4 is more preferably a morpholino group, a morpholino
group substituted by 1 or 2 C.sub.1-6 alkyl groups (e.g., methyl),
or a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.
[0497] In the formula (I), when m is 0, then Y is a hydrogen
atom.
[0498] Compound (I) is preferably a compound represented by the
formula (Ia):
##STR00020##
or a salt thereof (hereinafter sometimes to be referred to as
"compound (Ia)").
[0499] Preferable examples of compound (I) and compound (Ia)
include the following compounds.
[0500] Compound (I) or compound (Ia) wherein
[0501] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0502] wherein [0503] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0504] each of X.sup.2 is independently [0505] (i)
a bond, or [0506] (ii) a group represented by the formula:
[0506] ##STR00021## [0507] wherein n is an integer of 1 or 2,
[0508] m is an integer of 0 to 8, and [0509] Y is [0510] (i) a
hydrogen atom, or [0511] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0512] wherein [0513] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0514] Z.sup.1
is [0515] (i) a cyano group, [0516] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0517] (iii) a 3-
to 6-membered monocyclic oxygen-containing non-aromatic
heterocyclic group (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), or (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0518] wherein [0519] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0520] Z.sup.2 is a 5- or
6-membered monocyclic nitrogen-containing aromatic heterocyclic
group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl).
[0521] Compound (I) or compound (Ia) wherein
[0522] R.sup.1 is a methyl group;
[0523] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0524] wherein [0525] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), each of X.sup.2 is independently [0526] (i) a bond,
or [0527] (ii) a group represented by the formula:
[0527] ##STR00022## [0528] wherein n is an integer of 1 or 2,
[0529] m is an integer of 0 to 8, and [0530] Y is [0531] (i) a
hydrogen atom, or [0532] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0533] wherein [0534] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0535] Z.sup.1
is [0536] (i) a cyano group, [0537] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0538] (iii) a 3-
to 6-membered monocyclic oxygen-containing non-aromatic
heterocyclic group (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), or (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0539] wherein [0540] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0541] Z.sup.2 is a 5- or
6-membered monocyclic nitrogen-containing aromatic heterocyclic
group (e.g., oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl);
[0542] R.sup.3 is a cyano group or a chlorine atom; and
[0543] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0544] Compound (I) or compound (Ia) wherein R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0545] wherein [0546] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0547] X.sup.2 is a bond, [0548] m is an integer of 0 to 2, and
[0549] Y is [0550] (i) a hydrogen atom, or [0551] (ii) a C.sub.1-6
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0552] wherein
[0553] X.sup.3 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0554] Z.sup.1 is
a C.sub.1-6 alkylsulfonyl group (e.g., methylsulfonyl), or (3) a
group represented by the formula: --O--X.sup.4--Z.sup.2: [0555]
wherein [0556] X.sup.4 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--), and [0557] Z.sup.2 is a 5- or 6-membered monocyclic
aromatic heterocyclic group (e.g., pyridyl).
[0558] Compound (I) or compound (Ia) wherein
[0559] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0560] wherein [0561] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0562] X.sup.2 is a bond, [0563] m is an integer of 0 to 2, and
[0564] Y is [0565] (i) a hydrogen atom, or [0566] (ii) a C.sub.1-3
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0567] wherein
[0568] X.sup.3 is a C.sub.1-3 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0569] Z.sup.1 is
a C.sub.1-3 alkylsulfonyl group (e.g., methylsulfonyl), or (3) a
group represented by the formula: --O--X.sup.4--Z.sup.2: [0570]
wherein [0571] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--), and [0572] Z.sup.2 is a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group (e.g.,
pyridyl).
[0573] Compound (I) or compound (Ia) wherein
[0574] R.sup.1 is a methyl group;
[0575] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0576] wherein [0577] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--),
[0578] X.sup.2 is a bond, [0579] m is an integer of 0 to 2, and
[0580] Y is [0581] (i) a hydrogen atom, or [0582] (ii) a C.sub.1-3
alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted
by 1 to 3 halogen atoms (e.g., a fluorine atom), (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0583] wherein
[0584] X.sup.3 is a C.sub.1-3 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0585] Z.sup.1 is
a C.sub.1-3 alkylsulfonyl group (e.g., methylsulfonyl), or (3) a
group represented by the formula: --O--X.sup.4--Z.sup.2: [0586]
wherein [0587] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--), and [0588] Z.sup.2 is a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group (e.g.,
pyridyl);
[0589] R.sup.3 is a cyano group or a chlorine atom; and
[0590] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0591] Compound (I) or compound (Ia) wherein
[0592] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0593] wherein [0594] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, [0595] wherein * is
the bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), each of X.sup.2 is independently [0596] (i) a bond,
or [0597] (ii) a group represented by the formula:
[0597] ##STR00023## [0598] wherein n is an integer of 1 or 2,
[0599] m is an integer of 0 to 8 (preferably an integer of 1 to 8),
and [0600] Y is [0601] (i) a hydrogen atom, or [0602] (ii) a
C.sub.1-3 alkyl group (the C.sub.1-3 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0603] wherein [0604] X.sup.3 is a C.sub.1-3
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0605] Z.sup.1 is [0606] (i) a
cyano group, [0607] (ii) a C.sub.1-3 alkylsulfonyl group (e.g.,
methylsulfonyl, ethylsulfonyl), or [0608] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0609]
wherein [0610] X.sup.4 is a bond or a C.sub.1-3 alkylene group
(e.g., --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl,
pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-3 alkyl
groups (e.g., methyl).
[0611] Compound (I) or compound (Ia) wherein
[0612] R.sup.1 is a methyl group;
[0613] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0614] wherein [0615] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
fluorine atom), [0616] each of X.sup.2 is independently [0617] (i)
a bond, or [0618] (ii) a group represented by the formula:
[0618] ##STR00024## [0619] wherein n is an integer of 1 or 2,
[0620] m is an integer of 0 to 8 (preferably an integer of 1 to 8),
and [0621] Y is [0622] (i) a hydrogen atom, or [0623] (ii) a
C.sub.1-3 alkyl group (the C.sub.1-3 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0624] wherein [0625] X.sup.3 is a C.sub.1-3
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0626] Z.sup.1 is [0627] (i) a
cyano group, [0628] (ii) a C.sub.1-3 alkylsulfonyl group (e.g.,
methylsulfonyl, ethylsulfonyl), or [0629] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0630]
wherein [0631] X.sup.4 is a bond or a C.sub.1-3 alkylene group
(e.g., --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--)
optionally substituted by 1 to 4 halogen atoms (e.g., a fluorine
atom), and [0632] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl,
pyrimidinyl) optionally substituted by 1 to 3 C.sub.1-3 alkyl
groups (e.g., methyl);
[0633] R.sup.3 is a cyano group or a chlorine atom; and
[0634] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0635] Compound (I) or compound (Ia) wherein
[0636] R.sup.1 is a methyl group;
[0637] R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0638]
wherein [0639] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, *--CH.sub.2--CH(CH.sub.3)--**,
*--CH(CH.sub.3)--CH.sub.2--CH.sub.2--**,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
*--CH.sub.2--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--C(CH.sub.3).sub.2--**,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2) optionally substituted by 1 to 4 halogen atoms (e.g., a
[0640] fluorine atom), X.sup.2 is [0641] (i) a bond, or [0642] (ii)
a group represented by the formula:
[0642] ##STR00025## [0643] wherein n is an integer of 1 or 2,
[0644] p is an integer of 0 to 7, and [0645] Y is [0646] (i) a
hydrogen atom, or [0647] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0648] wherein [0649] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--) optionally substituted
by 1 to 4 halogen atoms (e.g., a fluorine atom), and [0650] Z.sup.1
is [0651] (i) a cyano group, [0652] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl, ethylsulfonyl), or [0653] (iii) a 3-
to 6-membered monocyclic non-aromatic heterocyclic group
(preferably a 3- to 6-membered monocyclic oxygen-containing
non-aromatic heterocyclic group) (e.g., oxetanyl, tetrahydrofuryl,
tetrahydropyranyl), (3) a group represented by the formula:
--O--X.sup.4--Z.sup.2: [0654] wherein [0655] X.sup.4 is a bond or a
C.sub.1-3 alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--) optionally substituted by 1 to 4 halogen
atoms (e.g., a fluorine atom), and [0656] Z.sup.2 is a 5- or
6-membered monocyclic aromatic heterocyclic group (preferably a 5-
or 6-membered monocyclic nitrogen-containing aromatic heterocyclic
group) (e.g., oxazolyl, thiazolyl, pyrazolyl, triazolyl,
imidazolyl, isoxazolyl, pyridyl, pyrimidinyl) optionally
substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g., methyl), or (4)
a hydroxy group;
[0657] R.sup.3 is a cyano group or a chlorine atom; and
[0658] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0659] Compound (I) or compound (Ia) wherein
[0660] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0661] wherein [0662] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0663] X.sup.2 is a bond, [0664] m is an integer of 0 to
2 (preferably an integer of 1 or 2), and [0665] Y is [0666] (i) a
hydrogen atom, or [0667] (ii) a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0668] wherein [0669] X.sup.3
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0670] Z.sup.1 is
[0671] (i) a cyano group, [0672] (ii) a C.sub.1-6 alkylsulfonyl
group (e.g., methylsulfonyl), or [0673] (iii) a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydrofuryl, tetrahydropyranyl), or (3) a group represented by
the formula: --O--X.sup.4--Z.sup.2: [0674] wherein [0675] X.sup.4
is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0676] Z.sup.2 is
a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl,
pyridyl) optionally substituted by 1 to 3 C.sub.1-6 alkyl groups
(e.g., methyl).
[0677] Compound (I) or compound (Ia) wherein
[0678] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0679] wherein [0680] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0681] X.sup.2 is a bond, [0682] m is an integer of 0 to
2 (preferably an integer of 1 or 2), and [0683] Y is [0684] (i) a
hydrogen atom, or [0685] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0686] wherein [0687] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0688] Z.sup.1 is
[0689] (i) a cyano group, [0690] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl), or [0691] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0692]
wherein [0693] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and
[0694] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl).
[0695] Compound (I) or compound (Ia) wherein
[0696] R.sup.1 is a methyl group;
[0697] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0698] wherein [0699] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0700] X.sup.2 is a bond, [0701] m is an integer of 0 to
2 (preferably an integer of 1 or 2), and [0702] Y is [0703] (i) a
hydrogen atom, or [0704] (ii) a C.sub.1-3 alkyl group (the
C.sub.1-3 alkyl group may be labeled with .sup.2H (e.g., methyl,
ethyl, isopropyl, deuteromethyl)) optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom), (2) a group represented by
the formula: --O--X.sup.3--Z.sup.1: [0705] wherein [0706] X.sup.3
is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0707] Z.sup.1 is
[0708] (i) a cyano group, [0709] (ii) a C.sub.1-3 alkylsulfonyl
group (e.g., methylsulfonyl), or [0710] (iii) a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), or (3)
a group represented by the formula: --O--X.sup.4--Z.sup.2: [0711]
wherein [0712] X.sup.4 is a C.sub.1-3 alkylene group (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and
[0713] Z.sup.2 is a 5- or 6-membered monocyclic aromatic
heterocyclic group (preferably a 5- or 6-membered monocyclic
nitrogen-containing aromatic heterocyclic group) (e.g., oxazolyl,
thiazolyl, pyrazolyl, triazolyl, imidazolyl, isoxazolyl, pyridyl)
optionally substituted by 1 to 3 C.sub.1-3 alkyl groups (e.g.,
methyl);
[0714] R.sup.3 is a cyano group or a chlorine atom; and
[0715] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0716] Compound (I) or compound (Ia) wherein
[0717] R.sup.1 is a methyl group;
[0718] R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0719]
wherein [0720] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
*--CH.sub.2--CH(CH.sub.3)--**,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0721] X.sup.2 is a bond, [0722] p is an integer of 0 or
1, and [0723] Y is [0724] (i) a hydrogen atom, or [0725] (ii) a
C.sub.1-3 alkyl group (the C.sub.1-3 alkyl group may be labeled
with .sup.2H (e.g., methyl, ethyl, isopropyl, deuteromethyl))
optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine
atom), (2) a group represented by the formula:
--O--X.sup.3--Z.sup.1: [0726] wherein [0727] X.sup.3 is a C.sub.1-3
alkylene group (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--), and [0728] Z.sup.1 is [0729] (i) a cyano
group, [0730] (ii) a C.sub.1-3 alkylsulfonyl group (e.g.,
methylsulfonyl), or [0731] (iii) a 3- to 6-membered monocyclic
non-aromatic heterocyclic group (preferably a 3- to 6-membered
monocyclic oxygen-containing non-aromatic heterocyclic group)
(e.g., oxetanyl, tetrahydrofuryl, tetrahydropyranyl), (3) a group
represented by the formula: --O--X.sup.4--Z.sup.2: [0732] wherein
[0733] X.sup.4 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--), and [0734] Z.sup.2 is
a 5- or 6-membered monocyclic aromatic heterocyclic group
(preferably a 5- or 6-membered monocyclic nitrogen-containing
aromatic heterocyclic group) (e.g., oxazolyl, thiazolyl, pyrazolyl,
triazolyl, imidazolyl, isoxazolyl, pyridyl) optionally substituted
by 1 to 3 C.sub.1-3 alkyl groups (e.g., methyl), or (4) a hydroxy
group;
[0735] R.sup.3 is a cyano group or a chlorine atom; and
[0736] R.sup.4 is a morpholino group or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, each optionally
substituted by 1 to 3 C.sub.1-6 alkyl groups (e.g., methyl).
[0737] Compound (I) or compound (Ia) wherein
[0738] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0739] wherein [0740] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0741] X.sup.2 is a bond, [0742] m is an integer of 1 or
2, and [0743] Y is [0744] (i) a hydrogen atom, or [0745] (ii) a
C.sub.1-6 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0746] wherein
[0747] X.sup.3 is a C.sub.1-6 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0748] Z.sup.1 is a 3- to 8-membered
monocyclic non-aromatic heterocyclic group (e.g., oxetanyl,
tetrahydropyranyl).
[0749] Compound (I) or compound (Ia) wherein
[0750] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0751] wherein [0752] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0753] X.sup.2 is a bond, [0754] m is an integer of 1 or
2, and [0755] Y is [0756] (i) a hydrogen atom, or [0757] (ii) a
C.sub.1-3 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0758] wherein
[0759] X.sup.3 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0760] Z.sup.1 is a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydropyranyl).
[0761] Compound (I) or compound (Ia) wherein
[0762] R.sup.1 is a methyl group;
[0763] R.sup.2 is
(1) a group represented by the formula:
--O--[X.sup.1-X.sup.2--O].sub.m--Y: [0764] wherein [0765] each of
X.sup.1 is independently a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0766] X.sup.2 is a bond, [0767] m is an integer of 1 or
2, and [0768] Y is [0769] (i) a hydrogen atom, or [0770] (ii) a
C.sub.1-3 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0771] wherein
[0772] X.sup.3 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0773] Z.sup.1 is a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydropyranyl);
[0774] R.sup.3 is a cyano group or a chlorine atom; and
[0775] R.sup.4 is a morpholino group, a morpholino group
substituted by 1 or 2 C.sub.1-6 alkyl groups (e.g., methyl), or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.
[0776] Compound (I) or compound (Ia) wherein
[0777] R.sup.1 is a methyl group;
[0778] R.sup.2 is
(1) a group represented by the formula:
--O--X.sup.1-X.sup.2--O--(CH.sub.2--CH.sub.2--O).sub.p--Y: [0779]
wherein [0780] X.sup.1 is a C.sub.1-6 alkylene group (e.g.,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
*--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.2--**, wherein * is the
bonding site to the oxygen atom, and ** is the bonding site to
X.sup.2), [0781] X.sup.2 is a bond, [0782] p is an integer of 0 or
1, and [0783] Y is [0784] (i) a hydrogen atom, or [0785] (ii) a
C.sub.1-3 alkyl group (e.g., methyl, ethyl), or (2) a group
represented by the formula: --O--X.sup.3--Z.sup.1: [0786] wherein
[0787] X.sup.3 is a C.sub.1-3 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--), and [0788] Z.sup.1 is a 3- to 6-membered
monocyclic non-aromatic heterocyclic group (preferably a 3- to
6-membered monocyclic oxygen-containing non-aromatic heterocyclic
group) (e.g., oxetanyl, tetrahydropyranyl);
[0789] R.sup.3 is a cyano group or a chlorine atom; and
[0790] R.sup.4 is a morpholino group, a morpholino group
substituted by 1 or 2 C.sub.1-6 alkyl groups (e.g., methyl), or a
3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.
[0791] Compound (I) or compound (Ia), which is v selected from
[0792]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyr-
azol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0793]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile, [0794]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0795]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile, [0796]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-
-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-py-
razol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0797]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile, [0798]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride, [0799]
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1--
ol, [0800]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)--
4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-
-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0801]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile, [0802]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)--
1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0803]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile, [0804]
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexy-
l)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol, [0805]
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimid-
in-2-amine, [0806]
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and [0807]
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine-
, or a salt thereof.
[0808] Specific examples of compound (I) include the compounds of
Examples 1 to 194, 196 to 483 and 485-513.
[0809] When compound (I) is a salt, examples of the salt include
metal salts, ammonium salts, salts with organic base, salts with
inorganic acid, salts with organic acid, and salts with basic or
acidic amino acid. Preferable examples of the metal salt include
alkali metal salts such as sodium salts, potassium salts and the
like; alkali earth metal salts such as calcium salts, magnesium
salts, barium salts and the like; and aluminum salts. Preferable
examples of the salt with organic base include salts with
trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,
ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,
dicyclohexylamine, N,N'-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts
with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, phosphoric acid and the like. Preferable examples of the salt
with organic acid include salts with formic acid, acetic acid,
trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,
tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and the like. Preferable examples of the salts with basic amino
acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include
salts with aspartic acid, glutamic acid and the like. Among them, a
pharmaceutically acceptable salt is preferable. For example, when a
compound has an acidic functional group, examples of the salt
include inorganic salts such as alkali metal salts (e.g., sodium
salt, potassium salt etc.), alkaline earth metal salts (e.g.,
calcium salt, magnesium salt etc.) and the like, ammonium salt
etc., and when a compound has a basic functional group, examples of
the salt include salts with inorganic acid such as hydrochloric
acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
and the like, and salts with organic acid such as acetic acid,
phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic
acid, citric acid, succinic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like.
[0810] When compound (I) contains isomers such as tautomers,
optical isomers, stereoisomers, position isomers and rotational
isomers, any of isomers or mixture are also encompassed in the
compound of the present invention. Further, when compound (I)
contains an optical isomer, the optical isomer separated from the
racemate is encompassed in compound (I).
[0811] Compound (I) can be obtained in the crystal form. Either
single crystalline form or crystalline mixture can be encompassed
in compound (I).
[0812] Compound (I) can be a pharmaceutically acceptable co-crystal
or a co-crystal salt. The co-crystal or co-crystal salt as used
herein means a crystalline material composed of two or more unique
solids at room temperature, each of which has distinctive physical
characteristics such as structure, melting point, and heats of
fusion, hygroscopicity, solubility, and stability. A co-crystal or
a co-crystal salt can be produced according to co-crystallization
method known per se.
[0813] Compound (I) may be a solvate (e.g., a hydrate) or a
non-solvate and both are encompassed in compound (I).
[0814] Compounds labeled with or substituted by isotopes (e.g.,
.sup.2H, .sup.3H, .sup.11C, .sup.14C, .sup.18F, .sup.35S,
.sup.125I, etc.) are also encompassed in compound (I). The compound
labeled with or substituted by isotopes can be used as, for
example, a tracer used for Positron Emission Tomography (PET) (PET
tracer), and are expected to be useful in the field of medical
diagnosis and the like.
[0815] The production method of the compound of the present
invention is explained below.
[0816] The raw material compound and reagent used and the compound
obtained in each step in the following production method may be
each in a form of a salt, and examples of such salt include those
similar to the salts of the compound of the present invention and
the like.
[0817] When the compound obtained in each step is a free form, it
can be converted to the objective salt according to a method known
per se. When the compound obtained in each step is a salt, it can
be converted to the objective free form or the other salt according
to a method known per se.
[0818] The compound obtained in each step can be used directly as
the reaction mixture or as a crude product for the next reaction.
Alternatively, the compound obtained in each step can be isolated
and purified from a reaction mixture according to a method known
per se, for example, a separation means such as concentration,
crystallization, recrystallization, distillation, solvent
extraction, fractional distillation, column chromatography and the
like.
[0819] When the raw material compound and reagent used in each step
are commercially available, the commercially available product can
also be used directly.
[0820] In the reaction in each step, while the reaction time varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 min-48 hr, preferably 10 min-8 hr, unless otherwise
specified.
[0821] In the reaction in each step, while the reaction temperature
varies depending on the kind of the reagent and solvent to be used,
it is generally -78.degree. C.-300.degree. C., preferably
-78.degree. C.-150.degree. C., unless otherwise specified.
[0822] In the reaction in each step, while the pressure varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 atm-20 atm, preferably 1 atm-3 atm, unless otherwise
specified.
[0823] Microwave synthesizer such as Initiator manufactured by
Biotage and the like may be used for the reaction in each step.
While the reaction temperature varies depending on the kind of the
reagent and solvent to be used, it is generally room
temperature--300.degree. C., preferably 50.degree. C.-250.degree.
C., unless otherwise specified. While the reaction time varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 min-48 hr, preferably 1 min-8 hr, unless otherwise
specified.
[0824] In the reaction in each step, the reagent is used in an
amount of 0.5 equivalents-20 equivalents, preferably 0.8
equivalents-5 equivalents, relative to the substrate, unless
otherwise specified. When the reagent is used as a catalyst, the
reagent is used in an amount of 0.001 equivalent-1 equivalent,
preferably 0.01 equivalent-0.2 equivalent, relative to the
substrate. When the reagent is used as a ligand, the reagent is
used in an amount of 0.001 equivalent-1 equivalent, preferably 0.01
equivalent-0.2 equivalent, relative to the substrate. When the
reagent is used as a reaction solvent, the reagent is used in a
solvent amount.
[0825] Unless otherwise specified, the reaction in each step is
carried out without solvent, or by dissolving or suspending the raw
material compound in a suitable solvent. Examples of the solvent
include those described in Examples and the following solvents.
alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol,
benzyl alcohol and the like; ethers: diethyl ether, diphenyl ether,
tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic
hydrocarbons: chlorobenzene, toluene, xylene and the like;
saturated hydrocarbons: cyclohexane, hexane and the like; amides:
N,N-dimethylformamide, N-methylpyrrolidone and the like;
halogenated hydrocarbons: dichloromethane, carbon tetrachloride and
the like; nitriles: acetonitrile and the like; sulfoxides: dimethyl
sulfoxide and the like; aromatic organic bases: pyridine and the
like; anhydrides: acetic anhydride and the like; organic acids:
formic acid, acetic acid, trifluoroacetic acid and the like;
inorganic acids: hydrochloric acid, sulfuric acid and the like;
esters: ethyl acetate and the like; ketones: acetone, methyl ethyl
ketone and the like; water.
[0826] The above-mentioned solvent can be used in a mixture of two
or more kinds thereof in an appropriate ratio.
[0827] When a base is used for the reaction in each step, examples
thereof include those described in Examples and the following
bases.
inorganic bases: sodium hydroxide, magnesium hydroxide, sodium
carbonate, calcium carbonate, sodium hydrogen carbonate and the
like; organic bases: triethylamine, diethylamine, pyridine,
4-dimethylaminopyridine, N,N-dimethylaniline,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,
imidazole, piperidine and the like; metal alkoxides: sodium
ethoxide, potassium tert-butoxide and the like; alkali metal
hydrides: sodium hydride and the like; metal amides: sodium amide,
lithium diisopropylamide, lithium hexamethyldisilazide and the
like; organic lithiums: n-butyllithium and the like.
[0828] When an acid or an acid catalyst is used for the reaction in
each step, examples thereof include those described in Examples and
the following acids and acid catalysts.
inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,
hydrobromic acid, phosphoric acid and the like; organic acids:
acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic
acid, 10-camphorsulfonic acid and the like; Lewis acid: boron
trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum
chloride, anhydrous zinc chloride, anhydrous iron chloride and the
like.
[0829] Unless otherwise specified, the reaction in each step is
carried out according to a method known per se, for example, the
method described in Jikken Kagaku Kouza, 5th Edition, vol. 13-19
(the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.
14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry,
Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic
Name Reactions, the Reaction Mechanism and Essence, Revised Edition
(Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII
(John Wiley & Sons Inc.); Modern Organic Synthesis in the
Laboratory A Collection of Standard Experimental Procedures (Jie
Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry
III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of
Named Reactions in Organic Synthesis (translated by Kiyoshi
Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH
Publishers Inc.), 1989, or the like, or the method described in
Examples.
[0830] In each step, the protection or deprotection reaction of a
functional group is carried out according to a method known per se,
for example, the method described in "Protective Groups in Organic
Synthesis, 4th Ed", Wiley-Interscience, Inc., 2007 (Theodora W.
Greene, Peter G. M. Wuts); "Protecting Groups 3rd Ed." Thieme, 2004
(P. J. Kocienski), or the like, or the method described in
Examples.
[0831] Examples of the protecting group for a hydroxy group of an
alcohol and the like and a phenolic hydroxy group include
ether-type protecting groups such as methoxymethyl ether, benzyl
ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and
the like; carboxylate ester-type protecting groups such as acetate
ester and the like; sulfonate ester-type protecting groups such as
methanesulfonate ester and the like; carbonate ester-type
protecting groups such as tert-butylcarbonate and the like, and the
like.
[0832] Examples of the protecting group for a carbonyl group of an
aldehyde include acetal-type protecting groups such as
dimethylacetal and the like; cyclic acetal-type protecting groups
such as 1,3-dioxane and the like, and the like.
[0833] Examples of the protecting group for a carbonyl group of a
ketone include ketal-type protecting groups such as dimethylketal
and the like; cyclic ketal-type protecting groups such as
1,3-dioxane and the like; oxime-type protecting groups such as
O-methyloxime and the like; hydrazone-type protecting groups such
as N,N-dimethylhydrazone and the like, and the like.
[0834] Examples of the protecting group for a carboxyl group
include ester-type protecting groups such as methyl ester and the
like; amide-type protecting groups such as N,N-dimethylamide and
the like, and the like.
[0835] Examples of the protecting group for a thiol include
ether-type protecting groups such as benzyl thioether and the like;
ester-type protecting groups such as thioacetate ester,
thiocarbonate, thiocarbamate and the like, and the like.
[0836] Examples of the protecting group for an amino group and an
aromatic heterocycle such as imidazole, pyrrole, indole and the
like include carbamate-type protecting groups such as benzyl
carbamate and the like; amide-type protecting groups such as
acetamide and the like; alkyl amine-type protecting groups such as
N-triphenylmethylamine and the like; sulfonamide-type protecting
groups such as methanesulfonamide and the like, and the like.
[0837] The protecting groups can be removed according to a method
known per se, for example, by employing a method using acid, base,
ultraviolet rays, hydrazine, phenylhydrazine, sodium
N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium
acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,
trimethylsilyl bromide) and the like, a reduction method, and the
like.
[0838] When reduction reaction is carried out in each step,
examples of the reducing agent to be used include metal hydrides
such as lithium aluminum hydride, sodium triacetoxyborohydride,
sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H),
sodium borohydride, tetramethylammonium triacetoxyborohydride and
the like; boranes such as borane tetrahydrofuran complex and the
like; Raney nickel; Raney cobalt; hydrogen; formic acid;
triethylsilane and the like. When carbon-carbon double bond or
triple bond or a nitro group or a benzyloxycarbonyl group is
reduced, a method using a catalyst such as palladium-carbon,
Lindlar's catalyst and the like may be employed.
[0839] When oxidation reaction is carried out in each step,
examples of the oxidizing agent to be used include peroxides such
as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide,
tert-butylhydroperoxide and the like; perchlorates such as
tetrabutylammonium perchlorate and the like; chlorates such as
sodium chlorate and the like; chlorites such as sodium chlorite and
the like; periodates such as sodium periodate and the like;
hypervalent iodine reagents such as iodosylbenzene and the like;
reagents containing manganese such as manganese dioxide, potassium
permanganate and the like; leads such as lead tetraacetate and the
like; reagents containing chromium such as pyridinium
chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent
and the like; halogen compounds such as N-bromosuccinimide (NBS)
and the like; oxygen; ozone; sulfur trioxide-pyridine complex;
osmium tetroxide; selenium dioxide;
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), oxone and the
like.
[0840] When radical cyclization reaction is carried out in each
step, examples of the radical initiator to be used include azo
compounds such as azobisisobutyronitrile (AIBN) and the like;
water-soluble radical initiators such as
4-4'-azobis-4-cyanopentanoic acid (ACPA) and the like;
triethylboron in the presence of air or oxygen; benzoyl peroxide
and the like. Examples of the radical reagent to be used include
tributylstannane, tristrimethylsilylsilane,
1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and
the like.
[0841] When Wittig reaction is carried out in each step, examples
of the Wittig reagent to be used include alkylidene phosphoranes
and the like. The alkylidene phosphoranes can be prepared according
to a method known per se, for example, by reacting a phosphonium
salt with a strong base.
[0842] When Horner-Emmons reaction is carried out in each step,
examples of the reagent to be used include phosphonoacetates such
as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate
and the like; and bases such as alkali metal hydrides, organic
lithiums and the like.
[0843] When Friedel-Crafts reaction is carried out in each step, a
combination of a Lewis acid and an acid chloride or a combination
of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an
alcohol, an olefin etc.) is used as a reagent. Alternatively, an
organic acid or an inorganic acid can also be used instead of a
Lewis acid, and an anhydride such as acetic anhydride and the like
can also be used instead of an acid chloride.
[0844] When aromatic nucleophilic substitution reaction is carried
out in each step, a combination of a nucleophile (e.g., a hydroxy,
an amine, imidazole etc.) and a base (e.g., an organic base etc.),
or a combination of a nucleophile and an acid (e.g., an organic
acid etc.) is used as a reagent.
[0845] When nucleophilic addition reaction by a carbo anion,
nucleophilic 1,4-addition reaction (Michael addition reaction) by a
carbo anion or nucleophilic substitution reaction by a carbo anion
is carried out in each step, and examples of the base to be used
for generation of the carbo anion include organic lithiums, metal
alkoxides, inorganic bases, organic bases and the like.
[0846] When Grignard reaction is carried out in each step, examples
of the Grignard reagent to be used include arylmagnesium halides
such as phenylmagnesium bromide and the like; and alkylmagnesium
halides such as methylmagnesium bromide and the like. The Grignard
reagent can be prepared according to a method known per se, for
example, by reacting an alkyl halide or an aryl halide with a metal
magnesium in an ether or tetrahydrofuran as a solvent.
[0847] When Knoevenagel condensation reaction is carried out in
each step, a compound having an activated methylene group with two
electron withdrawing groups (e.g., malonic acid, diethyl malonate,
malononitrile etc.) and a base (e.g., an organic base, a metal
alkoxide, an inorganic base) are used as a reagent.
[0848] When Vilsmeier-Haack reaction is carried out in each step,
phosphoryl chloride and an amide derivative (e.g.,
N,N-dimethylformamide etc.) are used as a reagent.
[0849] When azidation reaction of an alcohol, an alkyl halide or a
sulfonate is carried out in each step, examples of the azidating
agent to be used include diphenylphosphorylazide (DPPA),
trimethylsilylazide, sodium azide and the like. For example, for
the azidation reaction of an alcohol, a method using
diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), a method using trimethylsilylazide and a Lewis acid, and the
like are employed.
[0850] When reductive amination reaction is carried out in each
step, examples of the reducing agent to be used include sodium
triacetoxyborohydride, sodium cyanoborohydride,
borane-2-methylpyridine complex, hydrogen, formic acid and the
like. When the substrate is an amine compound, examples of the
carbonyl compound to be used include paraformaldehyde, aldehydes
such as acetaldehyde and the like, and ketones such as
cyclohexanone and the like. When the substrate is a carbonyl
compound, examples of the amine to be used include ammonia, primary
amines such as methylamine and the like; secondary amines such as
dimethylamine and the like, and the like.
[0851] When Mitsunobu reaction is carried out in each step, a
combination of an azodicarboxylate (e.g., diethyl azodicarboxylate
(DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and
triphenylphosphine, or a phosphorane reagent (e.g.,
cyanomethylenetributylphosphorane (Tsunoda reagent) is used as a
reagent.
[0852] When esterification reaction, amidation reaction or urea
formation reaction is carried out in each step, examples of the
reagent to be used include acyl halides such as acid chlorides,
acid bromides and the like; activated carboxylic acids such as
anhydrides, activated esters, sulfates and the like. Examples of
the activating agent of the carboxylic acid include carbodiimide
condensing agents such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD)
and the like; triazine condensing agents such as
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
n-hydrate (DMT-MM) and the like; carbonate condensing agents such
as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl
azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium
salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama
reagent); thionyl chloride; lower alkyl haloformates such as ethyl
chloroformate and the like;
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphorate (HATU); sulfuric acid; combinations thereof
and the like. When carbodiimide condensing agent is used, an
additive such as 1-hydroxybenzotriazole (HOBt),
N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the
like may be added to the reaction system.
[0853] When coupling reaction is carried out in each step, examples
of the metal catalyst to be used include palladium compounds such
as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
dichlorobis(triethylphosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium(0),
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride,
(tri-tert-butylphosphine)palladium(0) and the like; nickel
compounds such as tetrakis(triphenylphosphine)nickel(0) and the
like; rhodium compounds such as
tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt
compounds; copper compounds such as copper oxide, copper(I) iodide,
copper(II) diacetate and the like; platinum compounds and the like.
In addition, a base can be added to the reaction system, and
examples thereof include organic bases (e.g.,
1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-diisopropylethylamine),
inorganic bases and the like. Moreover, a ligand can be added to
the reaction system, and examples thereof include organic amines
such as N,N'-dimethylethylenediamine,
N,N'-dimethyl-cyclohexane-1,2-diamine, 2,2-bipyridyl and the like;
organophosphorus compounds such as triphenylphosphine,
tri-tert-butylphosphine, tricyclohexylphosphine, BINAP
(2,2'-bis(diphenylphosphino)-1,1-binaphthyl) and the like, and the
like.
[0854] When thiocarbonylation reaction is carried out in each step,
phosphorus pentasulfide is typically used as the thiocarbonylating
agent. Alternatively, a reagent having a
1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
(Lawesson reagent) etc.) can also be used instead of phosphorus
pentasulfide.
[0855] When Wohl-Ziegler reaction is carried out in each step,
examples of the halogenating agent to be used include
N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide
(NCS), bromine, sulfuryl chloride and the like. In addition, the
reaction can be accelerated by subjecting a radical initiator such
as heat, light, benzoyl peroxide, azobisisobutyronitrile and the
like to the reaction system reaction.
[0856] When halogenation reaction of a hydroxy group is carried out
in each step, examples of the halogenating agent to be used include
hydrohalic acids and acid halides of inorganic acids, specifically,
hydrochloric acid, thionyl chloride, phosphorus oxychloride and the
like for chlorination, 48% hydrobromic acid and the like for
bromination. In addition, a method of producing an alkyl halide by
reacting an alcohol with triphenylphosphine and carbon
tetrachloride or carbon tetrabromide or the like can be employed.
Alternatively, a method of producing an alkyl halide via two steps
comprising converting an alcohol to the corresponding sulfonate,
and then reacting the sulfonate with lithium bromide, lithium
chloride or sodium iodide can also be employed.
[0857] When Arbuzov reaction is carried out in each step, examples
of the reagent to be used include alkyl halides such as ethyl
bromoacetate and the like; and phosphites such as triethyl
phosphite, tri(isopropyl) phosphite and the like.
[0858] When sulfonate esterification reaction is carried out in
each step, examples of the sulfonating agent to be used include
methanesulfonyl chloride, p-toluenesulfonyl chloride,
methanesulfonic anhydride, p-toluenesulfonic anhydride and the
like.
[0859] When hydrolysis reaction is carried out in each step, an
acid or a base is used as a reagent. For acid hydrolysis reaction
of tert-butyl ester, formic acid, triethylsilane and the like may
be added to reductively-trap tert-butyl cation which is
by-produced.
[0860] When dehydration reaction is carried out in each step,
examples of the dehydrating agent to be used include sulfuric acid,
diphosphorus pentaoxide, phosphorus oxychloride,
N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the
like.
[0861] When Curtius reaction is carried out in each step, a
combination of an azidating agent (e.g., diphenylphosphorylazide
(DPPA) and sodium azide etc.) and water or alcohols and base (e.g.,
triethylamine) is used as a reagent.
[0862] When Strecker reaction is carried out in each step, examples
of the cyanation agent to be used include sodium cyanide,
cyanotrimethylsilane and the like.
[0863] When Bruylants reaction is carried out in each step,
examples of the alkylation agent to be used include arylmagnesium
halides such as phenylmagnesium bromide and the like; and
alkylmagnesium halides such as methylmagnesium bromide and the
like.
[0864] When Corey-Chaykovsky reaction is carried out in each step,
examples of the epoxydation agent to be used include
trialkylsulfonium salt, trialkylsulfoxonium salt and the like. In
addition, a base can be added to the reaction system, and examples
thereof include metal alkoxides (e.g., potassium tert-butoxide) or
alkali metal hydrides (e.g., sodium hydride) and the like.
[0865] When cyanation reaction is carried out in each step,
examples of the metal catalyst to be used include palladium
compounds such as
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)
(2'-amino-1,1'-biphenyl-2-yl) palladium(II), palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium(0),
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride,
(tri-tert-butylphosphine)palladium(0) and the like; nickel
compounds such as tetrakis(triphenylphosphine)nickel(0) and the
like; rhodium compounds such as
tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt
compounds; copper compounds such as copper oxide, copper(I) iodide,
copper(II) diacetate and the like; platinum compounds and the like.
Examples of the cyano compound to be used include potassium
hexacyanoferrate (II) trihydrate, copper(I) cyanide, zinc cyanide,
potassium cyanide, sodium cyanide and the like. In addition, a base
can be added to the reaction system, and examples thereof include
organic bases, inorganic bases and the like. Moreover, a ligand can
be added to the reaction system, and examples thereof include
organic amines such as N,N'-dimethylethylenediamine,
N,N'-dimethyl-cyclohexane-1,2-diamine, 2,2-bipyridyl and the like;
organophosphorus compounds such as
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl,
triphenylphosphine, tri-tert-butylphosphine,
tricyclohexylphosphine, BINAP
(2,2'-bis(diphenylphosphino)-1,1-binaphthyl) and the like.
[0866] When nitration reaction is carried out in each step,
examples of the nitrating agent to be used include mineral acids
such as mixed acid, nitric acid and the like; nitrates such as
potassium nitrate, sodium nitrate, tetramethylammonium nitrate,
silver nitrate and the like.
[0867] When nucleophilic substitution reaction is carried out in
each step, examples of the base to be used include organic lithiums
(e.g., lithium bis(trimehylsilyl)amide), metal alkoxides (e.g.,
potassium tert-butoxide), alkali metal hydrides (e.g., sodium
hydride), inorganic bases, organic bases and the like.
[0868] When O-alkylation reaction or N-alkylation reaction is
carried out in each step, a combination of an alkylating agent
(e.g., an alkyl halide, an alkyl sulfonate ester etc.) and a base
(e.g., an organic base, an inorganic base, alkali metal hydrides
etc.) is used as a reagent.
[0869] Compound (I) of the present invention can be produced
according to the methods explained below.
[0870] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A in the following
schemes are as defined above.
[0871] Compound (I) can be produced from compound (2) according to
the method shown in Scheme 1-1.
##STR00026##
wherein L.sup.1 and L.sup.2 are each independently a leaving group,
M.sup.1 is a boronic acid group (--B(OH).sub.2), or a boronate
ester group (--B(OR).sub.2; R is a C.sub.1-6 alkyl group) or a
cyclic group thereof (e.g., a
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, etc.), and the other
symbols are as defined above.
[0872] Examples of the "leaving group" for L.sup.1 or L.sup.2
include a halogen atom (e.g., a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom etc.), an optionally halogenated
C.sub.1-6 alkylsulfonyloxy group (e.g., methanesulfonyloxy,
ethanesulfonyloxy, trifluoromethanesulfonyloxy etc.), an optionally
substituted C.sub.6-14 arylsulfonyloxy group [e.g., a C.sub.6-14
arylsulfonyloxy group optionally having 1 to 3 substituents
selected from a C.sub.1-6 alkyl group (e.g., methyl, etc.)], an
optionally halogenated C.sub.1-6 alkylsulfide group, an optionally
substituted C.sub.6-14 arylsulfide group, a C.sub.1-6 alkoxy group
(e.g., methoxy, etc.), a nitro group, m-nitrobenzenesulfonyloxy and
naphthylsulfonyloxy and the like.
[0873] Compounds (3), (4) and (6) may be a commercially available
product, or can be produced according to a method known per se.
[0874] Compound (I) wherein R.sup.3 is a cyano group, can also be
produced from compound (2) according to the method shown in Scheme
1-2.
##STR00027##
wherein L.sup.3 is a leaving group, and the other symbols are as
defined above.
[0875] Examples of the "leaving group" for L.sup.3 include those
exemplified as the "leaving group" for L.sup.1 or L.sup.2.
[0876] Compounds (7) and (8) may be a commercially available
product, or can be produced according to a method known per se.
[0877] Compound (I) can also be produced from compound (10)
according to the method shown in Scheme 1-3.
##STR00028##
wherein P.sup.1 is a hydrogen atom or a protecting group for a
hydroxy group, and the other symbols are as defined above.
[0878] When R.sup.3 is a chloro atom, R.sup.3 of compound (I) can
be changed to a cyano group by cyanation (Step F).
[0879] Compounds (10) may be a commercially available product, or
can be produced according to a method known per se.
[0880] Compound (3), compound (6), compound (7) and compound (8)
can be produced from compound (13) according to the method shown in
Scheme 2-1, respectively.
##STR00029##
wherein E.sup.1 is a hydroxyl group or a leaving group, E.sup.2 and
L.sup.4 are each independently a leaving group, R.sup.3 is a cyano
group or a leaving group, R.sup.6 is an optionally substituted
C.sub.1-6 alkyl group, and the other symbols are as defined
above.
[0881] Examples of the "leaving group" for E.sup.1, E.sup.2,
L.sup.4 and R.sup.5 include those exemplified as the "leaving
group" for L.sup.1 or L.sup.2.
[0882] Compounds (13) and (14) may be a commercially available
product, or can be produced according to a method known per se.
[0883] Compound (3), compound (6), compound (7) and compound (8)
can also be produced from compound (19) according to the method
shown in Scheme 2-2, respectively.
##STR00030##
wherein L.sup.5 is a leaving group, and the other symbols are as
defined above.
[0884] Examples of the "leaving group" for L.sup.5 include those
exemplified as the "leaving group" for L.sup.1 or L.sup.2.
[0885] Compound (19) and (21) may be a commercially available
product, or can be produced according to a method known per se.
[0886] Compound (2) can be produced from compound (22) according to
the method shown in Scheme 3-1.
##STR00031##
wherein Cy is a 1,4-substituted cyclohexane group wherein the
substitutions are such as an amino group, or a carbonyl group, or
hydroxyl group and the like, P.sup.2 is a protecting group for
5-membered monocyclic aromatic heterocycle group and the like,
P.sup.3 is a protecting group for an amino group, or a carbonyl
group, or a hydroxyl group and the like, P.sup.4 is a protecting
group for an amino group and the like, E.sup.3 is a hydroxyl group
or a leaving group, and the other symbols are as defined above.
[0887] Examples of the "leaving group" for E.sup.3 include those
exemplified as the "leaving group" for L.sup.1 or L.sup.2.
[0888] Compound (22) and compound (24) may be a commercially
available product, or can be produced according to a method known
per se.
[0889] Compound (2) can also be produced from compound (29)
according to the method shown in Scheme 3-2.
##STR00032##
wherein each symbol is as defined above.
[0890] Compound (29) may be a commercially available product, or
can be produced according to a method known per se.
[0891] Compound (10) can be produced from compound (22) according
to the method shown in Scheme 3-3.
##STR00033##
wherein each symbol is as defined above.
[0892] The starting compound and/or production intermediate for
compound (I) may form a salt. While the salt is not particularly
limited as long as the reaction can be performed, examples thereof
include those similar to the salts optionally formed by compound
(I) and the like, and the like.
[0893] As for the configurational isomers (E, Z forms) of compound
(I), they can be isolated and purified when isomerization occurs,
for example, according to a conventional separation means such as
extraction, recrystallization, distillation, chromatography and the
like to obtain a pure compound. In addition, the corresponding pure
isomer can also be obtained by isomerizing a double bond using
heating, an acid catalyst, a transition metal complex, a metal
catalyst, a radical catalyst, light irradiation, a strong base
catalyst and the like, according to the method described in Shin
Jikken Kagaku Kouza 14 (The Chemical Society of Japan ed.), pages
251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical
Society of Japan ed.), pages 273 to 274 or a method analogous
thereto.
[0894] Compound (I) contains a stereoisomer depending on the kind
of a substituent, and each stereoisomer and a mixture thereof are
encompassed in the present invention.
[0895] Compound (I) may be a hydrate or a non-hydrate.
[0896] When desired, compound (I) can be synthesized by performing
deprotection reaction, acylation reaction, alkylation reaction,
hydrogenation reaction, oxidation reaction, reduction reaction,
reaction of carbon chain extension, halogenation reaction,
substituent exchange reaction, coupling reaction, reductive
amination, nucleophilic addition reaction by a carbo anion,
Grignard reagent and deoxofluorination reaction singly or two or
more thereof in combination.
[0897] When the objective product is obtained as a free form by the
above-mentioned reaction, it can be converted to a salt according
to a conventional method, or when the objective product is obtained
as a salt, it can be converted to a free form or other salt
according to a conventional method. The thus-obtained compound (I)
can also be isolated and purified from a reaction mixture according
to a known method such as phase transfer, concentration, solvent
extraction, distillation, crystallization, recrystallization,
chromatography and the like.
[0898] When compound (I) contains a configurational isomer, a
diastereomer, a conformer and the like, each can be isolated
according to the above-mentioned separation and purification
methods, if desired. In addition, when compound (I) is racemic,
d-form and 1-form can be isolated according to a conventional
optical resolution.
[0899] The thus-obtained compound (I), other reaction intermediate
therefor and starting compounds thereof can be isolated and
purified from a reaction mixture according to a method known per
se, for example, extraction, concentration, neutralization,
filtration, distillation, recrystallization, column chromatography,
thin layer chromatography, preparative high performance liquid
chromatography (preparative HPLC), moderate-pressure preparative
liquid chromatography (moderate-pressure preparative LC) and the
like.
[0900] A salt of compound (I) can be produced according to a method
known per se. For example, when compound (I) is a basic compound,
it can be produced by adding an inorganic acid or organic acid, or
when compound (I) is an acidic compound, by adding an organic base
or inorganic base.
[0901] When compound (I) contains an optical isomer, each optical
isomer and a mixture thereof are encompassed in the scope of the
present invention, and these isomers can be subjected to optical
resolution or can be produced respectively, according to a method
known per se, if desired.
[0902] When compound (I) contains a configurational isomer, a
diastereomer, a conformer and the like, each can be isolated
according to the above-mentioned separation and purification
methods, if desired. In addition, when compound (I) is racemic,
S-form and R-form can be isolated according to a conventional
optical resolution.
[0903] When compound (I) contains a stereoisomer, each isomer and a
mixture thereof are encompassed in the present invention.
[0904] Compound (I) may be a prodrug. A prodrug of compound (I)
means a compound which is converted to compound (I) with a reaction
due to an enzyme, an gastric acid, etc. under the physiological
condition in the living body, that is, a compound which is
converted to compound (I) with oxidation, reduction, hydrolysis,
etc. according to an enzyme; a compound which is converted to
compound (I) by hydrolysis etc. due to gastric acid, etc.
[0905] A prodrug for compound (I) may be a compound obtained by
subjecting an amino group in compound (I) to an acylation,
alkylation or phosphorylation (e.g., a compound obtained by
subjecting an amino group in compound (I) to an eicosanoylation,
alanylation, pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation or tert-butylation, etc.); a compound
obtained by subjecting a hydroxy group in compound (I) to an
acylation, alkylation, phosphorylation or boration (e.g., a
compound obtained by subjecting an hydroxy group in compound (I) to
an acetylation, palmitoylation, propanoylation, pivaloylation,
succinylation, fumarylation, alanylation or
dimethylaminomethylcarbonylation, etc.); a compound obtained by
subjecting a carboxyl group in compound (I) to an esterification or
amidation (e.g., a compound obtained by subjecting a carboxyl group
in compound (I) to an ethyl esterification, phenyl esterification,
carboxymethyl esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl
esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,
cyclohexyloxycarbonylethyl esterification or methylamidation, etc.)
and the like. Any of these compounds can be produced from compound
(I) by a method known per se. The prodrug of compound (I) may be a
compound that converts to compound (I) under physiological
conditions as described in Development of Pharmaceutical Products,
vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990).
[0906] Compound (I) or a prodrug thereof (to be abbreviated as the
compound of the present invention) is superior in vivo kinetics
(e.g., plasma drug half-life, intracerebral transferability,
metabolic stability), shows low toxicity (e.g., more superior as a
medicament in terms of liver/hepatotoxicity, acute toxicity,
chronic toxicity, genetic toxicity, reproductive toxicity,
cardiotoxicity, cytotoxicity, drug interaction, carcinogenicity
etc.; especially cytotoxicity, liver/hepatotoxicity). The compound
of the present invention is extremely useful as a medicament in
terms of improved cytotoxicity. The compound of the present
invention is directly used as a medicament or a pharmaceutical
composition mixed with a pharmaceutically acceptable carrier or the
like to be orally or parenterally administered to mammals (e.g.,
humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits,
cats, dogs, sheep and goats) in safety. Examples of the
"parenteral" include intravenous, intramuscular, subcutaneous,
intra-organ, intranasal, intradermal, instillation, intracerebral,
intrarectal, intravaginal, intraperitoneal and intratumor
administrations, administration to the vicinity of tumor etc. and
direct administration to the lesion.
[0907] Since the compound of the present invention has a superior
CaMKII inhibitory action, it is expected to be useful for the
prophylaxis or treatment of, for example, cardiac diseases (cardiac
hypertrophy, acute heart failure and chronic heart failure
including congestive heart failure, cardiomyopathy, angina,
myocarditis, atrial/ventricular arrhythmia, tachycardia, myocardial
infarction, etc.), myocardial ischemia, venous insufficiency,
post-myocardial infarction transition to heart failure,
hypertension, cor pulmonale, arteriosclerosis including
atherosclerosis (aneurysm, coronary arterial sclerosis, cerebral
arterial sclerosis, peripheral arterial sclerosis, etc.), vascular
thickening, vascular thickening/occlusion and organ damages after
intervention (percutaneous coronary angioplasty, stent placement,
coronary angioscopy, intravascular ultrasound, coronary
thrombolytic therapy, etc.), vascular reocclusion/restenosis after
bypass surgery, cardiac hypofunction after artificial heart lung
surgery, respiratory diseases (cold syndrome, pneumonia, asthma,
pulmonary hypertension, pulmonary thrombus/pulmonary embolism,
etc.), bone disorders (nonmetabolic bone disorders such as bone
fracture, refracture, bone malformation/spondylosis deformans,
osteosarcoma, myeloma, dysostosis and scoliosis, bone defect,
osteoporosis, osteomalacia, rickets, osteitis fibrosis, renal
osteodystrophy, Paget's disease of bone, myelitis with rigidity,
chronic rheumatoid arthritis, gonarthrosis and articular tissue
destruction in similar disorders thereof, etc.), inflammatory
diseases (diabetic complication such as retinopathy, nephropathy,
nerve damage, macroangiopathy etc.; arthritis such as chronic
rheumatoid arthritis, osteoarthritis, rheumatoid myelitis,
periostitis etc.; inflammation after surgery/trauma; reduction of
swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis;
inflammatory enteric diseases such as Crohn's disease, ulcerative
colitis etc.; meningitis; inflammatory eye diseases; inflammatory
pulmonary diseases such as pneumonia, silicosis, pulmonary
sarcoidosis, pulmonary tuberculosis etc, and the like), allergic
diseases (allergic rhinitis, conjunctivitis, gastrointestinal
allergy, pollen allergy, anaphylaxis, etc.), drug dependence,
neurodegenerative diseases (Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.),
central nervous system damage (disorders such as cerebral
hemorrhage and cerebral infarction and aftereffects and
complications thereof, head injury, spinal damage, cerebral edema,
sensory dysfunction, sensory abnormality, autonomic dysfunction,
abnormal autonomic function, multiple sclerosis etc.), dementia,
disturbed memory, disturbed consciousness, amnesia, anxiety
symptoms, nervous symptoms, unpleasant condition, mental disorders
(depression, epilepsy, alcohol dependency, etc.), ischemic
peripheral circulatory disorder, deep-vein thrombosis, occlusive
peripheral circulatory disorder, arteriosclerosis obliterans (ASO),
occlusive thromboangiitis, diabetes (type 1 diabetes, type 2
diabetes, pregnancy diabetes etc.), diabetic complications (nerve
damage, nephropathy, retinopathy, cataract, macroangiopathy,
osteopenia, diabetic hyperosmolar diabetic coma, infectious
diseases, diabetic gangrene, xerostomia, deterioration in hearing,
cerebrovascular damage, peripheral circulatory disorder, etc.),
urinary incontinence, metabolic/nutritional disorders (obesity,
hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose
tolerance, hyperuricemia, hyperkalemia, hypernatremia etc.),
metabolic syndrome, vesceral obesity syndrome, male or female
sexual dysfunction and the like, and for the prophylaxis or
treatment of dysgeusia, smell disturbance, abnormal circadian
rhythm of blood pressure, cerebrovascular damage (asymptomatic
cerebrovascular damage, transient cerebral ischemia attack, stroke,
cerebrovascular dementia, hypertensive encephalopathy, cerebral
infarction, etc.), cerebral edema, cerebral circulatory
disturbance, recurrence and aftereffects of cerebrovascular damages
(neurological symptoms, mental symptoms, subjective symptoms,
impairment of activities of daily living, etc.), kidney diseases
(nephritis, glomerulonephritis, glomerulosclerosis, renal failure,
thrombotic microangiopathy, diabetic nephropathy, nephrotic
syndrome, hypertensive nephrosclerosis, complications of dialysis,
organ damage including nephropathy by irradiation, etc.),
erythrocytosis/hypertension/organ damage/vascular thickening after
transplantations rejection after transplantation, ocular disorders
(glaucoma, ocular hypertension, etc.), thrombosis, multiple organ
failure, endothelial dysfunction, hypertensive tinnitus, other
circulatory diseases (ischemic cerebral circulatory disturbance,
Raynaud's disease, Buerger's disease, etc.), chronic occlusive
pulmonary diseases, interstitial pneumonia, carinii pneumonia,
connective tissue disorders (e.g., systemic erythematosus,
scleroderma, polyarteritis, etc.), liver disorders (hepatitis and
cirrhosis including chronic types, etc.), portal hypertension,
digestive disorders (gastritis, gastric ulcer, gastric cancer,
disorder after gastric surgery, poor digestion, esophageal ulcer,
pancreatitis, colon polyp, cholelithiasis, hemorrhoidal problem,
esophageal and gastric variceal rupture, etc.),
hematological/hematopoietic disorders (erythrocytosis, vascular
purpura, autoimmune hemolytic anemia, disseminated intravascular
coagulation syndrome, multiple myelosis, etc.), solid tumor, tumors
(malignant melanoma, malignant lymphoma, digestive organs (e.g.,
stomach, intestine, etc.) cancers, etc.), cancers and cachexia
associated therewith, cancer metastases, endocrine disorders
(Addison's disease, Cushing's syndrome, pheochromocytoma, primary
aldosteronism, etc.), Creutzfeldt-Jakob disease, urological/male
genital diseases (cystitis, prostatic enlargement, prostate cancer,
sexually transmitted diseases, etc.), gynecological disorders
(menopausal disorders, pregnancy toxemia, endometriosis, uterine
fibroid, ovarian diseases, mammary gland diseases, sexually
transmitted diseases, etc.), diseases caused by
environmental/occupational factor (e.g., radiation damage, damage
from ultraviolet/infrared/laser beam, altitude sickness etc.),
infectious diseases (viral infectious diseases of, for example,
cytomegalovirus, influenza virus and herpesvirus, rickettsial
infectious diseases, bacterial infectious diseases, etc.), toxemia
(septicemia, septic shock, endotoxic shock, gram-negative
septicemia, toxin shock syndrome, etc.), ear nose throat diseases
(Meniere's disease, tinnitus, dysgeusia, vertigo, balance disorder,
deglutition disorder etc.), cutaneous diseases (keloid, hemangioma,
psoriasis, etc.), dialysis hypotension, myasthenia gravis, systemic
diseases such as chronic fatigue syndrome, and the like,
particularly cardiac diseases (particularly catecholaminergic
polymorphic ventricular tachycardia, postoperative atrial
fibrillation, heart failure, fatal arrhythmia) and the like,
in animals, particularly mammals (e.g., humans, monkeys, cats,
pigs, horses, bovines, mice, rats, guinea pigs, dogs, rabbits
etc.).
[0908] Herein, the concept of prophylaxis of cardiac diseases
include treatment of prognosis of myocardial infarction, angina
attack, cardiac bypass surgery, thrombolytic therapy, coronary
revascularization and the like, and the concept of treatment of
cardiac diseases include suppress of progress or severity of heart
failure (including both contractile failure HFrEF, and heart
failure HFpEF with maintained ejection fraction), and maintenance
of cardiac function when performing non-drug therapies (e.g., an
implantable defibrillator, resection of cardiac sympathetic nerve,
catheter ablation, cardiac pacemaker, intra aortic balloon pumping,
auxiliary artificial heart, Batista operation, cell
transplantation, gene therapy, heart transplantation and the like)
for severe heart failure/arrhythmia, and the like. When the
compound of the present invention is applied to prophylaxis or
treatment of heart failure, improvement of heart contractility or
atomicity is expected to be achieved by short-time administration,
without side effects such as pressure decrease, tachycardia,
reduced renal blood flow and the like, regardless of differences in
causative diseases such as ischemic cardiac disease,
cardiomyopathy, hypertension and the like and symptoms such as
contractile failure, diastolic failure and the like. Moreover,
long-term improvement of prognosis (survival rate, readmission
rate, cardiac event rate etc.) is expected to be achieved, in
addition to short-term improvement of cardiac function. When the
compound of the present invention is applied to prophylaxis or
treatment of arrhythmia, improvement or remission of the symptom is
expected to be achieved, regardless of differences in etiology and
atrial/ventricular. In addition, long-term improvement of prognosis
(survival rate, readmission rate, cardiac event rate etc.) is
expected to be achieved.
[0909] While the dose of the compound of the present invention
varies depending on the administration route, symptom and the like,
when, for example, the compound is orally administered to a patient
with cardiac disease (adult, body weight 40-80 kg, for example, 60
kg), it is, for example, 0.001-1000 mg/kg body weight/day,
preferably 0.01-100 mg/kg body weight/day, more preferably 0.1-10
mg/kg body weight/day. This amount can be administered in 1 to 3
portions per day.
[0910] A medicament containing the compound of the present
invention can be used alone or as a pharmaceutical composition
containing the compound of the present invention and a
pharmaceutically acceptable carrier according to a method known per
se as a production method of a pharmaceutical preparation (e.g.,
the method described in the Japanese Pharmacopoeia etc.). A
medicament containing the compound of the present invention can be
safely administered in the form of, for example, tablet (including
sugar-coated tablet, film-coated tablet, sublingual tablet, orally
disintegrating tablet, buccal and the like), pill, powder, granule,
capsule (including soft capsule, microcapsule), troche, syrup,
liquid, emulsion, suspension, release control preparation (e.g.,
immediate-release preparation, sustained-release preparation,
sustained-release microcapsule), aerosol, film (e.g., orally
disintegrating film, oral mucosa-adhesive film), injection (e.g.,
subcutaneous injection, intravenous injection, intramuscular
injection, intraperitoneal injection), drip infusion, transdermal
absorption type preparation, ointment, lotion, adhesive
preparation, suppository (e.g., rectal suppository, vaginal
suppository), pellet, nasal preparation, pulmonary preparation
(inhalant), eye drop and the like, orally or parenterally (e.g.,
intravenous, intramuscular, subcutaneous, intraorgan, intranasal,
intradermal, instillation, intracerebral, intrarectal,
intravaginal, intraperitoneal administrations, and administration
to the lesion).
[0911] As the aforementioned "pharmaceutically acceptable carrier",
various organic or inorganic carriers conventionally used as
preparation materials (starting materials) can be used. For
example, excipient, lubricant, binder, disintegrant and the like
are used for solid preparations, and solvent, solubilizing agent,
suspending agent, isotonicity agent, buffer, soothing agent and the
like are used for liquid preparations. Where necessary, preparation
additives such as preservative, antioxidant, colorant, sweetening
agent and the like can also be used.
[0912] Examples of the excipient include lactose, sucrose,
D-mannitol, starch, corn starch, crystalline cellulose, light
anhydrous silicic acid and the like.
[0913] Examples of the lubricant include magnesium stearate,
calcium stearate, talc, colloidal silica and the like.
[0914] Examples of the binding agent include crystalline cellulose,
white sugar, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch,
sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium
and the like.
[0915] Examples of the disintegrant include starch,
carboxymethylcellulose, carboxymethylcellulose calcium, sodium
carboxymethyl starch, L-hydroxypropylcellulose and the like.
[0916] Examples of the solvent include water for injection,
alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive
oil and the like.
[0917] Examples of the solubilizing agent include polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like. Examples of the suspending agent
include surfactants such as stearyl triethanolamine, sodium lauryl
sulfate, laurylaminopropionic acid, lecithin, benzalkonium
chloride, benzetonium chloride, glycerin monostearate and the like;
hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like; and the like.
[0918] Examples of the isotonic agent include glucose, D-sorbitol,
sodium chloride, glycerin, D-mannitol and the like.
[0919] Examples of the buffering agent include buffer solutions
such as phosphates, acetates, carbonates, citrates and the
like.
[0920] Examples of the soothing agent include benzyl alcohol and
the like.
[0921] Examples of the preservative include p-oxybenzoates,
chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic
acid, sorbic acid and the like.
[0922] Examples of the antioxidant include sulfite, ascorbic acid,
.alpha.-tocopherol and the like.
[0923] While the pharmaceutical composition varies according to the
dosage form, administration method, carrier and the like, it can be
produced according to a conventional method by adding the compound
of the present invention in a proportion of generally 0.01-100%
(w/w), preferably 0.1-95% (w/w), of the total amount of the
preparation.
[0924] When the compound of the present invention is applied to
each of the above-mentioned diseases, it can be used in appropriate
combination with a pharmaceutical agent (hereinafter to be
abbreviated as a concomitant drug) or a treatment method generally
employed for such diseases. For heart failure, for example, it can
be used concurrently with angiotensin converting enzyme (ACE)
inhibitors (e.g., alacepril, captopril, cilazapril, delapril,
enalapril, lisinopril, temocapril, trandolapril, quinapril,
imidapril, benazepril, perendopril and the like), angiotensin II
receptor antagonists (e.g., losartan, candesartan cillexetil,
valsartan, termisartan, irbesartan, forasartan and the like),
angiotensin II receptor antagonist/NEP inhibitor combination agent
(entresto), .beta. receptor antagonists (e.g., propranolol,
nadolol, timolol, nipradilol, bunitorolol, indenolol, penbutolol,
carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol,
metoprolol, labetalol, amosulalol, arotinolol and the like), Ca
antagonists (e.g., manidipine, nicardipine, nilvadipine,
nisoldipine, nitrendipine, benidipine, amlodipine, aranidipine and
the like), diuretics (e.g., thiazide diuretics such as
benzylhydrochlorothiazide, cyclopentiazide, ethiazide,
hydrochlorothiazide, hydroflumethiazide, methyclothiazide,
penfluthiazide, polythiazide, trichlormethiazide and the like; loop
diuretics such as chlorthalidone, clofenamide, indapamide,
mefruside, meticrane, sotolazone, tribamide, quinetazone,
metolazone, furosemide, mefruside and the like; potassium retention
diuretics such as spironolactone, triamterene and the like; and the
like), digitalis preparations (e.g., digitoxin, digoxin,
methyldigoxin, lanatoside C, proscillaridin and the like), ANP or
BNP preparations, Ca sensitizers (e.g., pimobendan and the like),
anticoagulants (e.g., warfarin, sodium citrate, activated protein
C, tissue factor pathway inhibitor, antithrombin III, dalteparin
sodium, aragatroban, gabexate, sodium ozagrel, ethyl icosapentate,
beraprost sodium, alprostadil, pentoxifyline, tisokinase,
streptokinase and the like), antiarrhythmic drugs (e.g., sodium
channel blockers such as quinidine, procainamide, disopyramide,
ajmaline, cibenzoline, lidocain, diphenylhydantoin, mexiletine,
propafenone, flecainide, pilsicainide, phenytoin and the like;
potassium channel blockers such as amiodarone and the like; calcium
channel blockers such as verapamil, diltiazem and the like; and the
like), PDE inhibitors (e.g., amrinone, milrinone, olprinone
hydrochloride and the like), therapeutic drugs for diabetes (e.g.,
sulfonylureas such as tolbutamide, chlorpropamide, glyclopyramide,
acetohexamide, tolazamide, glibenclamide, glybuzole and the like;
biguanides such as metformin hydrochloride, buformin hydrochloride
and the like; .alpha.-glucosidase inhibitors such as voglibose,
acarbose and the like, insulin sensitizers such as pioglitazone,
troglitazone and the like; SGLT2 inhibitors such as ipragliflozin,
dapagliflozin, ruseogurifurojin, tofogliflozin, canagliflozin,
empagliflozin and the like; insulin, glucagon; therapeutic drugs
for diabetic complications such as epalrestat and the like; and the
like), anti-obesity drugs and the like, and is also applicable when
an implantable artificial heart, an implantable defibrillator, a
ventricular pacing, Batista operation, heart transplantation or
cell transplantation is performed. In addition, for arrhythmia, for
example, it can be used concurrently with other antiarrhythmic
drugs (e.g., sodium channel blockers such as flecainide, quinidine,
procainamide, disopyramide, ajmaline, cibenzoline, lidocain,
diphenylhydantoin, mexiletine, propafenone, pilsicainide, phenytoin
and the like; potassium channel blockers such as amiodarone and the
like; calcium channel blockers such as verapamil, diltiazem and the
like, and the like) and .beta. receptor antagonists, non-drug
therapies (e.g., an implantable defibrillator, resection of cardiac
sympathetic nerve, catheter ablation, cardiac pacemaker and the
like). In addition, after acute myocardial infarction or during
myocardial infarction prognosis, for example, the compound can be
used in combination with antithrombotics (e.g., anticoagulants such
as heparin sodium, heparin calcium, warfarin and the like;
thrombolytic agents such as urokinase and the like; anti-platelet
drugs such as aspirin, sulfinpyrazone (anturan), dipyridamole
(persantin), ticropidine (panaldine), cilostazol (pletal),
clopidogrel and the like; and the like), angiotensin converting
enzyme inhibitors, angiotensin II receptor antagonists, .beta.
receptor antagonists, therapeutic drugs for diabetes, therapeutic
drugs for hyperlipidemia (e.g., HMG-CoA reductase inhibitors such
as pravastatine, fluvastatine, cerivastatine, atorvastatine and the
like; fibrate drugs such as sinfibrate, clofibrate aluminum,
clinofibrate, fenofibrate and the like; and the like), coronary
vessel reconstructive surgery such as PTCA, CABG and the like; and
the like. Furthermore, in chronic rheumatoid arthritis, for
example, the compound can be used in combination with non-steroidal
antiinflammatory agents (e.g., acetaminophen, phenacetin,
ethenzamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic
acid, flufenamic acid, diclofenac sodium, loxoprofen sodium,
phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,
oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine,
epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate,
camostat mesilate, ulinastatine, colchicine, probenecid,
sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate,
sodium hyaluronate, sodium salicylate, morphine hydrochloride,
salicylic acid, atropine, scopolamine, morphine, pethidine,
levorphanol, ketoprofen, naproxen, oxymorphone or a salt thereof
and the like), immunomodulators or immunosuppressants (e.g.,
methotrexate, cyclosporine, tacrolimus, gusperimus, azathioprine,
antilymphocyte serum, dried sulfonated immunoglobulin,
erythropoietin, colony stimulating factor, interleukin, interferon
and the like), steroids (e.g., dexamethasone, hexestrol,
methimazole, betamethasone, triamcinolone, triamcinoloneacetonide,
fluocinonide, fluocinoloneacetonide, prednisolone,
methylprednisolone, cortisone acetate, hydrocortisone,
fluorometholone, beclometasone dipropionate, estriol and the like),
p38 MAP kinase inhibitors, anti-TNF-.alpha. drugs (e.g.,
etanercept, infliximab, D2E7, CDP-571, PASS TNF-.alpha., soluble
TNF-.alpha. receptor, TNF-.alpha. binding protein, anti-TNF-.alpha.
antibody and the like), cyclooxygenase inhibitors (e.g., salicylic
acid derivatives such as celecoxib, rofecoxib, aspirin and the
like, MK-663, valdecoxib, SC-57666, tiracoxib, S-2474, diclofenac,
indomethacin, loxoprofen and the like) and the like.
[0925] Moreover, it is possible to use the compound of the present
invention in combination with biological products (e.g.: antibody,
vaccine preparation and the like) when applying to the
above-mentioned respective diseases, and it is also possible to
apply the compound in combination with a gene therapy and the like
as a combination therapy. As antibody and vaccine preparation, for
example, vaccine preparation to angiotensin II, vaccine preparation
to CETP, CETP antibody, TNF a antibody, antibody to other cytokine,
amiloid .beta. vaccine preparation, type 1 diabetes vaccine
(DIAPEP-277 of Peptor Ltd. and the like), anti-HIV antibody, HIV
vaccine preparation and the like, antibody and vaccine preparation
to cytokine, renin-angiotensin enzyme and products thereof,
antibody and vaccine preparation to enzyme and protein involved in
blood lipid metabolism, antibody and vaccine preparation to enzyme
and protein involved in blood coagulation-fibrinolytic system,
antibody and vaccine preparation to protein involved in glucose
metabolism and insulin resistance and the like can be mentioned. In
addition, a combined use with biological products involved in
growth factors such as GH, IGF and the like is possible. As a gene
therapy, for example, a treatment method using a gene relating to
cytokine, renin-angiotensin enzyme and products thereof, G protein,
G protein-coupled receptor and phosphorylation enzyme thereof, a
therapeutic method using a DNA decoy such as NF.kappa.B decoy and
the like, a therapeutic method using antisense, a therapeutic
method using a gene relating to enzyme and protein involved in
blood lipid metabolism (e.g., gene relating to metabolism,
excretion and absorption of cholesterol or triglyceride or
HDL-cholesterol or blood phospholipid, and the like), a therapeutic
method using a gene relating to enzyme and protein (e.g., growth
factors such as HGF, VEGF and the like, and the like) involved in
angiogenetic therapy aiming at obstruction of peripheral vessel and
the like, a therapeutic method using a gene relating protein
involved in glucose metabolism and insulin resistance, antisense to
cytokine such as TNF-.alpha. and the like, and the like can be
mentioned. In addition, it is possible to use the compound in
combination with various organ regeneration methods such as heart
regeneration, kidney regeneration, pancreas regeneration, blood
vessel regeneration and the like, cell transplantation therapy
using bone marrow cells (bone marrow mononuclear cell, bone marrow
mesenchymal stem cell and the like), and artificial organs
(artificial blood vessels and cardiac muscle cell sheet) using
tissue engineering.
[0926] By combining the compound of the present invention and a
concomitant drug, a superior effect such as
(1) the dose can be reduced as compared to single administration of
the compound of the present invention or a concomitant drug, (2)
the drug to be combined with the compound of the present invention
can be selected according to the condition of patients (mild case,
severe case and the like), (3) the period of treatment can be set
longer by selecting a concomitant drug having different action and
mechanism from the compound of the present invention, (4) a
sustained treatment effect can be designed by selecting a
concomitant drug having different action and mechanism from the
compound of the present invention, (5) a synergistic effect can be
afforded by a combined use of the compound of the present invention
and a concomitant drug, and the like, can be achieved.
[0927] Hereinafter the compound of the present invention and a
concomitant drug used in combination are referred to as the
"combination agent of the present invention".
[0928] When using the combination agent of the present invention,
the administration time of the compound of the present invention
and the concomitant drug is not restricted, and the compound of the
present invention or a pharmaceutical composition thereof and the
concomitant drug or a pharmaceutical composition thereof can be
administered to an administration subject simultaneously, or may be
administered at different times. The dosage of the concomitant drug
may be determined according to the dose clinically used, and can be
appropriately selected depending on an administration subject,
administration route, disease, combination and the like.
[0929] The administration mode of the concomitant drug of the
present invention is not particularly restricted, and it is
sufficient that the compound of the present invention and the
concomitant drug are combined in administration. Examples of such
administration mode include the following methods:
(1) administration of a single preparation obtained by
simultaneously processing the compound of the present invention and
the concomitant drug, (2) simultaneous administration of two kinds
of preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route, (3) administration of two kinds of
preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route in a staggered manner, (4) simultaneous
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes, (5)
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes in a
staggered manner (for example, administration in the order of the
compound of the present invention and the concomitant drug, or in
the reverse order) and the like.
[0930] The combination agent of the present invention exhibits low
toxicity. For example, the compound of the present invention
or(and) the aforementioned concomitant drug can be combined with a
pharmacologically acceptable carrier according to the known method
to prepare a pharmaceutical composition such as tablets (including
sugar-coated tablet and film-coated tablet), powders, granules,
capsules (including soft capsule), liquids, injections,
suppositories, sustained-release agents, etc. These compositions
can be administered safely orally or non-orally (e.g., topical,
rectal, intravenous administration etc.). Injection can be
administered intravenously, intramuscularly, subcutaneously, or by
intraorgan administration or directly to the lesion.
[0931] Examples of the pharmacologically acceptable carriers usable
for the production of a combination agent of the present invention,
various organic or inorganic carrier substances conventionally used
as preparation materials can be mentioned. For solid preparations,
for example, excipient, lubricant, binder and disintegrant can be
used. For liquid preparations, for example, solvent, solubilizing
agent, suspending agent, isotonic agent, buffering agent, soothing
agent and the like can be used. Where necessary, an appropriate
amount of conventional preservative, antioxidant, colorant,
sweetening agent, adsorbent, wetting agent and the like can be used
as appropriate.
[0932] Examples of the excipient include lactose, sucrose,
D-mannitol, starch, corn starch, crystalline cellulose, light
anhydrous silicic acid and the like.
[0933] Examples of the lubricant include magnesium stearate,
calcium stearate, talc, colloidal silica and the like.
[0934] Examples of the binding agent include crystalline cellulose,
white sugar, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch,
sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium
and the like.
[0935] Examples of the disintegrant include starch,
carboxymethylcellulose, carboxymethylcellulose calcium, sodium
carboxymethyl starch, L-hydroxypropylcellulose and the like.
[0936] Examples of the solvent include water for injection,
alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive
oil and the like.
[0937] Examples of the solubilizing agent include polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0938] Examples of the suspending agent include surfactants such as
stearyl triethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride,
benzetonium chloride, glycerin monostearate and the like;
hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like; and the like.
[0939] Examples of the isotonic agent include glucose, D-sorbitol,
sodium chloride, glycerin, D-mannitol and the like.
[0940] Examples of the buffering agent include buffer solutions
such as phosphates, acetates, carbonates, citrates and the
like.
[0941] Examples of the soothing agent include benzyl alcohol and
the like.
[0942] Examples of the preservative include p-oxybenzoates,
chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic
acid, sorbic acid and the like.
[0943] Examples of the antioxidant include sulfite, ascorbic acid,
.alpha.-tocopherol and the like.
[0944] The mixing ratio of the compound of the present invention to
the concomitant drug in the combination agent of the present
invention can be appropriately selected depending on an
administration subject, administration route, diseases and the
like.
[0945] For example, the content of the compound of the present
invention in the combination agent of the present invention differs
depending on the form of a preparation, and usually from about 0.01
to about 100 wt %, preferably from about 0.1 to about 50 wt %,
further preferably from about 0.5 to about 20 wt %, based on the
preparation.
[0946] The content of the concomitant drug in the combination agent
of the present invention differs depending on the form of a
preparation, and usually from about 0.01 to about 100 wt %,
preferably from about 0.1 to about 50 wt %, further preferably from
about 0.5 to about 20 wt %, based on the preparation.
[0947] The content of additives such as a carrier and the like in
the combination agent of the present invention differs depending on
the form of a preparation, and usually from about 1 to about 99.99
wt %, preferably from about 10 to about 90 wt %, based on the
preparation.
[0948] When the compound of the present invention and a concomitant
drug are separately formulated into preparations, the contents
thereof are similar to the above.
EXAMPLES
[0949] The present invention is explained in detail in the
following by referring to Examples, Experimental Examples and
Formulation Examples, which are not to be construed as limitative,
and the invention may be changed within the scope of the present
invention.
[0950] In the following Examples, the "room temperature" generally
means about 10.degree. C. to about 35.degree. C. The ratios
indicated for mixed solvents are volume mixing ratios, unless
otherwise specified. % means wt %, unless otherwise specified.
[0951] Unless particularly specified, the elution in column
chromatography in Example was performed under observation by TLC
(Thin Layer Chromatography). For TLC observation, 60F.sub.254
manufactured by Merck was used as a TLC plate, and the solvent used
as an elution solvent for column chromatography was used as a
developing solvent. For detection, a UV detector was adopted. In
silica gel column chromatography, NH means use of
aminopropylsilane-bonded silica gel, and Diol means use of
3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In
preparative HPLC (high performance liquid chromatography), C18
means use of octadecyl-bonded silica gel. The ratios indicated for
elution solvents are volume mixing ratios, unless otherwise
specified.
[0952] For 1H NMR analysis, ACD/SpecManager (trade name) software
and the like were used. Peaks of a hydroxy group, an amino group
and the like, which having very mild protons, may not be
described.
[0953] MS was measured by LC/MS. As ionization method, ESI method
or APCI method was used. The data indicates actual measured value
(found). Generally, molecular ion peaks are observed, and may be
observed as a fragment ion. In the case of a salt, a molecular ion
peak or fragment ion peak of free form is generally observed.
[0954] The unit of sample concentration (c) for optical rotation
([.alpha.].sub.D) is g/100 mL.
[0955] Elemental analysis value (Anal.) was described as calculated
value (Calcd) and actual measured value (Found).
[0956] The peak by powder X-RAY diffraction in Example means the
peak measured using Cu K.alpha.-ray as a source by Ultima IV
(Rigaku Corporation, Japan) at room temperature. The measurement
conditions are as follows.
[0957] Electric pressure/Electric current: 40 kV/50 mA Scan speed:
6 degree/min
[0958] Scan range of 2 Theta: 2-35 degree
[0959] The crystallinity by powder X-RAY diffraction in Example was
calculated by Hermans method.
[0960] In Examples, the following abbreviations are used.
mp: melting point MS: mass spectrum M: mol concentration N:
normality CDCl.sub.3: deuterochloroform DMSO-d.sub.6:
deuterodimethyl sulfoxide 1H NMR: proton nuclear magnetic resonance
LC/MS: liquid chromatograph mass spectrometer ESI: electrospray
ionization, Electron Spray Ionization APCI: atmospheric pressure
chemical ionization, atmospheric pressure chemical ionization AcOH:
acetic acid Boc: tert-butoxycarbonyl n-BuOH: normal butanol
CH.sub.3CN: acetonitrile CPME: cyclopentyl methyl ether DIAD:
diisopropyl azodicarboxylate
DMA: N,N-dimethylacetamide
DMF: N,N-dimethylformamide
[0961] DME: 1,2-dimethoxyethane DMSO: dimethyl sulfoxide DPPA:
diphenylphosphoryl azide EtOH: ethanol IPE: diisopropyl ether MeOH:
methanol
NMP: N-methylpyrrolidone
[0962] Pd(dppf)Cl.sub.2: dichloro[1,1'-bis(diphenylphosphino)
ferrocene]palladium(II) Pd(PPh.sub.3).sub.4:
tetrakis(triphenylphosphine)palladium(0) TFA: trifluoroacetic acid
THF: tetrahydrofuran XPhos:
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G2:
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)
(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
Example 1
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-methoxyethoxy)-1--
((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benz-
onitrile
A) methyl (2S)-2-(5-bromo-2-cyanophenoxy)propanoate
[0963] To a mixture of 4-bromo-2-hydroxybenzonitrile (14.5 g),
methyl (2R)-2-hydroxypropanoate (15.3 g), triphenylphosphine (57.6
g) and THF (dry) (150 mL) was added 2.2M diethyl
(E)-diazene-1,2-dicarboxylate toluene solution (116 mL) at
0.degree. C. The mixture was stirred at room temperature overnight
under nitrogen atmosphere. To the mixture was added water at room
temperature, and the mixture was extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(20.0 g).
[0964] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.72 (d, J=8.3 Hz,
1H), 7.47 (d, J=1.6 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 5.40 (q,
J=6.8 Hz, 1H), 3.71 (s, 3H), 1.57 (d, J=6.8 Hz, 3H).
B) 4-bromo-2-(((2S)-1-hydroxypropan-2-yl)oxy)benzonitrile
[0965] To a mixture of methyl
(2S)-2-(5-bromo-2-cyanophenoxy)propanoate (20.0 g), THF (dry) (100
mL) and MeOH (170 mL) was added sodium tetrahydroborate (2.66 g) at
0.degree. C., and the mixture was stirred at room temperature under
nitrogen atmosphere. After being stirred for 3 hr, additional
sodium tetrahydroborate (2.13 g) was added to the mixture at
0.degree. C., and the mixture was stirred at room temperature
overnight. To the mixture was added saturated aqueous ammonium
chloride solution at 0.degree. C., and the mixture was concentrated
under reduced pressure, and the residue was extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give the title compound
(18.0 g). This product was subjected to the next reaction without
further purification.
[0966] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.66 (d, J=8.3 Hz,
1H), 7.60 (d, J=1.7 Hz, 1H), 7.28 (dd, J=8.3, 1.7 Hz, 1H), 4.97 (t,
J=5.5 Hz, 1H), 4.71 (sxt, J=5.7 Hz, 1H), 3.50-3.57 (m, 2H), 1.23
(d, J=6.1 Hz, 3H).
C) (2S)-2-(5-bromo-2-cyanophenoxy)propyl methanesulfonate
[0967] To a mixture of
4-bromo-2-(((2S)-1-hydroxypropan-2-yl)oxy)benzonitrile (32.6 g),
triethylamine (25.8 g) and THF (dry) (300 mL) was added
methanesulfonyl chloride (20.4 g) at 0.degree. C. The mixture was
stirred at room temperature for 2 hr under nitrogen atmosphere. To
the mixture was added water at room temperature, and the mixture
was extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate) to give the title compound (42.5 g).
[0968] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.71 (d, J=8.3 Hz,
1H), 7.66 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.3, 1.7 Hz, 1H), 5.07
(quind, J=6.2, 3.0 Hz, 1H), 4.42-4.49 (m, 1H), 4.31-4.40 (m, 1H),
3.21-3.25 (m, 3H), 1.33 (d, J=6.2 Hz, 3H); MS m/z 334.1
[M+H].sup.+.
D)
4-bromo-2-(((2S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)benzonitrile
[0969] To a mixture of (2S)-2-(5-bromo-2-cyanophenoxy)propyl
methanesulfonate (25.0 g), 1H-tetrazole (10.5 g) and DMF (dry) (100
mL) was added potassium carbonate (20.7 g) at room temperature, and
the mixture was stirred at 80.degree. C. overnight. To the mixture
was added water at room temperature, and the mixture was extracted
with ethyl acetate. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (ethyl acetate/hexane) to give
the title compound (10.3 g).
[0970] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.88-9.02 (m, 1H),
7.42 (d, J=8.2 Hz, 1H), 7.21 (dd, J=8.3, 1.7 Hz, 1H), 7.01 (d,
J=1.6 Hz, 1H), 4.79-4.89 (m, 2H), 4.64-4.77 (m, 1H), 1.44-1.51 (m,
3H); MS m/z 308.2 [M+H].sup.+.
E)
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(((2S)-1-(1H-tetrazol-
-1-yl)propan-2-yl)oxy)benzonitrile
[0971] To a mixture of
4-bromo-2-(((2S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)benzonitrile
(6.30 g) and DMSO (120 mL) were added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (7.79 g)
and Pd(dppf)Cl.sub.2 dichloromethane adduct (1.67 g) at room
temperature, and the mixture was stirred at 100.degree. C. for 3 hr
under nitrogen atmosphere. To the reaction solution was added water
at room temperature, and the insoluble material was removed by
filtration. The filtrate was partitioned with ethyl acetate-water,
and the organic layer was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to give the title compound. The obtained title
compound was used in the next reaction without purification.
[0972] MS m/z 356.3 [M+H].sup.+.
F)
(S)-2-((1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-chloropyrimidin-5-yl)-
benzonitrile
[0973] A mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(((2S)-1-(1H-tetrazol-1-
-yl)propan-2-yl)oxy)benzonitrile (7.26 g),
5-bromo-2-chloropyrimidine (5.93 g), Pd(dppf)Cl.sub.2
dichloromethane adduct (1.67 g) and cesium carbonate (20.0 g) in
DME (80 mL) and water (20 mL) was stirred at 100.degree. C. under
nitrogen atmosphere for 5 hr. The mixture was quenched with water.
The insoluble material was removed by filtration, and the filtrate
was extracted with ethyl acetate. The organic layer was separated,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) and crystallized from ethyl
acetate/IPE to give the title compound (2.00 g).
[0974] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
9.14-9.24 (m, 2H), 7.89 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.55 (d,
J=8.3 Hz, 1H), 5.28-5.45 (m, 1H), 4.79-5.03 (m, 2H), 1.37 (d, J=6.0
Hz, 3H); MS m/z 342.1[M+1].sup.+.
G) 1-[3-(2-methoxyethoxy)-1H-pyrazol-1-yl]ethan-1-one
[0975] Potassium carbonate (4.90 g) was added to a mixture of
1-acetyl-2,3-dihydro-1H-pyrazol-3-one (3.00 g) and
1-bromo-2-methoxyethane (3.44 g) in DMF (20 mL) at 80.degree. C.,
and the mixture was stirred for 1 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure to give
the title compound (3.22 g). This product was subjected to the next
reaction without further purification.
[0976] MS m/z 143.2 [M+H-Ac].
H) 3-(2-methoxyethoxy)-1H-pyrazole
[0977] 8 M Aqueous sodium hydroxide solution (6.5 mL) was added to
a solution of 1-[3-(2-methoxyethoxy)-1H-pyrazol-1-yl]ethan-1-one
(3.22 g) in MeOH (20 mL) at room temperature, and the mixture was
stirred at 50.degree. C. for 1 hr. The mixture was neutralized with
1 M aqueous hydrogen chloride solution and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (2.50 g). This
product was subjected to the next reaction without further
purification.
[0978] MS m/z 143.2 [M+H].sup.+.
I) 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole
[0979] Nitric acid (fuming) (2.82 g) was added to a mixture of
3-(2-methoxyethoxy)-1H-pyrazole (2.50 g) and sulfuric acid (10 mL)
at room temperature, and the mixture was stirred at 50.degree. C.
for 15 hr. The mixture was poured into water and extracted with
ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (590 mg).
[0980] MS m/z 188.2 [M+H]+.
J) tert-butyl
N-[(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexyl]carb-
amate
[0981] Potassium carbonate (1.30 g) was added to a mixture of
3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (590 mg) and tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (1.84 g) in
DMA (10 mL) at 120.degree. C., and the mixture was stirred for 3
hr. The mixture was poured into water and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give the title
compound (840 mg).
[0982] MS m/z 407.2 [M+Na]+.
K)
(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexan-1-ami-
ne hydrochloride
[0983] 4 M Hydrogen chloride-ethyl acetate (1.6 mL) was added to a
solution of tert-butyl
N-[(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexyl]carb-
amate (820 mg) in THF (10 mL) at room temperature, and the mixture
was stirred at 50.degree. C. for 2 hr. The reaction mixture was
concentrated under reduced pressure and the precipitate was
collected by filtration, washed with IPE and dried under reduced
pressure to give the title compound (690 mg).
[0984] MS m/z 285.2 [M+H]+.
L)
4-[(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexyl]mo-
rpholine
[0985] 1-Chloro-2-(2-chloroethoxy)ethane (307 mg) was added to a
mixture of
(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexan-1-am-
ine hydrochloride (690 mg), sodium iodide (482 mg) and potassium
carbonate (1.18 g) in DMA (10 mL) at 100.degree. C., and the
mixture was stirred for 3 hr. The mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the title compound (514 mg).
[0986] MS m/z 355.3 [M+H]+.
M)
3-(2-methoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-
-4-amine hydrochloride
[0987] A mixture of
4-[(1r,4r)-4-[3-(2-methoxyethoxy)-4-nitro-1H-pyrazol-1-yl]cyclohexyl]morp-
holine (514 mg) and 10% palladium-carbon (50 mg) in EtOH (10 mL)
was stirred at 50.degree. C. for 15 hr under normal pressure of
hydrogen atmosphere. The catalyst was removed by filtration, and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give a brown oil. To the obtained brown oil was
added 4 M hydrogen chloride-ethyl acetate (1.0 mL), and the mixture
was concentrated under reduced pressure to give the title compound
(390 mg).
[0988] MS m/z 325.3 [M+H]+.
N)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-methoxyethoxy)-
-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)b-
enzonitrile
[0989] To a solution of
3-(2-methoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4-
-amine hydrochloride (190 mg) in NMP (0.50 mL) was added
(S)-2-((1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-chloropyrimidin-5-yl)be-
nzonitrile (179 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 5 hr. The mixture was quenched with 1
M aqueous hydrogen chloride solution and washed with ethyl acetate.
The aqueous layer was neutralized with 2 M aqueous sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) and silica gel column chromatography (MeOH/ethyl
acetate) to give the title compound (154 mg).
[0990] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.72 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.47 (s,
1H), 7.37-7.43 (m, 1H), 5.28-5.39 (m, 1H), 4.79-5.00 (m, 2H),
4.17-4.24 (m, 2H), 3.83-3.95 (m, 1H), 3.53-3.64 (m, 6H), 3.26 (s,
3H), 2.45-2.50 (m, 4H), 2.22-2.34 (m, 1H), 2.02-2.11 (m, 2H),
1.88-1.98 (m, 2H), 1.58-1.78 (m, 2H), .delta. 1.29-1.45 (m, 5H); MS
m/z 630.27 [M+1].sup.+.
Example 2
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-methoxyethoxy)-1-((1r,4r)-4-morp-
holinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
A) methyl (2S)-2-(5-bromo-2-chlorophenoxy)propanoate
[0991] To a mixture of 5-bromo-2-chlorophenol (31.0 g), methyl
(2R)-2-hydroxypropanoate (31.1 g), triphenylphosphine (118 g) and
THF (dry) (250 mL) was added 2.2M diethyl
(E)-diazene-1,2-dicarboxylate toluene solution (238 mL) at
0.degree. C., and the mixture was stirred at room temperature
overnight under nitrogen atmosphere. To the mixture was added water
at room temperature, and the mixture was extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. To the obtained residue were
added hexane and IPE (1:1, 200 mL), the mixture was stirred at
0.degree. C. for 20 min, and the reaction solution was
concentrated. To the obtained solid were added IPE and ethyl
acetate (2:1, 400 mL) and the mixture was stirred at 0.degree. C.
for 30 min. The insoluble material was removed by filtration, and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (43.9 g).
[0992] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.41 (d, J=8.4 Hz,
1H), 7.26 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.4, 2.1 Hz, 1H), 5.24 (q,
J=6.8 Hz, 1H), 3.70 (s, 3H), 1.54 (d, J=6.7 Hz, 3H).
B) (2S)-2-(5-bromo-2-chlorophenoxy)propan-1-ol
[0993] To a solution of methyl
(2S)-2-(5-bromo-2-chlorophenoxy)propanoate (43.9 g) in MeOH (204
mL) and THF (dry) (120 mL) was added sodium tetrahydroborate (5.66
g) at 0.degree. C. The mixture was stirred at room temperature
overnight. To the mixture was added saturated aqueous ammonium
chloride solution at 0.degree. C., and the mixture was concentrated
under reduced pressure. The obtained residue was extracted with
ethyl acetate. The organic layer was separated, washed with water
and saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (40.4 g).
[0994] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.43 (d, J=2.2 Hz,
1H), 7.37 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.4, 2.2 Hz, 1H), 4.91 (t,
J=5.6 Hz, 1H), 4.47-4.62 (m, 1H), 3.44-3.62 (m, 2H), 1.22 (d, J=6.2
Hz, 3H).
C) (2S)-2-(5-bromo-2-chlorophenoxy)propyl methanesulfonate
[0995] To a mixture of (2S)-2-(5-bromo-2-chlorophenoxy)propan-1-ol
(40.4 g) and triethylamine (30.8 g) in THF (dry) (200 mL) was added
methanesulfonyl chloride (24.4 g) at 0.degree. C. The mixture was
stirred at room temperature for 1 hr under nitrogen atmosphere. To
the mixture was added water at room temperature, and the mixture
was extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate) to give the title compound (52.0 g).
[0996] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.49 (s, 1H), 7.40
(d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 4.85-5.02 (m, 1H),
4.37-4.46 (m, 1H), 4.27-4.37 (m, 1H), 3.21 (s, 3H), 1.30 (d, J=6.2
Hz, 3H).
D) 1-((2S)-2-(5-bromo-2-chlorophenoxy)propyl)-1H-tetrazole
[0997] To a mixture of (2S)-2-(5-bromo-2-chlorophenoxy)propyl
methanesulfonate (52.0 g), potassium carbonate (41.8 g) and DMF
(dry) (100 mL) was added 1H-tetrazole (21.2 g) at room temperature.
The mixture was stirred at 80.degree. C. overnight. To the mixture
was added water at room temperature, and the mixture was extracted
with ethyl acetate. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (ethyl acetate/hexane) to give
the title compound (26.0 g).
[0998] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.92 (s, 1H), 7.09 (d,
J=8.5 Hz, 1H), 6.97 (s, 1H), 4.64-4.87 (m, 3H), 1.40 (d, J=5.9 Hz,
3H); MS m/z 317.0 [M+H].sup.+.
E)
1-((2S)-2-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy)propyl)-1H-tetrazole
[0999] To a mixture of
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (12.0
g), 1-((2S)-2-(5-bromo-2-chlorophenoxy)propyl)-1H-tetrazole (10.0
g), potassium acetate (9.27 g) and DMSO (100 mL) was added
Pd(dppf)Cl2 dichloromethane adduct (2.57 g) at room temperature.
The mixture was stirred at 100.degree. C. for 2 hr under nitrogen
atmosphere. To the mixture were added water and ethyl acetate at
room temperature, the insoluble material was removed by filtration
through celite, and the filtrate was extracted with ethyl acetate.
The organic layer was separated, washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure to give the title compound (16.9 g). This
product was subjected to the next reaction without further
purification.
[1000] MS m/z 365.2 [M+H].sup.+.
F)
2-chloro-5-(4-chloro-3-(((2S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)pheny-
l)pyrimidine
[1001] To a mixture of
1-((2S)-2-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenox-
y)propyl)-1H-tetrazole (12.3 g), 5-bromo-2-chloropyrimidine (9.82
g) and cesium carbonate (33.1 g) in DME (100 mL) and water (25 mL)
was added Pd(dppf)Cl2 (2.76 g) at room temperature. The mixture was
stirred at 100.degree. C. for 5 hr under nitrogen atmosphere. To
the reaction solution were added ethyl acetate and water at room
temperature, and the insoluble material was removed by filtration.
The filtrate was partitioned with ethyl acetate-water, and the
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (3.18 g).
[1002] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.33-9.40 (m, 1H),
7.51-7.61 (m, 2H), 7.37-7.44 (m, 1H), 5.21 (td, J=6.6, 3.6 Hz, 1H),
4.76-5.00 (m, 2H), 1.34 (d, J=6.3 Hz, 3H); MS m/z 351.1
[M+H].sup.+.
G)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-
-methoxyethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimid-
in-2-amine
[1003] To a solution of
3-(2-methoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4-
-amine hydrochloride (190 mg) in NMP (0.50 mL) was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (184 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 5 hr. The mixture was quenched with 1
M aqueous hydrogen chloride solution and washed with ethyl acetate.
The aqueous layer was neutralized with 2 M aqueous sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) and silica gel column chromatography (MeOH/ethyl
acetate) to give the title compound (123 mg).
[1004] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.53 (s, 1H), 7.73 (s, 1H), 7.43-7.46 (m, 1H), 7.37
(s, 1H), 7.23-7.26 (m, 1H), 5.14-5.21 (m, 1H), 4.76-4.94 (m, 2H),
4.19-4.22 (m, 2H), 3.84-3.94 (m, 1H), 3.52-3.62 (m, 6H), 3.26 (s,
3H), 2.45-2.50 (m, 4H), 2.22-2.33 (m, 1H), 2.02-2.10 (m, 2H),
1.88-1.95 (m, 2H), 1.62-1.75 (m, 2H), 1.29-1.45 (m, 5H); MS m/z
639.27 [M+1].sup.+.
Example 8
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-ethoxyethoxy)-1-(-
(1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzo-
nitrile
A) ethyl 1-acetyl-3-(2-ethoxyethoxy)-1H-pyrazole-4-carboxylate
[1005] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (5.15 g),
2-ethoxyethane-1-ol (3.02 g), triphenylphosphane (8.13 g) and
toluene (80 mL) was added DIAD (6.26 g). After being stirred at
60.degree. C. for 15 hr, magnesium chloride (20.0 g) was added
thereto, and the mixture was stirred for 30 min. The insoluble
materials were removed by filtration to give the title compound
(7.00 g). This product was subjected to the next reaction without
further purification.
[1006] MS m/z 271.1 [M+H].sup.+.
B) ethyl 3-(2-ethoxyethoxy)-1H-pyrazole-4-carboxylate
[1007] To a solution of ethyl
1-acetyl-3-(2-ethoxyethoxy)-1H-pyrazole-4-carboxylate (7.00 g) in
DMF (50 mL) was added potassium carbonate (17.8 g) at 100.degree.
C., and the mixture was stirred for 3 hr. The mixture was poured
into water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (4.15 g).
[1008] MS m/z 229.2 [M+H].sup.+.
C) ethyl
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyc-
lohexyl]-1H-pyrazole-4-carboxylate
[1009] Potassium carbonate (8.33 g) was added to a mixture of ethyl
3-(2-ethoxyethoxy)-1H-pyrazole-4-carboxylate (4.60 g) and
tert-butyl N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate
(10.0 g) in DMF (50 mL) at 120.degree. C., and the mixture was
stirred for 3 hr. The mixture was poured into water and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (3.37 g).
[1010] MS m/z 426.3 [M+H]+.
D)
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexy-
l]-1H-pyrazole-4-carboxylic acid
[1011] 2 M Aqueous sodium hydroxide solution (12 mL) was added to a
solution of ethyl
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-
-1H-pyrazole-4-carboxylate (3.37 g) in EtOH (30 mL) at 50.degree.
C., and the mixture was stirred for 15 hr. The mixture was
neutralized with 1 M aqueous hydrogen chloride solution and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the title compound
(3.10 g).
[1012] MS m/z 398.2 [M+H]+.
E) benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino-
}cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1013] DPPA (2.27 g) was added to a mixture of
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-
-1H-pyrazole-4-carboxylic acid (3.10 g), benzyl alcohol (1.67 g)
and triethylamine (1.17 g) in toluene (30 mL) at 100.degree. C.,
and the mixture was stirred for 3 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (2.49 g).
[1014] MS m/z 503.4 [M+H]+.
F) benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-aminocyclohexyl]-1H-pyrazol-4-
-yl]carbamate trifluoroacetate
[1015] A solution of benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohex-
yl]-1H-pyrazol-4-yl]carbamate (2.49 g) in TFA (10 mL) was stirred
at 50.degree. C. for 2 hr. The reaction mixture was concentrated
under reduced pressure to give the title compound (2.60 g). This
product was subjected to the next reaction without further
purification.
[1016] MS m/z 402.3 [M+H]+.
G) benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1-
H-pyrazol-4-yl]carbamate
[1017] 1-Chloro-2-(2-chloroethoxy)ethane (709 mg) was added to a
mixture of benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-aminocyclohexyl]-1H-pyrazol--
4-yl]carbamate trifluoroacetate (2.60 g), sodium iodide (1.11 g)
and potassium carbonate (3.41 g) in DMA (20 mL) at 100.degree. C.,
and the mixture was stirred for 2 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (680 mg).
[1018] MS m/z 473.3 [M+H]+.
H)
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol--
4-amine hydrochloride
[1019] A mixture of benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-
-4-yl]carbamate (680 mg) and 10% palladium-carbon (60.0 mg) in EtOH
(20 mL) was stirred under normal pressure of hydrogen atmosphere at
room temperature for 14 hr. The catalyst was removed by filtration,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give a brown oil. To the obtained brown oil was
added 4 M hydrogen chloride-ethyl acetate (1.0 mL), and the mixture
was concentrated under reduced pressure to give the title compound
(520 mg).
[1020] MS m/z 339.3 [M+H]+.
I)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-ethoxyethoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile
[1021] To a solution of
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4--
amine hydrochloride (250 mg) in NMP (1.0 mL) was added
(S)-2-((1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-chloropyrimidin-5-yl)be-
nzonitrile (273 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 5 hr. The mixture was quenched with 1
M aqueous hydrogen chloride solution and washed with ethyl acetate.
The aqueous layer was neutralized with 2 M aqueous sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane). The residue was purified by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA) The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (207 mg).
[1022] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.71 (s, 1H), 7.72-7.76 (m, 2H), 7.46 (s, 1H),
7.38-7.41 (m, 1H), 5.29-5.41 (m, 1H), 4.80-4.97 (m, 2H), 4.18-4.21
(m, 2H), 3.82-3.95 (m, 1H), 3.62-3.66 (m, 2H), 3.52-3.60 (m, 4H),
3.45 (q, J=7.2 Hz, 2H), 2.45-2.50 (m, 4H), 2.22-2.33 (m, 1H),
2.01-2.10 (m, 2H), 1.87-1.97 (m, 2H), 1.62-1.75 (m, 2H), 1.30-1.44
(m, 5H), 1.08 (t, J=7.2 Hz, 3H); MS m/z 644.37 [M+1].sup.+.
Example 9
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-ethoxyethoxy)-1-((1r,4r)-4-morph-
olinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1023] To a solution of
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4--
amine hydrochloride (250 mg) in NMP (1.0 mL) was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (280 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 5 hr. The mixture was quenched with 1
M aqueous hydrogen chloride solution and washed with ethyl acetate.
The aqueous layer was neutralized with 2 M aqueous sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) and silica gel column chromatography (MeOH/ethyl
acetate) to give the title compound (212 mg).
[1024] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.53 (s, 1H), 7.73 (s, 1H), 7.42-7.43 (m, 1H), 7.37
(s, 1H), 7.21-7.26 (m, 1H), 5.12-5.22 (m, 1H), 4.77-4.94 (m, 2H),
4.18-4.21 (m, 2H), 3.84-3.95 (m, 1H), 3.61-3.67 (m, 2H), 3.53-3.60
(m, 4H), 3.44 (q, J=7.2 Hz, 2H), 2.45-2.50 (m, 4H), 2.21-2.33 (m,
1H), 2.01-2.10 (m, 2H), 1.88-1.99 (m, 2H), 1.60-1.75 (m, 2H),
1.29-1.45 (m, 5H), 1.08 (t, J=7.2 Hz, 3H); MS m/z 653.33
[M+1].sup.+.
Example 12
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)--
3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile
A) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-ethoxyethoxy)-1H-pyrazole--
4-carboxylate
[1025] A mixture of ethyl
3-(2-ethoxyethoxy)-1H-pyrazole-4-carboxylate (4.10 g),
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (5.90 g) and cesium
carbonate (7.55 g) in DMF (100 mL) was stirred at 100.degree. C.
for 12 hr. The mixture was poured into water and extracted with
ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (5.52 g).
[1026] MS m/z 369.2 [M+H].sup.+.
B)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-ethoxyethoxy)-1H-pyrazole-4-carb-
oxylic acid
[1027] To a mixture of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-ethoxyethoxy)-1H-pyrazole-4-carbox-
ylate (4.71 g) and EtOH (30 mL) was added 2 M aqueous sodium
hydroxide solution (20 mL). After being stirred at 80.degree. C.
for 1 hr, the mixture was neutralized with 1 M aqueous hydrogen
chloride solution at room temperature and extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to give the title compound (4.35 g). This product was
subjected to the next reaction without further purification.
[1028] MS m/z 341.2 [M+H].sup.+.
C) benzyl
N-[3-(2-ethoxyethoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbam-
ate
[1029] To a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-ethoxyethoxy)-1H-pyrazole-4-carbox-
ylic acid (4.35 g), triethylamine (2.06 g) and benzyl alcohol (2.07
g) in toluene (100 mL) was added DPPA (5.28 g). After being stirred
at room temperature for 1 hr and at 100.degree. C. for 2 hr, the
mixture was concentrated. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give a colorless
oil. To a solution of the obtained oil in THF (20 mL) was added 1 M
aqueous hydrogen chloride solution (20 mL) at room temperature, and
the mixture was stirred at 60.degree. C. for 2 hr. The mixture was
poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give the title compound (2.85 g).
[1030] MS m/z 402.2 [M+H].sup.+.
D) benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3-
.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1031] 2-Methylpyridine-borane (744 mg) was added to a mixture of
benzyl
N-[3-(2-ethoxyethoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(1.40 g), (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride
(781 mg) and triethylamine (528 mg) in MeOH (30 mL) and AcOH (1.0
mL) at 50.degree. C., and the mixture was stirred for 1 hr. The
mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (580 mg).
[1032] MS m/z 499.3 [M+H]+.
E)
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-
-8-yl]cyclohexyl]-1H-pyrazol-4-amine
[1033] A mixture of benzyl
N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octa-
n-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate (580 mg) and 10%
palladium-carbon (50 mg) in EtOH (20 mL) was stirred under normal
pressure of hydrogen atmosphere at 50.degree. C. for 14 hr. The
catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (353 mg).
[1034] MS m/z 365.2 [M+H]+.
F)
5-bromo-N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[-
3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine
[1035] To a solution of
3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-
-yl]cyclohexyl]-1H-pyrazol-4-amine (353 mg) in NMP (3.0 mL) were
added 5-bromo-2-chloropyrimidine (224 mg) and methanesulfonic acid
(278 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 6 hr. The mixture was poured into saturated
aqueous sodium hydrogencarbonate solution and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) to give the title
compound (224 mg).
[1036] MS m/z 521.2, 523.2 [M+H]+.
G)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5-
S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-p-
yrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1037] To a mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[(2S)-1-(1H-tetrazol-1-
-yl)propan-2-yl]oxy}benzonitrile (184 mg),
5-bromo-N-[3-(2-ethoxyethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.-
2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine (226
mg) and 2 M aqueous sodium carbonate solution (0.45 mL) in DME (5.0
mL) was added Pd(dppf)Cl2 dichloromethane adduct (15.8 mg), and the
mixture was stirred under nitrogen atmosphere at 90.degree. C. for
1 hr. The mixture was poured into water and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) and
silica gel column chromatography (MeOH/ethyl acetate) to give the
title compound (154 mg).
[1038] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.72 (s, 1H), 7.72-7.76 (m, 2H), 7.46 (s, 1H),
7.36-7.42 (m, 1H), 5.28-5.39 (m, 1H), 4.80-4.98 (m, 2H), 4.15-4.23
(m, 2H), 3.84-3.95 (m, 1H), 3.61-3.67 (m, 2H), 3.37-3.66 (m, 6H),
3.26-3.28 (m, 2H), 1.96-2.17 (m, 5H), 1.62-1.83 (m, 6H), 1.35 (d,
J=6.0 Hz, 3H), 1.12-1.24 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); MS m/z
670.41 [M+1].sup.+.
Example 14
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-isopropoxyethoxy)-
-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)b-
enzonitrile
A) ethyl
1-acetyl-3-[2-(propan-2-yloxy)ethoxy]-1H-pyrazole-4-carboxylate
[1039] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.20 g),
2-(propan-2-yloxy)ethan-1-ol (1.49 g), triphenylphosphine (3.48 g)
and toluene (30 mL) was added DIAD (2.6 mL). After being stirred at
60.degree. C. for 1 hr, the mixture was concentrated. The residue
was purified by silica gel column chromatography (ethyl acetate) to
give the title compound (3.08 g)
[1040] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.54 (s, 1H), 4.45
(s, 2H), 4.30 (d, J=7.15 Hz, 2H), 3.80-3.88 (m, 2H), 3.64-3.77 (m,
1H), 2.61 (s, 3H), 1.34 (t, J=7.11 Hz, 3H), 1.20 (d, J=6.14 Hz,
6H).
B) ethyl 3-[2-(propan-2-yloxy)ethoxy]-1H-pyrazole-4-carboxylate
[1041] To a solution of ethyl
1-acetyl-3-[2-(propan-2-yloxy)ethoxy]-1H-pyrazole-4-carboxylate
(3.05 g) in EtOH (50 mL) was added sodium ethanolate (871 mg) at
room temperature. The mixture was stirred at 40.degree. C. under
nitrogen atmosphere for 1 hr. After cooling, the mixture was
neutralized with 2 M aqueous hydrogen chloride solution at
0.degree. C. and extracted with ethyl acetate. The organic layer
was separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.72 g).
[1042] 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88 (s, 1H), 4.36-4.44
(m, 2H), 4.28 (d, J=7.06 Hz, 2H), 3.82 (s, 2H), 3.64-3.77 (m, 1H),
1.33 (s, 3H), 1.17-1.22 (m, 6H) (NH peak was omitted).
C) ethyl
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl-
]amino}cyclohexyl]-1H-pyrazole-4-carboxylate
[1043] To a solution of ethyl
3-[2-(propan-2-yloxy)ethoxy]-1H-pyrazole-4-carboxylate (2.72 g) and
cesium carbonate (10.9 g) in DMA (6.0 mL) was added tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (4.89 g) at
room temperature. The mixture was stirred at 80.degree. C. under
nitrogen atmosphere for 14 hr. Additional tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (1.64 g) and
DMA (5.0 mL) were added to the mixture, and the mixture was stirred
at 80.degree. C. for 3 hr. Additional tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (1.64 g) and
DMA (5.0 mL) were added to the mixture, and the mixture was stirred
at 80.degree. C. for 3 hr. The mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the crude title compound (2.22 g).
[1044] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.68-7.71 (m, 1H),
4.39-4.57 (m, 1H), 4.31-4.39 (m, 2H), 4.19-4.31 (m, 2H), 3.84-3.94
(m, 1H), 3.77-3.83 (m, 2H), 3.65-3.76 (m, 1H), 3.40-3.60 (m, 1H),
2.12-2.24 (m, 4H), 1.65-1.85 (m, 2H), 1.45 (s, 9H), 1.22-1.36 (m,
5H), 1.18 (d, J=6.05 Hz, 6H).
D)
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino-
}cyclohexyl]-1H-pyrazole-4-carboxylic acid
[1045] To a solution of the crude ethyl
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}c-
yclohexyl]-1H-pyrazole-4-carboxylate (3.84 g) in EtOH (30 mL) was
added 2 M aqueous sodium hydroxide solution (12 mL), and the
mixture was stirred at 50.degree. C. for 14 hr. After cooling, the
reaction mixture was diluted with water (20 mL) and washed with IPE
(20 mL.times.2). The aqueous phase was acidified with 2 M aqueous
hydrogen chloride solution (13 mL) and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the crude title compound (2.77
g).
[1046] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.78 (s, 1H),
4.39-4.48 (m, 3H), 3.84-3.96 (m, 1H), 3.75-3.81 (m, 2H), 3.62-3.73
(m, 1H), 3.43-3.61 (m, 1H), 2.12-2.24 (m, 4H), 1.70-1.87 (m, 2H),
1.45 (s, 9H), 1.23-1.38 (m, 2H), 1.18 (d, J=6.05 Hz, 6H) CO.sub.2H
peak was omitted.
E) benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carb-
onyl]amino}cyclohexyl]-1H-pyrazol-4-yl}carbamate
[1047] To a mixture of
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}c-
yclohexyl]-1H-pyrazole-4-carboxylic acid (2.25 g), benzyl alcohol
(1.76 g) and triethylamine (828 mg) in toluene (50 mL) was added
DPPA (2.65 g) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 3 hr. The mixture was
poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the crude title
compound (3.12 g). This product was subjected to the next reaction
without further purification.
[1048] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.57-7.63 (m, 1H),
7.32-7.42 (m, 5H), 6.90-7.00 (m, 1H), 5.17 (s, 2H), 4.23-4.29 (m,
2H), 3.76-3.90 (m, 1H), 3.67-3.72 (m, 2H), 3.57-3.66 (m, 1H),
2.06-2.20 (m, 4H), 1.68-1.87 (m, 2H), 1.45 (s, 9H), 1.24-1.33 (m,
4H), 1.17 (d, J=6.05 Hz, 6H).
F) benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-aminocyclohexyl]-1H-
-pyrazol-4-yl}carbamate hydrochloride
[1049] A solution of benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amin-
o}cyclohexyl]-1H-pyrazol-4-yl}carbamate (3.02 g) in 4 M hydrogen
chloride-cyclopentyl methyl ether (20 mL) and ethyl acetate (10 mL)
was stirred at room temperature for 14 hr. The reaction mixture was
concentrated under reduced pressure. The precipitate was collected
by filtration, washed with ethyl acetate and dried in reduced
pressure to give the title compound (2.03 g).
[1050] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.63-8.71 (m, 1H),
7.96-8.09 (m, 3H), 7.58-7.62 (m, 1H), 7.28-7.44 (m, 5H), 5.04-5.11
(m, 2H), 4.09-4.17 (m, 2H), 3.84-3.96 (m, 1H), 3.57-3.67 (m, 3H),
1.95-2.11 (m, 4H), 1.65-1.83 (m, 2H), 1.37-1.59 (m, 3H), 1.08 (d,
J=6.05 Hz, 6H).
G) benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyc-
lohexyl]-1H-pyrazol-4-yl}carbamate
[1051] To a mixture of benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-aminocyclohexyl]-1H-pyrazol--
4-yl}carbamate hydrochloride (2.01 g) and potassium carbonate (2.44
g) in DMA (20 mL) was added 1-chloro-2-(2-chloroethoxy)ethane (759
mg) at room temperature. The mixture was stirred at 90.degree. C.
under argon atmosphere for 4 hr. The mixture was concentrated under
reduced pressure, and the residue was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated aqueous ammonium chloride solution and
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the crude title compound (1.93 g).
[1052] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.57-7.65 (m, 1H),
7.31-7.47 (m, 5H), 6.94-7.02 (m, 1H), 5.17 (s, 2H), 4.22-4.30 (m,
2H), 3.58-3.88 (m, 9H), 2.52-2.62 (m, 4H), 2.18-2.34 (m, 2H),
1.97-2.04 (m, 2H), 1.66 (brs, 2H), 1.32-1.47 (m, 2H), 1.12-1.19 (m,
6H).
H)
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1-
H-pyrazol-4-amine dihydrochloride
[1053] A mixture of benzyl
N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]--
1H-pyrazol-4-yl}carbamate (1.39 g), 10% palladium-carbon (606 mg)
and 4 M hydrogen chloride-ethyl acetate (2.9 mL) in EtOH (50 mL)
was stirred under normal pressure of hydrogen atmosphere at room
temperature for 2 hr. The catalyst was removed by filtration, and
the filtrate was concentrated under reduced pressure to give the
crude title compound (1.10 g). This product was subjected to the
next reaction without further purification.
[1054] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.09-11.76 (m, 1H),
9.87-10.40 (m, 3H), 7.76-7.81 (m, 1H), 4.21-4.27 (m, 2H), 3.95
(brs, 5H), 3.66-3.72 (m, 2H), 3.21-3.42 (m, 4H), 3.01-3.17 (m, 2H),
2.22-2.35 (m, 2H), 2.04-2.16 (m, 2H), 1.61-1.83 (m, 4H), 1.10 (d,
J=6.05 Hz, 6H).
I)
5-bromo-N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cy-
clohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine
[1055] To a solution of
3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H--
pyrazol-4-amine dihydrochloride (1.05 g) in NMP (15 mL) was added
5-bromo-2-chloropyrimidine (617 mg) at room temperature. The
mixture was stirred at 120.degree. C. under argon atmosphere for 14
hr. The mixture was poured into water, basified with sodium
hydrogencarbonate and extracted with ethyl acetate. The organic
layer was extracted with 2 M aqueous hydrogen chloride solution.
The aqueous layer was washed with ethyl acetate and basified with 8
M aqueous sodium hydroxide solution. The aqueous solution was
extracted with ethyl acetate, and the organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (1.01 g).
[1056] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.36 (s, 2H), 7.80 (s,
1H), 7.08-7.16 (m, 1H), 4.30-4.39 (m, 2H), 3.80-3.95 (m, 1H),
3.70-3.79 (m, 7H), 2.58 (brs, 4H), 2.27-2.37 (m, 1H), 2.04-2.25 (m,
4H), 1.67-1.83 (m, 2H), 1.31-1.48 (m, 2H), 1.21 (d, J=6.14 Hz,
6H).
J)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-isopropoxyetho-
xy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-y-
l)benzonitrile
[1057] To a mixture of
5-bromo-N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cycl-
ohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (113 mg),
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-
-dioxaborolane (67.5 mg) and potassium acetate (65.3 mg) in DME
(4.0 mL) was added Pd(dppf)Cl.sub.2 (8.13 mg) at room temperature.
The mixture was stirred at 85.degree. C. under argon atmosphere for
14 hr. After cooling to room temperature, DME (4.0 mL), 2 M aqueous
sodium carbonate solution (332 uL),
4-bromo-2-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}benzonitri- le
(61.5 mg) and Pd(dppf)Cl.sub.2 (8.13 mg) were added to the mixture.
The mixture was stirred at 85.degree. C. under argon atmosphere for
7 hr. The mixture was poured into water and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) to give the title
compound (101 mg).
[1058] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.97-9.02 (m, 1H), 8.56
(s, 2H), 7.92 (s, 1H), 7.61 (d, J=8.07 Hz, 1H), 7.43-7.48 (m, 1H),
7.13-7.21 (m, 1H), 6.88-6.93 (m, 1H), 4.94-5.04 (m, 1H), 4.83-4.93
(m, 1H), 4.68-4.79 (m, 1H), 4.32-4.41 (m, 2H), 3.82-3.95 (m, 1H),
3.63-3.79 (m, 7H), 2.54-2.65 (m, 4H), 2.20-2.38 (m, 3H), 2.06-2.17
(m, 2H), 1.68-1.86 (m, 2H), 1.52 (d, J=6.14 Hz, 3H), 1.32-1.48 (m,
2H), 1.21 (d, J=6.14 Hz, 6H); MS m/z 658.44 [M+1].sup.+.
Example 16
2-(((S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-isopropoxyet-
hoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-
-yl)benzonitrile
A)
4-bromo-2-(((2S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl)oxy)benzonitrile
[1059] To a mixture of (2S)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol
(6.79 g) and DMF (120 ml) was added 60% sodium hydride (2.56 g) at
0.degree. C. The mixture was stirred at 0.degree. C. for 15 min,
4-bromo-2-fluorobenzonitrile (11.8 g) was added to the mixture, and
the mixture was stirred at room temperature for 2 days. To the
mixture was added water at 0.degree. C., and the mixture was
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane). A mixture of the obtained solid and IPE was
stirred at room temperature for 1 hr, and the precipitated solid
was collected by filtration to give the title compound (9.60
g).
[1060] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.46 (s, 1H),
7.95 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.28
(dd, J=8.3, 1.7 Hz, 1H), 5.05-5.19 (m, 1H), 4.52 (d, J=5.6 Hz, 2H),
1.32 (d, J=6.1 Hz, 3H); MS m/z 306.9 [M+H].sup.+.
B)
2-(((S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-isopropox-
yethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidi-
n-5-yl)benzonitrile
[1061] To a mixture of
4-bromo-2-{[(2S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl]oxy}benzonitrile
(361 mg),
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)-1,3,2-dioxaborolane (358 mg) and potassium acetate (230 mg) in
DME (10 mL) was added Pd(dppf)Cl.sub.2 (48.1 mg) at room
temperature. The mixture was stirred at 80.degree. C. under
nitrogen atmosphere for 14 hr. After cooling to room temperature,
DME (5.0 mL), 2 M aqueous sodium carbonate solution (3.0 mL),
5-bromo-N-{3-[2-(propan-2-yloxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cycl-
ohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (220 mg) and
Pd(dppf)Cl.sub.2 (48.1 mg) were added to the mixture. The mixture
was stirred at 80.degree. C. under nitrogen atmosphere for 2 hr.
The mixture was poured into water and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (200
mg).
[1062] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.55 (s, 2H), 8.29 (s,
1H), 7.93 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.29-7.41 (m,
1H), 7.12 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 4.92-5.04 (m, 1H),
4.42-4.56 (m, 2H), 4.31-4.41 (m, 2H), 3.82-3.99 (m, 1H), 3.65-3.81
(m, 7H), 2.60 (brs, 4H), 2.30-2.47 (m, 1H), 2.24 (br d, J=11.6 Hz,
2H), 2.10 (d, J=12.0 Hz, 2H), 1.67-1.96 (m, 5H), 1.35-1.47 (m, 2H),
1.22 (d, J=6.2 Hz, 6H); MS m/z 657.37 [M+1].sup.+.
Example 26
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)-1-
-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ben-
zonitrile
A) ethyl
1-acetyl-3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate
[1063] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.20 g),
3-methoxypropan-1-ol (1.29 g), triphenylphosphine (3.48 g) and
toluene (50 mL) was added DIAD (2.68 g). After being stirred at
60.degree. C. for 1 hr, the mixture was concentrated. The residue
was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (3.04 g).
[1064] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.54 (s, 1H), 4.41 (t,
J=6.33 Hz, 2H), 4.30 (d, J=7.06 Hz, 2H), 3.58 (t, J=6.14 Hz, 2H),
3.36 (s, 3H), 2.61 (s, 3H), 2.11 (t, J=6.28 Hz, 2H), 1.34 (t,
J=7.11 Hz, 3H).
B) ethyl 3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate
[1065] To a solution of ethyl
1-acetyl-3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate (3.04 g) in
EtOH (30 mL) was added sodium ethanolate (837 mg) at room
temperature. The mixture was stirred at 40.degree. C. under
nitrogen atmosphere for 1 hr. After cooling, the mixture was
neutralized with 2 M aqueous hydrogen chloride solution at
0.degree. C. and extracted with ethyl acetate. The organic layer
was separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.50 g).
[1066] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85-7.92 (m, 1H),
4.36 (s, 2H), 4.23-4.33 (m, 2H), 3.53-3.62 (m, 2H), 3.36 (s, 3H),
2.10 (t, J=6.37 Hz, 2H), 1.34 (s, 3H), NH proton was not
detected.
C) ethyl
3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}c-
yclohexyl]-1H-pyrazole-4-carboxylate
[1067] To a solution of ethyl
3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate (1.00 g) and cesium
carbonate (4.26 g) in DMA (6.0 mL) was added tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (1.92 g) at
room temperature. The mixture was stirred at 80.degree. C. under
nitrogen atmosphere for 14 hr. Additional tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (642 mg) and
DMA (5.0 mL) were added to the mixture, and the mixture was stirred
at 80.degree. C. for 3 hr. Additional tert-butyl
N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate (642 mg) and
DMA (5.0 mL) were added to the mixture, and the mixture was stirred
at 80.degree. C. for 3 hr. The mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the crude title compound (2.21 g). This
product was subjected to the next reaction without further
purification.
[1068] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.67-7.71 (m, 1H),
4.38-4.55 (m, 1H), 4.21-4.35 (m, 4H), 3.78-3.98 (m, 1H), 3.57 (t,
J=6.37 Hz, 2H), 3.35 (s, 3H), 2.09-2.25 (m, 4H), 1.74 (d, J=4.49
Hz, 4H), 1.45 (s, 9H), 1.21-1.37 (m, 6H).
D)
3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohe-
xyl]-1H-pyrazole-4-carboxylic acid
[1069] To a solution of ethyl
3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexy-
l]-1H-pyrazole-4-carboxylate (2.21 g) in EtOH (30 mL) was added 2 M
aqueous sodium hydroxide solution (7.8 mL). The mixture was stirred
at 50.degree. C. for 14 hr. After cooling, the reaction mixture was
diluted with water and washed with IPE. The aqueous phase was
acidified with 2 M aqueous hydrogen chloride solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(1.23 g).
[1070] 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.76-7.80 (m, 1H), 4.39
(s, 2H), 3.82-3.97 (m, 1H), 3.52-3.60 (m, 2H), 3.35 (s, 3H),
2.13-2.26 (m, 4H), 2.04-2.12 (m, 3H), 1.66-1.88 (m, 2H), 1.45 (s,
9H), 1.18-1.36 (m, 3H), CO.sub.2H proton was not detected.
E) benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]ami-
no}cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1071] To a mixture of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexy-
l]-1H-pyrazole-4-carboxylic acid (1.23 g), benzyl alcohol (1.00 g)
and triethylamine (468 mg) in toluene (30 mL) was added DPPA (1.50
g) at room temperature. The mixture was stirred at 100.degree. C.
under nitrogen atmosphere for 3 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (1.07 g).
[1072] 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.55-7.60 (m, 1H), 7.37
(brs, 5H), 6.45-6.54 (m, 1H), 5.17 (s, 2H), 4.23 (s, 2H), 3.73-3.95
(m, 1H), 3.49-3.55 (m, 2H), 3.34 (s, 3H), 2.08-2.20 (m, 4H),
1.66-1.86 (m, 2H), 1.45 (s, 9H), 1.26 (s, 6H).
F) benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-aminocyclohexyl]-1H-pyrazol-
-4-yl]carbamate hydrochloride
[1073] To a solution of benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cycloh-
exyl]-1H-pyrazol-4-yl]carbamate (1.05 g) in EtOH (5.0 mL) was added
4 M hydrogen chloride-ethyl acetate (5.1 mL) at room temperature.
The mixture was stirred at room temperature for 14 hr. The mixture
was concentrated under reduced pressure to give the crude title
compound (920 mg). This product was subjected to the next reaction
without further purification.
[1074] MS m/z 403.3 [M+H]+.
G) benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-
-1H-pyrazol-4-yl]carbamate
[1075] To a mixture of benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-aminocyclohexyl]-1H-pyrazol-4-yl]car-
bamate hydrochloride (915 mg), 1-chloro-2-(2-chloroethoxy)ethane
(356 mg) and potassium carbonate (1.14 g) in DMA (10 mL) was added
sodium iodide (0.935 g) at room temperature. The mixture was
stirred at 90.degree. C. under argon atmosphere for 2 hr. The
mixture was concentrated under reduced pressure, and the residue
was poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with saturated aqueous ammonium
chloride solution and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (791 mg).
[1076] 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.59 (s, 1H), 7.38 (dd,
J=1.47, 3.48 Hz, 6H), 6.47-6.55 (m, 1H), 5.17 (s, 2H), 4.24 (s,
2H), 3.77-3.89 (m, 1H), 3.68-3.76 (m, 4H), 3.52 (s, 2H), 3.34 (s,
3H), 2.52-2.62 (m, 4H), 2.10-2.31 (m, 3H), 1.94-2.03 (m, 2H), 1.66
(s, 2H), 1.32-1.48 (m, 2H) (NH peak was omitted).
H)
3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazo-
l-4-amine dihydrochloride
[1077] A mixture of benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyraz-
ol-4-yl]carbamate (790 mg), 10% palladium-carbon (354 mg) and 4 M
hydrogen chloride-ethyl acetate (1.7 mL) in EtOH (20 mL) was
stirred under normal pressure of hydrogen atmosphere at room
temperature for 14 hr. The catalyst was removed by filtration, and
then the filtrate was concentrated under reduced pressure to give
the crude title compound (669 mg). This product was subjected to
the next reaction without further purification.
[1078] MS m/z 339.3 [M+H]+.
I)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy-
)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-
benzonitrile
[1079] To a solution of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol--
4-amine dihydrochloride (173 mg) in NMP (1.0 mL) was added
(S)-2-((1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-chloropyrimidin-5-yl)be-
nzonitrile (143 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 15 hr. The mixture was quenched with
1 M aqueous hydrogen chloride solution and washed with ethyl
acetate. The aqueous layer was basified with 2 M aqueous sodium
hydroxide solution and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA). The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (105 mg). The
obtained title compound (67.0 mg) was crystallized from MeOH to
give the title compound (47.0 mg) as pale yellow crystals.
[1080] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.32-9.39 (m, 1H),
8.78-8.83 (m, 2H), 8.74-8.77 (m, 1H), 7.71-7.78 (m, 2H), 7.45-7.49
(m, 1H), 7.35-7.42 (m, 1H), 5.24-5.42 (m, 1H), 4.90-5.00 (m, 1H),
4.78-4.88 (m, 1H), 4.13 (s, 2H), 3.83-3.96 (m, 1H), 3.53-3.64 (m,
4H), 3.37-3.47 (m, 2H), 3.21 (s, 3H), 2.45-2.50 (m, 4H), 2.20-2.34
(m, 1H), 2.01-2.11 (m, 2H), 1.83-1.97 (m, 4H), 1.58-1.76 (m, 2H),
1.29-1.45 (m, 5H); MS m/z 644.41 [M+1].sup.+.
Example 27
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-methoxypropoxy)-1-((1r,4r)-4-mor-
pholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1081] To a solution of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol--
4-amine dihydrochloride (175 mg) in NMP (1.0 mL) was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (149 mg) at room temperature, and the mixture was
stirred at 110.degree. C. for 15 hr. The mixture was quenched with
1 M aqueous hydrogen chloride solution and washed with ethyl
acetate. The aqueous layer was basified with 2 M aqueous sodium
hydroxide solution and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, MeOH/ethyl acetate) and silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (128
mg).
[1082] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.58 (s, 1H), 7.73 (s, 1H), 7.41-7.48 (m, 1H),
7.33-7.39 (m, 1H), 7.20-7.27 (m, 1H), 5.08-5.27 (m, 1H), 4.86-4.95
(m, 1H), 4.73-4.84 (m, 1H), 4.12 (t, J=6.42 Hz, 2H), 3.82-3.96 (m,
1H), 3.52-3.63 (m, 4H), 3.42 (t, J=6.33 Hz, 2H), 3.21 (s, 3H), 2.49
(brs, 4H), 2.19-2.36 (m, 1H), 2.01-2.12 (m, 2H), 1.89 (d, J=6.42
Hz, 4H), 1.58-1.78 (m, 2H), 1.33 (d, J=6.14 Hz, 5H); MS m/z 653.36
[M+1].sup.+.
Example 28
2-(((S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropo-
xy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-y-
l)benzonitrile
A)
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl-
]-1H-pyrazol-4-yl]pyrimidin-2-amine
[1083] A mixture of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol--
4-amine dihydrochloride (320 mg) and 5-bromo-2-chloropyrimidine
(195 mg) in NMP (15 mL) was stirred at 120.degree. C. for 7 hr. The
mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution at room temperature and extracted with
ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (150 mg).
[1084] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.37 (s, 2H),
7.77-7.79 (m, 1H), 6.91-6.97 (m, 1H), 4.30 (s, 2H), 3.80-3.93 (m,
1H), 3.70-3.77 (m, 4H), 3.49-3.58 (m, 2H), 3.36 (s, 3H), 2.55-2.62
(m, 4H), 2.17-2.32 (m, 3H), 2.01-2.13 (m, 4H), 1.66-1.79 (m, 2H),
1.35-1.48 (m, 2H).
B)
2-(((S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypr-
opoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin--
5-yl)benzonitrile
[1085] To a mixture of
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]--
1H-pyrazol-4-yl]pyrimidin-2-amine (140 mg),
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-
-dioxaborolane (86.0 mg) and potassium acetate (83.1 mg) in DME
(4.0 mL) was added Pd(dppf)Cl.sub.2 (10.3 mg) at room temperature.
The mixture was stirred at 85.degree. C. under argon atmosphere for
14 hr. After cooling to room temperature, DME (4.0 mL), 2 M aqueous
sodium carbonate solution (423 uL),
4-bromo-2-{[(2S)-1-(1H-1,2,4-triazol-1-yl)propan-2-yl]oxy}benzo-
nitrile (78.0 mg) and Pd(dppf)Cl.sub.2 (10.3 mg) were added to the
mixture. The mixture was stirred at 85.degree. C. under argon for 7
hr. The mixture was poured into water and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) and purified by
preparative HPLC (water/CH.sub.3CN containing 0.1% TFA). The
desired fraction was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the title compound
(61.0 mg).
[1086] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.55 (s, 2H), 8.28 (s,
1H), 7.86-7.98 (m, 2H), 7.56-7.62 (m, 1H), 7.10-7.16 (m, 1H),
7.04-7.09 (m, 1H), 6.81-6.86 (m, 1H), 4.91-5.06 (m, 1H), 4.49-4.52
(m, 1H), 4.48 (s, 1H), 4.32 (t, J=6.28 Hz, 2H), 3.84-3.97 (m, 1H),
3.70-3.77 (m, 4H), 3.56 (t, J=6.33 Hz, 2H), 3.37 (s, 3H), 2.55-2.65
(m, 4H), 2.30-2.39 (m, 1H), 2.18-2.30 (m, 2H), 2.06 (d, J=6.33 Hz,
4H), 1.76-1.85 (m, 2H), 1.50 (d, J=6.24 Hz, 3H), 1.34-1.47 (m, 2H);
MS m/z 643.42 [M+1].sup.+.
Example 30
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)--
3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-py-
razol-4-yl)amino)pyrimidin-5-yl)benzonitrile
A) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyrazol-
e-4-carboxylate
[1087] To a mixture of ethyl
3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate (1.45 g) and
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (2.24 g) in DMF (25
mL) was added cesium carbonate (6.19 g) at room temperature. The
mixture was stirred at 90.degree. C. under argon atmosphere for 14
hr. Additional 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (749
mg) was added to the mixture, and the mixture was stirred at
90.degree. C. under argon atmosphere for 4 hr. To remove remaining
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate, the mixture was
stirred at 120.degree. C. for 1 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the crude title compound (2.29 g).
[1088] 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H), 4.79-4.91
(m, 1H), 4.30-4.36 (m, 2H), 4.20-4.29 (m, 2H), 3.97 (s, 4H), 3.57
(s, 2H), 3.35 (s, 3H), 1.96-2.03 (m, 4H), 1.80-1.92 (m, 4H),
1.66-1.77 (m, 2H), 1.32 (t, J=7.15 Hz, 3H).
B)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyrazole-4-ca-
rboxylic acid
[1089] 2 M aqueous sodium hydroxide solution (10 mL) was added to a
solution of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyrazole-4-carb-
oxylate (2.00 g) in EtOH (20 mL) at room temperature, and the
mixture was stirred for 15 h. The mixture was neutralized with 1 M
aqueous hydrogen chloride solution and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (1.80 g). This
product was subjected to the next reaction without further
purification.
[1090] MS m/z 341.2 [M+H]+.
C) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyr-
azol-4-yl)carbamate
[1091] DPPA (1.53 g) was added to a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyrazole-4-carb-
oxylic acid (1.80 g), benzyl alcohol (1.13 g) and triethylamine
(801 mg) in toluene (20 mL) at 100.degree. C., and the mixture was
stirred for 3 hr. The mixture was poured into water and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (1.58 g).
[1092] MS m/z 446.3 [M+H]+
D) benzyl
N-[3-(3-methoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carb-
amate
[1093] 1 M Aqueous hydrogen chloride solution (10 mL) was added to
a solution of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methoxypropoxy)-1H-pyrazol-4-yl-
)carbamate (1.58 g) in THF (10 mL) at 50.degree. C., and the
mixture was stirred for 2 h. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(1.45 g). This product was subjected to the next reaction without
further purification.
[1094] MS m/z 402.2 [M+H]+.
E) benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo-
[3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1095] 2-Methylpyridine-borane (755 mg) was added to a mixture of
benzyl
N-[3-(3-methoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(1.42 g), (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride
(791 mg) and triethylamine (1.06 g) in MeOH (30 mL) and AcOH (1.0
mL) at 50.degree. C., and the mixture was stirred for 1 h. The
mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (583 mg).
[1096] MS m/z 499.3 [M+H]+.
F)
3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]oct-
an-8-yl]cyclohexyl]-1H-pyrazol-4-amine
[1097] A mixture of benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]oc-
tan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate (583 mg) and 10%
palladium-carbon (50.0 mg) in EtOH (10 mL) was stirred under normal
pressure of hydrogen atmosphere at 50.degree. C. for 14 hr. The
catalyst was removed by filtration, and then the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (421 mg).
[1098] MS m/z 365.2 [M+H]+.
G)
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicycl-
o[3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine
[1099] To a solution of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-
-8-yl]cyclohexyl]-1H-pyrazol-4-amine (421 mg) in NMP (3.0 mL) were
added 5-bromo-2-chloropyrimidine (332 mg) and methanesulfonic acid
(330 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 6 hr. The mixture was poured into saturated
aqueous sodium hydrogencarbonate solution and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) to give the title
compound (434 mg).
[1100] MS m/z 521.2, 523.2 [M+H]+.
H)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5-
S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-
-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1101] To a mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[(2S)-1-(1H-tetrazol-1-
-yl)propan-2-yl]oxy}benzonitrile (440 mg),
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[-
3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine (432
mg) and 2 M aqueous sodium carbonate solution (1.0 mL) in DME (10
mL) was added Pd(dppf)Cl2 dichloromethane adduct (30.3 mg) at room
temperature. The mixture was stirred under nitrogen atmosphere at
90.degree. C. for 14 hr. The mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) and
silica gel column chromatography (MeOH/ethyl acetate) to give the
title compound (331 mg).
[1102] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.80 (s, 2H), 8.77 (s, 1H), 7.72-7.77 (m, 2H), 7.46 (s, 1H),
7.38-7.41 (m, 1H), 5.28-5.39 (m, 1H), 4.80-4.97 (m, 2H), 4.10-4.14
(m, 2H), 3.86-3.95 (m, 1H), 3.48-3.55 (m, 2H), 3.37-3.44 (m, 4H),
3.25-3.34 (m, 3H), 3.21 (s, 3H), 1.96-2.20 (m, 4H), 1.84-1.94 (m,
2H), 1.58-1.64 (m, 6H), 1.34 (d, J=6.0 Hz, 3H), 1.09-1.24 (m, 2H);
MS m/z 670.39 [M+1].sup.+.
Example 33
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1--
((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benz-
onitrile
[1103] To a mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-e-
thoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-
-2-amine (310 mg), potassium hexacyanoferrate(II) trihydrate (391
mg), XPhos (44.2 mg) and potassium acetate (136 mg) in CPME (15 mL)
and water (15 mL) was added XPhos Pd G2 (36.5 mg) at room
temperature. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 14 hr. The mixture was quenched with water
at room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and crystallized from
ethyl acetate/hexane to give the title compound (212 mg).
[1104] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.72-8.84 (m, 3H), 7.70-7.78 (m, 2H), 7.47 (s, 1H), 7.39 (dd,
J=1.24, 8.12 Hz, 1H), 5.34 (dt, J=3.81, 6.35 Hz, 1H), 4.77-5.01 (m,
2H), 4.13 (t, J=6.42 Hz, 2H), 3.89 (tt, J=3.79, 11.70 Hz, 1H),
3.52-3.63 (m, 4H), 3.27-3.48 (m, 8H), 2.19-2.34 (m, 1H), 1.99-2.11
(m, 2H), 1.81-1.98 (m, 4H), 1.59-1.77 (m, 2H), 1.27-1.46 (m, 5H),
1.07 (t, J=7.01 Hz, 3H); MS m/z 658.40 [M+1].sup.+.
Example 34
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-ethoxypropoxy)-1-((1r,4r)-4-morp-
holinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
A) ethyl 1-acetyl-3-(3-ethoxypropoxy)-1H-pyrazole-4-carboxylate
[1105] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (5.00 g),
triphenylphosphane (7.92 g) and 3-ethoxypropan-1-ol (3.40 g) in
toluene (100 mL) was added (Z)--N-{[(propan-2-yloxy)carbonyl]imino}
(propan-2-yloxy)formamide (6.10 g). The mixture was stirred at
60.degree. C. for 2 hr. The mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(6.10 g).
[1106] MS m/z 285.2 [M+H].sup.+.
B) ethyl 3-(3-ethoxypropoxy)-1H-pyrazole-4-carboxylate
[1107] To a solution of ethyl
1-acetyl-3-(3-ethoxypropoxy)-1H-pyrazole-4-carboxylate (6.10 g) in
EtOH (70 mL) was added sodium ethanolate (1.59 g) at room
temperature. The mixture was stirred at 40.degree. C. under
nitrogen atmosphere for 1 hr. After cooled, the mixture was
neutralized with 2 M aqueous hydrogen chloride solution at
0.degree. C. and extracted with ethyl acetate. The organic layer
was separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give the title compound (2.50 g).
[1108] MS m/z 243.2 [M+H].sup.+.
C) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyrazole-
-4-carboxylate
[1109] To a mixture of ethyl
3-(3-ethoxypropoxy)-1H-pyrazole-4-carboxylate (3.04 g) and cesium
carbonate (12.2 g) in DMF (35 mL) was added
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (4.41 g) at room
temperature. The mixture was stirred at 100.degree. C. for 4 hr.
The mixture was poured into water and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (4.78 g).
[1110] MS m/z 383.2 [M+H].sup.+.
D)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyrazole-4-car-
boxylic acid
[1111] 1 M aqueous sodium hydroxide solution (25 ml) was added to a
solution of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyrazole-4-carbo-
xylate (4.78 g) in EtOH (50 ml) at room temperature, and the
mixture was stirred at room temperature for 15 hr. 2 M aqueous
sodium hydroxide solution (25 mL) was added to the mixture, and the
mixture was stirred at 60.degree. C. for 2 hr. The mixture was
evaporated under reduced pressure to reduce the amount of EtOH,
neutralized with 2 M aqueous hydrogen chloride solution and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the title compound
(4.16 g). This product was subjected to the next reaction without
further purification.
[1112] MS m/z 355.2 [M+H].sup.+.
E) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyra-
zol-4-yl)carbamate
[1113] DPPA (3.40 g) was added to a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyrazole-4-carbo-
xylic acid (4.16 g), benzyl alcohol (2.53 g) and triethylamine
(1.77 g) in toluene (50 ml) at room temperature, and the mixture
was stirred at 100.degree. C. under nitrogen atmosphere for 2 hr.
The mixture was poured into water and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(4.79 g).
[1114] MS m/z 460.3 [M+H].sup.+.
F) benzyl
N-[3-(3-ethoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carba-
mate
[1115] To a solution of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-ethoxypropoxy)-1H-pyrazol-4-yl)-
carbamate (3.41 g) in THF (35 mL) was added 1 M aqueous hydrogen
chloride solution (22 mL) at room temperature. The mixture was
stirred at 50.degree. C. for 2 hr. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (1.40 g).
[1116] MS m/z 416.2 [M+H].sup.+.
G) benzyl
N-[3-(3-ethoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]--
1H-pyrazol-4-yl]carbamate
[1117] To a mixture of benzyl
N-[3-(3-ethoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(1.24 g) and morpholine (389 mg) in MeOH (20 mL) and AcOH (1.0 mL)
was added 2-methylpyridine-borane (637 mg) at room temperature. The
mixture was stirred at room temperature for 14 hr. The mixture was
neutralized with saturated aqueous sodium hydrogencarbonate
solution at 0.degree. C. and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (650 mg).
[1118] MS m/z 487.2 [M+H].sup.+.
H)
3-(3-ethoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-
-4-amine
[1119] A mixture of benzyl
N-[3-(3-ethoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazo-
l-4-yl]carbamate (650 mg) and 10% palladium-carbon (140 mg) in EtOH
(20 mL) was stirred under normal pressure of hydrogen atmosphere at
room temperature for 2 hr. The catalyst was removed by filtration,
and then the filtrate was concentrated under reduced pressure to
give the title compound (468 mg). This product was subjected to the
next reaction without further purification.
[1120] MS m/z 353.3 [M+H].sup.+.
I)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-
-ethoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimid-
in-2-amine
[1121] To a mixture of
3-(3-ethoxypropoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4-
-amine (410 mg) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (611 mg) in NMP (4.0 mL) was added methanesulfonic acid
(334 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 14 h. The mixture was neutralized with saturated
aqueous sodium hydrogencarbonate solution at 0.degree. C. and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the title compound (510 mg).
[1122] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.57 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.34 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.93, 8.25 Hz, 1H), 5.09-5.26
(m, 1H), 4.73-4.97 (m, 2H), 4.13 (t, J=6.42 Hz, 2H), 3.88 (tt,
J=3.69, 11.58 Hz, 1H), 3.52-3.63 (m, 4H), 3.24-3.50 (m, 8H),
2.19-2.35 (m, 1H), 2.05 (d, J=11.46 Hz, 2H), 1.82-1.97 (m, 4H),
1.59-1.76 (m, 2H), 1.26-1.46 (m, 5H), 1.07 (t, J=7.01 Hz, 3H); MS
m/z 667.35 [M+1].sup.+.
Example 36
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)--
3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-pyr-
azol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1123] To a mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethox-
ypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine (300 mg), potassium
hexacyanoferrate(II) trihydrate (364 mg), XPhos (41.1 mg) and
potassium acetate (126 mg) in CPME (15 mL) and water (15 mL) was
added XPhos Pd G2 (33.9 mg) at room temperature. The mixture was
stirred at 100.degree. C. under nitrogen atmosphere for 14 hr. The
mixture was quenched with water at room temperature and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) and
crystallized from ethyl acetate/hexane to give the title compound
(214 mg).
[1124] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.73-8.84 (m, 3H), 7.70-7.79 (m, 2H), 7.46 (s, 1H), 7.39 (dd,
J=1.28, 8.16 Hz, 1H), 5.34 (dt, J=3.85, 6.28 Hz, 1H), 4.77-5.01 (m,
2H), 4.13 (t, J=6.37 Hz, 2H), 3.83-3.98 (m, 1H), 3.25-3.56 (m,
10H), 1.95-2.23 (m, 5H), 1.59-1.93 (m, 8H), 1.35 (d, J=6.24 Hz,
3H), 1.13-1.27 (m, 2H), 1.07 (t, J=6.97 Hz, 3H); MS m/z 684.40
[M+1].sup.+.
Example 46
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-(2,2-difluoroetho-
xy)propoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrim-
idin-5-yl)benzonitrile
[1125] To a mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-(-
2,2-difluoroethoxy)
propoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-a-
mine (105 mg), potassium hexacyanoferrate(II) trihydrate (110 mg)
and potassium acetate (44 mg) in water (5.0 mL) and CPME (5.0 mL)
were added XPhos Pd G2 (12 mg) and XPhos (14 mg). After being
stirred under nitrogen atmosphere at 100.degree. C. for 14 hr, the
mixture was poured into water and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (80.0 mg).
[1126] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.76-8.82 (m, 3H), 7.72-7.78 (m, 2H), 7.46 (s, 1H), 7.40 (dd,
J=1.24, 8.12 Hz, 1H), 6.11 (tt, J=3.76, 55.02 Hz, 1H), 5.28-5.41
(m, 1H), 4.90-4.99 (m, 1H), 4.79-4.89 (m, 1H), 4.14 (t, J=6.37 Hz,
2H), 3.83-3.96 (m, 1H), 3.61-3.71 (m, 3H), 3.53-3.61 (m, 5H),
2.43-2.49 (m, 4H), 2.21-2.34 (m, 1H), 2.00-2.12 (m, 2H), 1.86-1.98
(m, 4H), 1.59-1.77 (m, 2H), 1.28-1.45 (m, 5H); MS m/z 694.40
[M+1].sup.+.
Example 47
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(3-(2,2-difluoroethoxy)propoxy)-1-(-
(1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1127] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(200 mg) and 3-(2,2-difluoroethoxy)propan-1-ol (57 mg) in toluene
(5.0 mL) was added cyanomethylenetributylphosphorane (92.0 mg).
After being stirred at 100.degree. C. for 2 hr, additional
3-(2,2-difluoroethoxy)propan-1-ol (57 mg) and
cyanomethylenetributylphosphorane (92.0 mg) were added to the
mixture. After being stirred at 100.degree. C. for 1 hr, the
mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) and
silica gel column chromatography (MeOH/ethyl acetate). The obtained
product was purified by preparative HPLC (water/CH.sub.3CN
containing 0.1% TFA). The desired fraction was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give the title compound (114 mg).
[1128] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.60 (s, 1H), 7.74 (s, 1H), 7.45 (d, J=8.25 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.93, 8.34 Hz, 1H), 6.12 (tt,
J=3.85, 55.02 Hz, 1H), 5.11-5.24 (m, 1H), 4.86-4.95 (m, 1H),
4.75-4.85 (m, 1H), 4.14 (t, J=6.33 Hz, 2H), 3.82-3.96 (m, 1H),
3.61-3.71 (m, 3H), 3.52-3.61 (m, 5H), 2.44-2.49 (m, 4H), 2.22-2.33
(m, 1H), 1.99-2.11 (m, 2H), 1.86-1.98 (m, 4H), 1.59-1.77 (m, 2H),
1.28-1.45 (m, 5H); MS m/z 703.40 [M+1].sup.+.
Example 48
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-(2-methoxyethoxy)-
ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-
-5-yl)benzonitrile hydrochloride
A)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-(2-methoxyetho-
xy)ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile
[1129] A mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-(-
2-methoxyethoxy)ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl-
)pyrimidin-2-amine (135 mg), potassium hexacyanoferrate(II)
trihydrate (166 mg), XPhos Pd G2 (15.5 mg), XPhos (19.1 mg) and
potassium acetate (58.1 mg) in CPME (6.0 mL) and water (6.0 mL) was
stirred at 110.degree. C. for 14.5 hr under argon atmosphere. The
residue was partitioned between ethyl acetate and water. The
organic layer was washed with saturated brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (117 mg).
[1130] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 8.54
(s, 2H), 7.90 (s, 1H), 7.62 (d, J=8.07 Hz, 1H), 7.29 (s, 1H), 7.17
(dd, J=1.42, 8.02 Hz, 1H), 6.85 (d, J=1.19 Hz, 1H), 4.90-5.01 (m,
1H), 4.82-4.89 (m, 1H), 4.68-4.77 (m, 1H), 4.38-4.43 (m, 2H),
3.83-3.94 (m, 3H), 3.70-3.76 (m, 6H), 3.59-3.63 (m, 2H), 3.40 (s,
3H), 2.56-2.61 (m, 4H), 2.20-2.38 (m, 3H), 2.05-2.14 (m, 2H), 1.77
(dq, J=2.52, 12.64 Hz, 2H), 1.52 (d, J=6.24 Hz, 3H), 1.34-1.48 (m,
2H).
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-(2-methoxyetho-
xy)ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile hydrochloride
[1131] 4 M Hydrogen chloride in ethyl acetate (42 uL) was added to
a solution of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(2-(2-methoxyethoxy-
)
ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimid-
in-5-yl)benzonitrile (112 mg) in ethyl acetate (3.0 mL) at room
temperature. EtOH (0.30 mL) was added at room temperature. The
mixture was stirred at room temperature for 16 hr. The reaction
mixture was concentrated with hexane under reduced pressure to give
the title compound (81 mg).
[1132] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.79
(s, 2H), 8.71 (brs, 1H), 7.71-7.78 (m, 2H), 7.46 (s, 1H), 7.39 (dd,
J=1.28, 8.16 Hz, 1H), 5.29-5.39 (m, 1H), 4.90-4.98 (m, 1H),
4.80-4.88 (m, 1H), 4.20 (dd, J=3.94, 5.50 Hz, 2H), 3.73-4.10 (m,
2H), 3.68 (dd, J=3.99, 5.46 Hz, 2H), 3.51-3.64 (m, 5H), 3.38-3.42
(m, 2H), 3.29 (brs, 1H), 3.20 (s, 3H), 1.86-2.16 (m, 4H), 1.48-1.83
(m, 3H), 1.37-1.47 (m, 1H), 1.35 (d, J=6.14 Hz, 3H). 4H were hidden
by DMSO, HCl protons weren't detected; MS m/z 674.40
[M+1].sup.+.
Example 49
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-(2-methoxyethoxy)
ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-am-
ine hydrochloride
A) ethyl
1-acetyl-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazole-4-carboxylate
[1133] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (3.33 g), DIAD (4.06
g) and triphenylphosphine (5.27 g) in toluene (50 mL) was added
2-(2-methoxyethoxy)ethan-1-ol (2.61 g) at room temperature. After
being stirred at 60.degree. C. for 2 hr, the mixture was
concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(4.57 g).
[1134] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.54 (s, 1H), 4.50 (dd,
J=4.40, 5.59 Hz, 2H), 4.29 (d, J=7.15 Hz, 2H), 3.86-3.96 (m, 2H),
3.72-3.79 (m, 2H), 3.54-3.62 (m, 2H), 3.39 (s, 3H), 2.60 (s, 3H),
1.34 (t, J=7.11 Hz, 3H)
B) ethyl
3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazole-4-carboxylate
[1135] To a solution of ethyl
1-acetyl-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazole-4-carboxylate
(4.50 g) in EtOH (40 mL) was added sodium ethanolate (1.10 g) at
room temperature. The mixture was stirred at 50.degree. C. for 2
hr. The mixture was neutralized with 1 M aqueous hydrogen chloride
solution at 0.degree. C. and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(3.81 g).
[1136] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.86 (s, 1H),
4.38-4.50 (m, 2H), 4.21-4.35 (m, 2H), 3.87-3.95 (m, 2H), 3.72-3.80
(m, 2H), 3.53-3.63 (m, 2H), 3.40 (s, 3H), 1.33 (t, J=7.15 Hz, 3H),
NH proton was not detected.
C) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethoxy]-1-
H-pyrazole-4-carboxylate
[1137] A mixture of ethyl
3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazole-4-carboxylate (3.81 g),
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (6.94 g) and cesium
carbonate (9.57 g) in DMA (70 mL) was stirred at 100.degree. C. for
17.5 hr. The reaction mixture was partitioned between ethyl acetate
and water. The organic layer was separated, washed with saturated
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(3.94 g) as colorless oil.
[1138] MS m/z 399.2 [M+H]+.
D)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyra-
zole-4-carboxylic acid
[1139] A mixture of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazo-
le-4-carboxylate (3.93 g) and 2 M aqueous sodium hydroxide solution
(25 mL) was stirred at 50.degree. C. for 3 hr. The reaction mixture
was concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and 1 M aqueous hydrogen chloride
solution. The organic layer was washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound (3.65 g).
[1140] MS m/z 371.2 [M+H]+.
E) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethox-
y]-1H-pyrazol-4-yl)carbamate
[1141] A mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyrazo-
le-4-carboxylic acid (3.65 g), triethylamine (1.99 g),
phenylmethanol (3.19 g) and DPPA (3.24 g) in toluene (40 mL) was
stirred at 100.degree. C. for 2 hr. The reaction mixture was cool
to room temperature. The resulting mixture was partitioned between
ethyl acetate and aqueous sodium hydrogen carbonate. The organic
layer was washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (3.61 g).
[1142] MS m/z 476.3 [M+H]+.
F) benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-(4-oxocyclohexyl)-1H-pyrazol--
4-yl}carbamate
[1143] A mixture of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[2-(2-methoxyethoxy)ethoxy]-1H-pyr-
azol-4-yl)carbamate (2.04 g) and 1 M aqueous hydrogen chloride
solution (21 mL) was stirred at 50.degree. C. for 2.5 hr. The
reaction mixture was partitioned between ethyl acetate and aqueous
sodium hydrogen carbonate. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound
(1.80 g).
[1144] MS m/z 432.2 [M+H]+.
G) benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cy-
clohexyl]-1H-pyrazol-4-yl}carbamate
[1145] A mixture of benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl}carb-
amate (900 mg), morpholine (543 mg) and 2-methylpyridine-borane
(654 mg) in MeOH (10 mL) and acetic acid (1.0 mL) was stirred at
60.degree. C. for 1 hr under argon atmosphere. The reaction mixture
was concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and aqueous sodium hydrogen
carbonate. The organic layer was washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (450 mg).
[1146] MS m/z 503.3 [M+H]+.
H)
3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]--
1H-pyrazol-4-amine dihydrochloride
[1147] A mixture of benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-
-1H-pyrazol-4-yl}carbamate (447 mg) and 10% palladium-carbon (86.0
mg) in 4 M hydrogen chloride-ethyl acetate (2.2 mL) and MeOH (10
mL) was stirred at room temperature for 1.5 hr under normal
pressure of hydrogen atmosphere. The reaction mixture was filtered.
The filtrate was concentrated under reduced pressure to give the
title compound. This product was subjected to the next reaction
without further purification.
[1148] MS m/z 369.3 [M+H]+.
I)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-
-(2-methoxyethoxy)
ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-am-
ine
[1149] A mixture of
3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-
-pyrazol-4-amine dihydrochloride (392 mg) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (467 mg) in NMP (3.0 mL) was stirred at 120.degree. C.
for 16 hr. The residue was partitioned between ethyl acetate and
aqueous sodium hydrogen carbonate. The organic layer was washed
with saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (368 mg).
[1150] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.52 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.25 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H), 5.17 (dt,
J=3.99, 6.53 Hz, 1H), 4.87-4.95 (m, 1H), 4.75-4.84 (m, 1H), 4.19
(dd, J=3.94, 5.50 Hz, 2H), 3.83-3.96 (m, 1H), 3.65-3.71 (m, 2H),
3.51-3.60 (m, 6H), 3.39-3.44 (m, 2H), 3.20 (s, 3H), 2.47 (brs, 4H),
2.22-2.33 (m, 1H), 2.00-2.10 (m, 2H), 1.88-1.96 (m, 2H), 1.61-1.75
(m, 2H), 1.34-1.46 (m, 2H), 1.33 (d, J=6.14 Hz, 3H)
J)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(2-
-(2-methoxyethoxy)
ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-am-
ine hydrochloride
[1151] 4 M Hydrogen chloride-ethyl acetate (68 uL) was added to a
solution of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(-
2-(2-methoxyethoxy)ethoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-
-yl)pyrimidin-2-amine (187 mg) in ethyl acetate (5.0 mL) at room
temperature. EtOH (1.0 mL) was added at room temperature. The
mixture was stirred at room temperature for 16 hr. The reaction
mixture was concentrated with hexane under reduced pressure to give
the title compound (176 mg).
[1152] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.21-10.39 (m,
1H), 9.37 (s, 1H), 8.70 (s, 2H), 8.57 (s, 1H), 7.77 (s, 1H), 7.45
(d, J=8.25 Hz, 1H), 7.35 (d, J=1.47 Hz, 1H), 7.24 (dd, J=1.88, 8.30
Hz, 1H), 5.12-5.22 (m, 1H), 4.87-4.94 (m, 1H), 4.76-4.84 (m, 1H),
4.20 (dd, J=3.99, 5.46 Hz, 2H), 3.95-4.03 (m, 2H), 3.78 (t, J=12.38
Hz, 2H), 3.69 (dd, J=3.99, 5.46 Hz, 2H), 3.52-3.56 (m, 2H),
3.37-3.49 (m, 4H), 3.20 (s, 3H), 3.02-3.19 (m, 2H), 2.06-2.34 (m,
4H), 1.54-1.89 (m, 4H), 1.33 (d, J=6.14 Hz, 3H), 2H were hidden by
DMSO; MS m/z 683.37 [M+1].sup.+.
Example 86
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicy-
clo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-(methylsulfonyl)ethoxy)-1H-pyrazol-4-
-yl)pyrimidin-2-amine
A) ethyl 3-(2-methanesulfonylethoxy)-1H-pyrazole-4-carboxylate
[1153] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (6.00 g),
triphenylphosphane (11.8 g), 2-methanesulfonylethan-1-ol (5.62 g)
and toluene (100 mL) was added DIAD (9.16 g), and the mixture was
stirred at 70.degree. C. for 15 hr. The mixture was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give the title
compound (2.80 g).
[1154] MS m/z 262.9 [M+H]+.
B) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-1H--
pyrazole-4-carboxylate
[1155] 1,4-Dioxaspiro[4.5]decan-8-yl methanesulfonate (4.04 g) was
added to a mixture of ethyl
3-(2-methanesulfonylethoxy)-1H-pyrazole-4-carboxylate (2.65 g) and
potassium carbonate (4.18 g) in DMF (20 mL) at 100.degree. C., and
the mixture was stirred for 2 hr. The mixture was poured into water
and extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the title compound (2.34 g).
[1156] MS m/z 403.0 [M+H]+.
C)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-1H-pyrazo-
le-4-carboxylic acid
[1157] 1 M Aqueous sodium hydroxide solution (11 ml) was added to a
solution of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-1H-pyrazole-
-4-carboxylate (2.34 g) in EtOH (20 mL) at 50.degree. C., and the
mixture was stirred for 15 hr. The mixture was poured into water
and washed with ethyl acetate. The aqueous layer was neutralized
with 1 M aqueous hydrogen chloride solution and extracted with
ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(2.00 g). This product was subjected to the next reaction without
further purification.
[1158] MS m/z 375.0 [M+H]+.
D) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-
-1H-pyrazol-4-yl)carbamate
[1159] DPPA (1.55 g) was added to a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-1H-pyrazole-
-4-carboxylic acid (2.00 g), benzyl alcohol (1.14 g) and
triethylamine (810 mg) in toluene (20 mL) at 100.degree. C., and
the mixture was stirred for 15 hr. The mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (1.25 g).
[1160] MS m/z 480.1 [M+H]+.
E) benzyl
N-[3-(2-methanesulfonylethoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4--
yl]carbamate
[1161] 1 M Aqueous hydrogen chloride solution (10 ml) was added to
a solution of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(2-methanesulfonylethoxy)-1H-pyraz-
ol-4-yl)carbamate (1.25 g) in THF (10 ml) at 50.degree. C., and the
mixture was stirred for 2 hr. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(1.10 g). This product was subjected to the next reaction without
further purification.
[1162] MS m/z 436.1 [M+H]+.
F) benzyl
N-[3-(2-methanesulfonylethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-aza-
bicyclo[3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1163] 2-Methylpyridine-borane (539 mg) was added to a mixture of
benzyl
N-[3-(2-methanesulfonylethoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbam-
ate (1.10 g), (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride
(565 mg) and triethylamine (765 mg) in MeOH (10 mL) and AcOH (0.50
mL) at 50.degree. C., and the mixture was stirred for 1 hr. The
mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (445 mg).
[1164] MS m/z 533.2 [M+H]+.
G)
3-(2-methanesulfonylethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.-
2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-amine
[1165] A mixture of benzyl
N-[3-(2-methanesulfonylethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3-
.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate (445 mg) and
10% palladium-carbon (50.0 mg) in EtOH (10 mL) was stirred under
normal pressure of hydrogen atmosphere at 50.degree. C. for 1 hr.
The catalyst was removed by filtration, and then the filtrate was
concentrated under reduced pressure to give the title compound (327
mg).
[1166] MS m/z 399.1 [M+H]+.
H)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-(me-
thylsulfonyl)ethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1167] To a solution of
3-(2-methanesulfonylethoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.-
1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-amine (320 mg) in NMP (3.0
mL) were added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}p-
henyl)pyrimidine (421 mg) and methanesulfonic acid (330 mg) at room
temperature, and the mixture was stirred at 110.degree. C. for 6
hr. The mixture was poured into saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (345 mg).
[1168] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.71 (s, 2H), 8.59 (s, 1H), 7.84 (s, 1H), 7.44-7.47 (m, 1H), 7.36
(s, 1H), 7.23-7.26 (m, 1H), 5.13-5.22 (m, 1H), 4.76-4.94 (m, 2H),
4.33-4.48 (m, 3H), 3.58-3.65 (m, 2H), 3.47-3.54 (m, 2H), 3.36-3.43
(m, 2H), 3.18-3.28 (m, 2H), 2.91 (s, 3H), 2.05-2.16 (m, 3H),
1.85-1.96 (m, 2H), 1.65-1.77 (m, 4H), 1.29-1.47 (m, 5H), 1.06-1.21
(m, 2H); MS m/z 713.23 [M+1].sup.+.
Example 129
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-morpholin-
ocyclohexyl)-3-(pyridin-2-ylmethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-
benzonitrile
[1169] A mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-morpholinocyclohexyl)-3-(pyridin-2-ylmethoxy)-1H-pyrazol-4-yl)pyrim-
idin-2-amine (42.0 mg), potassium hexacyanoferrate(II) trihydrate
(46.0 mg), XPhos Pd G2 (5.00 mg), XPhos (6.00 mg), potassium
acetate (18.0 mg), CPME (2.0 mL) and water (2.0 mL) was stirred
under nitrogen atmosphere at 100.degree. C. for 24 hr. After being
cooled to room temperature, the mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by preparative HPLC (water/CH.sub.3CN containing 0.1% TFA). The
desired fraction was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, dried over anhydrous sodium sulfate
and concentrated under reduced pressure to give the title compound
(10.0 mg).
[1170] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
9.05 (s, 1H), 8.82 (s, 2H), 8.51-8.56 (m, 1H), 7.73-7.84 (m, 3H),
7.62 (d, J=7.79 Hz, 1H), 7.47 (s, 1H), 7.40 (dd, J=1.10, 8.16 Hz,
1H), 7.28-7.34 (m, 1H), 5.29-5.40 (m, 1H), 5.25 (s, 2H), 4.90-4.99
(m, 1H), 4.80-4.89 (m, 1H), 3.84-3.98 (m, 1H), 3.52-3.60 (m, 4H),
2.42-2.49 (m, 4H), 2.20-2.34 (m, 1H), 2.00-2.11 (m, 2H), 1.87-1.97
(m, 2H), 1.59-1.76 (m, 2H), 1.31-1.45 (m, 5H); MS m/z 663.34
[M+1].sup.+.
Example 130
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3--
(pyridin-2-ylmethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
A) ethyl
1-acetyl-3-[(pyridin-2-yl)methoxy]-1H-pyrazole-4-carboxylate
[1171] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (5.03 g),
2-pyridinemethanol (4.18 g) and triphenylphosphine (10.1 g) in
toluene (100 mL) was added DIAD (7.6 mL). After being stirred at
80.degree. C. for 14 hr, the mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) and subjected to the next
reaction without further purification.
[1172] MS m/z 290.2 [M+H].sup.+.
B) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1H-py-
razole-4-carboxylate
[1173] To a mixture of ethyl
1-acetyl-3-[(pyridin-2-yl)methoxy]-1H-pyrazole-4-carboxylate (7.31
g), 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (11.4 g) and DMF
(80 mL) was added potassium carbonate (10.5 g). After being stirred
at 100.degree. C. for 4 hr, the mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was dissolved
in toluene, and the solution was passed through NH silica gel pad
(ethyl acetate/hexane) and concentrated under reduced pressure. The
residue was subjected to the next reaction without further
purification.
[1174] MS m/z 388.2 [M+H]+.
C)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1H-pyrazole-
-4-carboxylic acid
[1175] To a mixture of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1H-pyrazole-4-
-carboxylate (9.76 g) and EtOH (80 mL) was added 2 M aqueous sodium
hydroxide solution (25 mL). After being stirred at room temperature
for 14 hr and at 80.degree. C. for 1 hr, the mixture was diluted
with ethyl acetate and extracted with water. The aqueous layer was
separated, acidified with 6 M aqueous hydrogen chloride solution
(ca. pH4) and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the title
compound (4.74 g).
[1176] MS m/z 360.2 [M+H]+.
D) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1-
H-pyrazol-4-yl)carbamate
[1177] To a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1H-pyrazole-4-
-carboxylic acid (4.74 g) and triethylamine (2.7 mL) in toluene (50
mL) was added DPPA (3.2 mL). After being stirred at room
temperature for 5 min, benzyl alcohol (4.0 mL) was added to the
mixture. After being stirred at 100.degree. C. for 1 hr, the
mixture was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate/hexane)
to give the title compound (4.16 g).
[1178] MS m/z 465.3 [M+H]+.
E) benzyl
N-[1-(4-oxocyclohexyl)-3-[(pyridin-2-yl)methoxy]-1H-pyrazol-4-yl-
]carbamate
[1179] To a solution of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[(pyridin-2-yl)methoxy]-1H-pyrazol-
-4-yl)carbamate (1.18 g) in THF (20 mL) was added 2 M aqueous
hydrogen chloride solution (3.0 mL). After being stirred at
60.degree. C. for 2 hr, the mixture was neutralized with saturated
aqueous sodium hydrogencarbonate solution at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was subjected
to the next reaction without further purification.
[1180] MS m/z 421.2 [M+H]+.
F) benzyl
N-{3-[(pyridin-2-yl)methoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cycloh-
exyl]-1H-pyrazol-4-yl}carbamate
[1181] To a mixture of benzyl
N-[1-(4-oxocyclohexyl)-3-[(pyridin-2-yl)methoxy]-1H-pyrazol-4-yl]carbamat-
e (1.06 g), MeOH (10 mL) and AcOH (1.0 mL) was added morpholine
(0.45 mL). After being stirred at room temperature for 5 min,
2-methylpyridine-borane (540 mg) was added to the mixture. After
being stirred at room temperature for 1 hr, the mixture was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (380 mg).
[1182] MS m/z 492.3 [M+H]+.
G)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-morpholinocyclohexyl)-3-(pyridin-2-ylmethoxy)-1H-pyrazol-4-yl)pyr-
imidin-2-amine
[1183] To a mixture of benzyl
N-{3-[(pyridin-2-yl)methoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H--
pyrazol-4-yl}carbamate (380 mg), 10% palladium-carbon (83.0 mg) and
MeOH (10 mL) was added methanesulfonic acid (60 .mu.L). After being
stirred under hydrogen atmosphere at room temperature for 1 hr, the
insoluble material was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
NMP (1.0 mL), and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (329 mg) was added to the mixture. After being stirred
at 110.degree. C. for 4 hr, the mixture was cooled to room
temperature. The mixture was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and by silica gel column
chromatography (diol, ethyl acetate/hexane) to give the title
compound (53.0 mg) and
4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)pyrim-
idin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-3-ol
(140 mg).
Data for the Title Compound
[1184] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.87
(s, 1H), 8.72 (s, 2H), 8.51-8.56 (m, 1H), 7.75-7.88 (m, 2H), 7.62
(d, J=7.70 Hz, 1H), 7.45 (d, J=8.25 Hz, 1H), 7.37 (d, J=1.74 Hz,
1H), 7.28-7.34 (m, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H), 5.25 (s,
2H), 5.13-5.21 (m, 1H), 4.86-4.95 (m, 1H), 4.75-4.85 (m, 1H),
3.82-3.98 (m, 1H), 3.51-3.61 (m, 4H), 2.40-2.48 (m, 4H), 2.22-2.32
(m, 1H), 1.99-2.12 (m, 2H), 1.84-1.98 (m, 2H), 1.57-1.78 (m, 2H),
1.28-1.47 (m, 5H); MS m/z 672.38 [M+1].sup.+.
Data for the Other Compound
[1185] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.94 (brs, 1H), 9.37
(s, 1H), 8.81 (s, 1H), 8.73 (s, 2H), 7.60 (s, 1H), 7.45 (d, J=8.34
Hz, 1H), 7.38 (d, J=1.83 Hz, 1H), 7.25 (dd, J=1.88, 8.30 Hz, 1H),
5.11-5.24 (m, 1H), 4.87-4.95 (m, 1H), 4.75-4.85 (m, 1H), 3.75-3.92
(m, 1H), 3.52-3.62 (m, 4H), 2.42-2.49 (m, 4H), 2.19-2.32 (m, 1H),
1.98-2.07 (m, 2H), 1.86-1.96 (m, 2H), 1.57-1.74 (m, 2H), 1.26-1.43
(m, 5H); m/z 571.3 [M+H]+.
Example 142
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicy-
clo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-(methylsulfonyl)propoxy)-1H-pyrazol--
4-yl)pyrimidin-2-amine
A) ethyl
1-acetyl-3-[3-(methylsulfanyl)propoxy]-1H-pyrazole-4-carboxylate
[1186] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (6.00 g),
triphenylphosphane (11.8 g) and 3-(methylsulfanyl)propan-1-ol (4.80
g) in toluene (100 mL) was added DIAD (9.16 g) stirred at
70.degree. C. for 15 hr. The mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(1.97 g).
[1187] MS m/z 287.2 [M+H]+.
B) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(methylsulfanyl)propoxy]-1-
H-pyrazole-4-carboxylate
[1188] Cesium carbonate (6.71 g) was added to a solution of ethyl
1-acetyl-3-[3-(methylsulfanyl)propoxy]-1H-pyrazole-4-carboxylate
(1.97 g) in DMF (30 mL) at 100.degree. C., and the mixture was
stirred for 1 hr. To the mixture was added
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (2.74 g), and the
mixture was stirred at 100.degree. C. for 2 hr. The mixture was
poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.54 g).
[1189] MS m/z 385.2 [M+H]+.
C) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy)-1H-
-pyrazole-4-carboxylate
[1190] A solution of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(methylsulfanyl)propoxy]-1H-pyrazo-
le-4-carboxylate (2.54 g) in MeOH (30 ml) was added dropwise to a
solution of oxone (10.1 g) in water (30 mL) at 0.degree. C., and
the mixture was stirred for 1 hr. The mixture was poured into
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(2.90 g). This product was subjected to the next reaction without
further purification.
[1191] MS m/z 417.2 [M+H]+.
D)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy)-1H-pyraz-
ole-4-carboxylic acid
[1192] 1 M Aqueous sodium hydroxide solution (14 mL) was added to a
solution of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy)-1H-pyrazol-
e-4-carboxylate (2.90 g) in EtOH (20 mL) at room temperature, and
the mixture was stirred for 3 days. The mixture was poured into
water and washed with ethyl acetate. The aqueous layer was
neutralized with 1 M aqueous hydrogen chloride solution and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the title compound
(2.70 g). This product was subjected to the next reaction without
further purification.
[1193] MS m/z 389.2 [M+H]+.
E) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy-
)-1H-pyrazol-4-yl)carbamate
[1194] DPPA (3.57 g) was added to a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy)-1H-pyrazol-
e-4-carboxylic acid (4.80 g), benzyl alcohol (2.66 g) and
triethylamine (1.86 g) in toluene (50 mL) at 100.degree. C., and
the mixture was stirred for 1 hr. The mixture was poured into water
and extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the title compound (4.40 g).
[1195] MS m/z 494.2 [M+H]+.
F) benzyl
N-[3-(3-methanesulfonylpropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-
-yl]carbamate
[1196] 1 M Aqueous hydrogen chloride solution (6.0 mL) was added to
a solution of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-(3-methanesulfonylpropoxy)-1H-pyra-
zol-4-yl)carbamate (1.54 g) in THF (10 mL) at 50.degree. C., and
the mixture was stirred for 2 hr. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound
(1.40 g). This product was subjected to the next reaction without
further purification.
[1197] MS m/z 450.2 [M+H]+.
G) benzyl
N-[3-(3-methanesulfonylpropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-az-
abicyclo[3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1198] 2-Methylpyridine-borane (665 mg) was added to a mixture of
benzyl
N-[3-(3-methanesulfonylpropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carba-
mate (1.40 g), (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane
hydrochloride (697 mg) and triethylamine (944 mg) in MeOH (10 mL)
and AcOH (0.50 mL) at 50.degree. C., and the mixture was stirred
for 15 hr. The mixture was neutralized with saturated aqueous
sodium hydrogencarbonate solution and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (720 mg).
[1199] MS m/z 547.3 [M+H]+.
H)
3-(3-methanesulfonylpropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3-
.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-amine
[1200] A mixture of benzyl
N-[3-(3-methanesulfonylpropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[-
3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate (610 mg) and
10% palladium-carbon (70 mg) in EtOH (20 mL) was stirred under
normal pressure of hydrogen atmosphere at 50.degree. C. for 1 hr.
The catalyst was removed by filtration, and then the filtrate was
concentrated under reduced pressure to give the title compound (445
mg).
[1201] MS m/z 413.3 [M+H]+.
I)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-(me-
thylsulfonyl)propoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1202] To a solution of
3-(3-methanesulfonylpropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2-
.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-amine (425 mg) in NMP (3.0
mL) were added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}p-
henyl)pyrimidine (540 mg) and methanesulfonic acid (296 mg) at room
temperature, and the mixture was stirred at 110.degree. C. for 15
hr. The mixture was poured into saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (375 mg).
[1203] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.77 (s, 1H), 8.72 (s, 2H), 7.79 (s, 1H), 7.44-7.47 (m, 1H), 7.37
(s, 1H), 7.23-7.26 (m, 1H), 5.13-5.22 (m, 1H), 4.77-4.94 (m, 2H),
4.18-4.22 (m, 3H), 3.87-3.96 (m, 1H), 3.50-3.54 (m, 2H), 3.39-3.43
(m, 2H), 3.27-3.34 (m, 4H), 2.97 (s, 3H), 2.05-2.16 (m, 2H),
1.97-2.17 (m, 5H), 1.61-1.81 (m, 6H), 1.33 (d, J=6 Hz, 2H),
1.11-1.22 (m, 2H); MS m/z 727.33 [M+1].sup.+.
Example 143
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)am-
ino)pyrimidin-5-yl)benzonitrile
A) benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpho-
lin-4-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1204] To a mixture of benzyl
N-[3-(3-methoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(4.31 g), cis-2,6-dimethylmorpholine (2.46 g) and AcOH (3.0 mL) in
MeOH (20 mL) and THF (20 mL) was added 2-methylpyridine-borane
(3.42 g) at room temperature. The mixture was stirred at 60.degree.
C. for 2 hr. The mixture was neutralized with saturated aqueous
sodium hydrogencarbonate solution at 0.degree. C. and extracted
with ethyl acetate. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (1.26 g).
[1205] MS m/z 501.3 [M+H].sup.+.
B)
3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]c-
yclohexyl]-1H-pyrazol-4-amine dihydrochloride
[1206] A mixture of benzyl
N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-
cyclohexyl]-1H-pyrazol-4-yl]carbamate (1.24 g), 4 M hydrogen
chloride-ethyl acetate (10 mL) and 10% palladium-carbon (300 mg) in
EtOH (50 mL) was stirred under normal pressure of hydrogen
atmosphere at 80.degree. C. for 2 hr. The catalyst was removed by
filtration, and then the filtrate was concentrated under reduced
pressure to give the title compound (850 mg). This product was
subjected to the next reaction without further purification.
[1207] MS m/z 367.3 [M+H]+.
C)
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorph-
olin-4-yl]cyclohexyl]-1H-pyrazol-4-yl] pyrimidin-2-amine
[1208] To a solution of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyc-
lohexyl]-1H-pyrazol-4-amine dihydrochloride (840 mg) in NMP (30 mL)
were added 5-bromo-2-chloropyrimidine (529 mg) and methanesulfonic
acid (659 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 12 hr. The mixture was poured into saturated
aqueous sodium hydrogencarbonate solution and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) to give the title
compound (730 mg).
[1209] MS m/z 523.22 [M+H].sup.+.
D)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile
[1210] To a mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[(2S)-1-(1H-tetrazol-1-
-yl)propan-2-yl]oxy}benzonitrile (731 mg),
5-bromo-N-[3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorphol-
in-4-yl]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine (360 mg) and
2 M aqueous sodium carbonate solution (3.0 mL) in DME (5.0 mL) was
added Pd(dppf)Cl.sub.2 (75.8 mg). After being stirred under
nitrogen atmosphere at 80.degree. C. for 12 hr, the mixture was
diluted with ethyl acetate and water, and passed through celite
powder. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) and silica gel
column chromatography (MeOH/ethyl acetate) and crystallized from
EtOH/IPE to give the title compound (110 mg).
[1211] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 8.55 (s,
2H), 7.88 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.12-7.24 (m, 1H), 7.06
(s, 1H), 6.85 (s, 1H), 4.91-5.01 (m, 1H), 4.82-4.91 (m, 1H),
4.68-4.80 (m, 1H), 4.32 (t, J=6.2 Hz, 2H), 3.89 (t, J=11.8 Hz, 1H),
3.61-3.73 (m, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.38 (s, 3H), 2.77 (d,
J=10.7 Hz, 2H), 2.17-2.37 (m, 3H), 1.99-2.13 (m, 4H), 1.95 (t,
J=10.6 Hz, 2H), 1.67-1.84 (m, 2H), 1.35-1.54 (m, 5H), 1.18 (d,
J=6.2 Hz, 6H); MS m/z 672.45 [M+1].sup.+.
Example 150
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(4-methoxybutoxy)-1--
((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benz-
onitrile
[1212] A mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(4-m-
ethoxybutoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-
-2-amine (30.0 mg), potassium hexacyanoferrate(II) trihydrate (35.0
mg), XPhos Pd G2 (4.00 mg), XPhos (5.00 mg), potassium acetate
(14.0 mg), CPME (2.0 mL) and water (2.0 mL) was stirred under
nitrogen atmosphere at 100.degree. C. for 14 hr. After being cooled
to room temperature, the mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (MeOH/ethyl acetate) and by
silica gel column chromatography (NH, ethyl acetate/hexane). The
obtained solid was crystallized from ethyl acetate/hexane to give
the title compound (15.0 mg).
[1213] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.72-8.82 (m, 3H), 7.70-7.78 (m, 2H), 7.46 (s, 1H), 7.39 (dd,
J=1.28, 8.16 Hz, 1H), 5.28-5.43 (m, 1H), 4.90-4.98 (m, 1H),
4.79-4.89 (m, 1H), 4.08 (t, J=6.19 Hz, 2H), 3.78-3.96 (m, 1H),
3.50-3.72 (m, 4H), 3.28-3.30 (m, 2H), 3.18 (s, 3H), 2.45-2.49 (m,
4H), 2.23-2.33 (m, 1H), 2.00-2.13 (m, 2H), 1.85-1.98 (m, 2H),
1.52-1.77 (m, 6H), 1.27-1.46 (m, 5H); MS m/z 658.42
[M+1].sup.+.
Example 151
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(3-(4-methoxybutoxy)-1-((1r,4r)-4-morp-
holinocyclohexyl)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1214] To a mixture of
4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)pyrim-
idin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-3-ol
(127 mg), 4-methoxybutan-1-ol (37 .mu.L) and triphenylphosphine
(85.0 mg) in THF (5.0 mL) was added DIAD (65 .mu.L). After being
stirred at 70.degree. C. for 24 hr, the mixture was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane), by silica gel
column chromatography (MeOH/ethyl acetate) and by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA). The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give the title compound (35.0 mg).
[1215] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.69 (s, 2H), 8.56 (s, 1H), 7.71 (s, 1H), 7.45 (d, J=8.44 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.23 (dd, J=1.83, 8.25 Hz, 1H), 5.11-5.23
(m, 1H), 4.86-4.95 (m, 1H), 4.75-4.85 (m, 1H), 4.08 (t, J=6.14 Hz,
2H), 3.80-3.95 (m, 1H), 3.50-3.63 (m, 4H), 3.28-3.31 (m, 2H), 3.18
(s, 3H), 2.41-2.49 (m, 4H), 2.20-2.33 (m, 1H), 1.99-2.12 (m, 2H),
1.85-1.98 (m, 2H), 1.52-1.75 (m, 6H), 1.28-1.45 (m, 5H); MS m/z
667.35 [M+1].sup.+.
Example 240
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyrazol-4-yl)pyrimidi-
n-2-amine hydrochloride
A) benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimet-
hylmorpholin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}carbamate
[1216] A mixture of benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl}carb-
amate (900 mg), cis-2,6-dimethylmorpholine (718 mg) and
2-methylpyridine-borane (654 mg) in MeOH (10 mL) and AcOH (1.0 mL)
was stirred at 60.degree. C. for 1.5 hr under argon atmosphere. The
reaction mixture was concentrated under reduced pressure. The
residue was partitioned between ethyl acetate and aqueous sodium
hydrogen carbonate. The organic layer was washed with saturated
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (425 mg).
[1217] MS m/z 531.4 [M+H]+.
B)
3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorphol-
in-4-yl]cyclohexyl]-1H-pyrazol-4-amine dihydrochloride
[1218] A mixture of benzyl
N-{3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpho-
lin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}carbamate (422 mg) and 10%
palladium-carbon (76.9 mg) in 4 M hydrogen chloride-ethyl acetate
(2.0 mL) was stirred at 50.degree. C. for 1 hr under normal
pressure of hydrogen atmosphere. The reaction mixture was filtered.
The filtrate was concentrated under reduced pressure to give the
title compound. This product was subjected to the next reaction
without further purification.
[1219] MS m/z 397.3 [M+H]+.
C)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy-
)ethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1220] A mixture of
3-[2-(2-methoxyethoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-
-4-yl]cyclohexyl]-1H-pyrazol-4-amine dihydrochloride (373 mg) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (361 mg) in NMP (3.0 mL) was stirred at 120.degree. C.
for 13 hr. The reaction mixture was partitioned between ethyl
acetate and aqueous sodium hydrogen carbonate. The organic layer
was washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (342 mg).
[1221] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.52 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.25 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.83, 8.34 Hz, 1H), 5.17 (dt,
J=3.71, 6.30 Hz, 1H), 4.87-4.95 (m, 1H), 4.75-4.85 (m, 1H),
4.17-4.23 (m, 2H), 3.82-3.94 (m, 1H), 3.68 (dd, J=3.85, 5.59 Hz,
2H), 3.47-3.57 (m, 4H), 3.39-3.43 (m, 2H), 3.20 (s, 3H), 2.69-2.74
(m, 2H), 2.23-2.31 (m, 1H), 2.01-2.10 (m, 2H), 1.81-1.94 (m, 4H),
1.60-1.74 (m, 2H), 1.34-1.46 (m, 2H), 1.33 (d, J=6.14 Hz, 3H), 1.04
(d, J=6.33 Hz, 6H).
D)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy-
)ethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride
[1222] 4 M Hydrogen chloride-ethyl acetate (65 uL) was added to a
solution of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-(-
(1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethox-
y)ethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine (185 mg) in ethyl
acetate (5.0 mL) and EtOH (1.0 mL). The mixture was stirred at room
temperature for 16 hr. The reaction mixture was concentrated with
hexane under reduced pressure to give the title compound (169
mg).
[1223] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.30-10.52 (m,
1H), 9.38 (s, 1H), 8.70 (s, 2H), 8.57 (s, 1H), 7.77 (s, 1H), 7.45
(d, J=8.34 Hz, 1H), 7.35 (d, J=1.65 Hz, 1H), 7.24 (dd, J=1.83, 8.25
Hz, 1H), 5.10-5.23 (m, 1H), 4.86-4.94 (m, 1H), 4.76-4.85 (m, 1H),
4.20 (dd, J=3.94, 5.50 Hz, 2H), 3.87-4.05 (m, 3H), 3.66-3.72 (m,
2H), 3.52-3.56 (m, 2H), 3.46 (brs, 1H), 3.39-3.43 (m, 3H), 3.26
(dd, J=3.16, 4.26 Hz, 1H), 3.20 (s, 3H), 2.61-2.74 (m, 2H),
2.10-2.32 (m, 4H), 1.59-1.84 (m, 4H), 1.33 (d, J=6.14 Hz, 3H), 1.16
(d, J=5.87 Hz, 6H); MS m/z 711.35 [M+1].sup.+.
Example 241
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyrazo-
l-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride
A)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyr-
azol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1224] A mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)e-
thoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine (135 mg), potassium
hexacyanoferrate(II) trihydrate (160 mg), XPhos Pd G2 (14.9 mg),
XPhos (18.0 mg) and potassium acetate (55.8 mg) in CPME (6.0 mL)
and water (6.0 mL) was stirred at 110.degree. C. for 14.5 hr under
argon atmosphere. The reaction mixture was partitioned between
ethyl acetate and water. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (86.2 mg).
[1225] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 8.54
(s, 2H), 7.89 (s, 1H), 7.62 (d, J=7.98 Hz, 1H), 7.29 (s, 1H), 7.17
(dd, J=1.47, 8.07 Hz, 1H), 6.85 (d, J=1.28 Hz, 1H), 4.91-5.01 (m,
1H), 4.83-4.90 (m, 1H), 4.68-4.76 (m, 1H), 4.38-4.42 (m, 2H),
3.83-3.93 (m, 3H), 3.71-3.75 (m, 2H), 3.64-3.70 (m, 2H), 3.59-3.63
(m, 2H), 3.40 (s, 3H), 2.77 (d, J=10.27 Hz, 2H), 2.21-2.37 (m, 3H),
2.05-2.12 (m, 2H), 1.95 (t, J=10.68 Hz, 2H), 1.68-1.83 (m, 2H),
1.52 (d, J=6.14 Hz, 3H), 1.34-1.47 (m, 2H), 1.18 (d, J=6.24 Hz,
6H).
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyr-
azol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride
[1226] 4 M Hydrogen chloride-ethyl acetate (29 uL) was added to a
solution of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,-
6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-py-
razol-4-yl)amino)pyrimidin-5-yl)benzonitrile (81.2 mg) in ethyl
acetate (3.0 mL) and EtOH (0.30 mL). The mixture was stirred at
room temperature for 16 hr. The reaction mixture was concentrated
with hexane under reduced pressure to give the title compound (57.2
mg).
[1227] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.69-8.76 (m, 1H), 7.75 (d, J=8.07 Hz, 2H), 7.46 (s,
1H), 7.39 (dd, J=1.24, 8.21 Hz, 1H), 5.30-5.39 (m, 1H), 4.91-4.98
(m, 1H), 4.80-4.89 (m, 1H), 4.20 (dd, J=3.90, 5.55 Hz, 2H),
3.82-4.05 (m, 2H), 3.68 (dd, J=3.94, 5.41 Hz, 2H), 3.51-3.56 (m,
3H), 3.37-3.45 (m, 3H), 3.20 (s, 3H), 2.65-2.77 (m, 2H), 2.14-2.38
(m, 2H), 2.00-2.13 (m, 2H), 1.81-1.96 (m, 3H), 1.57-1.79 (m, 3H),
1.35 (d, J=6.05 Hz, 3H), 0.95-1.13 (m, 6H); MS m/z 702.42
[M+1].sup.+.
Example 242
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicy-
clo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-pyrazol-4-yl)pyrim-
idin-2-amine
A) benzyl
N-[3-(3-ethoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[-
3.2.1]octan-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1228] A mixture of (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane
hydrochloride (1.00 g) and triethylamine (1.87 mL) in MeOH (20 mL)
was stirred at room temperature for 10 min. Benzyl
N-[3-(3-ethoxypropoxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(1.87 g), AcOH (1.0 mL) and 2-methylpyridine-borane (962 mg) were
added to the mixture at room temperature. The mixture was stirred
at 50.degree. C. for 14 hr. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution at 0.degree. C.
and extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the title compound (900 mg).
[1229] MS m/z 513.3 [M+H].sup.+.
B)
3-(3-ethoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octa-
n-8-yl]cyclohexyl]-1H-pyrazol-4-amine
[1230] A mixture of benzyl
N-[3-(3-ethoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]oct-
an-8-yl]cyclohexyl]-1H-pyrazol-4-yl]carbamate (900 mg) and 10%
palladium-carbon (186 mg) in EtOH (30 mL) and THF (10 mL) was
stirred under normal pressure of hydrogen atmosphere at room
temperature for 2 hr. The catalyst was removed by filtration, and
then the filtrate was concentrated under reduced pressure to give
the title compound (662 mg). This product was subjected to the next
reaction without further purification.
[1231] MS m/z 379.3 [M+H].sup.+.
C)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-eth-
oxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1232] To a mixture of
3-(3-ethoxypropoxy)-1-[(1r,4r)-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan--
8-yl]cyclohexyl]-1H-pyrazol-4-amine (662 mg) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (916 mg) in NMP (6.0 mL) was added methanesulfonic acid
(501 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 15 h. The mixture was neutralized with saturated
aqueous sodium hydrogencarbonate solution at 0.degree. C. and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) and
crystallized from ethyl acetate/hexane to give the title compound
(759 mg).
[1233] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.70
(s, 2H), 8.58 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.34 Hz, 1H), 7.36
(d, J=1.74 Hz, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H), 5.09-5.26 (m,
1H), 4.73-4.97 (m, 2H), 4.12 (t, J=6.42 Hz, 2H), 3.82-3.99 (m, 1H),
3.23-3.57 (m, 10H), 1.95-2.24 (m, 5H), 1.58-1.93 (m, 8H), 1.33 (d,
J=6.14 Hz, 3H), 1.13-1.26 (m, 2H), 1.07 (t, J=6.97 Hz, 3H); MS m/z
693.35 [M+1].sup.+.
Example 462
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimid-
in-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
A) ethyl 3-(benzyloxy)-1H-pyrazole-4-carboxylate
[1234] To a mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (10.0 g), benzyl
alcohol (6.53 g) and triphenylphosphine (19.8 g) in toluene (100
mL) was added dropwise DIAD (14.7 mL) at room temperature. The
mixture was stirred at room temperature under nitrogen atmosphere
for 2 hr. The mixture was concentrated in vacuo. To a solution of
the residue in EtOH (100 mL) was added potassium carbonate (13.8 g)
at 0.degree. C. The mixture was stirred at room temperature for 1
hr. The mixture was concentrated in vacuo. The residue was diluted
with water, and the mixture was extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
containing DIAD derivative (18.0 g).
[1235] MS m/z 247.2 [M+H].sup.+.
B) ethyl
3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohex-
yl]-1H-pyrazole-4-carboxylate
[1236] To a mixture of ethyl
3-(benzyloxy)-1H-pyrazole-4-carboxylate (13.0 g) and tert-butyl
N-[(1s,4s)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate
(29.1 g) in DMF (100 mL) was added cesium carbonate (34.2 g) at
room temperature. The mixture was stirred at 90.degree. C. under
nitrogen atmosphere overnight. The mixture was quenched with water
at room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (17.0 g).
[1237] MS m/z 444.3 [M+H].sup.+.
C)
3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-1H-
-pyrazole-4-carboxylic acid
[1238] To a solution of ethyl
3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-1H-p-
yrazole-4-carboxylate (17.0 g) in EtOH (100 mL) and THF (100 mL)
was added 8 M aqueous sodium hydroxide solution (11.9 mL) at room
temperature. The mixture was stirred at room temperature for 14 hr.
Additional 8 M aqueous sodium hydroxide solution (10 mL) was added
to the mixture. The mixture was stirred at 40.degree. C. for 4 hr.
The mixture was acidified with 6 M aqueous hydrogen chloride
solution (ca. pH2-3) and concentrated in reduced pressure. The
residue was extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(10.0 g).
[1239] MS m/z 416.3 [M+H].sup.+.
D) benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cycl-
ohexyl]-1H-pyrazol-4-yl]carbamate
[1240] To a mixture of
3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-1H-p-
yrazole-4-carboxylic acid (10.0 g) and triethylamine (3.84 g) in
toluene (200 mL) was added DPPA (9.76 g) at room temperature. After
being stirred at room temperature for 3 hr, benzyl alcohol (3.91 g)
was added to the reaction mixture. The mixture was stirred at
90.degree. C. under nitrogen atmosphere for 14 hr. The mixture was
quenched with water at room temperature and extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound (12.0 g).
[1241] MS m/z 521.3 [M+H].sup.+.
E) benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyr-
azol-4-yl]carbamate
[1242] A solution of benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]-1-
H-pyrazol-4-yl]carbamate (12 g) in 4 M hydrogen chloride-ethyl
acetate (6.70 g) was stirred at room temperature under nitrogen
atmosphere for 2 hr. The mixture was concentrated under reduced
pressure. To a mixture of the residue, sodium iodide (10.2 g) and
potassium carbonate (3.21 g) in DMA (150 mL) was added
1-chloro-2-(2-chloroethoxy)ethane (3.27 g) at room temperature. The
mixture was stirred at 90.degree. C. under nitrogen atmosphere for
2 hr. The mixture was quenched with water at 60.degree. C. After
being stirred at 60.degree. C. for 1 hr, additional water was added
to the reaction mixture. The mixture was stirred at room
temperature for 30 min and extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound
(7.73 g).
[1243] MS m/z 491.3 [M+H].sup.+.
F)
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyri-
midin-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
[1244] A mixture of benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-4-yl-
]carbamate (7.50 g), 10% palladium-carbon (322 mg) and
methanesulfonic acid (2.92 g) in MeOH (100 mL) was stirred at
normal pressure of hydrogen atmosphere at 50.degree. C. for 3 hr.
The catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. To a solution of the residue
in NMP (24 mL) was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (7.93 g) at room temperature. The mixture was stirred at
120.degree. C. under nitrogen atmosphere for 14 hr. After cooled to
room temperature, the reaction mixture were added 2 M aqueous
hydrogen chloride solution and ethyl acetate. The organic layer was
extracted with 2 M aqueous hydrogen chloride solution. The combined
aqueous layer was basified with 8 M aqueous sodium hydroxide
solution. The insoluble material was collected by filtration,
washed with water and dried in vacuo to give the title compound
(3.50 g).
[1245] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.94 (s, 1H),
9.37 (s, 1H), 8.81 (s, 1H), 8.73 (s, 2H), 7.60 (s, 1H), 7.45 (d,
J=8.25 Hz, 1H), 7.38 (d, J=1.56 Hz, 1H), 7.25 (dd, J=1.65, 8.25 Hz,
1H), 5.12-5.22 (m, 1H), 4.86-4.96 (m, 1H), 4.74-4.83 (m, 1H),
3.75-3.88 (m, 1H), 3.54-3.61 (m, 4H), 2.42-2.48 (m, 4H), 2.22-2.29
(m, 1H), 1.99-2.08 (m, 2H), 1.87-1.95 (m, 2H), 1.57-1.72 (m, 2H),
1.31-1.43 (m, 5H); MS m/z 581.22 [M+1].sup.+.
[1246] The compounds of Examples 243, 244 and 461 were produced
according to the methods described in the above-mentioned Examples
or methods analogous thereto. The compounds of Examples 1, 2, 8, 9,
12, 14, 16, 26, 27, 28, 30, 33, 34, 36, 46, 47, 48, 49, 86, 129,
130, 142, 143, 150, 151, 240, 241, 242, 243, 244, 461 and 462 are
shown in the following Table 1. The activity (IC.sub.50) in the
table is calculated in Experimental Example 1 and classified
according to the following three activity ranks;
A: less than 10 nM, B: 10 nM or more and less than 100 nM, C: 100
nM or more.
TABLE-US-00001 TABLE 1 Ex. ACTI- No. IUPAC NAME STRUCTURE VITY 1
2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)- 4-(2-((3-(2-
methoxyethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00034## A 2
5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(3-(2- methoxyethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00035## A 8 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((3-(2- ethoxyethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00036## A
9 5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(3-(2- ethoxyethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00037## A 12 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(2- ethoxyethoxy)-1H- pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00038## A 14
2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)- 4-(2-((3-(2-
isopropoxyethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00039## A
16 2-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2- yl)oxy)-4-(2-((3-(2-
isopropoxyethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl))-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00040## A
26 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)- 4-(2-((3-(3-
methoxypropoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00041## A 27
5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(3-(3- methoxypropoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00042## A 28 2-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-(2-((3-(3- methoxypropoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00043## A 30 2-(((S)-1-(1H-tetrazol-
1-yl)propan-2-yl)oxy)- 4-(2-((1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(3- methoxypropoxy)-1H-
pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00044## A 33
2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)- 4-(2-((3-(3-
ethoxypropoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00045## A 34
5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(3-(3- ethoxypropoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00046## A 36 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(3- ethoxypropoxy)-1H- pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00047## A 46
2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)- 4-(2-((3-(3-(2,2-
difluroethoxy)propoxy)- 1-((1r,4r)-4- morpholinocyclohexyl)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00048## A
47 5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(3-(3- (2,2- difluoroethoxy)propoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00049## A 48 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((3-(2-(2- methoxyethoxy)ethoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile hydrochloride ##STR00050## A 49 5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2- yl)oxy)-4- chlorophenyl)-N-(3-(2- (2-
methoxyethoxy)ethoxy)- 1-((1r,4r)-4- morpholinocyclohexyl)-
1H-pyrazol-4- yl)pyrimidin-2-amine hydrochloride ##STR00051## A 86
5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3- oxa-8-
azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(2-
(methylsulfonyl)ethoxy)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00052## A 129 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((1-((1r,4r)-4- morpholinocyclohexyl)- 3-(pyridin-2-
ylmethoxy)-1H-pyrazol- 4-yl)amino)pyrimidin-5- yl)benzonitrile
##STR00053## A 130 5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-
yl)oxy)-4- chlorophenyl)-N-(1- ((1r,4r)-4- morpholinocyclohexyl)-
3-(pyridin-2- ylmethoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine
##STR00054## A 142 5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-
yl)oxy)-4- chlorophenyl)-N-(1- ((1r,4r)-4-((1r,5S)-3- oxa-8-
azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(3-
(methylsulfonyl)propoxy)- 1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00055## A 143 2-(((S)-1-(1H-tetrazol- 1-yl)propan-2-yl)oxy)-
4-(2-((1-((1r,4r)-4- ((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-3-(3- methoxypropoxy)-1H- pryazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00056## A 150 2-(((S)-1-(1H-tetrazol-
1-yl)propan-2-yl)oxy)- 4-(2-((3-(4- methoxybutoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00057## A 151 5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2- yl)oxy)-4- chlorophenyl)-N-(3-(4-
methoxybutoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)- 1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00058## A 240 5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2- yl)oxy)-4- chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)- 2,6- dimethylmorpholino)cyclo- hexyl)-3-(2-(2-
methoxyethoxy)ethoxy)- 1H-pyrazol-4- yl)pyrimidin-2-amine
hydrochloride ##STR00059## A 241 2-(((S)-1-(1H-tetrazol-
1-yl)propan-2-yl)oxy)- 4-(2-((1-((1r,4r)-4- ((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(2-(2- methoxyethoxy)ethoxy)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile hydrochloride
##STR00060## A 242 5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-
yl)oxy)-4- chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3- oxa-8-
azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(3- ethoxypropoxy)-1H-
pyrazol-4-yl)pyrimidin- 2-amine ##STR00061## A 243
2-((4-((5-(3-(((S)-1- (1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin- 2-yl)amino)-1-((1r,4r)- 4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-1H-
pyrazol-3-yl)oxy)ethan- 1-ol ##STR00062## A 244 2-(((S)-1-(1H-
tetrazol-1-yl)propan- 2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-
oxa-8- azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-
(2-hydroxyethoxy)-1H- pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00063## A 461 2-(((S)-1-(1H-
tetrazol-1-yl)propan- 2-yl)oxy)-4-(2-((3- hydroxy-1-((1r,4r)-4-
morpholinocyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00064## A 462 4-((5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan- 2-yl)oxy)-4- chlorophenyl)pyrimidin-
2-yl)amino)-1- ((1r,4r)-4- morpholinocyclohexyl)- 1H-pyrazol-3-ol
##STR00065## A
[1247] The compounds of Examples 3-7, 10, 11, 13, 15, 17-25, 29,
31, 32, 35, 37-45, 50-85, 87-128, 131-141, 144-149, 152-194,
196-239, 245-460 and 463-472 in the following tables can be
produced according to the methods described in the above-mentioned
Examples or methods analogous thereto. The compounds of Examples
are shown in the following Table 2.
TABLE-US-00002 TABLE 2 Ex. No. IUPAC NAME STRUCTURE 3
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2- methoxyethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00066## 4 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
methoxyethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00067## 5 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
methoxyethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00068## 6 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
methoxyethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00069## 7
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-(2-methoxyethoxy)-1H-pyra- zol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00070## 10 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- ethoxyethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00071## 11 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-
ethoxyethoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00072## 13
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2- ethoxyethoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00073## 15
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2- isopropoxyethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00074## 17 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
isopropoxyethoxy)-1H-pyrazol- 4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00075## 18 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (trifluoromethoxy)ethoxy)-1H-
pryazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00076## 19
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(trifluoromethoxy)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00077## 20 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (difluoromethoxy)ethoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00078## 21
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2- (difluoromethoxy)ethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00079## 22 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (2,2,2-trifluoroethoxy)ethoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00080## 23
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(2,2,2-trifluoroethoxy)ethoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00081## 24 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (2,2-difluoroethoxy)ethoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00082## 25
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2-(2,2- difluoroethoxy)ethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00083## 29 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(3-
methoxypropoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00084## 31
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3- methoxypropoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00085## 32
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-l)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
methoxypropoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00086## 35
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
ethoxypropoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00087## 37
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3- ethoxypropoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00088## 38
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
isopropoxypropoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00089## 39
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3- isopropoxypropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00090## 40 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(3- (trifluoromethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00091## 41
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(3-
(trifluoromethoxy)propoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00092## 42 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(3- (difluoromethoxy)propoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00093## 43
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3- (difluoromethoxy)propoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00094## 44 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(3- (2,2,2-trifluoroethoxy)propoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00095## 45
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(3- (2,2,2-
trifluoroethoxy)propoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00096## 50 5-(3-((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-(2-
methoxyethoxy)ethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00097## 51
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-(((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-(2-
methoxyethoxy)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00098## 52 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(2-(2-methoxyethoxy)ethoxy)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00099## 53
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(2-hydroxyethoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00100## 54
2-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)ethan-1-ol ##STR00101##
55 2-((4-((5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)ethan-1-ol ##STR00102##
56 2-((4-((5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-((1R,5S)-
3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-1H-pyrazol-3-
yl)oxy)ethan-1-ol ##STR00103## 57 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- hydroxy-2-methylpropoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00104## 58
1-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)-2- methylpropan-2-ol
##STR00105## 59 1-((4-((5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-3-yl)oxy)-2- methylpropan-2-ol ##STR00106## 60
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2-hydroxy-2- methylpropoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00107## 61
1-((4-((5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-((1R,5S)-
3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-1H-pyrazol-3-
yl)oxy)-2-methylpropan-2-ol ##STR00108## 62
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-hydroxy-2-methylpropoxy)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00109## 63 2-((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((1-hydroxycyclopropyl)meth-
oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00110## 64
1-(((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3- yl)oxy)methyl)cyclopropan-1-ol
##STR00111## 65 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((1-hydroxycyclobutyl)methoxy)-
1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00112## 66
1-(((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3- yl)oxy)methyl)cyclobutan-2-ol
##STR00113## 67 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(3- hydroxypropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00114## 68 3-((4-((5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2-yl)oxy)- 4-chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-3-yl)oxy)propan-1-ol ##STR00115## 69
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
hydroxy-3-methylbutoxy)-1H- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00116## 70
4-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)-2-methylbutan- 2-ol
##STR00117## 71 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (1-hydroxycyclopropyl)ethoxy)-
1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00118## 72
1-(2-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3- yl)oxy)ethyl)cyclopropan-1-ol
##STR00119## 73 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (1-hydroxycyclobutyl)ethoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00120##
74 1-(2-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3- yl)oxy)ethyl)cyclobutan-1-ol
##STR00121## 75 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- (cyanomethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00122## 76 2-((4-((5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2-yl)oxy)- 4-chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-3-yl)oxy)acetonitrile ##STR00123## 77
2-((4-((5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)acetonitrile
##STR00124## 78 2-((4-((5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4-((1R,5S)- 3-oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-1H-pyrazol-3- yl)oxy)acetonitrile ##STR00125## 79
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(2-
cyanoethoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00126## 80
3-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)propanenitrile
##STR00127## 81 3-((4-((5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-3-yl)oxy)propanenitrile ##STR00128## 82
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
cyanopropoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00129## 83
4-((4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-
4-chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-3-yl)oxy)butanenitrile
##STR00130## 84 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (methylsulfonyl)ethoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00131## 85
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2- (methylsulfonyl)ethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00132## 87 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
(methylsulfonyl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00133## 88 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (ethylsulfonyl)ethoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00134## 89
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(2- (ethylsulfonyl)ethoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00135## 90 5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
(ethylsulfonyl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00136## 91 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-(ethylsulfonyl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00137## 92 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(3- (methylsulfonyl)propoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00138## 93
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3- (methylsulfonyl)propoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00139## 94 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(3- (ethylsulfonyl)propoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00140## 95
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3- (ethylsulfonyl)propoxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00141## 96 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-morpholino-
cyclohexyl)-3-(oxazol- 2-yloxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00142## 97 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
morpholinocyclohexyl)-3-(oxa- zol-2-yloxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00143## 98 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-morpholino-
cyclohexyl)-3-(oxazol- 2-ylmethoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00144## 99
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(oxa-
zol-2-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00145##
100 5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(oxa-
zol-2-ylmethoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine ##STR00146##
101 5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(oxazol-2-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00147## 102
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (oxazol-2-yl)ethoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00148## 103
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(oxazol-2-yl)ethoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine
##STR00149## 104 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(3- (oxazol-2-yl)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00150## 105
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(3-
(oxazol-2-yl)propoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00151## 106 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4- morpholinocyclohexyl)-3-
(thiazol-2-ylmethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00152## 107 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
morpholinocyclohexyl)-3- (thiazol-2-ylmethoxy)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00153## 108
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4- morpholinocyclohexyl)-3- (thiazol-2-ylmethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00154## 109
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (thiazol-2-yl)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00155## 110
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(thiazol-2-yl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00156## 111 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(3- (thiazol-2-yl)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00157## 112
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(3-
(thiazol-2-yl)propoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00158## 113 4-(2-((3-((1H-pyrazol-1- yl)methoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)-2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)benzonitrile
##STR00159## 114 N-(3-((1H-pyrazol-1-yl)meth- oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)-5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2-l)oxy)- 4-chlorophenyl)pyrimidin-2- amine
##STR00160## 115 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((1-methyl-1H-pyrazol-5-
yl)methoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00161## 116
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-((1-methyl- 1H-pyrazol-5-yl)methoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00162## 117
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-((1-methyl- 1H-pyrazol-5-yl)methoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00163## 118
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((1-methyl-1H- pyrazol-5-yl)methoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00164## 119
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
((1-methyl-1H-pyrazol-3- yl)methoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00165## 120 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-((1-methyl-
1H-pyrazol-3-yl)methoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00166## 121
4-(2-((3-(2-(1H-pyrazol-1- yl)ethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)-2-((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)benzonitrile
##STR00167## 122 N-(3-(2-(1H-pyrazol-1- yl)ethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)-5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2-yl)oxy)- 4-chlorophenyl)pyrimidin-2- amine
##STR00168## 123 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-(1H-
pyrazol-1-yl)ethoxy)-1-((1r,4r)- 4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00169## 124
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(2-
(1H-pyrazol-1-yl)ethoxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00170## 125
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(2-
(1-methyl-1H-pyrazol-5- yl)ethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00171## 126 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-(1-methyl-
1H-pyrazol-5-yl)ethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00172## 127
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(2-
(1-methyl-1H-pyrazol-3- y)ethoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00173## 128 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-(1-methyl-
1H-pyrazol-3-yl)ethoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00174## 131
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4- morpholinocyclohexyl)-3- (pyridin-2-ylmethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00175## 132
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-
(pyridin-2-ylmethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00176## 133 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(pyridin-2-
ylmethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00177## 134 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4- morpholinocyclohexyl)-3-
(pyrimidin-2-ylmethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00178##
135 5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-
(pyrimidin-2-ylmethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00179## 136 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(pyrimidin-2- ylmethoxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00180## 137
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(pyrimidin-2-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00181## 138
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (pyridin-2-yl)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00182## 139
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(pyridin-2-yl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00183## 140 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3-(2- (pyrimidin-2-yl)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00184## 141
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(2-
(pyrimidin-2-yl)ethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00185## 144 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-morpholino-
cyclohexyl)-3-(oxetan- 3-ylmethoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00186## 145
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-(oxe-
tan-3-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00187##
146 5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(oxetan-3-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00188## 147
5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(oxetan-3-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00189## 148
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-(oxetan-3-ylmethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00190## 149 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(oxetan-3-ylmethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00191## 152 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(4- methoxybutoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyraozl-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00192## 153 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(4-
methoxybutoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00193## 154
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(4- methoxybutoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00194## 155
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(4- methoxybutoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00195## 156
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
methoxy-3-methylbutoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00196## 157
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3-methoxy- 3-methylbutoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00197## 158 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(3- methoxy-3-methylbutoxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00198## 159
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-
morpholinocyclohexyl)-3- ((tetrahydrofuran-3-yl)methoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00199##
160 5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-
((tetrahydrofuran-3-yl)methoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00200## 161 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
morpholinocyclohexyl)-3- ((tetrahydrofuran-3-yl)methoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00201## 162
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3- ((tetrahydrofuran-3-yl)methoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00202##
163 5-(3-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-
((tetrahydrofuran-3-yl)methoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00203## 164 2-(((S)-1-(1H-1,2,4-triazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-((tetrahydrofuran-3-
yl)methoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00204## 165 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4- morpholinocyclohexyl)-3-
((tetrahydro-2H-pyran-4- yl)methoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00205## 166
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- morpholinocyclohexyl)-3-
((tetrahydro-2H-pyran-4- yl)methoxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00206## 167
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4- morpholinocyclohexyl)-3- ((tetrahydro-2H-pyran-4-
yl)methoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00207## 168 5-(3-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
morpholinocyclohexyl)-3- ((tetrahydro-2H-pyran-4-
yl)methoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00208## 169
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((tetrahydro- 2H-pyran-4-yl)methoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00209## 170
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((tetrahydro- 2H-pyran-4-yl)methoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00210## 171
2-(((S)-1-(1H-1,2,4-triazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-((tetrahydro-2H-pyran-4- yl)methoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00211## 172
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
(methoxy-d3)propxoy)-1-((1r,4r)- 4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00212## 173
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3-(methoxy- d3)propoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00213## 174 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(methoxy-
d3)propoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00214## 175 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-(methoxy-d3)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00215## 176
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2- (trifluoromethoxy)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00216## 177
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-(trifluoromethoxy)ethoxy)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00217## 178 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
(difluoromethoxy)ethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00218## 179 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- (difluoromethoxy)ethoxy)-1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00219##
180 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2-(2,2,2- trifluoroethoxy)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00220## 181
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-(2,2,2- trifluoroethoxy)ethoxy)-1H-
pyraozl-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00221## 182
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2-(2,2- difluoroethoxy)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00222## 183
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(2-
(2,2-difluoroethoxy)ethoxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00223## 184 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-ethoxypropoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00224## 185
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3- isopropoxypropoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00225## 186
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-isopropoxypropoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00226## 187 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
(trifluoromethoxy)propoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00227## 188 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-(trifluoromethoxy)propoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00228##
189 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3- (difluoromethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00229## 190
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
(difluoromethoxy)propoxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00230## 191 2-((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(2,2,2-
trifluoroethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00231## 192
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-(2,2,2- trifluoroethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00232## 193
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-(2,2- difluoroethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00233## 194
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
(2,2-difluoroethoxy)propoxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00234## 196 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(2-hydroxyethoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00235## 197
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2-hydroxy-2- methylpropoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00236## 198
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-hydroxy-2-methylpropoxy)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00237## 199 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-((1-hy-
droxycyclopropyl)methoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00238## 200 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-((1-hydroxy-
cyclopropyl)methoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00239## 201 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-((1-hy-
droxycyclobutyl)methoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00240## 202 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-((1-hydroxy-
cyclobutyl)methoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00241## 203 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
hydroxypropoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00242## 204 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-(3-hydroxypropoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00243## 205
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-hydroxy-3- methylbutoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00244## 206
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-(3-hydroxy-3-methylbutoxy)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00245## 207 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-(1-hy-
droxycyclopropyl)ethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00246## 208 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(2-(1-hydroxy-
cyclopropyl)ethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00247## 209 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-(1-
hydroxycyclobutyl)ethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00248## 210 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(2-(1-
hydroxycyclobutyl)ethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00249## 211 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8-yl) cyclohexyl)-3-(cyanomethoxy)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00250##
212 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(cyanomethoxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00251## 213 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-
cyanoethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00252## 214 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3-(2- cyanoethoxy)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
1H-pyrazol-4-yl)amino)pyrimi- din-5-yl)benzonitrile ##STR00253##
215 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3- cyanopropoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00254## 216
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-(3-
cyanopropoxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile ##STR00255## 217 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(oxazol-2-
ylmethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00256## 218 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(oxazol-2- ylmethoxy)-2H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00257## 219 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-(oxazol-2-ylmethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00258## 220
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 3-(oxazol-2-ylmethoxy)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00259## 221
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(thiazol-2- ylmethoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00260## 222
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(thiazol-2-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00261## 223
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-(thiazol-2-ylmethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00262## 224 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
3-(thiazol-2-ylmethoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00263## 225 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-((1-methyl-1H-
pyrazol-5-yl)methoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00264## 226 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((1-methyl-1H- pyrazol-5-yl)methoxy)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00265## 227
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-((1-methyl-1H-pyrazol-5- yl)methoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00266## 228
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-((1-methyl-1H-pyrazol-5-
yl)methoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00267## 229
4-(2-((3-(2-(1H-pyrazol-1- yl)ethoxy)-1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5-yl)-2-
(((S)-1-(1H-tetrazol-1- yl)propan-2- yl)oxy)benzonitrile
##STR00268## 230 N-(3-(2-(1H-pyrazol-1- yl)ethoxy)-1-((1r,4r)-4-
((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)-5-(3-(((S)-1-(1H-
tetrazol-1-yl)propan-2- yl)oxy)-4- chlorophenyl)pyrimidin-2- amine
##STR00269## 231 4-(2-((3-(2-(1H-pyrazol-1-
yl)ethoxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-yl)-2-
(((S)-1-(1H-tetrazol-1- yl)propan-2- yl)oxy)benzonitrile
##STR00270## 232 N-(3-(2-(1H-pyrazol-1- yl)ethoxy)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
1H-pyrazol-4-yl)-5-(3- (((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2- amine ##STR00271##
233 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(pyridin-2- ylmethoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00272## 234
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(pyridin-2-
ylmethoxy)-1H-pyrazol-4- yl)pyrimidnin-2-amine ##STR00273## 235
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
3-(pyridin-2-ylmethoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00274## 236 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
3-(pyridin-2-ylmethoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00275## 237 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(pyrimidin-
2-ylmethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00276## 238 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-(pyrimidin-2-ylmethoxy)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00277##
239 5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-(pyrimidin-2-ylmethoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00278## 245
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(2,2-difluoro-3- methoxypropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00279## 246 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2,2-
difluoro-3-methoxypropoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00280## 247
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-(2,2-difluoro-3- methoxypropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00281## 248 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
(2,2-difluoro-3- methoxypropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00282## 249
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2,2- difluoro-3-methoxypropoxy)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00283## 250
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2,2-
difluoro-3-methoxypropoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00284## 251 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((1R,5S)-3-
oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(2,2-
difluoro-3-methoxypropoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00285## 252 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2,2- difluoro-3-methoxypropoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00286## 253
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(2,2-difluoro-3- methoxypropoxy)-1-((1r,4r)-4- ((1S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00287## 254 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2,2-
difluoro-3-methoxypropoxy)-1- ((1r,4R)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00288## 255 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-(2,2-difluoro-3-
methoxypropoxy)-1-((1r,4r)-4- ((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00289## 256 5-((3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
(2,2-difluoro-3- methoxypropoxy)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
1H-pyrazol-4-yl)pyrimidin-2- 2-amine ##STR00290## 257
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(3-methoxy-2,2- dimethylpropoxy)-1-((1r,4r)-
4-morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00291## 258 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(3-
methoxy-2,2-dimethylpropoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00292## 259 2-((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-(3-methoxy-2,2-
dimethylpropoxy)-1-((1r,4r)- 4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00293## 260
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- (3-methoxy-2,2-
dimethylpropoxy)-1-((1r,4r)- 4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00294## 261
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-methoxy- 2,2-dimethylpropoxy)-1H-
pyrazol,-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00295## 262
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-methoxy-
2,2-dimethylpropoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00296## 263 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((1R,5S)-3-
oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-(3-
methoxy-2,2-dimethylpropoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00297## 264 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-methoxy- 2,2-dimethylpropoxy)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00298## 265
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-2,2- dimethylpropoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00299## 266
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-methoxy-2,2-
dimethylpropoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine ##STR00300##
267 2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-2,2- dimethylpropoxy)-1H-pyrazol-
4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00301## 268
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-methoxy-2,2-
dimethylpropoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine ##STR00302##
269 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(3-methoxy-2-methylpropoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin- 5
yl)benzonitrile ##STR00303## 270 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(3-
methoxy-2-methylpropoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00304## 271
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-(3-methoxy-2- methylpropoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00305## 272 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
(3-methoxy-2-methylpropoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00306## 273 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-methoxy-
2-methylpropoxy)-1H-pyrazol- 4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00307## 274 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-methoxy- 2-methylpropoxy)-1H-pyrazol-
4-yl)pyrimidin-2-amine ##STR00308## 275
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((1R,5S)-3- oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(3- methoxy-2-methylpropoxy)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00309## 276
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-1-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-methoxy-
2-methylpropoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine ##STR00310##
277 2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-2- methylpropoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00311## 278 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yloxy)-4- chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-methoxy-2-
methylpropoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00312## 279
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-2- methylpropoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00313## 280 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-2- methylpropoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00314## 281 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((4-methoxybutan-2-yl)oxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00315## 282 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-((4-
methoxybutan-2-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00316## 283
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((4-methoxybutan-2- yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00317## 284 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((4-methoxybutan-2-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00318## 285
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((4- methoxybutan-2-yl)oxy)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00319## 286
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(1-((1r,4r)- 4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-((4-
methoxybutan-2-yl)oxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00320## 287 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((1R,5S)-3-
oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-((4-
methoxybutan-2-yl)oxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00321## 288 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-((4- methoxybutan-2-yl)oxy)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00322## 289
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-((4-methoxybutan-2- yl)oxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00323## 290 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-((4-methoxybutan-2-
yl)oxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00324## 291
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-((4-methoxubutan-2- yl)oxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00325## 292 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-((4-methoxybutan-2- yl)oxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00326## 293 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- (3-methoxubutoxy)-1-((1r,4r)-
4-morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00327## 294 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(3-
methoxybutoxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00328## 295
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-(3-methoxybutoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00329## 296
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- (3-methoxybutoxy)-1-((1r,4r)-
4-morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00330## 297 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
methoxybutoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00331## 298 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
methoxybutoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00332## 299
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((1R,5S)-3- oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(3- methoxybutoxy)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00333## 300
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-
methoxybutoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00334## 301
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxybutoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00335## 302 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(3-methoxybutoxy)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00336## 303
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxybutoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00337## 304 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(3-methoxybutoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00338## 305 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- (2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00339## 306 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00340## 307 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00341## 308 5-(3-((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- (2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00342## 309 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00343## 310 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00344## 311
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((1R,5S)-3- oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00345##
312 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00346## 313 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00347## 314 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00348## 315 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 3-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00349## 316 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-
3-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00350## 317
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
(3-(2-methoxyethoxy)propoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00351## 318 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-(3-(2-
methoxyethoxy)propoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00352## 319
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2- ((3-(3-(2-
methoxyethoxy)propoxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00353## 320
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- (3-(2-methoxyethoxy)propoxy)-
1-((1r,4r)-4- morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-
amine ##STR00354## 321 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00355## 322 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-(2- methoxyethoxy)propoxy)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00356## 323
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((1R,5S)-3- oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(3-(2- methoxyethoxy)propoxy)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00357## 324
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00358## 325 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00359## 326 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)- 4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00360## 327 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00361## 328 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo- hexyl)-3-(3-(2-
methoxyethoxy)propoxy)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00362## 329 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- (3-(2-(2-methoxy-
ethoxy)ethoxy)propoxy)- 1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pryazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00363## 330
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3-(3-(2-(2- methoxyethoxy)ethoxy)pro-
poxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00364## 331
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-(3-(2-(2-methoxy- ethoxy)ethoxy)propoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00365## 332 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
(3-(2-(2-methoxy- ethoxy)ethoxy)propoxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00366## 333 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(2-(2-
methoxyethoxy)ethoxy)pro- poxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00367## 334 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-3-(3-(2-(2- methoxyethoxy)ethoxy)pro-
poxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine ##STR00368## 335
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((1R,5S)-3- oxa-8-azabicyclo[3.2.1]octan-
8-yl)cyclohexyl)-3-(3-(2-(2- methoxyethoxy)ethoxy)pro-
poxy)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00369## 336 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-(3-(2-(2-
methoxyethoxy)ethoxy)pro- poxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00370## 337 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(3-(2-(2-methoxy-
ethoxy)ethoxy)propoxy)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00371## 338 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(1-((1r,4r)-
4-((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
3-(3-(2-(2-methoxy- ethoxy)ethoxy)propoxy)-
1H-pyrazol-4-yl)pyrimidin-2- amine ##STR00372## 339
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-3-(3-(2-(2-methoxy- ethoxy)ethoxy)propoxy)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00373## 340
5-(3-(((S)-1-(1H-1,2,4- triazol-1-y)propan-2-
yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-3-(3-(2-(2-
methoxyethoxy)ethoxy)propoxy)- 1H-pyrazol-4-yl)pyrimidin-2- amine
##STR00374## 341 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11-tetraoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00375## 342
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11-tetrazoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00376## 343
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11- tetraoxatridecan-13-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00377## 344 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((2,5,8,11-tetrazoxatridecan- 13-yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00378## 345 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11-tetraoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octna-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00379## 346
5-(3-((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11-tetrazoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00380## 347 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11-
tetraoxatridecan-13-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00381## 348
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11-tetraoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00382## 349 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11-tetraoxatridecan-
13-yl)oxy)-1-((1r,4r)4- ((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00383## 350 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3-
((2,5,8,11-tetraoxatridecan- 13-yl)oxy)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)-
1H-pyrazol-4-yl)pyrimidin-
2-amine ##STR00384## 351 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11-
tetraoxatridecan-13-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00385## 352
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11-tetraoxatridecan-
13-yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00386## 353 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00387## 354 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00388## 355 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00389## 356 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00390## 357 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00391## 358
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14- pentaoxahexadecan-16-yl)oxy)-
1-((1r,4r)-4-((1R,5S)-3-oxa- 8-azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00392## 359
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14- pentaoxahexadecan-16-yl)oxy)-
1-((1r,4r)-4-((1R,5S)-3-oxa- 8-azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00393## 360 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00394## 361 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00395## 362
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14- pentaoxahexadecan-16-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
1H-pyrazol-4-yl)pyrimidin- 2-amine ##STR00396## 363
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14- pentaoxahexadecan-16-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00397## 364 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxahexadecan-16-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00398## 365 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00399## 366 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00400## 367 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00401## 368 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((2,5,8,11,14,17- hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00402## 369 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00403## 370
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17- hexaoxanonadecan-19-yl)oxy)-
1-((1r,4r)-4-((1R,5S)-3-oxa- 8-azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00404## 371
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17- hexaoxanonadecan-19-yl)oxy)-
1-((1r,4r)-4-((1R,5S)-3-oxa- 8-azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00405## 372 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxanonadecna-19-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00406## 373 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00407## 374
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17- hexaoxanonadecan-19-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
1H-pyrazol-4-yl)pyrimidin- 2-amine ##STR00408## 375
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17- hexaoxanonadecan-19-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00409##
376 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxanonadecan-19-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00410## 377 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00411## 378
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00412## 379
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17,20- heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00413## 380 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((2,5,8,11,14,1,7,20- heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00414## 381 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00415## 382
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00416## 383 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00417## 384
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00418## 385 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00419## 386
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1 ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00420## 387 2-(((S)-1-(1H-1,2,4- triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00421## 388
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxadocosan-22-yl)oxy)-1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00422## 389 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00423## 390 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00424## 391 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-y)oxy)-4-(2- ((3-((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00425## 392 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((2,5,8,11,14,17,20,23- octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00426## 393 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00427## 394
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pryazol-4-
yl)pyrimidin-2-amine ##STR00428## 395 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00429## 396
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00430## 397 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00431## 398
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4
chlorophenyl)-N-(3-
((2,5,8,11,14,17,20,23- octaoxapentacosan-25-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6-di- methylmorpholino)cyclohexyl)-
1H-pyrazol-4-yl)pyrimidin- 2-amine ##STR00432## 399
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17,20,23- octaoxapentacosan-25-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00433## 400 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxapentacosan-25-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00434## 401 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00435## 402
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00436## 403
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11- tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00437## 404 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11-
tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00438## 405 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00439## 406 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11-
tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00440## 407 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00441## 408 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00442## 409
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11-
tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4- ((2S,6)R-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00443## 410 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11-
tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00444## 411 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11- tetraoxatetradecan-14-
yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00445## 412 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11-
tetraoxatetradecan-14- yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00446## 413 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14- pentaoxaheptadecan-17-
yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00447## 414
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14- pentaoxaheptadecan-17-
yl)oxy)-1-((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00448## 415
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14- pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00449## 416 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00450## 417 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14- pentaoxaheptadecan-17-
yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00451## 418 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00452## 419 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14-
pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00453## 420
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14- pentaoxaheptadecan-17-
yl)oxy)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00454## 421
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
((2,5,8,11,14- pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)- 1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00455## 422
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14- pentaoxaheptadecan-17-
yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00456## 423 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14-
pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00457## 424 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14-
pentaoxaheptadecan-17- yl)oxy)-1-((1r,4r)-4- ((2S,6R)-2,6-dimethyl-
morpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00458## 425 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00459## 426
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17- hexaoxaicosan-20-yl)oxy)-1-
((1r,4r)-4- morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-
amine ##STR00460## 427 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00461## 428
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4- morpholinocyclohexyl)-1H-
pyrazol-4-yl)pyrimidin-2- amine ##STR00462## 429
2-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-(2-((3-
((2,5,8,11,14,17- hexaoxaicosan-20-yl)oxy)-1-
((1r,4r)-4-((1R,5S)-3-oxa-8- azabicyclo[3.2.1]octan-8-
yl)cyclohexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00463## 430 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00464## 431 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00465## 432
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00466## 433 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00467## 434
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17- hexaoxaicosan-20-yl)oxy)-1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00468## 435
2-(((S)-1-(1H-1,2,4-triazol- 1-yl)propan-1-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17- hexaoxaicosan-20-yl)oxy)-1-
((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00469## 436 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17-
hexaoxaicosan-20-yl)oxy)-1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00470## 437 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00471## 438 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00472## 439 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00473## 440 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-y)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
((2,5,8,11,14,17,20- heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00474## 441 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00475## 442
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00476## 443 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00477## 444
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00478## 445 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-(((3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00479## 446
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00480## 447 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2-
((3-((2,5,8,11,14,17,20- heptaoxatricosan-23-yl)oxy)-
1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclo-
hexyl)-1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile
##STR00481## 448 5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20-
heptaoxatricosan-23-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-yrazol-4- yl)pyrimidin-2-amine
##STR00482## 449 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00483## 450 5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00484## 451 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00485## 452 5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4-chlorophenyl)-N-(3-
(92,5,8,11,14,17,20,23- octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2- amine
##STR00486## 453 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00487## 454
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-y)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00488## 455 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00489## 456
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,23-
heptaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((1R,5S)-3-oxa-
8-azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00490## 457 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00491## 458
5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00492## 459 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclo- hexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00493## 460
5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2-
yl)oxy)-4-chlorophenyl)-N-(3- ((2,5,8,11,14,17,20,23-
octaoxahexacosan-26-yl)oxy)- 1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 1H-pyrazol-4-yl)pyrimidin- 2-amine
##STR00494## 463 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((3-hydroxy-1-((1r,4r)-4-
morpholinocyclohexyl)-1H- pyrazol-4-yl)amino)pyrimidin-
5-yl)benzonitrile ##STR00495## 464 4-((5-(3-(((S)-1-(1H-1,2,4-
triazol-1-yl)propan-2- yl)oxy)-4- chlorophenyl)pyrimidin-2-
yl)amino)-1-((1r,4r)-4- morpholinocyclohexyl)-1H- pyrazol-3-ol
##STR00496## 465 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-3-hydroxy-1H-
pyrazol-4-yl)amino)pyrimidin- 5-yl)benzonitrile ##STR00497## 466
4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-3- ol
##STR00498## 467 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((1R,5S)-3-
oxa-8-azabicyclo[3.2.1]octan- 8-yl)cyclohexyl)-3-hydroxy-
1H-pyrazol-4- yl)amino)pyrimidin-5- yl)benzonitrile ##STR00499##
468 4-((5-(3-(((S)-1-(1-1,2,4- triazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4- ((1R,5S)-3-oxa-8-
azabicyclo[3.2.1]octan-8- yl)cyclohexyl)-1H-pyrazol-3- ol
##STR00500## 469 2-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4-(2-((1- ((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-hydroxy-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00501## 470
4-((5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)- 1H-pyrazol-3-ol
##STR00502## 471 2-(((S)-1-(1H-1,2,4-triazol-
1-yl)propan-2-yl)oxy)-4-(2- ((1-((1r,4r)-4-((2S,6R)-2,6-di-
methylmorpholino)cyclohexyl)- 3-hydroxy-1H-pyrazol-4-
yl)amino)pyrimidin-5- yl)benzonitrile ##STR00503## 472
4-((5-(3-(((S)-1-(1H-1,2,4- triazol-1-yl)propan-2- yl)oxy)-4-
chlorophenyl)pyrimidin-2- yl)amino)-1-((1r,4r)-4-
((2S,6R)-2,6-dimethyl- morpholino)cyclohexyl)- 1H-pyrazol-3-ol
##STR00504##
Example 473
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1H-pyrazol-
-4-yl)pyrimidin-2-amine
A) ethyl
3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazole-4-car-
boxylate
[1248] To a solution of ethyl
3-(benzyloxy)-1H-pyrazole-4-carboxylate (15.0 g) and
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (21.5 g) in DMF (200
mL) was added cesium carbonate (39.4 g) at room temperature. The
mixture was stirred at 90.degree. C. under nitrogen atmosphere
overnight. The mixture was quenched with water at room temperature
and extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (21.5 g).
[1249] MS m/z 387.2 [M+H].sup.+.
B)
3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazole-4-carboxyli-
c acid
[1250] To a solution of ethyl
3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazole-4-carboxylate
(34.0 g) in EtOH (180 mL) was added 8 M aqueous sodium hydroxide
solution (17.2 mL) at room temperature. The mixture was stirred at
50.degree. C. for 15 hr. The reaction mixture was concentrated
under reduced pressure, and the residue was acidified with 6 M
hydrochloric acid at 0.degree. C. and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to give the title compound (31.3 g).
[1251] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.95 (brs, 1H), 8.03
(s, 1H), 7.43-7.51 (m, 2H), 7.29-7.42 (m, 3H), 5.21 (s, 2H),
4.06-4.21 (m, 1H), 3.85-3.92 (m, 4H), 1.90-1.98 (m, 4H), 1.72-1.82
(m, 2H), 1.58-1.71 (m, 2H).
C) benzyl
N-[3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazol-4--
yl]carbamate
[1252] To a mixture of
3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazole-4-carboxylic
acid (32.0 g) and triethylamine (14.2 g) in toluene (200 mL) was
added DPPA (36.3 g) at room temperature. After being stirred at
room temperature for 1 hr, benzyl alcohol (14.4 g) was added to the
reaction mixture. The mixture was stirred at 90.degree. C. under
nitrogen atmosphere for 2 hr. The mixture was quenched with water
at room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(38.0 g).
[1253] MS m/z 464.3 [M+H].sup.+.
D) benzyl
N-[3-(benzyloxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
[1254] 2 M Hydrochloric acid (8.60 g) was added to a solution of
benzyl
N-[3-(benzyloxy)-1-{1,4-dioxaspiro[4.5]decan-8-yl}-1H-pyrazol-4-yl]carbam-
ate (55.0 g) in THF (100 mL) at 50.degree. C., and the mixture was
stirred for 14 hr. The mixture was neutralized with 8 M aqueous
sodium hydroxide solution at 0.degree. C. and extracted with ethyl
acetate. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (MeOH/ethyl acetate) to give the title
compound (39.0 g).
[1255] MS m/z 420.2 [M+H].sup.+.
E) benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-y-
l]cyclohexyl]-1H-pyrazol-4-yl]carbamate
[1256] 2-Methylpyridine-borane (8.02 g) was added to a mixture of
benzyl
N-[3-(benzyloxy)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl]carbamate
(21.0 g) and cis-2,6-dimethylmorpholine (8.63 g) in AcOH (10 mL)
and MeOH (200 mL) at room temperature and the mixture was stirred
at 60.degree. C. for 10 hr. The mixture was quenched with 8 M
aqueous sodium hydroxide solution and extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane and MeOH/ethyl acetate) to
give the title compound (10.3 g).
[1257] MS m/z 519.4 [M+H].sup.+.
F)
3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohex-
yl]-1H-pyrazol-4-amine
[1258] To a mixture of benzyl
N-[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohe-
xyl]-1H-pyrazol-4-yl]carbamate (15.0 g) in EtOH (100 mL) was added
8 M aqueous sodium hydroxide solution (36.1 mL) at room
temperature. The mixture was stirred at 90.degree. C. for 14 hr.
The mixture was concentrated under reduced pressure. 6 M
Hydrochloric acid was added to the residue to bring the pH of the
solution to 7-8, and the mixture was extracted with ethyl acetate.
The organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to give the title compound (12.8 g).
[1259] MS m/z 385.3 [M+H].sup.+.
G)
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyri-
midin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-
-1H-pyrazol-3-ol
[1260] To a mixture of
3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohexyl-
]-1H-pyrazol-4-amine (12.0 g) in EtOH (5.0 ml) was added 4 M
hydrogen chloride-ethyl acetate (39.0 mL) at room temperature.
After being stirred at room temperature for 10 min, the mixture was
concentrated under reduced pressure. To a mixture of the residue in
NMP (35 mL) was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (13.1 g) at room temperature. The mixture was stirred at
110.degree. C. under nitrogen atmosphere for 14 hr. The mixture was
quenched with 2 M hydrochloric acid at room temperature and
extracted with ethyl acetate. The aqueous layer was separated.
Sodium hydroxide was added to the mixture to bring the pH of the
solution to 8-9. The mixture was azeotroped with toluene. The
insoluble material in EtOH/water (120 mL, 3:1) was collected by
filtration, washed with EtOH/EtOAc/water (3:3:1), and dried under
reduced pressure to give the title compound (19.0 g).
[1261] MS m/z 609.5 [M+H].sup.+.
H)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-((4-methyl-4H-1,2,4-
-triazol-3-yl)methoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1262] A mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (206 mg), (4-methyl-4H-1,2,4-triazol-3-yl)methanol
(38.2 mg), triphenylphosphine (106 mg) and 2.2 M diethyl
azodicarboxylate in toluene (184 uL) in THF (10 mL) was stirred at
room temperature under argon atmosphere for 40 min. The reaction
mixture was purified by silica gel column chromatography (NH, ethyl
acetate/hexane and MeOH/ethyl acetate), and the residue was
purified by preparative HPLC (water/CH.sub.3CN containing 0.1%
TFA). The desired fraction was neutralized with saturated aqueous
sodium hydrogencarbonate solution and extracted with ethyl acetate.
The organic layer was separated, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to give the title
compound (15.6 mg).
[1263] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.76 (s, 1H), 8.69 (s, 2H), 8.47 (s, 1H), 7.79 (s, 1H), 7.45 (d,
J=8.25 Hz, 1H), 7.35 (d, J=1.74 Hz, 1H), 7.23 (dd, J=1.97, 8.21 Hz,
1H), 5.30 (s, 2H), 5.14-5.20 (m, 1H), 4.87-4.94 (m, 1H), 4.76-4.84
(m, 1H), 3.88-3.97 (m, 1H), 3.67 (s, 3H), 3.48-3.56 (m, 2H), 2.73
(d, J=9.45 Hz, 2H), 2.25-2.30 (m, 1H), 2.02-2.12 (m, 2H), 1.81-1.94
(m, 4H), 1.63-1.77 (m, 2H), 1.35-1.46 (m, 2H), 1.33 (d, J=6.14 Hz,
3H), 1.05 (d, J=6.24 Hz, 6H); MS m/z 704.5 [M+H].sup.+.
Example 474
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1--
ol
A)
2-{3-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phe-
nyl)pyrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl-
]cyclohexyl]-1H-pyrazol-3-yl)oxy]propoxy}ethyl acetate
[1264] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (500 mg) and cyanomethylenetributylphosphorane (395
mg) in toluene (3.0 mL) was added 2-(3-hydroxypropoxy)ethyl acetate
(199 mg) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 10 min. The mixture
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (MeOH/ethyl acetate) to give
the crude title compound (370 mg). The obtained product (80.0 mg)
was purified by preparative HPLC (water/CH.sub.3CN containing 0.1%
TFA). The desired fraction was neutralized with saturated aqueous
sodium hydrogencarbonate solution and extracted with ethyl acetate.
The organic layer was separated, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to give the title
compound (50.0 mg).
[1265] MS m/z 753.0 [M+H].sup.+.
B)
2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophen-
yl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cycl-
ohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol
[1266] To a mixture of
2-{3-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}pheny-
l)pyrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]c-
yclohexyl]-1H-pyrazol-3-yl)oxy]propoxy}ethyl acetate (250 mg) in
methanol (5.0 mL) was added 2 M aqueous sodium hydroxide solution
(331 .mu.L) at room temperature. The mixture was stirred at
50.degree. C. for 4 hr. The mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound
(37.0 mg).
[1267] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.70
(s, 2H), 8.59 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.25 Hz, 1H), 7.37
(d, J=1.93 Hz, 1H), 7.24 (dd, J=1.97, 8.30 Hz, 1H), 5.12-5.22 (m,
1H), 4.86-4.96 (m, 1H), 4.75-4.84 (m, 1H), 4.57 (t, J=5.46 Hz, 1H),
4.14 (t, J=6.37 Hz, 2H), 3.81-3.93 (m, 1H), 3.43-3.56 (m, 6H),
3.35-3.39 (m, 2H), 2.68-2.75 (m, 2H), 2.24-2.31 (m, 1H), 2.04 (d,
J=11.10 Hz, 2H), 1.80-1.95 (m, 6H), 1.59-1.75 (m, 2H), 1.29-1.45
(m, 5H), 1.04 (d, J=6.24 Hz, 6H); MS m/z 711.6 [M+H].sup.+.
Example 475
3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyr-
imidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl-
)-1H-pyrazol-3-yl)oxy)propan-1-ol
A)
3-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl-
)pyrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cy-
clohexyl]-1H-pyrazol-3-yl)oxy]propyl acetate
[1268] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (400 mg) and 3-hydroxypropyl acetate (116 mg) in
toluene (3.0 mL) was added cyanomethylenetributylphosphorane (316
mg) at room temperature. The mixture was stirred at 100.degree. C.
under nitrogen atmosphere for 2 hr. The mixture was quenched with
water at room temperature and extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) and silica gel column
chromatography (NH, ethyl acetate/hexane) to give the crude title
compound (228 mg). The obtained product (80.0 mg) was purified by
preparative HPLC (water/CH.sub.3CN containing 0.1% TFA). The
desired fraction was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was washed
with ethyl acetate/hexane (1:5), and under reduced pressure to give
the title compound (30.0 mg).
[1269] MS m/z 709.5 [M+H].sup.+.
B)
3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-
pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohe-
xyl)-1H-pyrazol-3-yl)oxy)propan-1-ol
[1270] To a mixture of
3-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)p-
yrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cycl-
ohexyl]-1H-pyrazol-3-yl)oxy]propyl acetate (145 mg) in MeOH (5.0
mL) was added 2 M aqueous sodium hydroxide solution (204 .mu.L) at
room temperature. The mixture was stirred at 50.degree. C. for 4
hr. The mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(MeOH/ethyl acetate). The residue was crystallized from ethyl
acetate/hexane to give the title compound (55.0 mg).
[1271] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.70
(s, 2H), 8.58 (s, 1H), 7.73 (s, 1H), 7.45 (d, J=8.25 Hz, 1H), 7.37
(d, J=1.83 Hz, 1H), 7.24 (dd, J=1.79, 8.12 Hz, 1H), 5.12-5.22 (m,
1H), 4.87-4.95 (m, 1H), 4.76-4.84 (m, 1H), 4.47 (t, J=5.09 Hz, 1H),
4.15 (t, J=6.42 Hz, 2H), 3.81-3.93 (m, 1H), 3.47-3.63 (m, 4H),
2.68-2.74 (m, 2H), 2.23-2.32 (m, 1H), 2.00-2.08 (m, 2H), 1.74-1.94
(m, 6H), 1.58-1.72 (m, 2H), 1.28-1.45 (m, 5H), 1.04 (d, J=6.24 Hz,
6H); MS m/z 667.5 [M+H].sup.+.
Example 476
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-((2-methylthiazol-5-yl)methoxy)-1H-py-
razol-4-yl)amino)pyrimidin-5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[-
(2-methyl-1,3-thiazol-5-yl)methoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorp-
holin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine
[1272] 2.2 M Diethyl azodicarboxylate in toluene (159 uL) was added
to a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (178 mg), (2-methyl-1,3-thiazol-5-yl)methanol (37.7
mg) and triphenylphosphine (91.9 mg) in toluene (3.0 mL) at
0.degree. C. The mixture was stirred at room temperature for 25
min. The reaction mixture was purified by by silica gel column
chromatography (MeOH/ethyl acetate) and silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (38.3 mg).
[1273] MS m/z 720.5 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-((2-methylthiazol-5-yl)methoxy)-1H-
-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1274] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[(2-
-methyl-1,3-thiazol-5-yl)methoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpho-
lin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (133 mg),
potassium hexacyanoferrate(II) trihydrate (156 mg) and potassium
acetate (57.0 mg) in CPME (5.0 mL) and water (5.0 mL) were added
XPhos Pd G2 (16.0 mg) and XPhos (18.0 mg). After being stirred
under nitrogen atmosphere at 110.degree. C. for 24 hr, the mixture
was poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(MeOH/ethyl acetate) and by preparative HPLC (water/CH.sub.3CN
containing 0.1% TFA). The desired fraction was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and crystallized from
EtOH/diethyl ether to give the title compound (30.0 mg).
[1275] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.74-8.83 (m, 3H), 7.71-7.80 (m, 2H), 7.68 (s, 1H), 7.46 (s, 1H),
7.39 (dd, J=1.10, 8.16 Hz, 1H), 5.28-5.38 (m, 3H), 4.90-4.98 (m,
1H), 4.79-4.88 (m, 1H), 3.84-4.00 (m, 1H), 3.45-3.58 (m, 2H),
2.68-2.79 (m, 2H), 2.59 (s, 3H), 2.22-2.33 (m, 1H), 2.03-2.15 (m,
2H), 1.81-1.99 (m, 4H), 1.62-1.80 (m, 2H), 1.28-1.47 (m, 5H), 1.05
(d, J=6.24 Hz, 6H); MS m/z 711.4 [M+H].sup.+.
Example 477
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4--
yl)amino)pyrimidin-5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[-
2-(oxetan-3-yl)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cy-
clohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine
[1276] A mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (200 mg), 2-(oxetan-3-yl)ethanol (67.0 mg) and
cyanomethylenetributylphosphorane (332 mg) in toluene (10 mL) was
stirred at 100.degree. C. under argon atmosphere for 1.5 hr. The
reaction mixture was purified by silica gel column chromatography
(NH, ethyl acetate/hexane) and silica gel column chromatography
(MeOH/ethyl acetate) to give the title compound (113 mg).
[1277] MS m/z 693.4 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-
-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1278] A mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[2--
(oxetan-3-yl)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cycl-
ohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (105 mg), potassium
hexacyanoferrate(II) trihydrate (191 mg), XPhos Pd G2 (11.9 mg),
XPhos (14.4 mg) and potassium acetate (66.8 mg) in CPME (5.0 mL)
and water (5.0 mL) was stirred at 110.degree. C. under argon
atmosphere for 13 hr. The residue was partitioned between ethyl
acetate and water. The organic layer was washed with saturated
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) and crystallized from
EtOH/heptane to give the title compound (74.7 mg).
[1279] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.80
(s, 2H), 8.74 (s, 1H), 7.75 (d, J=8.07 Hz, 1H), 7.72 (s, 1H), 7.47
(s, 1H), 7.40 (d, J=8.25 Hz, 1H), 5.34 (dt, J=4.31, 6.33 Hz, 1H),
4.89-5.00 (m, 1H), 4.80-4.89 (m, 1H), 4.57 (dd, J=5.87, 7.79 Hz,
2H), 4.26 (t, J=6.14 Hz, 2H), 4.05 (t, J=6.19 Hz, 2H), 3.82-3.91
(m, 1H), 3.48-3.58 (m, 2H), 3.03-3.13 (m, 1H), 2.68-2.75 (m, 2H),
2.22-2.31 (m, 1H), 1.98-2.08 (m, 4H), 1.81-1.93 (m, 4H), 1.60-1.74
(m, 2H), 1.37-1.45 (m, 2H), 1.35 (d, J=6.05 Hz, 3H), 1.05 (d,
J=6.05 Hz, 6H); MS m/z 684.5 [M+H].sup.+.
Example 478
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxy-3-methylbutoxy)-1H-pyrazol-
-4-yl)amino)pyrimidin-5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-[3-(-
3-methoxy-3-methylbutoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl-
]cyclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine
[1280] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (111 mg) and 3-methoxy-3-methylbutan-1-ol (43.0 mg)
in toluene (4.0 mL) was added cyanomethylenetributylphosphorane
(175 mg) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 2 hr. The mixture was
quenched with water at room temperature and extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (MeOH/ethyl acetate) and
crystallized from MeOH/IPE to give the title compound (68.0
mg).
[1281] MS m/z 709.4 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxy-3-methylbutoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1282] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-[3-(3--
methoxy-3-methylbutoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]c-
yclohexyl]-1H-pyrazol-4-yl]pyrimidin-2-amine (87.0 mg) and
potassium hexacyanoferrate(II) trihydrate (103 mg) in CPME (5.5 mL)
and water (5.5 mL) were added XPhos Pd G2 (19.2 mg), XPhos (23.3
mg) and potassium acetate (36.0 mg) at room temperature. The
mixture was stirred at 100.degree. C. under argon atmosphere for 14
hr. The mixture was poured into water at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
twice by silica gel column chromatography (MeOH/ethyl acetate) and
crystallized from MeOH/IPE to give the title compound (38.0
mg).
[1283] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.97 (s, 1H),
8.52-8.59 (m, 2H), 7.86-7.89 (m, 1H), 7.58-7.65 (m, 1H), 7.14-7.21
(m, 1H), 7.01-7.05 (m, 1H), 6.84-6.89 (m, 1H), 4.92-5.01 (m, 1H),
4.82-4.91 (m, 1H), 4.67-4.77 (m, 1H), 4.29-4.38 (m, 2H), 3.84-3.96
(m, 1H), 3.62-3.76 (m, 2H), 3.24 (s, 3H), 2.73-2.83 (m, 2H),
2.18-2.42 (m, 3H), 2.05 (s, 7H), 1.67-1.86 (m, 4H), 1.33-1.50 (m,
2H), 1.24 (s, 6H), 1.18 (d, J=6.24 Hz, 6H); MS m/z 700.5
[M+H].sup.+.
Example 479
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)-
amino)pyrimidin-5-yl)benzonitrile
A)
N-[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclo-
hexyl]-1H-pyrazol-4-yl]-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2--
yl]oxy}phenyl)pyrimidin-2-amine
[1284] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (20.0 g) and potassium carbonate (566 mg) in DMF (50
mL) was added benzyl bromide (974 .mu.L) at room temperature. The
mixture was stirred at 70.degree. C. under nitrogen atmosphere for
2 hr. The mixture was quenched with water at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
twice by silica gel column chromatography (MeOH/ethyl acetate) to
give the title compound (2.00 g).
[1285] MS m/z 699.6 [M+H].sup.+.
B)
4-(2-{[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]c-
yclohexyl]-1H-pyrazol-4-yl]amino}pyrimidin-5-yl)-2-{[(2S)-1-(1H-tetrazol-1-
-yl)propan-2-yl]oxy}benzonitrile
[1286] To a mixture of
N-[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohe-
xyl]-1H-pyrazol-4-yl]-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl-
]oxy}phenyl)pyrimidin-2-amine (2.00 g) and potassium
hexacyanoferrate(II) trihydrate (3.62 g) in CPME (60 mL) and water
(60 mL) was added potassium acetate (1.25 g) at room temperature.
After being stirred at room temperature for 15 min, XPhos Pd G2
(225 mg) and XPhos (272 mg) were added to the reaction mixture. The
mixture was stirred at 90.degree. C. under nitrogen atmosphere for
14 hr. The mixture was quenched with water at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(MeOH/ethyl acetate) and the residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane) to give the title
compound (1.66 g).
[1287] MS m/z 690.6 [M+H].sup.+.
C)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-hydroxy-1H-pyrazol-4-yl)amino)pyri-
midin-5-yl)benzonitrile
[1288] To a mixture of
4-(2-{[3-(benzyloxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyc-
lohexyl]-1H-pyrazol-4-yl]amino}pyrimidin-5-yl)-2-{[(2S)-1-(1H-tetrazol-1-y-
l)propan-2-yl]oxy}benzonitrile (170 mg) in toluene (5.0 mL) was
added TFA (93.9 .mu.L) at room temperature. The mixture was stirred
at 50.degree. C. under nitrogen atmosphere for 14 hr. Additional
TFA (400 .mu.L) was added to the mixture. And then, the mixture was
stirred at 90.degree. C. under nitrogen atmosphere for 4 hr. The
mixture was neutralized with 2 M aqueous sodium hydroxide solution
and concentrated under reduced pressure. The residue was washed
with water/2-propanol (5:1) and dried under reduced pressure to
give the title compound (40.0 mg).
[1289] MS m/z 600.5 [M+H].sup.+.
D)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4--
yl)amino)pyrimidin-5-yl)benzonitrile
[1290] To a mixture of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-hydroxy-1H-pyrazol-4-yl)amino)pyrimi-
din-5-yl)benzonitrile (200 mg) and (oxetan-3-yl)methanol (44.0 mg)
in toluene (3.0 mL) was added cyanomethylenetributylphosphorane
(160 mg) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 1 hr. Additional
cyanomethylenetributylphosphorane (160 mg) and
(oxetan-3-yl)methanol (15 mg) were added to the mixture. The
mixture was stirred at 100.degree. C. under nitrogen atmosphere for
30 min. The mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(MeOH/ethyl acetate), and the residue was purified by silica gel
column chromatography (NH, ethyl acetate/hexane). The residue was
crystallized from ethyl acetate/hexane to give the title compound
(60.0 mg).
[1291] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.80 (s, 1H), 8.79 (s, 2H), 7.75 (t, J=4.08 Hz, 2H), 7.46 (s, 1H),
7.39 (dd, J=1.24, 7.75 Hz, 1H), 5.29-5.39 (m, 1H), 4.90-4.98 (m,
1H), 4.79-4.88 (m, 1H), 4.63 (dd, J=6.01, 7.93 Hz, 2H), 4.39 (t,
J=6.01 Hz, 2H), 4.31 (d, J=6.69 Hz, 2H), 3.82-3.96 (m, 1H),
3.45-3.57 (m, 2H), 2.67-2.74 (m, 2H), 2.44-2.47 (m, 1H), 2.22-2.30
(m, 1H), 2.00-2.10 (m, 2H), 1.80-1.94 (m, 4H), 1.59-1.75 (m, 2H),
1.29-1.46 (m, 5H), 1.05 (d, J=6.33 Hz, 6H); MS m/z 670.6
[M+H].sup.+.
Example 480
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)pyrimidin-2-ami-
ne
[1292] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (200 mg) and (oxetan-3-yl)methanol (43.3 mg) in
toluene (8.0 mL) was added cyanomethylenetributylphosphorane (316
mg) at room temperature. The mixture was stirred at 100.degree. C.
under nitrogen atmosphere for 1 hr. Additional
(oxetan-3-yl)methanol (43.3 mg) and
cyanomethylenetributylphosphorane (316 mg) were added to the
mixture. The mixture was stirred at 100.degree. C. under nitrogen
atmosphere for 2 hr. The mixture was quenched with water at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (116
mg).
[1293] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.62 (s, 1H), 7.74 (s, 1H), 7.45 (d, J=8.34 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H), 5.17 (dt,
J=3.76, 6.42 Hz, 1H), 4.87-4.96 (m, 1H), 4.74-4.84 (m, 1H), 4.63
(dd, J=6.01, 7.93 Hz, 2H), 4.39 (t, J=6.05 Hz, 2H), 4.31 (d, J=6.69
Hz, 2H), 3.80-3.94 (m, 1H), 3.45-3.57 (m, 2H), 3.25-3.37 (m, 1H),
2.72 (d, J=9.81 Hz, 2H), 2.22-2.33 (m, 1H), 2.01-2.12 (m, 2H),
1.80-1.95 (m, 4H), 1.60-1.77 (m, 2H), 1.25-1.47 (m, 5H), 1.05 (d,
J=6.24 Hz, 6H); MS m/z 679.4 [M+H].sup.+.
Example 481
2-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyr-
imidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl-
)-1H-pyrazol-3-yl)oxy)ethan-1-ol
A)
N-{3-[2-(tert-butoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholi-
n-4-yl]cyclohexyl]-1H-pyrazol-4-yl}-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1--
yl)propan-2-yl]oxy}phenyl)pyrimidin-2-amine
[1294] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (100 mg) and 2-(tert-butoxy)ethan-1-ol (38.7 mg) in
toluene (4.0 mL) was added cyanomethylenetributylphosphorane (158
mg) at room temperature. The mixture was stirred at 100.degree. C.
under nitrogen atmosphere for 4 hr. The mixture was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the crude title compound (105 mg).
[1295] MS m/z 709.4 [M+H].sup.+.
B)
2-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-
pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohe-
xyl)-1H-pyrazol-3-yl)oxy)ethan-1-ol
[1296] To a mixture of
N-{3-[2-(tert-butoxy)ethoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin--
4-yl]cyclohexyl]-1H-pyrazol-4-yl}-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl-
)propan-2-yl]oxy}phenyl)pyrimidin-2-amine (105 mg) in toluene (2.0
mL) was added TFA (16.8 mg) at room temperature. The mixture was
stirred at room temperature for 14 hr. After concentration, the
residue was purified by silica gel column chromatography (NH,
MeOH/ethyl acetate) and purified by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA). The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (7.10 mg).
[1297] 1H NMR (300 MHz, methanol-d.sub.6) .delta. 9.26 (s, 1H),
8.62 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.40-7.49 (m, 1H),
7.13-7.24 (m, 2H), 5.03-5.18 (m, 1H), 4.23-4.33 (m, 2H), 3.82-4.02
(m, 3H), 3.61-3.77 (m, 2H), 3.36 (s, 2H), 2.89 (d, J=10.64 Hz, 2H),
2.35-2.52 (m, 1H), 1.91-2.26 (m, 6H), 1.70-1.90 (m, 2H), 1.32-1.60
(m, 5H), 1.17 (d, J=6.33 Hz, 6H); MS m/z 653.4 [M+H].sup.+.
Example 482
(R)-1-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl-
)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cycloh-
exyl)-1H-pyrazol-3-yl)oxy)propan-2-ol
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[-
(2R)-2-(oxan-2-yloxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin--
4-yl]cyclohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine
[1298] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (100 mg) and (2R)-2-(oxan-2-yloxy)propan-1-ol (39.4
mg) in toluene (4.0 mL) was added cyanomethylenetributylphosphorane
(158 mg) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 2 hr. Additional
(2R)-2-(oxan-2-yloxy)propan-1-ol (39.4 mg) and
cyanomethylenetributylphosphorane (158 mg) were added to the
mixture. The mixture was stirred at 100.degree. C. under nitrogen
atmosphere for 2 hr. The mixture was quenched with water at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and silica gel column
chromatography (MeOH/ethyl acetate) to give the crude title
compound (161 mg).
[1299] MS m/z 751.3 [M+H].sup.+.
B)
(R)-1-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophe-
nyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyc-
lohexyl)-1H-pyrazol-3-yl)oxy)propan-2-ol
[1300] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[(2-
R)-2-(oxan-2-yloxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4--
yl]cyclohexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (123 mg) in MeOH
(3.0 mL) was added p-toluenesulfonic acid monohydrate (31.0 mg) at
room temperature. The mixture was stirred at room temperature for
14 hr. The mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (55.0 mg).
[1301] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H), 8.79
(s, 1H), 8.74 (s, 2H), 7.82 (s, 1H), 7.45 (d, J=8.34 Hz, 1H), 7.39
(d, J=1.74 Hz, 1H), 7.26 (dd, J=1.88, 8.30 Hz, 1H), 5.10-5.26 (m,
1H), 4.74-4.95 (m, 3H), 3.79-4.08 (m, 4H), 3.43-3.59 (m, 2H),
2.66-2.77 (m, 2H), 2.20-2.34 (m, 1H), 1.97-2.11 (m, 2H), 1.79-1.95
(m, 4H), 1.56-1.77 (m, 2H), 1.28-1.47 (m, 5H), 0.98-1.13 (m, 9H);
MS m/z 667.4 [M+H].sup.+.
Example 483
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-
H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[-
(oxan-4-yl)methoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclo-
hexyl]-1H-pyrazol-4-yl}pyrimidin-2-amine
[1302] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (201 mg), (tetrahydro-2H-pyran-4-yl)methanol (88.0
mg) and toluene (10 mL) was added cyanomethylenetributylphosphorane
(0.26 mL). After being stirred under nitrogen atmosphere at
100.degree. C. for 3 hr, the mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (185
mg).
[1303] MS m/z 707.4 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy-
)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1304] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[(o-
xan-4-yl)methoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohe-
xyl]-1H-pyrazol-4-yl}pyrimidin-2-amine (174 mg), potassium
hexacyanoferrate(II) trihydrate (209 mg) and potassium acetate
(77.0 mg) in CPME (8.0 mL) and water (8.0 mL) were added XPhos Pd
G2 (20.0 mg) and XPhos (25.0 mg). After being stirred under
nitrogen atmosphere at 110.degree. C. for 14 hr, the mixture was
poured into water and extracted with ethyl acetate. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA). The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give the title compound (54.0 mg).
[1305] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.77-8.89 (m, 3H), 7.72-7.80 (m, 2H), 7.46 (s, 1H), 7.39 (dd,
J=1.24, 8.12 Hz, 1H), 5.29-5.41 (m, 1H), 4.90-4.99 (m, 1H),
4.79-4.89 (m, 1H), 3.94 (d, J=6.51 Hz, 2H), 3.78-3.91 (m, 3H),
3.37-3.60 (m, 2H), 3.21-3.31 (m, 2H), 2.59-2.81 (m, 2H), 1.99-2.35
(m, 4H), 1.78-1.97 (m, 4H), 1.57-1.75 (m, 4H), 1.19-1.46 (m, 7H),
0.99-1.19 (m, 6H); MS m/z 698.5 [M+H].sup.+.
Example 485
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazol-
-4-yl)amino)pyrimidin-5-yl)benzonitrile
A)
4-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl-
)pyrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cy-
clohexyl]-1H-pyrazol-3-yl)oxy]-2-methylbutan-2-yl acetate
[1306] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1-
H-pyrazol-3-ol (395 mg), 4-hydroxy-2-methylbutan-2-yl acetate (195
mg) and toluene (20 mL) was added cyanomethylenetributylphosphorane
(460 mg). After being stirred under nitrogen atmosphere at
100.degree. C. for 2 hr, the mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) and silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (275 mg).
[1307] MS m/z 737.4 [M+H].sup.+.
B)
4-[(4-{[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyc-
lohexyl]-1H-pyrazol-3-yl)oxy]-2-methylbutan-2-yl acetate
[1308] To a mixture of
4-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)p-
yrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cycl-
ohexyl]-1H-pyrazol-3-yl)oxy]-2-methylbutan-2-yl acetate (160 mg),
potassium hexacyanoferrate(II) trihydrate (186 mg), potassium
acetate (67.0 mg), CPME (8.0 mL) and water (8.0 mL) were added
XPhos Pd G2 (18.0 mg) and XPhos (21.0 mg). After being stirred
under nitrogen atmosphere at 110.degree. C. for 3 hr, the mixture
was poured into water and extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(MeOH/ethyl acetate) and silica gel column chromatography (NH,
ethyl acetate/hexane) to give the title compound (116 mg).
[1309] MS m/z 728.4 [M+H].sup.+.
C)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyra-
zol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1310] To a solution of
4-[(4-{[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)py-
rimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclo-
hexyl]-1H-pyrazol-3-yl)oxy]-2-methylbutan-2-yl acetate (104 mg) in
MeOH (5.0 mL) was added 2 M aqueous sodium hydroxide solution (0.36
mL). After being stirred at 50.degree. C. for 14 hr, the mixture
was poured into water and extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (NH,
ethyl acetate/hexane) and crystallized from EtOH/diethyl
ether/hexane to give the title compound (77.0 mg).
[1311] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.72 (s, 1H), 7.71-7.78 (m, 2H), 7.46 (s, 1H), 7.39
(dd, J=1.19, 8.16 Hz, 1H), 5.29-5.41 (m, 1H), 4.90-4.99 (m, 1H),
4.80-4.89 (m, 1H), 4.30 (s, 1H), 4.19 (t, J=7.24 Hz, 2H), 3.82-3.95
(m, 1H), 3.44-3.60 (m, 2H), 2.65-2.81 (m, 2H), 2.20-2.35 (m, 1H),
2.01-2.12 (m, 2H), 1.75-1.97 (m, 6H), 1.58-1.74 (m, 2H), 1.29-1.48
(m, 5H), 1.11 (s, 6H), 1.05 (d, J=6.14 Hz, 6H); MS m/z 686.4
[M+H].sup.+.
Example 486
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyr-
imidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl-
)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol
[1312] To a mixture of
4-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)p-
yrimidin-2-yl]amino}-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cycl-
ohexyl]-1H-pyrazol-3-yl)oxy]-2-methylbutan-2-yl acetate (7.68 g)
and EtOH (50 mL) was added 2 M aqueous sodium hydroxide solution
(10 mL). After being stirred at 50.degree. C. for 3 hr, the mixture
was poured into water and extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(MeOH/ethyl acetate) and silica gel column chromatography (NH,
ethyl acetate/hexane) to give the title compound (1.67 g).
[1313] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.69 (s, 2H), 8.53 (s, 1H), 7.72 (s, 1H), 7.45 (d, J=8.25 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.23 (dd, J=1.93, 8.34 Hz, 1H), 5.10-5.24
(m, 1H), 4.86-4.95 (m, 1H), 4.74-4.85 (m, 1H), 4.30 (s, 1H), 4.18
(t, J=7.24 Hz, 2H), 3.79-3.97 (m, 1H), 3.44-3.57 (m, 2H), 2.67-2.79
(m, 2H), 2.23-2.34 (m, 1H), 1.99-2.12 (m, 2H), 1.74-1.95 (m, 6H),
1.58-1.73 (m, 2H), 1.29-1.45 (m, 5H), 1.11 (s, 6H), 1.05 (d, J=6.20
Hz, 6H); MS m/z 695.6 [M+H].sup.+.
Example 487
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimid-
in-2-amine hydrochloride
A) ethyl
1-acetyl-3-[3-(2-methoxyethoxy)propoxy]-1H-pyrazole-4-carboxylate
[1314] To the mixture of ethyl
1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (3.40 g),
triphenylphosphine (5.42 g) and 3-(2-methoxyethoxy)propan-1-ol
(2.55 g) in toluene (100 mL) was added DIAD (4.18 g) at room
temperature. The mixture was stirred at room temperature for 14 hr.
The mixture was quenched with water at room temperature and
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (ethyl acetate/hexane) to give
the title compound (8.25 g).
[1315] MS m/z 315.2 [M+H].sup.+.
B) ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propoxy]--
1H-pyrazole-4-carboxylate
[1316] To a solution of ethyl
1-acetyl-3-[3-(2-methoxyethoxy)propoxy]-1H-pyrazole-4-carboxylate
(5.40 g) in DMF (60 mL) was added potassium carbonate (7.08 g) at
room temperature. The mixture was stirred at 100.degree. C. for 2
hr. 1,4-Dioxaspiro[4.5]decan-8-yl methanesulfonate (6.85 g) was
added to the mixture at 100.degree. C. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 4 hr. Additional
1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (2.00 g) and
potassium carbonate (2.00 g) were added to the mixture at
100.degree. C. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 14 hr. The mixture was poured into water
and extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) to
give the crude title compound (10.3 g).
[1317] MS m/z 413.3 [M+H].sup.+.
C)
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propoxy]-1H-pyr-
azole-4-carboxylic acid
[1318] To a mixture of ethyl
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propoxy]-1H-pyraz-
ole-4-carboxylate (10.3 g) in EtOH (100 mL) was added 2 M aqueous
sodium hydroxide solution (50 mL) at room temperature. The mixture
was stirred at 70.degree. C. for 2 hr. The mixture was neutralized
with 2 M hydrochloric acid at 0.degree. C. and extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the crude title compound (8.00
g).
[1319] MS m/z 385.3 [M+H].sup.+.
D) benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propo-
xy]-1H-pyrazol-4-yl)carbamate
[1320] To a mixture of
1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propoxy]-1H-pyraz-
ole-4-carboxylic acid (8.00 g) and triethylamine (3.15 g) in
toluene (80 mL) was added DPPA (4.72 mL) at 0.degree. C. The
mixture was stirred at 0.degree. C. under nitrogen atmosphere for 5
min. Benzylalcohol (4.49 g) was added to the mixture at 0.degree.
C. The mixture was stirred at 100.degree. C. for 4 hr. The mixture
was stirred at room temperature for 14 hr. The mixture was quenched
with water at room temperature and extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(4.56 g).
[1321] MS m/z 490.3 [M+H].sup.+.
E) benzyl
N-{3-[3-(2-methoxyethoxy)propoxy]-1-(4-oxocyclohexyl)-1H-pyrazol-
-4-yl}carbamate
[1322] To a mixture of benzyl
N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}-3-[3-(2-methoxyethoxy)propoxy]-1H-py-
razol-4-yl)carbamate (4.56 g) in THF (45 mL) was added 1 M
hydrochloric acid (45 mL) at room temperature. The mixture was
stirred at 50.degree. C. for 4 hr. The mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give the crude title compound (3.98 g).
[1323] MS m/z 446.3 [M+H].sup.+.
F) benzyl
N-{3-[3-(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dime-
thylmorpholin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}carbamate
[1324] To a mixture of benzyl
N-{3-[3-(2-methoxyethoxy)propoxy]-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl}car-
bamate (1.48 g) and cis-2,6-dimethylmorpholine (572 mg) in MeOH (20
mL) and AcOH (1.0 mL) was added 2-methylpyridine-borane (710 mg) at
room temperature. The mixture was stirred at room temperature for
14 hr. The mixture was neutralized with saturated aqueous sodium
hydrogencarbonate solution at room temperature and extracted with
ethyl acetate. The organic layer was separated, washed with water
and saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (750 mg).
[1325] MS m/z 545.3 [M+H].sup.+.
G)
3-[3-(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpho-
lin-4-yl]cyclohexyl]-1H-pyrazol-4-amine
[1326] A mixture of benzyl
N-{3-[3-(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorph-
olin-4-yl]cyclohexyl]-1H-pyrazol-4-yl}carbamate (750 mg) and 10%
palladium-carbon (145 mg) in EtOH (10 mL) and THF (10 mL) was
stirred under normal pressure of hydrogen atmosphere at room
temperature for 2 hr. The catalyst was removed by filtration, and
then the filtrate was concentrated under reduced pressure to give
the title compound (524 mg).
[1327] MS m/z 411.3 [M+H].sup.+.
H)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy-
)propoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride
[1328] To a mixture of
3-[3-(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholi-
n-4-yl]cyclohexyl]-1H-pyrazol-4-amine (524 mg) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (667 mg) in NMP (6.0 ml) was added methanesulfonic acid
(366 mg) at room temperature, and the mixture was stirred at
110.degree. C. for 4 hr. The mixture was poured into saturated
aqueous sodium hydrogencarbonate solution at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) and silica gel column chromatography (MeOH/ethyl
acetate) to give the crude title compound (350 mg). To a solution
of the obtained solid (281 mg) in EtOH (5.0 mL) was added 4 M
hydrogen chloride-ethyl acetate (482 .mu.L) at room temperature.
Diethylether (10 mL) was added to the mixture dropwise at room
temperature. The mixture was stirred at room temperature for 14 hr.
The precipitating solid was collected by filtration. The solid was
washed with diethyl ether and dried under reduced pressure to give
the title compound (269 mg).
[1329] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.98-11.16 (m,
1H), 9.38 (s, 1H), 8.62-8.75 (m, 3H), 7.77 (s, 1H), 7.45 (d, J=8.25
Hz, 1H), 7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H),
5.11-5.23 (m, 1H), 4.75-4.95 (m, 2H), 4.14 (t, J=6.42 Hz, 2H),
3.70-4.10 (m, 3H), 3.36-3.54 (m, 8H), 3.15-3.30 (m, 4H), 2.57-2.74
(m, 2H), 2.22-2.35 (m, 2H), 2.05-2.20 (m, 2H), 1.89 (quin, J=6.35
Hz, 2H), 1.61-1.80 (m, 4H), 1.33 (d, J=6.14 Hz, 3H), 1.15 (d,
J=6.24 Hz, 6H); MS m/z 725.4 [M+H].sup.+.
Example 488
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyraz-
ol-4-yl)amino)pyrimidin-5-yl)benzonitrile
[1330] To a mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)p-
ropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine (70.0 mg), potassium
hexacyanoferrate(II) trihydrate (81.5 mg), XPhos (9.20 mg) and
potassium acetate (28.3 mg) in CPME (15 mL) and water (15 mL) was
added XPhos Pd G2 (7.59 mg) at room temperature. The mixture was
stirred at 100.degree. C. under nitrogen atmosphere for 14 hr. The
mixture was quenched with saturated aqueous sodium
hydrogencarbonate solution at room temperature and extracted with
ethyl acetate. The organic layer was separated, washed with water
and saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane). To a
mixture of the obtained solid, XPhos (9.20 mg), potassium
hexacyanoferrate(II) trihydrate (81.5 mg) and potassium acetate
(28.3 mg) in CPME (5.0 mL) and water (5.0 mL) was added XPhos Pd G2
(7.59 mg) at room temperature. The mixture was stirred at
100.degree. C. under nitrogen atmosphere for 14 hr. The mixture was
quenched with water at room temperature and extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane), and
the residue was purified by preparative HPLC (water/CH.sub.3CN
containing 0.1% TFA). The desired fraction was neutralized with
saturated aqueous sodium hydrogencarbonate solution and extracted
with ethyl acetate. The organic layer was separated, dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give the title compound (18.0 mg).
[1331] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.73-8.84 (m, 3H), 7.70-7.79 (m, 2H), 7.47 (s, 1H), 7.40 (dd,
J=1.24, 8.12 Hz, 1H), 5.27-5.40 (m, 1H), 4.78-4.99 (m, 2H), 4.13
(t, J=6.42 Hz, 2H), 3.81-3.96 (m, 1H), 3.36-3.61 (m, 8H), 3.21 (s,
3H), 2.62-2.85 (m, 2H), 2.18-2.41 (m, 1H), 1.99-2.13 (m, 2H),
1.78-1.98 (m, 6H), 1.58-1.76 (m, 2H), 1.28-1.48 (m, 5H), 1.05 (d,
J=6.24 Hz, 6H); MS m/z 716.4 [M+H].sup.+.
Example 489
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmor-
pholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1332] To a mixture of
3-(3-methoxypropoxy)-1-[(1r,4r)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyc-
lohexyl]-1H-pyrazol-4-amine dihydrochloride (2.62 g) in NMP (10 ml)
was added
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}p-
henyl)pyrimidine (3.42 g) at room temperature, and the mixture was
stirred at 110.degree. C. for 2 hr. The mixture was poured into 1 M
hydrochloric acid and washed with ethyl acetate. The aqueous layer
was neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, ethyl
acetate/hexane) to give the title compound (2.70 g).
[1333] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.34-9.41 (m, 1H),
8.67-8.75 (m, 2H), 8.53-8.62 (m, 1H), 7.67-7.76 (m, 1H), 7.41-7.48
(m, 1H), 7.32-7.38 (m, 1H), 7.19-7.27 (m, 1H), 5.10-5.25 (m, 1H),
4.72-4.96 (m, 2H), 4.08-4.17 (m, 2H), 3.81-3.94 (m, 1H), 3.46-3.57
(m, 2H), 3.38-3.45 (m, 2H), 3.18-3.24 (m, 3H), 2.66-2.78 (m, 2H),
2.20-2.34 (m, 1H), 2.00-2.12 (m, 2H), 1.77-1.95 (m, 6H), 1.59-1.77
(m, 2H), 1.28-1.47 (m, 5H), 1.00-1.08 (m, 6H); MS m/z 681.4
[M+H].sup.+.
Example 490
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-(2-methoxyethoxy)-
propoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidi-
n-5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[-
3-(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-py-
razol-4-yl}pyrimidin-2-amine
[1334] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(200 mg) and 3-(2-methoxyethoxy)propan-1-ol (69.2 mg) in toluene
(8.0 mL) was added cyanomethylenetributylphosphorane (248 mg) at
room temperature. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 14 hr. The mixture was quenched with water
at room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (184
mg).
[1335] MS m/z 697.4 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-(2-methoxyetho-
xy)propoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrim-
idin-5-yl)benzonitrile
[1336] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-{3-[3--
(2-methoxyethoxy)propoxy]-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyra-
zol-4-yl}pyrimidin-2-amine (130 mg) and potassium
hexacyanoferrate(II) trihydrate (468 mg) in CPME (5 mL) and water
(5.0 mL) was added potassium acetate (163 mg) at room temperature.
After being stirred at room temperature for 15 min, XPhos (53.2 mg)
and XPhos Pd G2 (43.9 mg) were added to the reaction mixture. The
mixture was stirred at 90.degree. C. under nitrogen atmosphere for
14 hr. The mixture was quenched with water at room temperature and
extracted with ethyl acetate. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(MeOH/ethyl acetate). The residue was washed with EtOH/hexane (1:2)
and dried under reduced pressure to give the title compound (56.0
mg).
[1337] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.80 (s, 2H), 8.76 (s, 1H), 7.72-7.77 (m, 2H), 7.46 (s, 1H), 7.39
(dd, J=1.28, 8.07 Hz, 1H), 5.28-5.38 (m, 1H), 4.89-4.98 (m, 1H),
4.80-4.88 (m, 1H), 4.13 (t, J=6.28 Hz, 2H), 3.83-3.94 (m, 1H),
3.53-3.59 (m, 4H), 3.37-3.52 (m, 6H), 3.21 (s, 3H), 2.45-2.48 (m,
4H), 2.22-2.32 (m, 1H), 2.00-2.10 (m, 2H), 1.82-1.98 (m, 4H),
1.60-1.75 (m, 2H), 1.29-1.44 (m, 5H); MS m/z 688.4 [M+H].sup.+.
Example 491
5-(3-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-morpholinocyclohexyl)-3--
(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine
[1338] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(100 mg) and (oxetan-3-yl)methanol (18.1 mg) in toluene (8.0 mL)
was added cyanomethylenetributylphosphorane (90.6 .mu.L) at room
temperature. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 1 hr. Additional (oxetan-3-yl)methanol
(18.1 mg) and cyanomethylenetributylphosphorane (90.6 .mu.L) were
added to the mixture. The mixture was stirred at 100.degree. C.
under nitrogen atmosphere for 2 hr. The mixture was quenched with
water at room temperature and extracted with ethyl acetate. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (100
mg).
[1339] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 1H),
8.70 (s, 2H), 8.62 (s, 1H), 7.74 (s, 1H), 7.45 (d, J=8.25 Hz, 1H),
7.36 (d, J=1.83 Hz, 1H), 7.24 (dd, J=1.88, 8.30 Hz, 1H), 5.09-5.23
(m, 1H), 4.86-4.96 (m, 1H), 4.74-4.83 (m, 1H), 4.63 (dd, J=6.05,
7.89 Hz, 2H), 4.39 (t, J=6.05 Hz, 2H), 4.31 (d, J=6.69 Hz, 2H),
3.83-3.96 (m, 1H), 3.51-3.62 (m, 4H), 2.44-2.48 (m, 4H), 2.24-2.30
(m, 1H), 2.01-2.10 (m, 2H), 1.88-1.97 (m, 2H), 1.60-1.77 (m, 2H),
1.24-1.45 (m, 6H); MS m/z 651.3 [M+H].sup.+.
Example 492
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-morpholin-
ocyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)b-
enzonitrile
[1340] To a mixture of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-morpholinocyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)pyrimi-
din-2-amine (100 mg) and potassium hexacyanoferrate(II) trihydrate
(389 mg) in CPME (5.0 mL) and water (5.0 mL) was added potassium
acetate (135 mg) at room temperature. After being stirred at room
temperature for 10 min, XPhos (43.9 mg) and XPhos Pd G2 (36.2 mg)
were added to the reaction mixture. The mixture was stirred at
90.degree. C. under nitrogen atmosphere for 14 hr. The mixture was
quenched with water at room temperature and extracted with ethyl
acetate. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (MeOH/ethyl acetate). The residue
was washed with EtOAc/hexane (1:2) and dried under reduced pressure
to give the title compound (55.0 mg).
[1341] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.77-8.82 (m, 3H), 7.75 (t, J=4.08 Hz, 2H), 7.46 (s, 1H), 7.39 (dd,
J=1.28, 8.07 Hz, 1H), 5.29-5.39 (m, 1H), 4.90-4.99 (m, 1H),
4.79-4.89 (m, 1H), 4.63 (dd, J=6.05, 7.89 Hz, 2H), 4.39 (t, J=6.05
Hz, 2H), 4.31 (d, J=6.79 Hz, 2H), 3.82-3.96 (m, 1H), 3.52-3.61 (m,
4H), 2.44-2.49 (m, 5H), 2.22-2.32 (m, 1H), 2.01-2.10 (m, 2H), 1.93
(d, J=13.30 Hz, 2H), 1.60-1.76 (m, 2H), 1.30-1.46 (m, 5H); MS m/z
642.4 [M+H].sup.+.
Example 493
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyr-
imidin-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-yl)oxy)-
butanenitrile
[1342] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(200 mg) and 4-hydroxybutanenitrile (58.5 mg) in toluene (8.0 mL)
was added cyanomethylenetributylphosphorane (181 .mu.L) at room
temperature. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 14 hr. The mixture was quenched with water
at room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (114
mg).
[1343] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35-9.39 (m, 1H),
8.71-8.76 (m, 3H), 7.80 (s, 1H), 7.45 (d, J=8.25 Hz, 1H), 7.37 (d,
J=1.93 Hz, 1H), 7.25 (dd, J=1.93, 8.25 Hz, 1H), 5.11-5.24 (m, 1H),
4.87-4.96 (m, 1H), 4.75-4.85 (m, 1H), 4.15 (t, J=5.96 Hz, 2H),
3.84-3.95 (m, 1H), 3.52-3.61 (m, 4H), 2.69 (t, J=7.15 Hz, 2H),
2.44-2.48 (m, 4H), 2.23-2.29 (m, 1H), 2.01-2.09 (m, 2H), 1.87-2.00
(m, 4H), 1.59-1.75 (m, 2H), 1.29-1.45 (m, 5H); MS m/z 648.4
[M+H].sup.+.
Example 494
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-cyanopropoxy)-1-(-
(1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzo-
nitrile
[1344] To a mixture of
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)py-
rimidin-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-yl)oxy-
)butanenitrile (110 mg) and potassium hexacyanoferrate(II)
trihydrate (143 mg) in CPME (5.0 mL) and water (5.0 mL) was added
potassium acetate (49.9 mg) at room temperature. After being
stirred at room temperature for 5 min, XPhos (16.1 mg) and XPhos Pd
G2 (13.3 mg) were added to the reaction mixture. The mixture was
stirred at 100.degree. C. under nitrogen atmosphere for 14 hr. The
mixture was quenched with water at room temperature and extracted
with ethyl acetate. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (MeOH/ethyl acetate). The
residue was washed with EtOAc/hexane (1:1) and dried under reduced
pressure to give the title compound (38.0 mg).
[1345] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.92
(s, 1H), 8.81 (s, 2H), 7.81 (s, 1H), 7.75 (d, J=8.07 Hz, 1H), 7.47
(s, 1H), 7.37-7.43 (m, 1H), 5.29-5.38 (m, 1H), 4.91-4.99 (m, 1H),
4.79-4.88 (m, 1H), 4.15 (t, J=5.91 Hz, 2H), 3.83-3.96 (m, 1H),
3.52-3.60 (m, 4H), 2.69 (t, J=7.20 Hz, 2H), 2.45-2.49 (m, 4H),
2.22-2.31 (m, 1H), 2.01-2.10 (m, 2H), 1.87-1.99 (m, 4H), 1.60-1.76
(m, 2H), 1.31-1.45 (m, 5H); MS m/z 639.4 [M+H].sup.+.
Example 495
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-hydroxy-3-methylb-
utoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin--
5-yl)benzonitrile
A)
4-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl-
)pyrimidin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-
-3-yl)oxy]-2-methylbutan-2-yl acetate
[1346] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(218 mg), 4-hydroxy-2-methylbutan-2-yl acetate (105 mg) and toluene
(5.0 mL) was added cyanomethylenetributylphosphorane (0.20 mL).
After being stirred under nitrogen atmosphere at 100.degree. C. for
2 hr, additional cyanomethylenetributylphosphorane (0.20 mL) was
added to the mixture. After being stirred under nitrogen atmosphere
at 100.degree. C. for 1 hr, the mixture was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) and silica gel column
chromatography (MeOH/ethyl acetate) to give the title compound (211
mg).
[1347] MS m/z 709.4 [M+H].sup.+.
B)
4-[(4-{[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol--
3-yl)oxy]-2-methylbutan-2-yl acetate
[1348] To a mixture of
4-[(4-{[5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)p-
yrimidin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-3-
-yl)oxy]-2-methylbutan-2-yl acetate (197 mg), potassium
hexacyanoferrate(II) trihydrate (236 mg), potassium acetate (86.0
mg), CPME (10 mL) and water (10 mL) were added XPhos Pd G2 (22.0
mg) and XPhos (27.0 mg). After being stirred under nitrogen
atmosphere at 100.degree. C. for 14 hr, the mixture was poured into
water and extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (NH,
ethyl acetate/hexane) and crystallized from EtOH/hexane to give the
title compound (150 mg).
[1349] MS m/z 700.5 [M+H].sup.+.
C)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-hydroxy-3-meth-
ylbutoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimid-
in-5-yl)benzonitrile
[1350] To a solution of
4-[(4-{[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)py-
rimidin-2-yl]amino}-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazol-3--
yl)oxy]-2-methylbutan-2-yl acetate (106 mg) in MeOH (2.0 mL) and
THF (2.0 mL) was added 2 M aqueous sodium hydroxide solution (0.23
mL). After being stirred at room temperature for 14 hr and then at
80.degree. C. for 1 hr, the mixture was poured into water and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (NH, ethyl acetate/hexane) and
crystallized from EtOH/hexane to give the title compound (80.0
mg).
[1351] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H),
8.79 (s, 2H), 8.71 (s, 1H), 7.71-7.77 (m, 2H), 7.46 (s, 1H), 7.39
(dd, J=1.10, 8.16 Hz, 1H), 5.27-5.41 (m, 1H), 4.90-4.98 (m, 1H),
4.79-4.89 (m, 1H), 4.29 (s, 1H), 4.19 (t, J=7.24 Hz, 2H), 3.82-3.96
(m, 1H), 3.52-3.61 (m, 4H), 2.44-2.49 (m, 4H), 2.21-2.34 (m, 1H),
2.01-2.12 (m, 2H), 1.87-1.97 (m, 2H), 1.78 (t, J=7.29 Hz, 2H),
1.59-1.73 (m, 2H), 1.31-1.45 (m, 5H), 1.11 (s, 6H); MS m/z 658.4
[M+H].sup.+.
Example 496
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxy-3-methylb-
utoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin--
5-yl)benzonitrile
A)
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-[3-(-
3-methoxy-3-methylbutoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyra-
zol-4-yl]pyrimidin-2-amine
[1352] To a mixture of
4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimi-
din-2-yl)amino)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-3-ol
(200 mg) and 3-methoxy-3-methylbutan-1-ol (48.7 mg) in toluene (8.0
mL) was added cyanomethylenetributylphosphorane (99.6 mg) at room
temperature. The mixture was stirred at 100.degree. C. under
nitrogen atmosphere for 1 hr. Additional
3-methoxy-3-methylbutan-1-ol (48.7 mg) and
cyanomethylenetributylphosphorane (99.6 mg) were added to the
mixture. The mixture was stirred at 100.degree. C. under nitrogen
atmosphere for 10 hr. The mixture was quenched with water at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(MeOH/ethyl acetate) and silica gel column chromatography (NH,
ethyl acetate/hexane). The residue was purified by preparative HPLC
(water/CH.sub.3CN containing 0.1% TFA) The desired fraction was
neutralized with saturated aqueous sodium hydrogencarbonate
solution and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the title compound (148 mg).
[1353] 681.4 [M+H].sup.+.
B)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxy-3-meth-
ylbutoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimid-
in-5-yl)benzonitrile
[1354] To a mixture of
5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-N-[3-(3--
methoxy-3-methylbutoxy)-1-[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]-1H-pyrazo-
l-4-yl]pyrimidin-2-amine (140 mg) and potassium
hexacyanoferrate(II) trihydrate (173 mg) in CPME (5.0 mL) and water
(5.0 mL) was added potassium acetate (60.4 mg) at room temperature.
After being stirred at room temperature for 10 min, XPhos Pd G2
(16.1 mg) and XPhos (19.5 mg) were added to the reaction mixture.
The mixture was stirred at 100.degree. C. under nitrogen atmosphere
for 14 hr. The mixture was quenched with water at room temperature
and extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (MeOH/ethyl acetate) to give
the title compound (51.0 mg).
[1355] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.79
(s, 2H), 8.68 (s, 1H), 7.70-7.78 (m, 2H), 7.46 (s, 1H), 7.39 (d,
J=8.44 Hz, 1H), 5.28-5.38 (m, 1H), 4.90-4.98 (m, 1H), 4.78-4.88 (m,
1H), 4.10-4.18 (m, 2H), 3.82-3.95 (m, 1H), 3.53-3.59 (m, 4H), 3.08
(s, 3H), 2.45-2.48 (m, 4H), 2.24-2.31 (m, 1H), 2.01-2.09 (m, 2H),
1.89-1.97 (m, 2H), 1.86 (t, J=7.24 Hz, 2H), 1.63-1.73 (m, 2H),
1.30-1.44 (m, 5H), 1.11 (s, 6H); MS m/z 672.4 [M+H].sup.+.
[1356] The compounds of the Examples 497 to 513 in the following
Table 4 were produced according to the methods described in the
above-mentioned Examples, or methods analogous thereto. The MS of
the compounds of Examples 497 to 513 are shown in the following
Table 3. MS in the tables means actual measured value.
TABLE-US-00003 TABLE 3 Ex. No. MS 497 679.4 498 665.4 499 679.3 500
667.3 501 378.2 502 675.3 503 662.3 504 678.2 505 675.3 506 690.3
507 675.3 508 690.3 509 673.3 510 686.3 511 727.3 512 656.4 513
675.3
[1357] The compounds of Examples 473 to 483 and 485 to 513 are
shown in the following Table 4. The activity (IC.sub.50) in the
table is calculated in Experimental Example 1 and classified
according to the following three activity ranks;
A: less than 10 nM, B: 10 nM or more and less than 100 nM, C: 100
nM or more.
TABLE-US-00004 TABLE 4 AC- Ex. TIV- No. IUPAC NAME STRUCTURE ITY
473 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-3- ((4-methyl-4H-1,2,4-triazol-3-
yl)methoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine ##STR00505## A 474
2-(3-((4-(5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-yl)amino)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-1H-
pyrazol-3-yl)oxy)propoxy)ethan-1-ol ##STR00506## A 475
3-((4-((5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-yl)amino)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-1H- pyrazol-3-yl)oxy)propan-1-ol
##STR00507## A 476 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)-
3-((2-methylthiazol-5-yl)methoxy)-
1H-pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00508## A
477 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)- 3-(2-(oxetan-3-yl)ethoxy)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00509## A 478
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)-
3-(3-methoxy-3-methylbutoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00510## A 479
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)-
3-(oxetan-3-ylmethoxy)-1H-pyrazol- 4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00511## A 480
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-3-
(oxetan-3-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00512## A 481 2-((4-((5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2-yl)amino)-
1-((1r,4r)-4-((2S,6R)-2,6- dimethylmorpholino)cyclohexyl)-1H-
pyrazol-3-yl)oxy)ethan-1-ol ##STR00513## A 482
(R)-1-((4-((5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-yl)amino)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-1H- pyrazol-3-yl)oxy)propan-2-ol
##STR00514## A 483 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)- 3-((tetrahydro-2H-pyran-4-
yl)methoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-yl)benzonitrile
##STR00515## A 485 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)-
3-(3-hydroxy-3-methylbutoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00516## A 486
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-yl)amino)- 1-((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-1H-
pyrazol-3-yl)oxy)-2-methylbutan-2-ol ##STR00517## A 487
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-3- (3-(2-methoxyethoxy)propoxy)-1H-
pyrazol-4-yl)pyrimidin-2-amine ##STR00518## A 488
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
2,6-dimethylmorpholino)cyclohexyl)-
3-(3-(2-methoxyethoxy)propoxy)-1H- pyrazol-4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00519## A 489
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-((2S,6R)-2,6-
dimethylmorpholino)cyclohexyl)-3- (3-methoxypropoxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00520## A 490
2-(((S)-1-(1H-tetrazol-1-yl)propan-2- yl)oxy)-4-(2-((3-(3-(2-
methoxyethoxy)propoxy)-1-((1r,4r)-
4-morpholinocyclohexyl)-1H-pyrazol- 4-yl)amino)pyrimidin-5-
yl)benzonitrile ##STR00521## A 491
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(oxetan-3-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00522## A 492 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((1-((1r,4r)-4- morpholinocyclohexyl)-3-(oxetan-3-
ylmethoxy)-1H-pyrazol-4- yl)amino)pyrimidin-5-yl)benzonitrile
##STR00523## A 493 4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-
yl)propan-2-yl)oxy)-4- chlorophenyl)pyrimidin-2-yl)amino)-
1-((1r,4r)-4-morpholinocyclohexyl)-
1H-pyrazol-3-yl)oxy)butanenitrile ##STR00524## A 494
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((3-(3-cyanopropoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)amino)pyrimidin-5- yl)benzonitrile ##STR00525## A 495
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((3-(3-hydroxy-3- methylbutoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5-yl)benzonitrile ##STR00526## A 496
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-
yl)oxy)-4-(2-((3-(3-methoxy-3- methylbutoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H-pyrazol-4-
yl)amino)pyrimidin-5-yl)benzonitrile ##STR00527## A 497
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
((tetrahydro-2H-pyran-4- yl)methoxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00528## A 498
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
((tetrahydrofuran-3-yl)methoxy)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00529## A 499 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
((tetrahydro-2H-pyran-3- yl)methoxy)-1H-pyrazol-4-
yl)pyrimidin-2-amine ##STR00530## A 500
4-((4-((5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-yl)amino)-
1-((1r,4r)-4-morpholinocyclohexyl)-
1H-pyrazol-3-yl)oxy)-2-methylbutan- 2-ol ##STR00531## A 501
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(thiazol-5-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00532## A 502 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(3-((1-
methyl-1H-pyrazol-5-yl)methoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00533## A 503 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(oxazol-2-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00534## A 504 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(thiazol-2-ylmethoxy)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00535## A 505 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(3-((1-
methyl-1H-pyrazol-5-yl)methoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00536## A 506 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(3-((3,5-
dimethylisoxazol-4-yl)methoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00537## A 507 N-(3-(2-(1H-imidazol-1-yl)ethoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)-5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-amine ##STR00538## A 508
N-(3-(3-(1H-1,2,4-triazol-1- yl)propoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H-pyrazol-4-
yl)-5-(3-(((S)-1-(1H-tetrazol-1- yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-amine ##STR00539## A 509
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(pyrimidin-2-ylmethoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine
##STR00540## B 510 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(1- ((1r,4r)-4-morpholinocyclohexyl)-3-
(2-(pyridin-3-yl)ethoxy)-1H-pyrazol- 4-yl)pyrimidin-2-amine
##STR00541## A 511 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(3-(2-(2-
(2-methoxyethoxy)ethoxy)ethoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H- pyrazol-4-yl)pyrimidin-2-amine
##STR00542## B 512 5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-
2-yl)oxy)-4-chlorophenyl)-N-(3-(3-
(methoxy-d3)propoxy)-1-((1r,4r)-4-
morpholinocyclohexyl)-1H-pyrazol-4- yl)pyrimidin-2-amine
##STR00543## A 513 N-(3-(2-(1H-pyrazol-1-yl)ethoxy)-1-
((1r,4r)-4-morpholinocyclohexyl)-1H-
pyrazol-4-yl)-5-(3-(((S)-1-(1H- tetrazol-1-yl)propan-2-yl)oxy)-4-
chlorophenyl)pyrimidin-2-amine ##STR00544## A
Example 514
2-(((S)-1-(1H-tetrazol-1-yl)
propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)-1-((1r,4r)-4-morpholinocyclo-
hexyl)-1H-pyrazol-4-yl)amino) pyrimidin-5-yl)benzonitrile
hydrochloride
[1358] 4 M Hydrogen chloride-ethyl acetate (174 uL) was added to a
suspension of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)--
1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)be-
nzonitrile (300 mg) in EtOH (5.0 mL) at room temperature. The
mixture was stirred at 60.degree. C. for a while. The mixture was
stirred at room temperature over night. The precipitate was
collected by filtration and washed with cold EtOH to give the title
compound (230 mg) as light yellow crystals.
[1359] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.82
(brs, 1H), 8.79 (s, 2H), 7.77 (s, 1H), 7.74 (s, 1H), 7.46 (s, 1H),
7.37-7.42 (m, 1H), 5.34 (dt, J=3.94, 6.37 Hz, 1H), 4.89-4.99 (m,
1H), 4.81-4.89 (m, 1H), 4.13 (t, J=6.37 Hz, 2H), 3.95-4.06 (m, 2H),
3.71-3.81 (m, 1H), 3.56 (brs, 1H), 3.42 (t, J=6.33 Hz, 3H), 3.21
(s, 3H), 3.02-3.19 (m, 2H), 2.07-2.29 (m, 4H), 1.89 (quin, J=6.28
Hz, 2H), 1.54-1.84 (m, 4H), 1.36 (d, J=6.14 Hz, 3H) 4H were hidden
by DMSO; MS m/z 644.5 [M+H].sup.+.
Example 515
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)am-
ino)pyrimidin-5-yl)benzonitrile hydrochloride
[1360] To a solution of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile (13.7 g) in EtOH (150 mL) was
added dropwise 4 M hydrogen chloride-ethyl acetate (7.6 mL) at
60.degree. C., and the mixture was stirred at room temperature for
16 hr. The precipitate was collected by filtration and washed with
EtOH (50 mL) and dried under reduced pressure to give the title
compound (13.9 g) as yellow crystals.
[1361] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.55-10.73 (m,
1H), 9.35 (s, 1H), 8.79 (s, 3H), 7.68-7.82 (m, 2H), 7.45 (s, 1H),
7.39 (dd, J=8.1, 1.3 Hz, 1H), 5.34 (td, J=6.4, 3.8 Hz, 1H),
4.78-5.00 (m, 2H), 4.13 (t, J=6.4 Hz, 2H), 3.97 (br dd, J=9.4, 6.0
Hz, 3H), 3.42 (t, J=6.4 Hz, 4H), 3.21 (s, 4H), 2.57-2.76 (m, 2H),
2.27 (dt, J=3.9, 1.7 Hz, 2H), 2.08-2.20 (m, 2H), 1.89 (quin, J=6.4
Hz, 2H), 1.59-1.83 (m, 4H), 1.36 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.4
Hz, 6H); MS m/z 672.5 [M+H].sup.+.
Example 516
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)am-
ino)pyrimidin-5-yl)benzonitrile phosphate
[1362] To a solution of
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-
-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)a-
mino)pyrimidin-5-yl)benzonitrile (1.03 g) in THF (10 mL) was added
phosphoric acid (149 mg) at room temperature. The mixture was
stirred at room temperature for 1 hr. IPE (30 mL) was added to the
mixture, and and the mixture was stirred at 0.degree. C. for 1 h.
The precipitate was collected by filtration, washed with IPE and
dried under reduced pressure to give the title compound (910 mg) as
yellow crystals.
[1363] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.33-9.37 (m, 1H),
8.77-8.84 (m, 3H), 7.72-7.79 (m, 2H), 7.44-7.50 (m, 1H), 7.35-7.43
(m, 1H), 5.25-5.42 (m, 1H), 4.79-5.00 (m, 2H), 4.07-4.16 (m, 2H),
3.80-3.97 (m, 2H), 3.47-3.64 (m, 2H), 3.39-3.45 (m, 2H), 2.68-2.82
(m, 2H), 2.25-2.42 (m, 2H), 2.01-2.10 (m, 2H), 1.82-1.98 (m, 4H),
1.61-1.74 (m, 2H), 1.31-1.47 (m, 5H), 1.02-1.09 (m, 9H) 3H were
hidden by solvent; MS m/z 672.5 [M+H].sup.+.
[1364] An alternative method to produce the Example 515 is
described in detail as follows.
Example 517
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)--
2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)am-
ino)pyrimidin-5-yl)benzonitrile hydrochloride
A) 4-hydroxycyclohexan-1-one
[1365] To a solution of 1,4-dioxaspiro[4.5]decan-8-one (50.0 g) in
MeOH (230 mL) was added portionwise sodium borohydride (9.50 g) at
0.degree. C., and the mixture was stirred at room temperature for 2
hr. The reaction mixture was concentrated under reduced pressure to
a volume of ca.70-80 mL. To the resulting solution was carefully
dropwise added 2 M hydrochloric acid (200 mL) at 0.degree. C., and
the mixture was stirred at room temperature for 72 hr. An aqueous
potassium carbonate solution was carefully added to the mixture,
and the mixture was extracted with ethyl acetate. The organic layer
was separated, washed with saturated brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was passed through a silica gel pad (ethyl acetate) to give the
crude title compound (24.8 g).
[1366] 1H NMR (300 MHz, CDCl.sub.3) .delta. 4.20 (td, J=6.6, 3.0
Hz, 1H), 2.52-2.69 (m, 2H), 2.23-2.39 (m, 2H), 1.89-2.13 (m, 4H),
1.68 (d, J=3.4 Hz, 1H).
B) 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-one
[1367] To a solution of the crude 4-hydroxycyclohexan-1-one (21.2
g), 4-dimethylaminopyridine (7.48 g) and triethylamine (22.5 g) in
DMF (350 mL) was slowly added tert-butyldimethylsilyl chloride
(30.2 g) at room temperature, and the mixture was stirred at room
temperature for 16 hr. Water was added to the mixture, and the
mixture was extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
passed through a silica gel pad (ethyl acetate/hexane) to give the
crude title compound (40.4 g).
[1368] 1H NMR (300 MHz, CDCl.sub.3) .delta. 4.13 (tt, J=5.0, 2.5
Hz, 1H), 2.58-2.76 (m, 2H), 2.17-2.31 (m, 2H), 1.81-2.05 (m, 4H),
0.92 (s, 9H), 0.10 (s, 6H).
C) 4-(cis-2,6-dimethylmorpholino)cyclohexan-1-ol (a Mixture of Cis
and Trans)
[1369] A mixture of
4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-one (36.2 g),
cis-2,6-dimethylmorpholine (18.3 g), AcOH (9.51 g) and 10%
palladium-carbon (8.60 g) in MeOH (700 mL) was stirred under normal
pressure of hydrogen atmosphere at room temperature for 16 hr. The
catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in 2
M hydrochloric acid (280 mL) and MeOH (200 mL), and the solution
was stirred at room temperature for 90 min. Ethyl acetate and
saturated brine were added to the mixture, and the mixture was
partitioned. The aqueous layer was washed with ethyl acetate,
adjusted to pH 9 with carefully adding potassium carbonate and
extracted with ethyl acetate. The extracts were washed with
saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was dried by
azeotroped with toluene to give the title compound (25.3 g,
cis:trans=87:13, determined by 1H NMR) MS m/z 214.2
[M+H].sup.+.
D) cis-4-(cis-2,6-dimethylmorpholino)cyclohexan-1-ol
[1370] The above obtained
4-(cis-2,6-dimethylmorpholino)cyclohexan-1-ol (32.4 g) was
dissolved in hexane (210 mL) at 65.degree. C., and the solution was
allowed to cool to room temperature and stirred at room temperature
for 16 hr. The precipitate was collected by filtration, washed with
cold hexane and dried under reduced pressure to give the title
compound (23.5 g, cis:trans=>98:2, determined by 1H NMR) .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 3.90-4.02 (m, 1H), 3.66 (dqd,
J=10.1, 6.3, 2.1 Hz, 2H), 2.70-2.80 (m, 2H), 2.15-2.27 (m, 1H),
1.91 (dd, J=11.3, 10.2 Hz, 2H), 1.76-1.86 (m, 2H), 1.47-1.75 (m,
6H), 1.33 (brs, 1H), 1.16 (d, J=6.4 Hz, 6H); MS m/z 214.2
[M+H].sup.+.
E) cis-4-(cis-2,6-dimethylmorpholino)cyclohexyl
methanesulfonate
[1371] To a solution of
cis-4-(cis-2,6-dimethylmorpholino)cyclohexan-1-ol (10.0 g) and
triethylamine (6.64 g) in THF (300 mL) was added a solution of
methanesulfonyl chloride (7.52 g) in THF (30 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 3 hr and concentrated under reduced pressure. The mixture was
quenched with aqueous potassium carbonate solution at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
passed through a NH silica gel pad (ethyl acetate) to give the
crude title compound (13.7 g)
[1372] MS m/z 292.1 [M+H].sup.+.
F) ethyl
1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-met-
hoxypropoxy)-1H-pyrazole-4-carboxylate
[1373] To a solution of
cis-4-(cis-2,6-dimethylmorpholino)cyclohexyl methanesulfonate (12.0
g) and ethyl 3-(3-methoxypropoxy)-1H-pyrazole-4-carboxylate (4.70
g) in n-butyl acetate (150 mL) was added cesium carbonate (13.4 g)
at room temperature. The reaction mixture was stirred at
110.degree. C. for 16 hr. Additional cesium carbonate (4.03 g) was
added to the mixture, and the mixture was stirred at 110.degree. C.
for 8 hr. DMF (120 mL) was added to the mixture, and the mixture
was stirred at 110.degree. C. for 2 hr. The mixture was quenched
with saturated aqueous sodium hydrogencarbonate solution and
extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate/hexane) to give the title
compound (5.50 g).
[1374] MS m/z 424.3 [M+H].sup.+.
G) benzyl
(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-m-
ethoxypropoxy)-1H-pyrazol-4-yl)carbamate
[1375] To a solution of ethyl
1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxyprop-
oxy)-1H-pyrazole-4-carboxylate (5.50 g) in EtOH (90 mL) was added a
2 M aqueous sodium hydroxide solution (16.2 mL) at room
temperature, and the mixture was stirred at 50.degree. C. for 24
hr. 2 M Hydrochloric acid (32.5 mL) was added to the mixture, and
the mixture was stirred at room temperature for 10 min.
Triethylamine (6.57 g) was added to the mixture, and the mixture
was stirred at room temperature for 15 min. The reaction mixture
was concentrated under reduced pressure. The residue was dried by
azeotroped with EtOH and with chlorobenzene to remove EtOH. To a
suspension of the residue, benzyl alcohol (7.02 g) and
triethylamine (2.63 g) in chlorobenzene (200 mL) was added DPPA
(5.36 g) at room temperature. After stirred at room temperature for
16 hr, the mixture was stirred at 100.degree. C. for 3 hr. The
mixture was quenched with aqueous potassium carbonate solution at
room temperature and extracted with ethyl acetate. The organic
layer was separated, washed with saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
IPE and 1 M hydrochloric acid were added to the residue, and the
mixture was partitioned. The aqueous layer was basified with
potassium carbonate to pH 8 and extracted with ethyl acetate. The
organic layer was separated, washed with saturated brine, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, ethyl acetate/hexane) to give
the title compound (6.24 g).
[1376] MS m/z 501.3 [M+H].sup.+.
H)
1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypr-
opoxy)-1H-pyrazol-4-amine dihydrochloride monohydrate
[1377] A mixture of benzyl
(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypro-
poxy)-1H-pyrazol-4-yl)carbamate (6.24 g) and 10% palladium-carbon
(1.80 g) in MeOH (120 mL) was stirred under normal pressure of
hydrogen atmosphere at room temperature for 16 hr. The catalyst was
removed by filtration, and the filtrate was concentrated under
reduced pressure. To a solution of the residue in 2-propanol (60
mL) was added 2 M hydrogen chloride-2-propanol (15.6 mL), and the
mixture was stirred at room temperature for 10 min. The reaction
mixture was concentrated under reduced pressure. To a solution of
the residue in 2-propanol (20 mL) was added dropwise ethyl acetate
(100 mL) at 60.degree. C. The mixture was allowed to cool to room
temperature and stirred at room temperature for 16 hr. The
precipitate was collected by filtration, washed with ethyl acetate
and dried under reduced pressure to give the title compound (3.96
g).
[1378] MS m/z 367.3 [M+H].sup.+.
I)
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((-
1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)--
1H-pyrazol-4-yl)pyrimidin-2-amine
[1379] A mixture of
1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxyprop-
oxy)-1H-pyrazol-4-amine dihydrochloride monohydrate (3.00 g) and
2-chloro-5-(4-chloro-3-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}phenyl)-
pyrimidine (2.53 g) in NMP (11 mL) was stirred at 110.degree. C.
under nitrogen atmosphere for 16 hr. To the mixture were added
ethyl acetate and 1 M hydrochloric acid, and the mixture was
partitioned. The organic layer was washed with saturated brine. The
combined aqueous layer was basified with 2 M aqueous sodium
hydroxide solution to pH 8 and extracted with ethyl acetate. The
organic layer was washed with saturated brine and concentrated
under reduced pressure. The residue was passed through silica pad
(NH, ethyl acetate/hexane). To a solution of the residue in EtOH
(20 mL) was added 4 M hydrogen chloride-ethyl acetate (3.0 mL) at
room temperature, and the mixture was stirred for 10 min. Ethyl
acetate was added dropwise to the mixture at 55.degree. C., and the
mixture was allowed to cool to room temperature. The mixture was
stirred at room temperature for 16 hr. The precipitate was
collected by filtration, washed with ethyl acetate and dried under
reduced pressure to give a HCl salt of the crude title compound as
solids. The solids were dissolved in potassium carbonate solution
and extracted with ethyl acetate. The organic layer was separated,
washed with saturated brine, and concentrated under reduced
pressure to give the title compound (2.71 g).
[1380] MS m/z 681.4 [M+H].sup.+.
J)
2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6-
R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl-
)amino)pyrimidin-5-yl)benzonitrile hydrochloride
[1381] To a suspension of
5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r-
,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-
-pyrazol-4-yl)pyrimidin-2-amine (2.71 g), potassium
hexacyanoferrate(II) trihydrate (6.72 g) and potassium acetate
(1.17 g) in CPME (42 mL) and water (42 mL) were added XPhos (379
mg) and XPhos Pd G2 (313 mg) at room temperature. The mixture was
stirred at 100.degree. C. under nitrogen atmosphere for 16 hr. The
reaction mixture was partitioned. The organic layer was washed with
saturated brine. The aqueous layers were extracted with ethyl
acetate. The organic layer was washed with saturated brine. The
combined organic layers were washed with aqueous 12% ammonia
solution, saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was passed through
silica pad (NH, ethyl acetate). To a solution of the residue in
ethyl acetate (50 mL) was added dropwise a solution of 4 M hydrogen
chloride-ethyl acetate (4.0 mL) at room temperature, and the
mixture was stirred at room temperature for 30 min. IPE (20 mL) was
added dropwise to the mixture, and the mixture was stirred at room
temperature for 1 hr. The precipitate was collected by filtration,
washed with IPE and dried under reduced pressure to give the crude
title compound (2.96 g). To a solution of the crude title compound
(2.96 g) in EtOH (45 mL) and water (15 mL) was added dropwise EtOH
(60 mL) at 70.degree. C. The mixture was allowed to cool to room
temperature and stirred at room temperature for 16 hr. The
precipitate was collected by filtration, washed with EtOH and dried
under reduced pressure to give the title compound (2.34 g, purity
98.2%). To a solution of the title compound (2.00 g) in ethyl
methyl ketone (18 mL) and water (5.0 mL) was added EtOH (1.5 mL) at
70.degree. C. The mixture was allowed to cool to room temperature
and stirred at room temperature for 16 hr. After stirred at
5.degree. C. for 2 hr, the precipitate was collected by filtration,
washed with ethyl methyl ketone and dried under reduced pressure to
give the title compound (1.42 g, purity 99.1%).
[1382] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.47 (br d, J=1.1
Hz, 1H), 9.35 (s, 1H), 8.79 (s, 3H), 7.71-7.81 (m, 2H), 7.45 (s,
1H), 7.39 (dd, J=8.1, 1.3 Hz, 1H), 5.34 (td, J=6.1, 4.0 Hz, 1H),
4.78-4.99 (m, 2H), 4.13 (t, J=6.4 Hz, 2H), 3.95 (br dd, J=9.3, 7.0
Hz, 3H), 3.42 (t, J=6.4 Hz, 4H), 3.17-3.27 (m, 4H), 2.57-2.76 (m,
2H), 2.20-2.32 (m, 2H), 2.09-2.19 (m, 2H), 1.89 (t, J=6.4 Hz, 2H),
1.60-1.84 (m, 4H), 1.36 (d, J=6.0 Hz, 3H), 1.16 (d, J=6.4 Hz, 6H);
MS m/z 672.4 [M+H].sup.+; Anal. Calcd for C34H46Cl1N11O4: C, 57.66;
H, 6.55; N, 21.75. Found: C, 57.58; H, 6.54; N, 21.57.
[1383] The melting point and the optical rotation of the compounds
of Example 26, Example 143 and Example 515 are shown in the
following Table 5.
TABLE-US-00005 TABLE 5 Example No. Melting Point (degC) Optical
Rotation(.degree. ) 26 153 [.varies.].sub.D.sup.25 -20.8 (c 1.01,
DMSO) 143 113 [.varies.].sub.D.sup.25 -19.6 (c 1.01, DMSO) 515
decomposed around 240 not measured
Experimental Example 1
Evaluation of In Vitro CaMKII Inhibitory Activity (Binding
Assay)
(i) Objective
[1384] In vitro CaMKII.delta. inhibitory activity was evaluated by
a binding assay.
(ii) Materials
[1385] Full-length, glutathione-S-transferase (GST)-tagged, human
CaMKII.delta. was purchased from Carna Biosciences (product
#02-111, Kobe, Japan). Full-length bovine calmodulin was purchased
from Wako Pure Chemical Industries (Osaka, Japan). Terbium-labeled
anti-GST antibody (Tb-anti-GST Ab) was purchased from Life
Technologies (Carlsbad, Calif., USA). Boron-dipyrromethene
(BODIPY)-labeled probe ligand was synthesized as described
below.
5,5-difluoro-7,9-dimethyl-3-(3-oxo-3-((3-((4-(3-(piperazin-1-yl)phenyl)pyr-
imidin-2-yl)amino)phenyl)amino)propyl)-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]d-
iazaborinin-4-ium-5-uide
##STR00545##
[1386] A) tert-butyl
4-(3-(2-chloropyrimidin-4-yl)phenyl)piperazine-1-carboxylate
[1387] A mixture of 2,4-dichloropyrimidine (500 mg), tert-butyl
4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-car-
boxylate (1.24 g), tetrakis(triphenylphosphine)palladium(0) (739
mg), sodium carbonate (508 mg), THF (20 mL) and water (2.0 mL) was
stirred at 60.degree. C. under nitrogen atmosphere for 24 hr. The
mixture was quenched with water at room temperature and extracted
with ethyl acetate. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (ethyl acetate/hexane) to give the title
compound.
[1388] MS m/z 375.1 [M+1].sup.+.
B) tert-butyl
4-(3-(2-((3-nitrophenyl)amino)pyrimidin-4-yl)phenyl)piperazine-1-carboxyl-
ate
[1389] A mixture of tert-butyl
4-(3-(2-chloropyrimidin-4-yl)phenyl)piperazine-1-carboxylate (704
mg), 3-nitroaniline (285 mg), palladium acetate (63.2 mg), BINAP
(234 mg), cesium carbonate (857 mg) and toluene (10 mL) was stirred
at 90.degree. C. under nitrogen atmosphere overnight. The mixture
was quenched with 1 M aqueous hydrogen chloride solution at room
temperature and extracted with ethyl acetate. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (NH,
ethyl acetate/hexane) to give the title compound (588 mg).
[1390] MS m/z 477.2 [M+1].sup.+.
C) tert-butyl
4-(3-(2-((3-aminophenyl)amino)pyrimidin-4-yl)phenyl)piperazine-1-carboxyl-
ate
[1391] A mixture of tert-butyl
4-(3-(2-((3-nitrophenyl)amino)pyrimidin-4-yl)phenyl)piperazine-1-carboxyl-
ate (588 mg) and 10% palladium-carbon (131 mg) in MeOH (15 mL) was
stirred under normal pressure of hydrogen atmosphere at room
temperature for 3 hr. The catalyst was removed by filtration, and
the filtrate was concentrated under reduced pressure to give the
title compound (167 mg).
[1392] MS m/z 447.3 [M+1].sup.+.
D)
3-(3-((3-((4-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)pyrimidin-
-2-yl)amino)phenyl)amino)-3-oxopropyl)-5,5-difluoro-7,9-dimethyl-5H-dipyrr-
olo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide
[1393] 1-Propanephosphonic acid cyclic anhydride (0.44 mL) was
added to a solution of tert-butyl
4-(3-(2-((3-aminophenyl)amino)pyrimidin-4-yl)phenyl)piperazine-1-carboxyl-
ate (167 mg),
3-(2-carboxyethyl)-5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][-
1,3,2]diazaborinin-4-ium-5-uide (109 mg), N,N-diisopropylethylamine
(0.196 mL) and N,N-dimethylaminopyridine (45.7 mg) in ethyl acetate
(4.0 mL) at room temperature. The mixture was stirred at 80.degree.
C. under a dry atmosphere (calcium chloride tube) for 5 hr. The
mixture was quenched with saturated aqueous sodium
hydrogencarbonate solution at room temperature and extracted with
ethyl acetate. The organic layer was separated, washed with water
and saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (ethyl acetate/hexane) to give the title
compound (110 mg).
[1394] MS m/z 721.1 [M+1].sup.+.
E)
5,5-difluoro-7,9-dimethyl-3-(3-oxo-3-((3-((4-(3-(piperazin-1-yl)phenyl)-
pyrimidin-2-yl)amino)phenyl)amino)propyl)-5H-dipyrrolo[1,2-c:2',1'-f][1,3,-
2]diazaborinin-4-ium-5-uide
[1395] 4 M Hydrogen chloride-cyclopentyl methyl ether (0.382 mL)
was added to a solution of
3-(3-((3-((4-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)pyrimidin-2-
-yl)amino)phenyl)amino)-3-oxopropyl)-5,5-difluoro-7,9-dimethyl-5H-dipyrrol-
o[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide (110 mg) in ethyl
acetate (2.0 mL) at room temperature. The mixture was stirred at
room temperature under a dry atmosphere (calcium chloride tube) for
5 hr. After evaporation of the solvent, the residue was purified by
preparative HPLC (water/CH.sub.3CN containing 0.1% TFA). The
desired fractions were neutralized with saturated aqueous sodium
hydrogencarbonate solution and extracted with ethyl acetate. The
organic layer was separated, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the title compound
(15.0 mg).
[1396] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.99 (s, 1H),
9.61 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.05 (s, 1H), 7.71 (s, 2H),
7.60 (d, J=8.3 Hz, 1H), 7.49-7.56 (m, 1H), 7.32-7.43 (m, 2H), 7.21
(d, J=7.7 Hz, 2H), 7.10 (d, J=3.9 Hz, 2H), 6.41 (d, J=3.9 Hz, 1H),
6.31 (s, 1H), 3.09-3.23 (m, 6H), 2.82-2.94 (m, 4H), 2.72-2.80 (m,
3H), 2.27 (s, 3H), 1.23 (s, 3H); MS m/z 621.2 [M+1].sup.+.
(iii) Methods
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
Assay
[1397] All assays were conducted using 384-well, white,
flat-bottomed plates (product #784075, Greiner Bio-One,
Frickenhausen, Germany) in kinase assay buffer, which consists of
50 mM HEPES pH 7.6, 10 mM MgCl.sub.2, 1 mM EGTA, 0.01% Brig-35, 0.1
mM DTT). The fluorescent probe ligand was added at a final
concentration of 300 nM to solutions containing 0.21 nM Tb-anti-GST
Ab, 1 mM CaCl.sub.2), 10 .mu.g/mL calmodulin, and 0.5 nM GST-tagged
CaMKII.delta.. After shaded incubation of the protein-probe mixture
on ice for 30 min, the premix was dispensed in the assay plate
including test inhibitors with 4 fold dilution series of eight
concentrations. After 1 hr incubation at room temperature, TR-FRET
signals were measured in duplicate using an EnVision microplate
reader (Perkin Elmer, Waltham, Mass., USA). The solution in each
well was excited with a laser (.lamda.=340 nm) reflected by a
dichroic mirror (D400/D505 (Perkin Elmer) through an excitation
filter (UV (TRF) 340, (Perkin Elmer)), and fluorescence from Tb and
BODIPY were detected through two emission filters (CFP 495 (Perkin
Elmer) for Tb, Emission 520 (Perkin Elmer) for BODIPY).
[1398] The percentage of inhibition of test compounds was
calculated according to equation (1)
Inhibition (%)=100.times.(.mu..sub.H-T)/(.mu..sub.H-.mu..sub.L)
(1)
[1399] Where T is the value of the wells containing test compounds
and .mu..sub.H and .mu..sub.L are the mean values of the 0% and
100% inhibition control wells, respectively. The values of the 0
and 100% controls were the signals obtained in the absence and
presence of 3 .mu.M its parent compound, respectively. The half
maximal inhibitory concentration (IC.sub.50) of test compounds was
calculated by fitting the data with the logistic equation using
XLfit (IDBS, Guildford, UK). The IC.sub.50 was classified according
to the following activity ranks.
[1400] A: less than 10 nM
[1401] B: 10 nM or more and less than 100 nM
[1402] C: 100 nM or more
[1403] The results are shown in Tables 1 and 4.
Experimental Example 2
[1404] Evaluation of in vivo cardiac CaMKII inhibition (oral
administration)
(i) Objective
[1405] To evaluate potency of test compounds to inhibit cardiac
CaMKII kinase in vivo, phosphorylation levels of CaMKII-specific
sites of phospholamban (Thr17, PLN) were measured in the heart of
rats administered orally with test compounds.
(ii) Materials and Methods
[1406] Test compounds were suspended in 0.5%
[w/v]methylcellulose/water solution and administered (30 mg/kg) to
male CD (SD) IGS rat (6-8 weeks old, n=4) by the p.o. route (5
mL/kg). At 4 hours after the administration, rats were sacrificed
and the hearts were harvested. After washing the isolated hearts
with ice-cold saline, connective tissues were removed on ice, and
the isolated left ventricle were frozen into liquid nitrogen gas
and stored at -80.degree. C.
[1407] The left ventricle samples were homogenized in RIPA-buffer
containing phosphatase inhibitors and protease inhibitors. Samples
were analyzed by Western blotting using anti-P-PLN (Thr17, Santa
Cruz Biotechnology, sc-17024-R) antibody. The band intensities were
quantified using an imaging system and were normalized relative to
the vehicle-treated group.
(iii) Results
[1408] The results of the in vivo cardiac CaMKII inhibition are
shown in Table 6.
TABLE-US-00006 TABLE 6 Results of P-PLN reduction rate of each test
compound in comparison with vehicle-treated group Test compound
Time after Reduction rate (Example No.) Dose administration of
P-PLN 12 30 mg/kg 4 hr >30% 26 30 mg/kg 4 hr >30% 30 30 mg/kg
4 hr >30% 33 30 mg/kg 4 hr >30% 36 30 mg/kg 4 hr >30% 143
30 mg/kg 4 hr >30% 486 30 mg/kg 4 hr >30% 487 30 mg/kg 4 hr
>30% 488 30 mg/kg 4 hr >30% 489 30 mg/kg 4 hr >30%
Experimental Example 3
Evaluation of In Vivo Cardiac CaMKII Inhibition (Intravenous
Administration)
(i) Objective
[1409] To evaluate potency of test compounds to inhibit cardiac
CaMKII kinase in vivo, phosphorylation levels of CaMKII-specific
sites of phospholamban (Thr17, PLN) were measured in the heart of
rats administered intravenously with test compounds.
(ii) Materials and Methods
[1410] Test compounds were dissolved in N,N-dimethylacetamide and
1,3-butanediol (1:1) solution and were injected (1 mg/kg) to male
CD (SD) IGS rats (8 weeks old, n=4) by bolus intravenous injection
via the lateral tail vein or the femoral vein (0.5-1 mL/kg). At
0.25 hours after the injection, rats were sacrificed and the hearts
were harvested. After washing the isolated hearts with ice-cold
saline, connective tissues were removed on ice, and the isolated
left ventricle were frozen into liquid nitrogen gas and stored at
-80.degree. C.
[1411] The left ventricle samples were homogenized in RIPA-buffer
containing phosphatase inhibitors and protease inhibitors. Samples
were analyzed by Western blotting using anti-P-PLN (Thr17, Santa
Cruz Biotechnology, sc-17024-R) antibody. The band intensities were
quantified using an imaging system and were normalized relative to
the vehicle-treated group.
(iii) Results
[1412] The results of the in vivo cardiac CaMKII inhibition are
shown in Table 7.
TABLE-US-00007 TABLE 7 Results of P-PLN reduction rate of each test
compound in comparison with vehicle-treated group Test compound
Time after Reduction rate (Example No.) Dose administration of
P-PLN 143 1 mg/kg 0.25 hr >30% 485 1 mg/kg 0.25 hr >30%
Experimental Example 4
Evaluation of In Vitro Cytotoxicity
(i) Objective
[1413] To evaluate in vitro cytotoxicity of test compounds, % ATP
reduction was determined in the presence of 33 .mu.M of each test
compound after 72 hr incubation.
(ii) Materials and Methods
[1414] HepG2 cells were seeded in DMEM (Invitrogen) containing 10%
FBS (Corning)+glucose (4.5 g/L) for 24 hr to allow cell adhesion.
For compound treatments, compounds were diluted in DMSO and the
media, followed by added to the wells (24 hr after the cell
seeding) to obtain the desired final concentration (33 .mu.M, n=2).
The final DMSO concentration was 1%. After 72 hr, cellular ATP
contents were measured using CellTiter-Glo Luminescent Cell
Viability Assay (Promega). The % ATP reduction was determined by
comparing the ATP contents in the absence and the presence of test
compounds.
(iii) Results
[1415] The results of cytotoxicity test are shown in Table 8.
TABLE-US-00008 TABLE 8 Results of % ATP reduction after 72 hr
incubation with each test compound Test compound (Example No.) %
ATP reduction 143 12% 26 9% 241 -2% 477 9% 485 7% 488 3% Ex. 772
described in >50% WO 2018/183112 A1 Ex. 817 described in 40% WO
2018/183112 A1
Formulation Examples
[1416] Medicaments containing the compound of the present invention
as an active ingredient can be produced, for example, by the
following formulations.
1. Capsule
TABLE-US-00009 [1417] (1) compound obtained in Example 1 10 mg (2)
lactose 90 mg (3) microcrystalline cellulose 70 mg (4) magnesium
stearate 10 mg 1 capsule 180 mg
[1418] The total amount of the above-mentioned (1), (2) and (3) and
5 mg of (4) are blended and granulated, and 5 mg of the remaining
(4) is added. The whole mixture is sealed in a gelatin capsule.
2. Tablet
TABLE-US-00010 [1419] (1) compound obtained in Example 1 10 mg (2)
lactose 35 mg (3) cornstarch 150 mg (4) microcrystalline cellulose
30 mg (5) magnesium stearate 5 mg 1 tablet 230 mg
[1420] The total amount of the above-mentioned (1), (2) and (3), 20
mg of (4) and 2.5 mg of (5) are blended and granulated, and 10 mg
of the remaining (4) and 2.5 mg of the remaining (5) are added and
the mixture is compression formed to give a tablet.
INDUSTRIAL APPLICABILITY
[1421] According to the present invention, a compound having a
superior CaMKII inhibitory action, which is expected to be useful
as an agent for the prophylaxis or treatment of cardiac diseases
(particularly catecholaminergic polymorphic ventricular
tachycardia, postoperative atrial fibrillation, heart failure,
fatal arrhythmia) and the like can be provided.
* * * * *