U.S. patent application number 14/001489 was filed with the patent office on 2015-10-01 for diaminopyrimidine derivatives and processes for the preparation thereof.
This patent application is currently assigned to YUHAN CORPORATION. The applicant listed for this patent is Kyoung-Kyu AHN, Myung-Hun CHA, Eun-Jung JUNG, Dong-Hoon KIM, Tae-Kyun KIM, Hyun-Joo LEE, Tai-Au LEE, Jae-Young SIM, Young-Ae YOON. Invention is credited to Kyoung-Kyu AHN, Myung-Hun CHA, Eun-Jung JUNG, Dong-Hoon KIM, Tae-Kyun KIM, Hyun-Joo LEE, Tai-Au LEE, Jae-Young SIM, Young-Ae YOON.
Application Number | 20150274700 14/001489 |
Document ID | / |
Family ID | 46721361 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150274700 |
Kind Code |
A2 |
LEE; Hyun-Joo ; et
al. |
October 1, 2015 |
DIAMINOPYRIMIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION
THEREOF
Abstract
The present invention provides a diaminopyrimidine derivative or
its pharmaceutically acceptable salt, a process for the preparation
thereof, a pharmaceutical composition comprising the same, and a
use thereof. The diaminopyrimidine derivative or its
pharmaceutically acceptable salt functions as a 5-HT.sub.4 receptor
agonist, and therefore can be usefully applied for preventing or
treating dysfunction in gastrointestinal motility, one of the
gastrointestinal diseases, such as gastroesophageal reflux disease
(GERD), constipation, irritable bowel syndrome (IBS), dyspepsia,
post-operative ileus, delayed gastric emptying, gastroparesis,
intestinal pseudo-obstruction, drug-induced delayed transit, or
diabetic gastric atony.
Inventors: |
LEE; Hyun-Joo; (Seoul,
KR) ; KIM; Dong-Hoon; (Gyeonggi-do, KR) ; KIM;
Tae-Kyun; (Gyeonggi-do, KR) ; YOON; Young-Ae;
(Seoul, KR) ; SIM; Jae-Young; (Gyeonggi-do,
KR) ; CHA; Myung-Hun; (Gyeonggi-do, KR) ;
JUNG; Eun-Jung; (Seoul, KR) ; AHN; Kyoung-Kyu;
(Gyeonggi-do, KR) ; LEE; Tai-Au; (Seoul,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LEE; Hyun-Joo
KIM; Dong-Hoon
KIM; Tae-Kyun
YOON; Young-Ae
SIM; Jae-Young
CHA; Myung-Hun
JUNG; Eun-Jung
AHN; Kyoung-Kyu
LEE; Tai-Au |
Seoul
Gyeonggi-do
Gyeonggi-do
Seoul
Gyeonggi-do
Gyeonggi-do
Seoul
Gyeonggi-do
Seoul |
|
KR
KR
KR
KR
KR
KR
KR
KR
KR |
|
|
Assignee: |
YUHAN CORPORATION
Seoul
KR
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130338179 A1 |
December 19, 2013 |
|
|
Family ID: |
46721361 |
Appl. No.: |
14/001489 |
Filed: |
February 24, 2012 |
PCT Filed: |
February 24, 2012 |
PCT NO: |
PCT/KR2012/001427 PCKC 00 |
371 Date: |
August 23, 2013 |
Current U.S.
Class: |
514/275;
544/297 |
Current CPC
Class: |
A61P 1/10 20180101; C07D
413/04 20130101; A61P 1/12 20180101; A61P 1/00 20180101; C07D
413/14 20130101; A61P 1/14 20180101; C07D 403/04 20130101; C07D
417/04 20130101; A61P 43/00 20180101; C07D 401/04 20130101; A61P
1/04 20180101 |
International
Class: |
C07D 403/04 20060101
C07D403/04 |
Claims
1. A method for treating or preventing a dysfunction in
gastrointestinal motility comprising administering an effective
amount of a compound of Formula 1 or a pharmaceutically acceptable
salt thereof to a subject in need thereof: ##STR00017## wherein,
R.sub.1 is a phenyl group substituted with one or more substituents
selected from the group consisting of hydroxy, amino, halogen,
cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the C.sub.1-5
alkyl is optionally substituted with halogen or amino), C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy (where the C.sub.1-5
alkoxy is optionally substituted with halogen), C.sub.1-5
alkylthio, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino, C.sub.1-6
alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or a heteroaryl
group selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl,
quinolinonyl, chromenonyl, dihydroindolonyl,
isoindoline-1,3-dionyl, dihydrobenzimidazolonyl, benzoxazolonyl,
benzofuranyl, benzothiophenyl, benzo[d][1,3]dioxolyl,
dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroaryl
group may be optionally substituted with one or more substituents
selected from the group consisting of amino, di-C.sub.1-5
alkylamino, cyano, nitro, halogen, C.sub.1-6 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen), C.sub.1-5
alkoxy (where the C.sub.1-5 alkoxy is optionally substituted with
halogen), acetyl, and C.sub.1-5 alkylsulfonyl, R.sub.2 is hydrogen;
a C.sub.1-5 alkyl group optionally substituted with a substituent
selected from the group consisting of hydroxy, C.sub.1-5 alkoxy,
benzylamino (where the benzylamino is optionally substituted with
halogen), phenylamino, C.sub.1-5 alkylamino, C.sub.3-6
cycloalkylamino, pyrrolidinyl, and hydroxy-C.sub.1-5 alkylamino; a
C.sub.1-5 alkoxycarbonyl group; a hydroxycarbonyl group; an
aminocarbonyl group; a formyl group; or an oxo(.dbd.O) group,
R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy group; a
phenoxy group; a benzyloxy group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1), ##STR00018## R.sub.4 is hydrogen; a hydroxyl group; or a
C.sub.1-5 alkyl group optionally substituted with hydroxy, R.sub.5
is a C.sub.1-5 alkyl group optionally substituted with phenyl; or a
C.sub.2-6 alkenyl group optionally substituted with phenyl or
C.sub.3-6 cycloalkyl, R.sub.6 is a C.sub.1-10 alkyl group
optionally substituted with a substituent selected from the group
consisting of hydroxy, halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5
alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-C.sub.1-5
alkylamino, C.sub.1-5 alkoxy-C.sub.1-5 alkyloxy, phenoxy,
benzyloxy, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
halogen, amino, C.sub.1-5 alkoxy, and hydroxy), thiophenyl,
pyridinyl, indolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group, R.sub.8 and
R.sub.9 are, independently each other, hydrogen; a C.sub.1-10 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, C.sub.1-5 alkoxycarbonylamino, hydroxy,
C.sub.1-5 alkylthio, C.sub.3-10 cycloalkyl, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of hydroxy, C.sub.1-5 alkyl,
mono- or di-C.sub.1-5 alkylamino, trifluoromethyl, halogen,
C.sub.1-5 alkoxy, and C.sub.1-5 alkylcarbonyloxy), thiophenyl,
pyrrolyl, furanyl (where the furanyl is optionally substituted with
mono- or alkyl), pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, and
benzyloxy; a piperidinyl group optionally substituted with benzyl,
benzoyl, C.sub.1-5 alkyl, or C.sub.1-5 alkylcarbonyl; an azetidinyl
group optionally substituted with C.sub.1-5 alkoxycarbonyl; a
C.sub.1-5 alkylsulfonyl group; a phenylsulfonyl group (where the
phenyl moiety is optionally substituted with halogen); or a
C.sub.3-10 cycloalkyl group.
2. The method of claim 1, wherein R.sub.1 is a phenyl group
substituted with one or more substituents selected from the group
consisting of hydroxy, amino, halogen, cyano, nitro,
hydroxycarbonyl, C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is
optionally substituted with halogen or amino), C.sub.1-5 alkoxy
(where the C.sub.1-5 alkoxy is optionally substituted with
halogen), C.sub.1-5 alkylthio, aminosulfonyl, aminocarbonyl,
C.sub.1-5 alkylaminocarbonyl, and benzyloxycarbonylamino; or a
heteroaryl group selected from the group consisting of quinolinyl,
chromenonyl, indolyl, indolinyl, and benzimidazolyl, wherein the
heteroaryl group may be optionally substituted with one or more
substituents selected from the group consisting of C.sub.1-5 alkyl
(where the C.sub.1-5 alkyl is optionally substituted with halogen),
and acetyl, R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxyl, C.sub.1-5 alkoxy, benzylamino (where the benzylamino
is optionally substituted with halogen), phenylamino, C.sub.1-5
alkylamino, C.sub.3-6 cycloalkylamino, and hydroxy-C.sub.1-5
alkylamino; a C.sub.1-5 alkoxycarbonyl group; or a formyl group,
R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the Formulas A, B, D and E, R.sub.4 is hydrogen,
R.sub.5 is a C.sub.1-5 alkyl group, R.sub.6 is a C.sub.1-10 alkyl
group optionally substituted with a substituent selected from the
group consisting of hydroxy, halogen, C.sub.1-5 alkoxy, amino,
C.sub.1-5 alkoxycarbonylamino, benzyloxycarbonylamino, mono- or
di-C.sub.1-5 alkylamino, C.sub.1-5 alkoxy-C.sub.1-5 alkyloxy,
phenoxy, benzyloxy, phenyl (where the phenyl is optionally
substituted with one or more substituents selected from the group
consisting of halogen, amino, C.sub.1-5 alkoxy, and hydroxy),
thiophenyl, pyridinyl, indolyl, piperidinyl, piperazinyl (where the
piperazinyl is optionally substituted with benzyl), C.sub.3-6
cycloalkyl, acetyl, and benzoyl; a C.sub.3-6 cycloalkyl group; a
piperidinyl group optionally substituted with C.sub.1-5
alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally substituted
with phenyl; a trifluoromethyl group; a trifluoroethyl group; or a
phenyl group optionally substituted with halogen, R.sub.7 is
hydrogen, R.sub.8 and R.sub.9 are, independently each other,
hydrogen; a C.sub.1-10 alkyl group optionally substituted with a
substituent selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or di-C.sub.1-5 alkyl),
pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
3. The method of claim 1, wherein the dysfunction in
gastrointestinal motility is gastroesophageal reflux disease
(GERD), constipation, irritable bowel syndrome (IBS), dyspepsia,
post-operative ileus, delayed gastric emptying, gastroparesis,
intestinal pseudo-obstruction, drug-induced delayed transit, or
diabetic gastric atony.
4. A pharmaceutical composition comprising an effective amount of a
compound of Formula 1 or a pharmaceutically acceptable salt
thereof; and a pharmaceutically acceptable carrier: ##STR00019##
wherein, R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-5 alkoxy (where the
C.sub.1-5 alkoxy is optionally substituted with halogen), C.sub.1-5
alkylthio, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino, C.sub.1-6
alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or a heteroaryl
group selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl,
quinolinonyl, chromenonyl, dihydroindolonyl,
isoindoline-1,3-dionyl, dihydrobenzimidazolonyl, benzoxazolonyl,
benzofuranyl, benzothiophenyl, benzo[d][1,3]dioxolyl,
dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroaryl
group may be optionally substituted with one or more substituents
selected from the group consisting of amino, di-C.sub.1-5
alkylamino, cyano, nitro, halogen, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen), C.sub.1-5
alkoxy (where the C.sub.1-5 alkoxy is optionally substituted with
halogen), acetyl, and C.sub.1-5 alkylsulfonyl, R.sub.2 is hydrogen;
a C.sub.1-5 alkyl group optionally substituted with a substituent
selected from the group consisting of hydroxy, C.sub.1-5 alkoxy,
benzylamino (where the benzylamino is optionally substituted with
halogen), phenylamino, C.sub.1-5 alkylamino, C.sub.3-6
cycloalkylamino, pyrrolidinyl, and hydroxy-C.sub.1-5 alkylamino; a
C.sub.1-5 alkoxycarbonyl group; a hydroxycarbonyl group; an
aminocarbonyl group; a formyl group; or an oxo(.dbd.O) group,
R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy group; a
phenoxy group; a benzyloxy group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1), ##STR00020## R.sub.4 is hydrogen; a hydroxyl group; or a
C.sub.1-5 alkyl group optionally substituted with hydroxy, R.sub.5
is a C.sub.1-5 alkyl group optionally substituted with phenyl; or a
C.sub.2-6 alkenyl group optionally substituted with phenyl or
C.sub.3-6 cycloalkyl, R.sub.6 is a C.sub.1-10 alkyl group
optionally substituted with a substituent selected from the group
consisting of hydroxy, halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5
alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-C.sub.1-5
alkylamino, C.sub.1-5 alkoxy-C.sub.1-5 alkyloxy, phenoxy,
benzyloxy, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
halogen, amino, C.sub.1-5 alkoxy, and hydroxy), thiophenyl,
pyridinyl, indolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group, R.sub.8 and
R.sub.9 are, independently each other, hydrogen; a C.sub.1-10 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, alkoxycarbonylamino, hydroxy, C.sub.1-5
alkylthio, C.sub.3-10 cycloalkyl, phenyl (where the phenyl is
optionally substituted with one or more substituents selected from
the group consisting of hydroxy, C.sub.1-5 alkyl, mono- or
di-C.sub.1-5 alkylamino, trifluoromethyl, halogen, C.sub.1-5
alkoxy, and C.sub.1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl,
furanyl (where the furanyl is optionally substituted with mono- or
alkyl), pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, tetrazolyl, oxazolyl, thiazolyl, and benzyloxy; a
piperidinyl group optionally substituted with benzyl, benzoyl,
C.sub.1-5 alkyl, or C.sub.1-5 alkylcarbonyl; an azetidinyl group
optionally substituted with C.sub.1-5 alkoxycarbonyl; a
alkylsulfonyl group; a phenylsulfonyl group (where the phenyl
moiety is optionally substituted with halogen); or a C.sub.3-10
cycloalkyl group.
5. The pharmaceutical composition of claim 4, wherein R.sub.1 is a
phenyl group substituted with one or more substituents selected
from the group consisting of hydroxy, amino, halogen, cyano, nitro,
hydroxycarbonyl, C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is
optionally substituted with halogen or amino), C.sub.1-5 alkoxy
(where the C.sub.1-5 alkoxy is optionally substituted with
halogen), C.sub.1-5 alkylthio, aminosulfonyl, aminocarbonyl,
C.sub.1-5 alkylaminocarbonyl, and benzyloxycarbonylamino; or a
heteroaryl group selected from the group consisting of quinolinyl,
chromenonyl, indolyl, indolinyl, and benzimidazolyl, wherein the
heteroaryl group may be optionally substituted with one or more
substituents selected from the group consisting of C.sub.1-5 alkyl
(where the C.sub.1-5 alkyl is optionally substituted with halogen)
and acetyl, R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxyl and C.sub.1-5 alkoxy, benzylamino (where the
benzylamino is optionally substituted with halogen), phenylamino,
C.sub.1-5 alkylamino, C.sub.3-6 cycloalkylamino, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; or
a formyl group, R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5
alkyl group optionally substituted with a substituent selected from
the group consisting of amino, C.sub.1-5 alkoxycarbonylamino, and
mono- or di-C.sub.1-5 alkylamino; or a group selected from the
group consisting of the Formulas A, B, D and E, R.sub.4 is
hydrogen, R.sub.5 is a C.sub.1-5 alkyl group, R.sub.6 is a
C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of hydroxy, halogen, C.sub.1-5
alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
R.sub.7 is hydrogen, R.sub.8 and R.sub.9 are, independently each
other, hydrogen; a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of amino,
C.sub.1-5 alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio,
C.sub.3-10 cycloalkyl, phenyl (where the phenyl is optionally
substituted with one or more substituents selected from the group
consisting of hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5
alkylamino, trifluoromethyl, halogen, C.sub.1-5 alkoxy, and
C.sub.1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where
the furanyl is optionally substituted with mono- or di-C.sub.1-5
alkyl), pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
6. The pharmaceutical composition of claim 4 for preventing or
treating a dysfunction in gastrointestinal motility selected from
the group consisting of gastroesophageal reflux disease (GERD),
constipation, irritable bowel syndrome (IBS), dyspepsia,
post-operative ileus, delayed gastric emptying, gastroparesis,
intestinal pseudo-obstruction, drug-induced delayed transit, or
diabetic gastric atony.
7. A compound of Formula 1 or its pharmaceutically acceptable salt:
##STR00021## wherein, R.sub.1 is a phenyl group substituted with
one or more substituents selected from the group consisting of
hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5
alkyl (where the C.sub.1-5 alkyl is optionally substituted with
halogen or amino), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-5
alkoxy (where the C.sub.1-5 alkoxy is optionally substituted with
halogen), C.sub.1-5 alkylthio, mono- or di-C.sub.1-5 alkylamino,
C.sub.1-5 alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino,
C.sub.1-5 alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or a heteroaryl
group selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl,
quinolinonyl, chromenonyl, dihydroindolonyl,
isoindoline-1,3-dionyl, dihydrobenzimidazolonyl, benzoxazolonyl,
benzofuranyl, benzothiophenyl, benzo[d][1,3]dioxolyl,
dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroaryl
group may be optionally substituted with one or more substituents
selected from the group consisting of amino, di-C.sub.1-5
alkylamino, cyano, nitro, halogen, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen), C.sub.1-5
alkoxy (where the C.sub.1-5 alkoxy is optionally substituted with
halogen), acetyl, and C.sub.1-5 alkylsulfonyl, R.sub.2 is hydrogen;
a C.sub.1-5 alkyl group optionally substituted with a substituent
selected from the group consisting of hydroxy, C.sub.1-5 alkoxy,
benzylamino (where the benzylamino is optionally substituted with
halogen), phenylamino, C.sub.1-5 alkylamino, C.sub.3-6
cycloalkylamino, pyrrolidinyl, and hydroxy-C.sub.1-5 alkylamino; a
C.sub.1-5 alkoxycarbonyl group; a hydroxycarbonyl group; an
aminocarbonyl group; a formyl group; or an oxo(.dbd.O) group,
R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy group; a
phenoxy group; a benzyloxy group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1), ##STR00022## R.sub.4 is hydrogen; a hydroxyl group; or a
C.sub.1-5 alkyl group optionally substituted with hydroxy, R.sub.5
is a C.sub.1-5 alkyl group optionally substituted with phenyl; or a
C.sub.2-6 alkenyl group optionally substituted with phenyl or
C.sub.3-6 cycloalkyl, R.sub.6 is a C.sub.1-10 alkyl group
optionally substituted with a substituent selected from the group
consisting of hydroxy, halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5
alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-C.sub.1-5
alkylamino, C.sub.1-5 alkoxy-C.sub.1-5 alkyloxy, phenoxy,
benzyloxy, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
halogen, amino, C.sub.1-5 alkoxy, and hydroxy), thiophenyl,
pyridinyl, indolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group, R.sub.8 and
R.sub.9 are, independently each other, hydrogen; a C.sub.1-10 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, alkoxycarbonylamino, hydroxy, C.sub.1-5
alkylthio, C.sub.3-10 cycloalkyl, phenyl (where the phenyl is
optionally substituted with one or more substituents selected from
the group consisting of hydroxy, C.sub.1-5 alkyl, mono- or
di-C.sub.1-5 alkylamino, trifluoromethyl, halogen, C.sub.1-5
alkoxy, and C.sub.1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl,
furanyl (where the furanyl is optionally substituted with mono- or
alkyl), pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, tetrazolyl, oxazolyl, thiazolyl, and benzyloxy; a
piperidinyl group optionally substituted with benzyl, benzoyl,
C.sub.1-5 alkyl, or C.sub.1-5 alkylcarbonyl; an azetidinyl group
optionally substituted with C.sub.1-5 alkoxycarbonyl; a C.sub.1-5
alkylsulfonyl group; a phenylsulfonyl group (where the phenyl
moiety is optionally substituted with halogen); or a C.sub.3-10
cycloalkyl group.
8. The compound or its pharmaceutically acceptable salt of claim 7,
wherein R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C1-5 alkoxy (where the C.sub.1-5 alkoxy is optionally substituted
with halogen), C.sub.1-5 alkylthio, aminosulfonyl, aminocarbonyl,
C.sub.1-5 alkylaminocarbonyl, and benzyloxycarbonylamino; or a
heteroaryl group selected from the group consisting of quinolinyl,
chromenonyl, indolyl, indolinyl, and benzimidazolyl, wherein the
heteroaryl group may be optionally substituted with one or more
substituents selected from the group consisting of C.sub.1-5 alkyl
(where the C.sub.1-5 alkyl is optionally substituted with halogen)
and acetyl, R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxyl and C.sub.1-5 alkoxy, benzylamino (where the
benzylamino is optionally substituted with halogen), phenylamino,
C.sub.1-5 alkylamino, C.sub.3-6 cycloalkylamino, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; or
a formyl group, R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5
alkyl group optionally substituted with a substituent selected from
the group consisting of amino, C.sub.1-5 alkoxycarbonylamino, and
mono- or di-C.sub.1-5 alkylamino; or a group selected from the
group consisting of the Formulas A, B, D and E, R.sub.4 is
hydrogen, R.sub.5 is a C.sub.1-5 alkyl group, R.sub.6 is a
C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of hydroxy, halogen, C.sub.1-5
alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
R.sub.7 is hydrogen, R.sub.8 and R.sub.9 are, independently each
other, hydrogen; a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of amino,
C.sub.1-5 alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio,
C.sub.3-10 cycloalkyl, phenyl (where the phenyl is optionally
substituted with one or more substituents selected from the group
consisting of hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5
alkylamino, trifluoromethyl, halogen, C.sub.1-5 alkoxy, and
C.sub.1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where
the furanyl is optionally substituted with mono- or di-C.sub.1-5
alkyl), pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
9. The compound or its pharmaceutically acceptable salt of claim 7,
which is selected from the group consisting of:
N-(4-fluorophenyl)-4-propyl-6-(pyrrolidin-1-yl)pyrimidin-2-amine;
(S)-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol;
1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ol;
(R)-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol;
{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl-
}methanol;
N-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidi-
n-2-amine;
(S)--N-(4-fluorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6--
propylpyrimidin-2-amine;
(R)--N-(4-fluorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyri-
midin-2-amine;
(S)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-carbox-
amide;
N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-y-
l}acetamide;
(R)--N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}acetamide;
2,2,2-trifluoro-N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrr-
olidin-3-yl}acetamide;
4-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin-2--
amine;
4-[3-(dimethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyr-
imidin-2-amine;
(S)--N-(4-fluorophenyl)-4-propyl-6-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
-yl]pyrimidin-2-amine;
(S)--N-(4-fluorophenyl)-4-{2-[(phenylamino)methyl]pyrrolidin-1-yl}-6-prop-
ylpyrimidin-2-amine;
(S)--N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}acetamide;
(S)-4-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidi-
n-2-amine; (S)-tert-butyl
1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamat-
e;
4-(3-aminopyrrolidin-1-yl)-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine-
;
4-[3-(diethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin-
-2-amine;
(S)--N-(4-fluorophenyl)-4-[3-(methylamino)pyrrolidin-1-yl]-6-pro-
pylpyrimidin-2-amine;
N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-N-m-
ethylacetamide;
(S)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ol;
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-i-
ndol-6-amine;
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-i-
ndol-5-amine;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(4-methoxyphenyl)-6-propylpyri-
midin-2-amine;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(3-methoxyphenyl)-6-propylpyri-
midin-2-amine;
(S)--N-(3-chlorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyri-
midin-2-amine;
(S)--N-(4-fluoro-3-nitrophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-pr-
opylpyrimidin-2-amine;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-propylpyrimi-
din-2-amine;
(S)--N-(4-chloro-3-nitrophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-pr-
opylpyrimidin-2-amine;
(S)-3-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-[3-(methylthio)phenyl]-6-propy-
lpyrimidin-2-amine;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propyl-N-[3-(trifluoromethyl)p-
henyl]pyrimidin-2-amine;
(S)-7-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
4-methyl-2H-chromen-2-one;
(S)--N-(5-chloro-2-methylphenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-p-
ropylpyrimidin-2-amine;
(S)--N-(3-chloro-4-methylphenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-p-
ropylpyrimidin-2-amine;
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine;
(S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[2-(methoxymethyl)pyrrolidi-
n-1-yl]-6-propylpyrimidin-2-amine;
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-3-(trifluoromethyl)benzene-1,4-diamine;
(S)-2-fluoro-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile;
(S)-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
2-methylbenzonitrile;
(S)-2-amino-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile;
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-3-nitrobenzene-1,4-diamine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluorophenyl)-6-propylpyrimidin-2-ami-
ne; (S)-tert-butyl
1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamate-
;
3-{4-[3-(diethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benzo-
nitrile;
(S)-3-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-N-me-
thylacetamide;
(S)-3-[4-(3-hydroxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile;
(R)-3-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzon-
itrile;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide;
(S)-3-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benz-
onitrile; (R)-tert-butyl
{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}methylc-
arbamate;
(R)-3-[4-(3-hydroxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-
benzonitrile;
(S)-3-[4-(3-methoxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile;
3-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile;
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]b-
enzonitrile;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
butyramide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
cyclopentanecarboxamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(piperidin-1-yl)propanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
benzamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}-4-fluorobenzamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-phenylacetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(4-fluorophenyl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-phenoxypropanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-isobutoxypropanamide;
(S)-2-(4-benzylpiperazin-1-yl)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrim-
idin-4-yl]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(piperidin-1-yl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-oxo-4-phenylbutanamide;
(S)-2-(4-aminophenyl)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl-
]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-cyclopentylacetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-methoxyacetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-2-yl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-3-yl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-4-yl)acetamide;
(S,E)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}-4-phenylbut-3-enamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(thiophen-2-yl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
isobutyramide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3,3,3-trifluoropropanamide;
3-[4-(2-oxopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile;
(S)-3-{4-[3-(hexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benz-
onitrile;
(S)-3-{4-propyl-6-[3-(propylamino)pyrrolidin-1-yl]pyrimidin-2-yl-
amino}benzonitrile;
(S)-3-{4-[3-(cyclohexylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile;
(S)-3-{4-[3-(benzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile;
(S)-3-{4-[3-(phenethylamino)pyrrolidin-1-yl]-6-propylpyrimidin--
2-ylamino}benzonitrile;
(S)-3-{4-[3-(3-phenylpropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)-3-{4-[3-(3-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)-3-{4-[3-(4-hydroxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile;
(S)-3-{4-[3-(4-ethylbenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile;
(S)-3-{4-[3-(isopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile;
(S)-3-{4-[3-(pentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile;
3-{4-[(3S)-3-(2-methylbutylamino)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-ylamino}benzonitrile;
(S)-3-{4-[3-(isobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile;
(S)-3-{4-[3-(4-methoxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile;
(S)-3-{4-[3-(4-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)-3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile;
(S)-3-(4-{3-[bis(cyclopropylmethyl)amino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile;
(S)-3-{4-propyl-6-[3-(pyridin-2-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile;
(S)-3-{4-propyl-6-[3-(pyridin-3-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile;
(S)-3-{4-propyl-6-[3-(pyridin-4-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile;
(S)-3-{4-[3-(2-ethylbutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}benzonitrile;
(S)-3-{4-[3-(neopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile;
(S)-3-{4-[3-(2-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)-3-(4-propyl-6-{3-[3-(trifluoromethyl)benzylamino]pyrrolidin-1-yl}pyri-
midin-2-ylamino)benzonitrile;
(S)-3-(4-propyl-6-{3-[4-(trifluoromethyl)benzylamino]pyrrolidin-1-yl}pyri-
midin-2-ylamino)benzonitrile;
(S)-4-({1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yla-
mino}methyl)phenylacetate;
(S)-3-(4-{3-[4-(dimethylamino)benzylamino]pyrrolidin-1-yl}-6-propylpyrimi-
din-2-ylamino)benzonitrile;
(S)-3-(4-{3-[(1H-pyrrol-2-yl)methylamino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile;
(S)-3-{4-propyl-6-[3-(thiophen-2-ylmethylamino)pyrrolidin-1-yl]pyrimidin--
2-ylamino}benzonitrile;
(S)-3-{4-propyl-6-[3-(thiophen-3-ylmethylamino)pyrrolidin-1-yl]pyrimidin--
2-ylamino}benzonitrile;
(S)-3-{4-[3-(dibutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}be-
nzonitrile;
(S)-3-(4-{3-bis[3-(methylthio)propyl]aminopyrrolidin-1-yl}-6-propylpyrimi-
din-2-ylamino)benzonitrile;
(S)-3-{4-[3-(butylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benz-
onitrile;
(S)-3-(4-{3-[3-(methylthio)propylamino]pyrrolidin-1-yl}-6-propyl-
pyrimidin-2-ylamino)benzonitrile;
(S)--N-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-ind-
ol-6-amine;
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
3-(trifluoromethyl)benzene-1,4-diamine;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
isopropane-2-sulfonamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
methanesulfonamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-fluorobenzenesulfonamide;
3-{4-[(3S)-3-(sec-butylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile;
(S)-3-{4-[3-(pentan-3-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile;
(S)-3-{4-[3-(2,6-dimethylheptan-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile;
(S)-3-{4-[3-(4,4-dimethylpentan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile;
(S)-3-{4-[3-(3-hydroxy-3-methylbutan-2-ylamino)pyrrolidin-1-yl]-6-propylp-
yrimidin-2-ylamino}benzonitrile;
(S)-3-{4-[3-(heptan-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile;
(S)-3-{4-[3-(n-hexan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}benzonitrile;
(S)-3-{4-[3-(5-methylhexan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-
-ylamino}benzonitrile;
(S)-3-{4-[3-(cyclohexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; (S)-tert-butyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
ethylcarbamate;
(S)-3-{4-[3-(1-benzylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimid-
in-2-ylamino}benzonitrile;
(S)-3-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile;
(S)-3-{4-[3-(1-benzoylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile;
(S)-3-{4-[3-(1-acetylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimid-
in-2-ylamino}benzonitrile;
(S)-3-{4-[3-(cyclooctylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile;
(S)-3-{4-[3-(cyclobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile;
(S)-3-{4-[3-(cyclopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile; (S)-tert-butyl
3-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
azetidine-1-carboxylate;
(S)-3-(4-{3-[2-(benzyloxy)ethylamino]pyrrolidin-1-yl}-6-propylpyrimidin-2-
-ylamino)benzonitrile;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
propionamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
pivalamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2,2-dimethylbutanamide;
(S,E)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}-2-methylbut-2-enamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
hexanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-phenylpropanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(1H-indol-3-yl)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-hydroxy-2-methylpropanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(4-methoxyphenyl)propanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(4-hydroxyphenyl)propanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-oxopentanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-hydroxyacetamide;
(S)-2-benzyloxy-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrro-
lidin-3-yl}acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-phenoxyacetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(dimethylamino)acetamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(dimethylamino)propanamide;
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-dimethylaminobutanamide;
N--(S)-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-ethoxyacetamide;
N--(S)-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(2-methoxyethoxyl)acetamide; (S)-benzyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
-2-oxoethylcarbamate; (S)-tert-butyl
3-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
-3-oxobutylcarbamate; (S)-tert-butyl
4-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbam-
oyl}pipendine-1-carboxylate;
(R)-2-methyl-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]b-
enzonitrile;
(R)-2-amino-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]be-
nzonitrile;
(S)-2-methyl-5-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile;
(S)-5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-2-m-
ethylbenzonitrile;
5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-2-methy-
lbenzonitrile;
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
3-nitrobenzene-1,4-diamine;
(S)--N.sup.1-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-3-
-nitrobenzene-1,4-diamine;
(R)-3-{4-[3-(aminomethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile;
(S)-2-fluoro-5-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyri-
midin-2-ylamino}benzonitrile;
(S)-2-fluoro-5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-fluorobenzon-
itrile;
N-(4-fluorophenyl)-4-methyl-6-(pyrrolidin-1-yl)pyrimidin-2-amine;
(3R,5S)-1-[2-(4-fluorophenyl)-6-propylpyrimidin-4-yl]-5-(hydroxymethyl)py-
rrolidin-3-ol;
(S)-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(R)-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2--
yl}methanol;
{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}methano-
l;
(R)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-
-indol-6-amine;
N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
(S)-methyl
1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidine-2-carboxylat-
e;
N-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}ace-
tamide;
(S)-3-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile;
(S)-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}pyrrolidin-2-
-yl)methanol;
(S)-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol;
(S)-{1-[2-(1H-indol-5-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(S)-{1-[2-(1H-benzo[d]imidazol-5-ylamino)-6-propylpyrimidin-4-yl]py-
rrolidin-2-yl}methanol;
(S)-(1-{6-propyl-2-[2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylamino]pyr-
imidin-4-yl}pyrrolidin-2-yl)methanol;
(S)-{1-[2-(4-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}m-
ethanol;
(S)-{1-[2-(3-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol;
(S)-{1-[2-(3-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}m-
ethanol;
(S)-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-4-yl-
}pyrrolidin-2-yl)methanol;
(S)-{1-[2-(5-chloro-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-2-yl}methanol;
(S)-{1-[2-(5-methoxy-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-2-yl}methanol;
(S)-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-2-yl}methanol;
(S)-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(S)-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrr-
olidin-2-yl}methanol;
(S)-{1-[6-propyl-2-(quinolin-6-ylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(S)-{1-[2-(4-methyl-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrr-
olidin-2-yl}methanol;
(S)-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-yl-
}pyrrolidin-2-yl)methanol;
(S)-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
2-yl}methanol;
(S)-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
2-methylbenzonitrile;
(S)-2-fluoro-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile;
(S)-2-amino-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile;
(S)-{1-[6-propyl-2-(quinolin-3-ylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(S)-{1-[2-(indolin-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-y-
l}methanol;
(S)-3-{4-[3-(aminoethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile;
(S)-3-{4-[3-(piperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)-3-{4-[3-(1-butylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidi-
n-2-ylamino}benzonitrile;
(S)--N-{1-[6-butyl-2-(3-cyanophenylamino)pyrimidin-4-yl]pyrrolidin-3-yl}a-
cetamide;
(S)-3-{4-butyl-6-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-2-y-
lamino}benzonitrile;
(R)-3-[4-butyl-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-ylamino]benzonitril-
e;
(S)-3-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}be-
nzonitrile; (S)-tert-butyl
1-[6-butyl-2-(3-cyanophenylamino)pyrimidin-4-yl]pyrrolidin-3-ylcarbamate;
(S)--N-{1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)-5-{4-butyl-6-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-
-methylbenzonitrile;
(R)-5-[4-butyl-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-ylamino]-2-methylbe-
nzonitrile;
(S)-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-m-
ethylbenzonitrile; (S)-tert-butyl
1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]pyrrolidin-3-ylc-
arbamate;
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]ben-
zonitrile;
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]-2-
-methylbenzonitrile;
(S)-3-{4-butyl-6-[3-(isopropylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}b-
enzonitrile;
(S)-3-{4-butyl-6-[3-(diethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}ben-
zonitrile;
(S)-3-{4-butyl-6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyr-
imidin-2-ylamino}benzonitrile;
(S)-5-{4-butyl-6-[3-(isopropylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}--
2-methyl benzonitrile;
(S)-5-{4-butyl-6-[3-(diethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2--
methyl benzonitrile;
(S)-5-{4-butyl-6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyrimidin-2-y-
lamino}-2-methylbenzonitrile;
(S)--N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide;
(S)--N-(1-{2-[3-(methylthio)phenylamino]-6-propyl
pyrimidin-4-yl}pyrrolidin-3-yl)acetamide;
(S)--N-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide;
(S)--N-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-
-4-yl}pyrrolidin-3-yl)acetamide;
(S)--N-{1-[2-(4-methyl-2-oxo-2H-chromen-7-ylamino)-6-propylpyrimidin-4-yl-
]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(3-chloro-4-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide;
(S)--N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4--
yl]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(4-methyl-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; (S)-benzyl
5-[4-(3-acetamidopyrrolidin-1-yl)-6-propyl
pyrimidin-2-ylamino]-2-methoxyphenylcarbamate;
(S)--N-{1-[2-(3-cyano-4-fluorophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide;
(S)--N-(1-{2-[4-fluoro-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin--
4-yl}pyrrolidin-3-yl)acetamide;
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(5-chloro-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}acetamide;
(S)-3-[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzami-
de;
(S)-3-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-N-
-methylbenzamide;
(S)--N-[1-(2-{[3-(aminomethyl)phenyl]amino}-6-propylpyrimidin-4-yl)pyrrol-
idin-3-yl]acetamide;
(S)-3-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-4-ch-
lorobenzamide;
(S)--N-{1-[2-(4-amino-3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide;
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide;
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide;
(S)--N-(1-{2-[(4-aminophenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidin-3-y-
l)acetamide;
(S)--N-(1-{2-[(4-chloro-3-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)-4-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-2-hy-
droxybenzoic acid;
(S)-5-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-2-hy-
droxybenzoic acid;
(S)--N-(1-{2-[(3-hydroxy-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)--N-(1-{2-[(3-chloro-4-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)--N-(1-{2-[(4-hydroxy-3-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)--N-(1-{2-[(3-fluoro-4-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)--N-(1-{2-[(3-hydroxy-4-methoxyphenyl)amino]-6-propylpyrimidin-4-yl}py-
rrolidin-3-yl)acetamide;
(S)--N-(1-{2-[(3-methoxy-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide;
(S)--N-[1-(2-{[4-methyl-3-(trifluoromethyl)phenyl]amino}-6-propylpyrimidi-
n-4-yl)pyrrolidin-3-yl]acetamide;
(S)--N-(1-{2-[(3,4-dimethylphenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidi-
n-3-yl)acetamide;
(S)--N-(1-{2-[(3-fluoro-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyrr-
olidin-3-yl)acetamide;
(S)--N-{1-[2-(3-amino-4-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide;
N-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3--
yl}acetamide
N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide;
N-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide;
N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]py-
rrolidin-3-yl}acetamide;
N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide;
N-{1-[2-(3-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}ace-
tamide;
N-{1-[2-(5-methoxy-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyr-
rolidin-3-yl}acetamide;
N-{1-[2-(4-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}ace-
tamide;
N-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-4-yl}py-
rrolidin-3-yl)acetamide;
N-{1-[2-(3-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}acet-
amide;
N-{1-[2-(5-chloro-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrro-
lidin-3-yl}acetamide;
N-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
3-yl}acetamide;
N-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}pyrrolidin-3-y-
l)acetamide;
N-{1-[2-(1H-indol-5-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide;
N-(1-{6-propyl-2-[2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylamino]-
pyrimidin-4-yl}pyrrolidin-3-yl)acetamide;
N-{1-[6-propyl-2-(quinolin-6-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide;
N-{1-[2-(4-methyl-2-oxo-2H-chromen-7-ylamino)-6-propylpyrimidin-4-yl-
]pyrrolidin-3-yl}acetamide;
N-{1-[6-propyl-2-(quinolin-3-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide;
N-{1-[2-(4-amino-3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide;
(R)--N-(4-chloro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine;
(R)-4-(2-methylpyrrolidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidi-
n-2-ylamine;
(R)--N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-am-
ine;
(R)-4-(2-methylpyrrolidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl-
]pyrimidin-2-amine;
(R)-4-methyl-7-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]--
2H-chromen-2-one;
(R)--N-(3-chloro-4-methylphenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyri-
midin-2-amine;
(R)-4-(2-methylpyrrolidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-yla-
mine;
(R)--N-(4-fluoro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propyl-
pyrimidin-2-amine;
(R)--N-(4-methyl-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine;
(R)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-(2-methylpyrrolidin-1-yl)-6-
-propylpyrimidin-2-ylamine;
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-(trif-
luoromethyl)benzene-1,4-diamine; (R)-benzyl
2-methoxy-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]phen-
ylcarbamate;
(R)-2-fluoro-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]b-
enzonitrile;
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-nitro-
benzene-1,4-diamine;
(R)-1-{6-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]indolin-
-1-yl}ethanone;
(R)--N-(5-chloro-2-methylphenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyri-
midin-2-amine;
(R)-4-methoxy-N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl-
]benzene-1,3-diamine;
(R)-4-chloro-N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]benzen-
e-1,3-diamine;
(R)-4-fluoro-N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]benzen-
e-1,3-diamine;
(R)-4-methyl-N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-
benzene-1,3-diamine;
(S)-3-{4-[3-(2-hydroxyethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile;
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide;
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3-
-nitrobenzene-1,4-diamine;
(S)--N-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-5-(trifluorome-
thyl)benzene-1,3-diamine;
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-methyl-
benzene-1,4-diamine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-chloro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidin-
-2-amine;
(S)--N-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-in-
dol-6-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl]pyri-
midin-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(5-chloro-2-methylphenyl)-6-propylpyrimi-
din-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-chloro-4-methylphenyl)-6-propylpyrimi-
din-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-amin-
e;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-methyl-3-nitrophenyl)-6-propylpyrim-
idin-2-amine;
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-(trifl-
uoromethyl)benzene-1,4-diamine;
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-fluorobe-
nzonitrile;
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile;
(S)-2-amino-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]ben-
zonitrile; (S)-benzyl
5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methoxypheny-
lcarbamate;
(S)-4-(3-aminopyrrolidin-1-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-p-
ropylpyrimidin-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine;
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-nitrob-
enzene-1,4-diamine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]-6-propy-
lpyrimidin-2-amine;
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3,5-dimethoxyphenyl)-6-propylpyrimidin--
2-amine;
(S)-3-amino-5-{[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}b-
enzonitrile;
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzenesulf-
onamide;
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-yl}benzene-1,3-diamine;
(S)-4-fluoro-N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-yl}benzene-1,3-diamine;
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-4-methylbenzene-1,3-diamine;
(S)-4-methoxy-N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}benzene-1,3-diamine;
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}indol-
in-6-amine;
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-methyl-
benzene-1,3-diamine;
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-fluoro-
benzene-1,3-diamine;
(S)--N-(4-chloro-3-nitrophenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-
-yl]-6-propylpyrimidin-2-amine;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-fluoro-3-nitrophen-
yl)-6-propylpyrimidin-2-amine;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophen-
yl)-6-propylpyrimidin-2-amine;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine;
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-fluorobenzonitrile;
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-methylbenzonitrile;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-[3-(methylthio)phenyl-
]-6-propylpyrimidin-2-amine;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propyl-N-[3-(trifluor-
omethyl)phenyl]pyrimidin-2-amine;
(S)--N-(5-chloro-2-methylphenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine;
(S)--N-(3-chloro-4-methylphenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine;
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluor-
omethyl)phenyl]-6-propylpyrimidin-2-amine;
(S)--N.sup.1-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}-4-methylbenzene-1,3-diamine;
(S)--N.sup.1-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}benzene-1,3-diamine;
3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile;
(S)-{1-[6-ethyl-2-(4-fluorophenylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol;
(S)--N-{1-[6-ethyl-2-(4-fluorophenylamino)pyrimidin-4-yl]pyrrolidin-
-3-yl}acetamide;
(S)-4-ethyl-N-(4-fluorophenyl)-6-(2-methoxymethylpyrrolidin-1-yl)pyrimidi-
n-2-amine;
4-ethyl-N-(4-fluorophenyl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-
-2-amine;
(S)-4-ethyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-
pyrimidin-2-amine;
(S)-3-[4-(3-phenoxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile;
(S)-2-amino-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrro-
lidin-3-yl}acetamide;
(S)-{1-[2-(3-amino-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol;
(S)-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol;
(S)-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol;
(S)-3-[4-(2-formylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitri-
le;
(S)-3-(4-{2-[(methylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidin-2--
ylamino)benzonitrile;
(S)-3-(4-{2-[(cyclobutylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidin-2-
-ylamino)benzonitrile;
(S)-3-(4-{2[(4-fluorobenzylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidi-
n-2-ylamino)benzonitrile;
(S)-3-(4-propyl-6-{2-[(propylamino)methyl]pyrrolidin-1-yl}pyrimidin-2-yla-
mino)benzonitrile;
(S)-3-(4-{2-[(2-hydroxyethylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile;
(S)-2-methyl-5-{4-propyl-6-[3-(propylamino)pyrrolidin-1-yl]pyrimidin-2-yl-
amino}benzonitrile;
(S)-2-methyl-5-(4-{3-[3-(methylthio)propylamino]pyrrolidin-1-yl}-6-propyl-
pyrimidin-2-ylamino)benzonitrile;
(S)-5-(4-{3-[(1H-pyrrol-2-yl)methylamino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)-2-methylbenzonitrile;
(S)-5-{4-[3-(4-hydroxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}-2-methylbenzonitrile;
(S)-5-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
-2-methylbenzonitrile;
(S)-5-{4-[3-(cyclobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}-2-methylbenzonitrile;
(S)-5-{4-[3-(cyclopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}-2-methylbenzonitrile;
(S)-5-{4-[3-(cyclohexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}-2-methylbenzonitrile;
(S)-2-methyl-5-{4-[3-(pentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile;
(S)-2-methyl-5-{4-[3-(neopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-
-ylamino}benzonitrile;
(S)-5-(4-{3-[(4,5-dimethylfuran-2-yl)methylamino]pyrrolidin-1-yl}-6-propy-
lpyrimidin-2-ylamino)-2-methylbenzonitrile;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}propionamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-phenylacetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(piperidin-1-yl)acetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(pyridin-3-yl)acetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(pyridin-4-yl)acetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(thiophen-2-yl)acetamide;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}methanesulfonamide;
(S)-1-(1-{2-[(3-cyano-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyrrol-
idin-3-yl)-3-ethylurea;
(R)-3-(4-{3-[(diethylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidin-2-yl-
amino)benzonitrile;
(S)--N-{1-[6-butyl-2-(4-methyl-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[6-butyl-2-(4-fluoro-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[6-butyl-2-(4-chloro-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide;
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-butylpyrimidin-4--
yl}pyrrolidin-3-yl)acetamide;
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-butylpyrimidin-4--
yl}pyrrolidin-3-yl)acetamide;
(S)--N-(1-{6-butyl-2-[4-fluoro-3-(trifluoromethyl)phenylamino]pyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide;
(S)--N-{1-[6-butyl-2-(3-cyano-4-fluorophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-butylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-butylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide;
(S)--N-{1-[2-(4-amino-3-cyanophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide;
(S)-2-amino-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylam-
ino}benzonitrile;
(S)-4-butyl-N-(4-methyl-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine;
(S)-4-butyl-N-(4-fluoro-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine;
(S)-4-butyl-N-(4-chloro-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine;
(S)-3-amino-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylam-
ino}benzonitrile;
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-5-
-(trifluoromethyl)benzene-1,3-diamine;
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3-
-(trifluoromethyl)benzene-1,4-diamine;
(S)-4-butyl-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-[3-(methylamino)pyrr-
olidin-1-yl]pyrimidin-2-amine;
(S)-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-f-
luorobenzonitrile;
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4-
-fluorobenzene-1,3-diamine;
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4-
-chlorobenzene-1,3-diamine;
(S)-2-amino-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}benzonitrile;
(S)-3-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}benzo-
nitrile;
(S)-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}-2-methylbenzonitrile;
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3--
nitrobenzene-1,4-diamine;
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophenyl)p-
yrimidin-2-amine;
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluoro-3-nitrophenyl)p-
yrimidin-2-amine;
(S)-4-butyl-N-(4-chloro-3-nitrophenyl)-6-[3-(ethylamino)pyrrolidin-1-yl]p-
yrimidin-2-amine;
(S)-3-amino-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}benzonitrile;
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-5--
(trifluoromethyl)benzene-1,3-diamine;
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3--
(trifluoromethyl)benzene-1,4-diamine;
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluoromet-
hyl)phenyl]pyrimidin-2-amine;
(S)-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-fl-
uorobenzonitrile;
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4--
fluorobenzene-1,3-diamine;
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4--
chlorobenzene-1,3-diamine;
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide;
(S)--N-{1-[2-(3-cyano-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide;
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}-2-hydroxyacetamide;
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)-2-hydroxyacetamide;
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)-2-hydroxyacetamide;
(S)--N-(1-{2-[4-fluoro-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin--
4-yl}pyrrolidin-3-yl)-2-hydroxyacetamide;
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide;
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide;
(S)--N-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}-2-hydroxyacetamide;
(S)-2-hydroxy-N-(1-{2-[4-methyl-3-(trifluoromethyl)phenylamino]-6-propylp-
yrimidin-4-yl}pyrrolidin-3-yl)acetamide;
(S)-4-fluoro-N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidi-
n-2-yl}benzene-1,3-diamine;
(S)-3-amino-5-({4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}amino)benzonitrile;
(S)-2-amino-5-({4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}amino)benzonitrile;
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
5-(trifluoromethyl)benzene-1,3-diamine;
(S)--N.sup.1-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-3-
-(trifluoromethyl)benzene-1,4-diamine;
(S)-2-amino-5-({4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-
amino)benzonitrile;
(S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[3-(methylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine;
(S)-4-[3-(ethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluoromethyl)phen-
yl]-6-propylpyrimidin-2-amine; and
(S)--N-(1-{2-[(3,4-diaminophenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidin-
-3-yl)acetamide.
10-15. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel 5-HT.sub.4 receptor
agonist, more specifically a novel diaminopyrimidine derivative or
its pharmaceutically acceptable salt having an activity as a
5-HT.sub.4 receptor agonist, a process for the preparation thereof,
a pharmaceutical composition comprising the same, and a use
thereof.
BACKGROUND ART
[0002] Serotonin (5-hydroxytryptamine, 5-HT), one of the
neurotransmitters, is broadly distributed throughout human body
including both the central nervous system and the peripheral
nervous system. Approximately 95% of the human body's total
serotonin is found in the gastrointestinal tract, while about 5%
thereof is found in the brain. Serotonin receptors are located in
intestinal nerves, enterochromaffin cells, intestinal smooth
muscle, immune tissues, etc. Serotonin receptor subtypes include
5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5,
5-HT.sub.6, and 5-HT.sub.7. Interactions between these various
receptors and serotonin are linked to various physiological
functions. Therefore, various researches have been performed for
developing therapeutic agents that are capable of interacting with
a specific serotonin subtype as a target. The researches include
identification of 5-HT.sub.4 receptors and active agents
interacting therewith (Langlois and Fischmeister, J. Med. Chem.
2003, 46, 319-344).
[0003] It has been found by the previous literatures that
5-HT.sub.4 receptor agonists are useful for treating an abnormal
gastrointestinal motility, i.e., dysfunction in gastrointestinal
motility. The abnormal gastrointestinal motility may result in
various disorders, for example irritable bowel syndrome (IBS),
constipation, dyspepsia, delayed gastric emptying, gastroesophageal
reflux disease (GERD), gastroparesis, post-operative ileus,
intestinal pseudo-obstruction, drug-induced delayed transit,
etc.
[0004] Representative 5-HT.sub.4 receptor agonists disclosed in
prior arts include tegaserod (an aminoguanidine derivative, U.S.
Pat. No. 5,510,353), prucalopride (a benzofuran carboxamide
derivative, EP0445862), cisapride (a benzamide derivative, U.S.
Pat. No. 4,962,115), mosapride (EP0243959), etc. These compounds
are known as an agent stimulating gastrointestinal motility.
DETAILED DESCRIPTION OF THE INVENTION
Technical Problem
[0005] The present inventors found that a certain diaminopyrimidine
derivative functions as a 5-HT.sub.4 receptor agonist, and
therefore can be usefully applied for preventing or treating
dysfunction in gastrointestinal motility.
[0006] Therefore, the present invention provides the above
diaminopyrimidine derivative or its pharmaceutically acceptable
salt, a process for the preparation thereof, a pharmaceutical
composition comprising the same, and a use thereof.
Technical Solution
[0007] According to an aspect of the present invention, there is
provided a use of a diaminopyrimidine derivative or its
pharmaceutically acceptable salt for the manufacture of a
medicament for preventing or treating a dysfunction in
gastrointestinal motility
[0008] According to another aspect of the present invention, there
is provided a pharmaceutical composition for preventing or treating
a dysfunction in gastrointestinal motility comprising a
diaminopyrimidine derivative or its pharmaceutically acceptable
salt as an active ingredient.
[0009] According to still another aspect of the present invention,
there is provided a diaminopyrimidine derivative or its
pharmaceutically acceptable salt.
[0010] According to still another aspect of the present invention,
there is provided a process for preparing the diaminopyrimidine
derivative or its pharmaceutically acceptable salt.
Advantageous Effects
[0011] The compound of the present invention, i.e., the
diaminopyrimidine derivative or its pharmaceutically acceptable
salt, functions as a 5-HT.sub.4 receptor agonist, and therefore can
be usefully applied for preventing or treating dysfunction in
gastrointestinal motility, one of the gastrointestinal diseases,
such as gastroesophageal reflux disease (GERD), constipation,
irritable bowel syndrome (IBS), dyspepsia, post-operative ileus,
delayed gastric emptying, gastroparesis, intestinal
pseudo-obstruction, drug-induced delayed transit, or diabetic
gastric atony.
BEST MODE FOR CARRYING OUT THE INVENTION
[0012] As used herein, the term "alkyl" refers to a straight or
branched aliphatic hydrocarbon radical. For example,
C.sub.1-C.sub.6 alkyl means a straight or branched aliphatic
hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl,
propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl,
tert-butyl, neopentyl, and isopentyl.
[0013] The term "alkoxy or alkyloxy" refers to a radical formed by
substituting the hydrogen atom of a hydroxyl group with an alkyl.
For example, C.sub.1-C.sub.6 alkoxy includes methoxy, ethoxy,
propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy,
tert-butoxy, neopentyloxy, and isopentyloxy.
[0014] The term "alkenyl" refers to a straight or branched
aliphatic hydrocarbon radical having one or more double bond(s).
For example, C.sub.2-C.sub.6 alkenyl includes ethenyl, propenyl,
butenyl, pentenyl, and hexenyl.
[0015] The term "alkynyl" refers to a straight or branched
aliphatic hydrocarbon radical having one or more triple bond(s).
For example, C.sub.2-C.sub.6 alkynyl includes ethynyl, propynyl,
butynyl, pentynyl, and hexynyl.
[0016] The present invention provides a use of a compound of
Formula 1 or its pharmaceutically acceptable salt for the
manufacture of a medicament for preventing or treating a
dysfunction in gastrointestinal motility:
[0017] <Formula 1>
##STR00001##
[0018] wherein,
[0019] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy (where the
C.sub.1-5 alkoxy is optionally substituted with halogen), C.sub.1-5
alkylthio, mono- or di-C.sub.1-5 alkylamino, C.sub.1-6
alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino, C.sub.1-5
alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or
[0020] a heteroaryl group selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl,
naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl,
dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzoimidazolonyl,
benzoxazolonyl, benzofuranyl, benzothiophenyl,
benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl,
indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and
indazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of amino, di-C.sub.1-5 alkylamino, cyano, nitro,
halogen, C.sub.1-6 alkyl (where the C.sub.1-5 alkyl is optionally
substituted with halogen), C.sub.1-5 alkoxy (where the C.sub.1-5
alkoxy is optionally substituted with halogen), acetyl, and
C.sub.1-5 alkylsulfonyl,
[0021] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxy, C.sub.1-5 alkoxy, benzylamino (where the benzylamino is
optionally substituted with halogen), phenylamino, C.sub.1-5
alkylamino, C.sub.3-6 cycloalkylamino, pyrrolidinyl, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; a
hydroxycarbonyl group; an aminocarbonyl group; a formyl group; or
an oxo(.dbd.O) group,
[0022] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy
group; a phenoxy group; a benzyloxy group; a C.sub.1-6 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1),
##STR00002##
[0023] R.sub.4 is hydrogen; a hydroxyl group; or a C.sub.1-5 alkyl
group optionally substituted with hydroxy,
[0024] R.sub.5 is a C.sub.1-5 alkyl group optionally substituted
with phenyl; or a C.sub.2-6 alkenyl group optionally substituted
with phenyl or C.sub.3-6 cycloalkyl,
[0025] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, piperidinyl, piperazinyl (where the piperazinyl
is optionally substituted with benzyl), C.sub.3-6 cycloalkyl,
acetyl, and benzoyl; a C.sub.3-6 cycloalkyl group; a piperidinyl
group optionally substituted with C.sub.1-5 alkoxycarbonyl; a
C.sub.1-10 alkenyl group optionally substituted with phenyl; a
trifluoromethyl group; a trifluoroethyl group; or a phenyl group
optionally substituted with halogen,
[0026] R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group,
[0027] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, alkoxycarbonylamino,
hydroxy, C.sub.1-5 alkylthio, C.sub.3-10 cycloalkyl, phenyl (where
the phenyl is optionally substituted with one or more substituents
selected from the group consisting of hydroxy, C.sub.1-5 alkyl,
mono- or di-C.sub.1-5 alkylamino, trifluoromethyl, halogen,
C.sub.1-5 alkoxy, and C.sub.1-5 alkylcarbonyloxy), thiophenyl,
pyrrolyl, furanyl (where the furanyl is optionally substituted with
mono- or alkyl), pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, and
benzyloxy; a piperidinyl group optionally substituted with benzyl,
benzoyl, C.sub.1-5 alkyl, or C.sub.1-5 alkylcarbonyl; an azetidinyl
group optionally substituted with C.sub.1-5 alkoxycarbonyl; a
alkylsulfonyl group; a phenylsulfonyl group (where the phenyl
moiety is optionally substituted with halogen); or a C.sub.3-10
cycloalkyl group.
[0028] In the use for the manufacture of a medicament for
preventing or treating a dysfunction in gastrointestinal motility
according to the present invention, the dysfunction in
gastrointestinal motility includes gastrointestinal diseases, such
as gastroesophageal reflux disease (GERD), constipation, irritable
bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed
gastric emptying, gastroparesis, intestinal pseudo-obstruction,
drug-induced delayed transit, or diabetic gastric atony. The
constipation includes chronic constipation, chronic idiopathic
constipation (CIC), opioid-induced constipation (OIC), etc. And
also, the dyspepsia includes functional dyspepsia.
[0029] In the use for the manufacture of a medicament for
preventing or treating a dysfunction in gastrointestinal motility
according to the present invention, the compound or its salt may be
the compound of Formula 1 or its pharmaceutically acceptable salt
wherein,
[0030] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.1-5 alkoxy (where the C.sub.1-5 alkoxy is optionally
substituted with halogen), C.sub.1-5 alkylthio, aminosulfonyl,
aminocarbonyl, C.sub.1-5 alkylaminocarbonyl, and
benzyloxycarbonylamino; or a heteroaryl group selected from the
group consisting of quinolinyl, chromenonyl, indolyl, indolinyl,
and benzimidazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is
optionally substituted with halogen) and acetyl,
[0031] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxy, C.sub.1-5 alkoxy, benzylamino (where the benzylamino is
optionally substituted with halogen), phenylamino, C.sub.1-5
alkylamino, C.sub.3-6 cycloalkylamino, and hydroxy-C.sub.1-5
alkylamino; a C.sub.1-5 alkoxycarbonyl group; or a formyl
group,
[0032] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono-
or di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the Formulas A, B, D and E,
[0033] R.sub.4 is hydrogen,
[0034] R.sub.5 is a C.sub.1-5 alkyl group,
[0035] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
[0036] R.sub.7 is hydrogen,
[0037] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or di-C.sub.1-5 alkyl),
pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
[0038] The present invention also provides a pharmaceutical
composition for preventing or treating a dysfunction in
gastrointestinal motility comprising a therapeutically effective
amount of a compound of Formula 1 or its pharmaceutically
acceptable salt; and a pharmaceutically acceptable carrier:
##STR00003##
[0039] wherein,
[0040] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy (where the
C.sub.1-5 alkoxy is optionally substituted with halogen), C.sub.1-5
alkylthio, mono- or di-C.sub.1-5 alkylamino, C.sub.1-6
alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino, C.sub.1-6
alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or
[0041] a heteroaryl group selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl,
naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl,
dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzimidazolonyl,
benzoxazolonyl, benzofuranyl, benzothiophenyl,
benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl,
indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and
indazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of amino, di-C.sub.1-5 alkylamino, cyano, nitro,
halogen, C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is optionally
substituted with halogen), C.sub.1-5 alkoxy (where the C.sub.1-5
alkoxy is optionally substituted with halogen), acetyl, and
C.sub.1-5 alkylsulfonyl,
[0042] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxy, C.sub.1-5 alkoxy, benzylamino (where the benzylamino is
optionally substituted with halogen), phenylamino, C.sub.1-5
alkylamino, C.sub.3-6 cycloalkylamino, pyrrolidinyl, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; a
hydroxycarbonyl group; an aminocarbonyl group; a formyl group; or
an oxo(.dbd.O) group,
[0043] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy
group; a phenoxy group; a benzyloxy group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1),
##STR00004##
[0044] R.sub.4 is hydrogen; a hydroxyl group; or a C.sub.1-5 alkyl
group optionally substituted with hydroxy,
[0045] R.sub.5 is a C.sub.1-5 alkyl group optionally substituted
with phenyl; or a C.sub.2-6 alkenyl group optionally substituted
with phenyl or C.sub.3-6 cycloalkyl,
[0046] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, piperidinyl, piperazinyl (where the piperazinyl
is optionally substituted with benzyl), C.sub.3-6 cycloalkyl,
acetyl, and benzoyl; a C.sub.3-6 cycloalkyl group; a piperidinyl
group optionally substituted with C.sub.1-5 alkoxycarbonyl; a
C.sub.1-10 alkenyl group optionally substituted with phenyl; a
trifluoromethyl group; a trifluoroethyl group; or a phenyl group
optionally substituted with halogen,
[0047] R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group,
[0048] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or alkyl), pyridinyl,
pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, thiazolyl, and benzyloxy; a piperidinyl group
optionally substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or
C.sub.1-5 alkylcarbonyl; an azetidinyl group optionally substituted
with C.sub.1-5 alkoxycarbonyl; a alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
[0049] In the pharmaceutical composition according to the present
invention, the dysfunction in gastrointestinal motility includes
gastrointestinal diseases, such as gastroesophageal reflux disease
(GERD), constipation, irritable bowel syndrome (IBS), dyspepsia,
post-operative ileus, delayed gastric emptying, gastroparesis,
intestinal pseudo-obstruction, drug-induced delayed transit, or
diabetic gastric atony. The constipation includes chronic
constipation, chronic idiopathic constipation (CIC), opioid-induced
constipation (OIC), etc. And also, the dyspepsia includes
functional dyspepsia.
[0050] In the pharmaceutical composition according to the present
invention, the compound or its salt may be the compound of Formula
1 or its pharmaceutically acceptable salt wherein,
[0051] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.1-5 alkoxy (where the C.sub.1-5 alkoxy is optionally
substituted with halogen), C.sub.1-5 alkylthio, aminosulfonyl,
aminocarbonyl, C.sub.1-5 alkylaminocarbonyl, and
benzyloxycarbonylamino; or a heteroaryl group selected from the
group consisting of quinolinyl, chromenonyl, indolyl, indolinyl,
and benzimidazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is
optionally substituted with halogen) and acetyl,
[0052] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxyl and C.sub.1-5 alkoxy, benzylamino (where the
benzylamino is optionally substituted with halogen), phenylamino,
C.sub.1-5 alkylamino, C.sub.3-6 cycloalkylamino, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; or
a formyl group,
[0053] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono-
or di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the Formulas A, B, D and E,
[0054] R.sub.4 is hydrogen,
[0055] R.sub.5 is a C.sub.1-5 alkyl group,
[0056] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
[0057] R.sub.7 is hydrogen,
[0058] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or di-C.sub.1-5 alkyl),
pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
[0059] The pharmaceutical composition of the present invention may
comprise a pharmaceutically acceptable carrier, such as diluents,
disintegrants, sweeteners, lubricants, or flavoring agents. The
pharmaceutical composition may be formulated to an oral dosage form
such as tablets, capsules, powders, granules, suspensions,
emulsions, or syrups; or a parenteral dosage form such as
injection. The dosage form may be various forms, e.g., dosage forms
for single administration or for multiple administrations.
[0060] The pharmaceutical composition of the present invention may
comprise, for example, a diluent (e.g., lactose, corn starch, etc),
a lubricant (e.g., magnesium stearate), an emulsifying agent, a
suspending agent, a stabilizer, and/or an isotonic agent. If
necessary, the composition further comprises sweeteners and/or
flavoring agents.
[0061] The composition of the present invention may be administered
orally or parenterally, including intravenous, intraperitoneal,
subcutaneous, rectal and topical routes of administration.
Therefore, the composition of the present invention may be
formulated into various forms such as tablets, capsules, aqueous
solutions or suspensions. In the case of tablets for oral
administration, carriers such as lactose, corn starch, and
lubricating agents, e.g. magnesium stearate, are conventionally
used. In the case of capsules for oral administration, lactose
and/or dried corn starch can be used as a diluent. When an aqueous
suspension is required for oral administration, the active
ingredient may be combined with emulsifying and/or suspending
agents. If desired, certain sweetening and/or flavoring agents may
be used. For intramuscular, intraperitoneal, subcutaneous and
intravenous administration, sterile solutions of the active
ingredient are usually prepared, and the pH of the solutions should
be suitably adjusted and buffered. For intravenous administration,
the total concentration of solutes should be controlled in order to
render the preparation isotonic. The composition of the present
invention may be in the form of an aqueous solution containing
pharmaceutically acceptable carriers, e.g., saline having a pH
level of 7.4. The solutions may be introduced into a patient's
intramuscular blood-stream by local bolus injection.
[0062] The compound of Formula 1 or its pharmaceutically acceptable
salt may be administered in a therapeutically effective amount
ranging from about 0.001 mg/kg to about 10 mg/kg per day to a
subject patient. Of course, the dosage may be changed according to
the patient's age, weight, susceptibility, symptom, or activity of
the compound.
[0063] The present invention also provides a method for treating a
dysfunction in gastrointestinal motility, such as gastroesophageal
reflux disease (GERD), constipation, irritable bowel syndrome
(IBS), dyspepsia, post-operative ileus, delayed gastric emptying,
gastroparesis, intestinal pseudo-obstruction, drug-induced delayed
transit, or diabetic gastric atony, in a patient, which comprises
administering a therapeutically effective amount of the compound of
Formula 1 or its pharmaceutically acceptable salt to the patient in
need thereof. The constipation includes chronic constipation,
chronic idiopathic constipation (CIC), opioid-induced constipation
(OIC), etc. And also, the dyspepsia includes functional
dyspepsia.
[0064] The present invention also provides a compound of Formula 1
or its pharmaceutically acceptable salt:
[0065] <Formula 1>
##STR00005##
[0066] wherein,
[0067] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy (where the
C.sub.1-5 alkoxy is optionally substituted with halogen), C.sub.1-5
alkylthio, mono- or di-C.sub.1-5 alkylamino, C.sub.1-6
alkylsulfonylamino, C.sub.1-5 alkylcarbonylamino, C.sub.1-5
alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C.sub.1-5
alkylaminocarbonyl, and benzyloxycarbonylamino; or
[0068] a heteroaryl group selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl,
naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl,
dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzimidazolonyl,
benzoxazolonyl, benzofuranyl, benzothiophenyl,
benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl,
indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and
indazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of amino, di-C.sub.1-5 alkylamino, cyano, nitro,
halogen, C.sub.1-6 alkyl (where the C.sub.1-5 alkyl is optionally
substituted with halogen), C.sub.1-5 alkoxy (where the C.sub.1-5
alkoxy is optionally substituted with halogen), acetyl, and
C.sub.1-5 alkylsulfonyl,
[0069] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxy, C.sub.1-5 alkoxy, benzylamino (where the benzylamino is
optionally substituted with halogen), phenylamino, C.sub.1-5
alkylamino, C.sub.3-6 cycloalkylamino, pyrrolidinyl, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; a
hydroxycarbonyl group; an aminocarbonyl group; a formyl group; or
an oxo(.dbd.O) group,
[0070] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkoxy
group; a phenoxy group; a benzyloxy group; a C.sub.1-5 alkyl group
optionally substituted with a substituent selected from the group
consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono- or
di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the following Formulas A to E (where * in Formulas A
to E represents the position attached to the compounds of Formula
1),
##STR00006##
[0071] R.sub.4 is hydrogen; a hydroxyl group; or a C.sub.1-5 alkyl
group optionally substituted with hydroxy,
[0072] R.sub.5 is a C.sub.1-5 alkyl group optionally substituted
with phenyl; or a C.sub.2-6 alkenyl group optionally substituted
with phenyl or C.sub.3-6 cycloalkyl,
[0073] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, pyrimidinyl,
pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl,
furanyl, pyrrolyl, piperidinyl, piperazinyl (where the piperazinyl
is optionally substituted with benzyl), C.sub.3-6 cycloalkyl,
acetyl, and benzoyl; a C.sub.3-6 cycloalkyl group; a piperidinyl
group optionally substituted with C.sub.1-5 alkoxycarbonyl; a
C.sub.1-10 alkenyl group optionally substituted with phenyl; a
trifluoromethyl group; a trifluoroethyl group; or a phenyl group
optionally substituted with halogen,
[0074] R.sub.7 is hydrogen; or a C.sub.1-5 alkyl group,
[0075] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or alkyl), pyridinyl,
pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, thiazolyl, and benzyloxy; a piperidinyl group
optionally substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or
C.sub.1-5 alkylcarbonyl; an azetidinyl group optionally substituted
with C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
[0076] Preferably, the compound or its salt may be the compound of
Formula 1 or its pharmaceutically acceptable salt wherein,
[0077] R.sub.1 is a phenyl group substituted with one or more
substituents selected from the group consisting of hydroxy, amino,
halogen, cyano, nitro, hydroxycarbonyl, C.sub.1-5 alkyl (where the
C.sub.1-5 alkyl is optionally substituted with halogen or amino),
C.sub.1-5 alkoxy (where the C.sub.1-5 alkoxy is optionally
substituted with halogen), C.sub.1-5 alkylthio, aminosulfonyl,
aminocarbonyl, C.sub.1-5 alkylaminocarbonyl, and
benzyloxycarbonylamino; or a heteroaryl group selected from the
group consisting of quinolinyl, chromenonyl, indolyl, indolinyl,
and benzimidazolyl, wherein the heteroaryl group may be optionally
substituted with one or more substituents selected from the group
consisting of C.sub.1-5 alkyl (where the C.sub.1-5 alkyl is
optionally substituted with halogen) and acetyl,
[0078] R.sub.2 is hydrogen; a C.sub.1-5 alkyl group optionally
substituted with a substituent selected from the group consisting
of hydroxyl and C.sub.1-5 alkoxy, benzylamino (where the
benzylamino is optionally substituted with halogen), phenylamino,
C.sub.1-5 alkylamino, C.sub.3-6 cycloalkylamino, and
hydroxy-C.sub.1-5 alkylamino; a C.sub.1-5 alkoxycarbonyl group; or
a formyl group,
[0079] R.sub.3 is hydrogen; a hydroxyl group; a C.sub.1-5 alkyl
group optionally substituted with a substituent selected from the
group consisting of amino, C.sub.1-5 alkoxycarbonylamino, and mono-
or di-C.sub.1-5 alkylamino; or a group selected from the group
consisting of the Formulas A, B, D and E,
[0080] R.sub.4 is hydrogen,
[0081] R.sub.5 is a C.sub.1-5 alkyl group,
[0082] R.sub.6 is a C.sub.1-10 alkyl group optionally substituted
with a substituent selected from the group consisting of hydroxy,
halogen, C.sub.1-5 alkoxy, amino, C.sub.1-5 alkoxycarbonylamino,
benzyloxycarbonylamino, mono- or di-C.sub.1-5 alkylamino, C.sub.1-5
alkoxy-C.sub.1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the
phenyl is optionally substituted with one or more substituents
selected from the group consisting of halogen, amino, C.sub.1-5
alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl,
piperazinyl (where the piperazinyl is optionally substituted with
benzyl), C.sub.3-6 cycloalkyl, acetyl, and benzoyl; a C.sub.3-6
cycloalkyl group; a piperidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-10 alkenyl group optionally
substituted with phenyl; a trifluoromethyl group; a trifluoroethyl
group; or a phenyl group optionally substituted with halogen,
[0083] R.sub.7 is hydrogen,
[0084] R.sub.8 and R.sub.9 are, independently each other, hydrogen;
a C.sub.1-10 alkyl group optionally substituted with a substituent
selected from the group consisting of amino, C.sub.1-5
alkoxycarbonylamino, hydroxy, C.sub.1-5 alkylthio, C.sub.3-10
cycloalkyl, phenyl (where the phenyl is optionally substituted with
one or more substituents selected from the group consisting of
hydroxy, C.sub.1-5 alkyl, mono- or di-C.sub.1-5 alkylamino,
trifluoromethyl, halogen, C.sub.1-5 alkoxy, and C.sub.1-5
alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl
is optionally substituted with mono- or di-C.sub.1-5 alkyl),
pyridinyl, and benzyloxy; a piperidinyl group optionally
substituted with benzyl, benzoyl, C.sub.1-5 alkyl, or C.sub.1-5
alkylcarbonyl; an azetidinyl group optionally substituted with
C.sub.1-5 alkoxycarbonyl; a C.sub.1-5 alkylsulfonyl group; a
phenylsulfonyl group (where the phenyl moiety is optionally
substituted with halogen); or a C.sub.3-10 cycloalkyl group.
[0085] The compound of Formula 1 or its pharmaceutically acceptable
salt may have substituents containing asymmetric carbon and
therefore be in the form of racemic mixture (RS) or in forms of
optical isomers, such as (R) or (S) isomer. The compound of Formula
1 or its pharmaceutically acceptable salt comprises both racemic
mixture (RS) and optical isomers such as (R) or (S) isomer. And
also, the compound of Formula 1 or its pharmaceutically acceptable
salt may be in the form of cis- or trans-geometrical isomer,
according to substituents having e.g., the double bond therein. The
compound of Formula 1 or its pharmaceutically acceptable salt
comprises both cis- and trans-geometrical isomers. And also, the
compound of Formula 1 or its pharmaceutically acceptable salt may
be in the form of one or more diastereomic isomer(s) or a mixture
thereof. The compound of Formula 1 or its pharmaceutically
acceptable salt comprises both diastereomic isomer(s) and a mixture
thereof.
[0086] The compound of Formula 1 of the present invention may be in
a pharmaceutically acceptable salt form. The salt may be an acid
addition salt form, which includes e.g., salts derived from an
inorganic acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, or
nitric acid; and salts derived from an organic acid such as acetic
acid, propionic acid, succinic acid, glycolic acid, stearic acid,
citric acid, maleic acid, malonic acid, methanesulfonic acid,
ethanesulfonic acid, tartaric acid, hydroxymaleic acid,
phenylacetic acid, glutamic acid, benzoic acid, salicylic acid,
2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid,
benzenesulfonic acid, oxalic acid or trifluoroacetic acid. The salt
may be prepared by reacting a compound of Formula 1 in the form of
free base with a salt-forming inorganic or organic acid in
stoichiometric amount or excessive amount, in a suitable solvent or
a mixture of two or more solvents.
[0087] In the use, the pharmaceutical composition, the treatment
method, and the compound according to the present invention, more
preferable compounds include a compound (or its pharmaceutically
acceptable salt) selected from the group consisting of: [0088]
N-(4-fluorophenyl)-4-propyl-6-(pyrrolidin-1-yl)pyrimidin-2-amine;
[0089]
(S)-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol; [0090]
1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ol;
[0091]
(R)-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol; [0092]
{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}methan-
ol; [0093]
N-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidi-
n-2-amine; [0094]
(S)--N-(4-fluorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyri-
midin-2-amine; [0095]
(R)--N-(4-fluorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyri-
midin-2-amine; [0096]
(S)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-carbox-
amide; [0097]
N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}acet-
amide; [0098]
(R)--N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}acetamide; [0099]
2,2,2-trifluoro-N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrr-
olidin-3-yl}acetamide; [0100]
4-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin-2--
amine; [0101]
4-[3-(dimethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin-
-2-amine; [0102]
(S)--N-(4-fluorophenyl)-4-propyl-6-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
-yl]pyrimidin-2-amine; [0103]
(S)--N-(4-fluorophenyl)-4-{2-[(phenylamino)methyl]pyrrolidin-1-yl}-6-prop-
ylpyrimidin-2-amine; [0104]
(S)--N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}acetamide; [0105]
(S)-4-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidi-
n-2-amine; [0106] (S)-tert-butyl
1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamat-
e; [0107]
4-(3-aminopyrrolidin-1-yl)-N-(4-fluorophenyl)-6-propylpyrimidin--
2-amine; [0108]
4-[3-(diethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin--
2-amine; [0109]
(S)--N-(4-fluorophenyl)-4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-amine; [0110]
N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-N-m-
ethylacetamide; [0111]
(S)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ol;
[0112]
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
l}-1H-indol-6-amine; [0113]
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-i-
ndol-5-amine; [0114]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(4-methoxyphenyl)-6-propylpyri-
midin-2-amine; [0115]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(3-methoxyphenyl)-6-propylpyri-
midin-2-amine; [0116]
(S)--N-(3-chlorophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyri-
midin-2-amine; [0117]
(S)--N-(4-fluoro-3-nitrophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-pr-
opylpyrimidin-2-amine; [0118]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-propylpyrimi-
din-2-amine; [0119]
(S)--N-(4-chloro-3-nitrophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-pr-
opylpyrimidin-2-amine; [0120]
(S)-3-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile; [0121]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-[3-(methylthio)phenyl]-6-propy-
lpyrimidin-2-amine; [0122]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propyl-N-[3-(trifluoromethyl)p-
henyl]pyrimidin-2-amine; [0123]
(S)-7-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
4-methyl-2H-chromen-2-one; [0124]
(S)--N-(5-chloro-2-methylphenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-p-
ropylpyrimidin-2-amine; [0125]
(S)--N-(3-chloro-4-methylphenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-p-
ropylpyrimidin-2-amine; [0126]
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine; [0127]
(S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[2-(methoxymethyl)pyrrolidi-
n-1-yl]-6-propylpyrimidin-2-amine; [0128]
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-3-(trifluoromethyl)benzene-1,4-diamine; [0129]
(S)-2-fluoro-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile; [0130]
(S)-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
2-methylbenzonitrile; [0131]
(S)-2-amino-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile; [0132]
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-3-nitrobenzene-1,4-diamine; [0133]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluorophenyl)-6-propylpyrimidin-2-ami-
ne; [0134] (S)-tert-butyl
1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamate-
; [0135]
3-{4-[3-(diethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile; [0136]
(S)-3-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile; [0137]
N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-N-me-
thylacetamide; [0138]
(S)-3-[4-(3-hydroxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile; [0139]
(R)-3-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitri-
le; [0140]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}acetamide; [0141]
(S)-3-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benz-
onitrile; [0142] (R)-tert-butyl
{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}methylc-
arbamate; [0143]
(R)-3-[4-(3-hydroxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile; [0144]
(S)-3-[4-(3-methoxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile;
3-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile; [0145]
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e; [0146]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}butyramide; [0147]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
cyclopentanecarboxamide; [0148]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(piperidin-1-yl)propanamide; [0149]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
benzamide; [0150]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-fluorobenzamide; [0151]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-phenylacetamide; [0152]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(4-fluorophenyl)acetamide; [0153]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-phenoxypropanamide; [0154]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-isobutoxypropanamide; [0155]
(S)-2-(4-benzylpiperazin-1-yl)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrim-
idin-4-yl]pyrrolidin-3-yl}acetamide; [0156]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(piperidin-1-yl)acetamide; [0157]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-oxo-4-phenylbutanamide; [0158]
(S)-2-(4-aminophenyl)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl-
]pyrrolidin-3-yl}acetamide; [0159]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-cyclopentylacetamide; [0160]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-methoxyacetamide; [0161]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-2-yl)acetamide; [0162]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-3-yl)acetamide; [0163]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-4-yl)acetamide; [0164]
(S,E)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}-4-phenylbut-3-enamide; [0165]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(thiophen-2-yl)acetamide; [0166]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
isobutyramide; [0167]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3,3,3-trifluoropropanamide; [0168]
3-[4-(2-oxopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile;
[0169]
(S)-3-{4-[3-(hexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}benzonitrile; [0170]
(S)-3-{4-propyl-6-[3-(propylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}ben-
zonitrile; [0171]
(S)-3-{4-[3-(cyclohexylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile; [0172]
(S)-3-{4-[3-(benzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile; [0173]
(S)-3-{4-[3-(phenethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile; [0174]
(S)-3-{4-[3-(3-phenylpropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0175]
(S)-3-{4-[3-(3-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0176]
(S)-3-{4-[3-(4-hydroxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile; [0177]
(S)-3-{4-[3-(4-ethylbenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile; [0178]
(S)-3-{4-[3-(isopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile; [0179]
(S)-3-{4-[3-(pentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile; [0180]
3-{4-[(3S)-3-(2-methylbutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0181]
(S)-3-{4-[3-(isobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile; [0182]
(S)-3-{4-[3-(4-methoxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile; [0183]
(S)-3-{4-[3-(4-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0184]
(S)-3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile; [0185]
(S)-3-(4-{3-[bis(cyclopropylmethyl)amino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile; [0186]
(S)-3-{4-propyl-6-[3-(pyridin-2-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile; [0187]
(S)-3-{4-propyl-6-[3-(pyridin-3-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile; [0188]
(S)-3-{4-propyl-6-[3-(pyridin-4-ylmethylamino)pyrrolidin-1-yl]pyrimidin-2-
-ylamino}benzonitrile; [0189]
(S)-3-{4-[3-(2-ethylbutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}benzonitrile; [0190]
(S)-3-{4-[3-(neopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile; [0191]
(S)-3-{4-[3-(2-fluorobenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0192]
(S)-3-(4-propyl-6-{3-[3-(trifluoromethyl)benzylamino]pyrrolidin-1-yl}pyri-
midin-2-ylamino)benzonitrile; [0193]
(S)-3-(4-propyl-6-{3-[4-(trifluoromethyl)benzylamino]pyrrolidin-1-yl}pyri-
midin-2-ylamino)benzonitrile; [0194]
(S)-4-({1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yla-
mino}methyl)phenylacetate; [0195]
(S)-3-(4-{3-[4-(dimethylamino)benzylamino]pyrrolidin-1-yl}-6-propylpyrimi-
din-2-ylamino)benzonitrile; [0196]
(S)-3-(4-{3-[(1H-pyrrol-2-yl)methylamino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile; [0197]
(S)-3-{4-propyl-6-[3-(thiophen-2-ylmethylamino)pyrrolidin-1-yl]pyrimidin--
2-ylamino}benzonitrile; [0198]
(S)-3-{4-propyl-6-[3-(thiophen-3-ylmethylamino)pyrrolidin-1-yl]pyrimidin--
2-ylamino}benzonitrile; [0199]
(S)-3-{4-[3-(dibutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}be-
nzonitrile; [0200]
(S)-3-(4-{3-bis[3-(methylthio)propyl]aminopyrrolidin-1-yl}-6-propylpyrimi-
din-2-ylamino)benzonitrile; [0201]
(S)-3-{4-[3-(butylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}benz-
onitrile; [0202]
(S)-3-(4-{3-[3-(methylthio)propylamino]pyrrolidin-1-yl}-6-propylpyrimidin-
-2-ylamino)benzonitrile; [0203]
(S)--N-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-1H-ind-
ol-6-amine; [0204]
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
3-(trifluoromethyl)benzene-1,4-diamine; [0205]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
isopropane-2-sulfonamide; [0206]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
methanesulfonamide; [0207]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-fluorobenzenesulfonamide; [0208]
3-{4-[(3S)-3-(sec-butylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; [0209]
(S)-3-{4-[3-(pentan-3-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile; [0210]
(S)-3-{4-[3-(2,6-dimethylheptan-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile; [0211]
(S)-3-{4-[3-(4,4-dimethylpentan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile; [0212]
(S)-3-{4-[3-(3-hydroxy-3-methylbutan-2-ylamino)pyrrolidin-1-yl]-6-propylp-
yrimidin-2-ylamino}benzonitrile; [0213]
(S)-3-{4-[3-(heptan-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile; [0214]
(S)-3-{4-[3-(n-hexan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}benzonitrile; [0215]
(S)-3-{4-[3-(5-methylhexan-2-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-
-ylamino}benzonitrile; [0216]
(S)-3-{4-[3-(cyclohexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; [0217] (S)-tert-butyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
ethylcarbamate; [0218]
(S)-3-{4-[3-(1-benzylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimid-
in-2-ylamino}benzonitrile; [0219]
(S)-3-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile; [0220]
(S)-3-{4-[3-(1-benzoylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-ylamino}benzonitrile; [0221]
(S)-3-{4-[3-(1-acetylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimid-
in-2-ylamino}benzonitrile; [0222]
(S)-3-{4-[3-(cyclooctylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; [0223]
(S)-3-{4-[3-(cyclobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; [0224]
(S)-3-{4-[3-(cyclopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}benzonitrile; [0225] (S)-tert-butyl
3-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
azetidine-1-carboxylate; [0226]
(S)-3-(4-{3-[2-(benzyloxy)ethylamino]pyrrolidin-1-yl}-6-propylpyrimidin-2-
-ylamino)benzonitrile; [0227]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
propionamide; [0228]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
pivalamide; [0229]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2,2-dimethylbutanamide; [0230]
(S,E)-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl-
}-2-methylbut-2-enamide; [0231]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
hexanamide; [0232]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-phenylpropanamide; [0233]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(1H-indol-3-yl)acetamide; [0234]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-hydroxy-2-methylpropanamide; [0235]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(4-methoxyphenyl)propanamide; [0236]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(4-hydroxyphenyl)propanamide;
[0237]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-3-yl}-4-oxopentanamide; [0238]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-hydroxyacetamide; [0239]
(S)-2-benzyloxy-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrro-
lidin-3-yl}acetamide; [0240]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-phenoxyacetamide; [0241]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(dimethylamino)acetamide; [0242]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-3-(dimethylamino)propanamide; [0243]
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-4-dimethylaminobutanamide; [0244]
N--(S)-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-ethoxyacetamide; [0245]
N--(S)-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(2-methoxyethoxyl)acetamide; [0246] (S)-benzyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
-2-oxoethylcarbamate; [0247] (S)-tert-butyl
3-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
-3-oxobutylcarbamate; [0248] (S)-tert-butyl
4-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbam-
oyl}pipendine-1-carboxylate; [0249]
(R)-2-methyl-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]b-
enzonitrile; [0250]
(R)-2-amino-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]be-
nzonitrile; [0251]
(S)-2-methyl-5-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile; [0252]
(S)-5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-2-m-
ethylbenzonitrile; [0253]
5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-2-methy-
lbenzonitrile; [0254]
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
3-nitrobenzene-1,4-diamine; [0255]
(S)--N.sup.1-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-3-
-nitrobenzene-1,4-diamine; [0256]
(R)-3-{4-[3-(aminomethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile; [0257]
(S)-2-fluoro-5-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile; [0258]
(S)-2-fluoro-5-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0259]
5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-fluorobenzon-
itrile; [0260]
N-(4-fluorophenyl)-4-methyl-6-(pyrrolidin-1-yl)pyrimidin-2-amine;
[0261]
(3R,5S)-1-[2-(4-fluorophenyl)-6-propylpyrimidin-4-yl]-5-(hydroxymethyl)py-
rrolidin-3-ol; [0262]
(S)-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0263] (R)-{1-[2-(1H-indol-6-ylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-2-yl}methanol; [0264]
{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}methano-
l; [0265]
(R)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-
-yl}-1H-indol-6-amine; [0266]
N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
[0267] (S)-methyl
1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidine-2-carboxylat-
e; [0268]
N-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide; [0269]
(S)-3-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile; [0270]
(S)-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}pyrrolidin-2-
-yl)methanol; [0271]
(S)-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0272]
(S)-{1-[2-(1H-indol-5-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0273]
(S)-{1-[2-(1H-benzo[d]imidazol-5-ylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-2-yl}methanol; [0274]
(S)-(1-{6-propyl-2-[2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylamino]pyr-
imidin-4-yl}pyrrolidin-2-yl)methanol; [0275]
(S)-{1-[2-(4-methoxyphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-2-yl}methanol; [0276]
(S)-{1-[2-(3-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol; [0277] (S)-{1-[2-(3-methoxyphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-2-yl}methanol; [0278]
(S)-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-4-yl}pyrroli-
din-2-yl)methanol; [0279] (S)-{1-[2-(5-chloro-2-methyl
phenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}methanol;
[0280]
(S)-{1-[2-(5-methoxy-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-2-yl}methanol; [0281]
(S)-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-2-yl}methanol; [0282]
(S)-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0283]
(S)-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0284]
(S)-{1-[6-propyl-2-(quinolin-6-ylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0285]
(S)-{1-[2-(4-methyl-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0286]
(S)-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-yl-
}pyrrolidin-2-yl)methanol; [0287]
(S)-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
2-yl}methanol; [0288]
(S)-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}--
2-methylbenzonitrile; [0289]
(S)-2-fluoro-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile; [0290]
(S)-2-amino-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-y-
lamino}benzonitrile; [0291]
(S)-{1-[6-propyl-2-(quinolin-3-ylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0292]
(S)-{1-[2-(indolin-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}meth-
anol; [0293]
(S)-3-{4-[3-(aminoethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile; [0294]
(S)-3-{4-[3-(piperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0295]
(S)-3-{4-[3-(1-butylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidi-
n-2-ylamino}benzonitrile; [0296]
(S)--N-{1-[6-butyl-2-(3-cyanophenylamino)pyrimidin-4-yl]pyrrolidin-3-yl}a-
cetamide; [0297]
(S)-3-{4-butyl-6-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-2-ylamino}be-
nzonitrile; [0298]
(R)-3-[4-butyl-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-ylamino]benzonitril-
e; [0299]
(S)-3-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yla-
mino}benzonitrile; [0300] (S)-tert-butyl
1-[6-butyl-2-(3-cyanophenylamino)pyrimidin-4-yl]pyrrolidin-3-ylcarbamate;
[0301]
(S)--N-{1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]p-
yrrolidin-3-yl}acetamide; [0302]
(S)-5-{4-butyl-6-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-
-methylbenzonitrile; [0303]
(R)-5-[4-butyl-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-ylamino]-2-methylbe-
nzonitrile; [0304]
(S)-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-m-
ethylbenzonitrile; [0305] (S)-tert-butyl
1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]pyrrolidin-3-ylc-
arbamate; [0306]
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]benzonitrile-
; [0307]
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]-2-m-
ethylbenzonitrile; [0308]
(S)-3-{4-butyl-6-[3-(isopropylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}b-
enzonitrile; [0309]
(S)-3-{4-butyl-6-[3-(diethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}ben-
zonitrile; [0310]
(S)-3-{4-butyl-6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyrimidin-2-y-
lamino}benzonitrile; [0311]
(S)-5-{4-butyl-6-[3-(isopropylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}--
2-methylbenzonitrile; [0312]
(S)-5-{4-butyl-6-[3-(diethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2--
methylbenzonitrile; [0313]
(S)-5-{4-butyl-6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyrimidin-2-y-
lamino}-2-methylbenzonitrile; [0314]
(S)--N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0315]
(S)--N-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}pyrrolidi-
n-3-yl)acetamide; [0316]
(S)--N-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide; [0317]
(S)--N-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-4-yl}pyrr-
olidin-3-yl)acetamide; [0318]
(S)--N-{1-[2-(4-methyl-2-oxo-2H-chromen-7-ylamino)-6-propylpyrimidin-4-yl-
]pyrrolidin-3-yl}acetamide; [0319]
(S)--N-{1-[2-(3-chloro-4-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide; [0320]
(S)--N-{1-[2-(3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide; [0321]
(S)--N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0322]
(S)--N-{1-[2-(4-methyl-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0323] (S)-benzyl
5-[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methoxyp-
henylcarbamate; [0324]
(S)--N-{1-[2-(3-cyano-4-fluorophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide; [0325]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0326]
(S)--N-(1-{2-[4-fluoro-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin--
4-yl}pyrrolidin-3-yl)acetamide; [0327]
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0328]
(S)--N-{1-[2-(5-chloro-2-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide; [0329]
(S)-3-[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzami-
de; [0330]
(S)-3-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]a-
mino}-N-methylbenzamide; [0331]
(S)--N-[1-(2-{[3-(aminomethyl)phenyl]amino}-6-propylpyrimidin-4-yl)pyrrol-
idin-3-yl]acetamide; [0332]
(S)-3-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-4-ch-
lorobenzamide; [0333]
(S)--N-{1-[2-(4-amino-3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0334]
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide; [0335]
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0336]
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0337]
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide; [0338]
(S)--N-(1-{2-[(4-aminophenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidin-3-y-
l)acetamide; [0339]
(S)--N-(1-{2-[(4-chloro-3-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0340]
(S)-4-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-2-hy-
droxybenzoic acid; [0341]
(S)-5-{[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}-2-hy-
droxybenzoic acid; [0342]
(S)--N-(1-{2-[(3-hydroxy-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0343]
(S)--N-(1-{2-[(3-chloro-4-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0344]
(S)--N-(1-{2-[(4-hydroxy-3-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0345]
(S)--N-(1-{2-[(3-fluoro-4-hydroxyphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0346]
(S)--N-(1-{2-[(3-hydroxy-4-methoxyphenyl)amino]-6-propylpyrimidin-4-yl}py-
rrolidin-3-yl)acetamide; [0347]
(S)--N-(1-{2-[(3-methoxy-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyr-
rolidin-3-yl)acetamide; [0348]
(S)--N-[1-(2-{[4-methyl-3-(trifluoromethyl)phenyl]amino}-6-propylpyrimidi-
n-4-yl)pyrrolidin-3-yl]acetamide; [0349]
(S)--N-(1-{2-[(3,4-dimethylphenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidi-
n-3-yl)acetamide; [0350]
(S)--N-(1-{2-[(3-fluoro-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyrr-
olidin-3-yl)acetamide; [0351]
(S)--N-{1-[2-(3-amino-4-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}acetamide; [0352]
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0353]
(S)--N-{1-[2-(3-amino-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}acetamide; [0354]
N-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3--
yl}acetamide [0355]
N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide; [0356]
N-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide; [0357]
N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide; [0358]
N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide; [0359]
N-{1-[2-(3-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}ace-
tamide; [0360]
N-{1-[2-(5-methoxy-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-3-yl}acetamide; [0361]
N-{1-[2-(4-methoxyphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}ace-
tamide; [0362]
N-(1-{6-propyl-2-[3-(trifluoromethyl)phenylamino]pyrimidin-4-yl}pyrrolidi-
n-3-yl)acetamide; [0363]
N-{1-[2-(3-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}acet-
amide; [0364]
N-{1-[2-(5-chloro-2-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
3-yl}acetamide; [0365]
N-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
3-yl}acetamide; [0366]
N-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}pyrrolidin-3-y-
l)acetamide; [0367]
N-{1-[2-(1H-indol-5-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide; [0368]
N-(1-{6-propyl-2-[2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylamino]pyrim-
idin-4-yl}pyrrolidin-3-yl)acetamide; [0369]
N-{1-[6-propyl-2-(quinolin-6-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide; [0370]
N-{1-[2-(4-methyl-2-oxo-2H-chromen-7-ylamino)-6-propylpyrimidin-4-yl]pyrr-
olidin-3-yl}acetamide; [0371]
N-{1-[6-propyl-2-(quinolin-3-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide; [0372]
N-{1-[2-(4-amino-3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3--
yl}acetamide; [0373]
N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-
-yl}acetamide; [0374]
(R)--N-(4-chloro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine; [0375]
(R)-4-(2-methylpyrrolidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidi-
n-2-ylamine; [0376]
(R)--N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-am-
ine; [0377]
(R)-4-(2-methylpyrrolidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl]pyr-
imidin-2-amine; [0378]
(R)-4-methyl-7-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]--
2H-chromen-2-one; [0379] (R)--N-(3-chloro-4-methyl
phenyl)-4-(2-methylpyrrolidin-1-yl)-6-propyl pyrimidin-2-amine;
[0380]
(R)-4-(2-methylpyrrolidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-yla-
mine; [0381]
(R)--N-(4-fluoro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine; [0382]
(R)--N-(4-methyl-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propyl
pyrimidin-2-amine; [0383]
(R)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-(2-methylpyrrolidin-1-yl)-6-
-propylpyrimidin-2-ylamine; [0384]
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-(trif-
luoromethyl)benzene-1,4-diamine; [0385] (R)-benzyl
2-methoxy-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]phen-
ylcarbamate; [0386]
(R)-2-fluoro-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]b-
enzonitrile; [0387]
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-nitro-
benzene-1,4-diamine; [0388]
(R)-1-{6-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]indolin-
-1-yl}ethanone; [0389]
(R)--N-(5-chloro-2-methylphenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyri-
midin-2-amine; [0390]
(R)-4-methoxy-N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl-
]benzene-1,3-diamine;
[0391]
(R)-4-chloro-N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidi-
n-2-yl]benzene-1,3-diamine; [0392]
(R)-4-fluoro-N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]benzen-
e-1,3-diamine; [0393]
(R)-4-methyl-N-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]benzen-
e-1,3-diamine; [0394]
(S)-3-{4-[3-(2-hydroxyethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile; [0395]
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide; [0396]
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3-
-nitrobenzene-1,4-diamine; [0397]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-5-(trifl-
uoromethyl)benzene-1,3-diamine; [0398]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-methyl-
benzene-1,4-diamine; [0399]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-chloro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine; [0400]
(S)-4-(3-aminopyrrolidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidin-
-2-amine; [0401]
(S)--N-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-ami-
ne; [0402]
(S)-4-(3-aminopyrrolidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)p-
henyl]pyrimidin-2-amine; [0403]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(5-chloro-2-methylphenyl)-6-propylpyrimi-
din-2-amine; [0404]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-chloro-4-methylphenyl)-6-propylpyrimi-
din-2-amine; [0405]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-amin-
e; [0406]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-methyl-3-nitrophenyl)-6-prop-
ylpyrimidin-2-amine; [0407]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-(trifl-
uoromethyl)benzene-1,4-diamine; [0408]
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-fluorobe-
nzonitrile; [0409]
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile; [0410]
(S)-2-amino-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]ben-
zonitrile; [0411] (S)-benzyl
5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methoxypheny-
lcarbamate; [0412]
(S)-4-(3-aminopyrrolidin-1-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-p-
ropylpyrimidin-2-amine; [0413]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine; [0414]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-nitrob-
enzene-1,4-diamine; [0415]
(S)-4-(3-aminopyrrolidin-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]-6-propy-
lpyrimidin-2-amine; [0416]
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3,5-dimethoxyphenyl)-6-propylpyrimidin--
2-amine; [0417]
(S)-3-amino-5-{[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]amino}b-
enzonitrile; [0418]
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzenesulf-
onamide; [0419]
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}benzene-1,3-diamine; [0420]
(S)-4-fluoro-N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimi-
din-2-yl}benzene-1,3-diamine; [0421]
(S)--N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}-4-methylbenzene-1,3-diamine; [0422]
(S)-4-methoxy-N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}benzene-1,3-diamine; [0423]
(S)--N-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}indol-
in-6-amine; [0424]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-methyl-
benzene-1,3-diamine; [0425]
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-fluoro-
benzene-1,3-diamine; [0426]
(S)--N-(4-chloro-3-nitrophenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-
-yl]-6-propylpyrimidin-2-amine; [0427]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-fluoro-3-nitrophen-
yl)-6-propylpyrimidin-2-amine; [0428]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophen-
yl)-6-propylpyrimidin-2-amine; [0429]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine; [0430]
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-fluorobenzonitrile; [0431]
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-methylbenzonitrile; [0432]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-[3-(methylthio)phenyl-
]-6-propylpyrimidin-2-amine; [0433]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propyl-N-[3-(trifluor-
omethyl)phenyl]pyrimidin-2-amine; [0434]
(S)--N-(5-chloro-2-methylphenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine; [0435]
(S)--N-(3-chloro-4-methylphenyl)-4-[3-(cyclopropylmethylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine; [0436]
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluor-
omethyl)phenyl]-6-propylpyrimidin-2-amine; [0437]
(S)--N.sup.1-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}-4-methylbenzene-1,3-diamine; [0438]
(S)--N.sup.1-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}benzene-1,3-diamine; [0439]
3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile; [0440]
(S)-{1-[6-ethyl-2-(4-fluorophenylamino)pyrimidin-4-yl]pyrrolidin-2-yl}met-
hanol; [0441]
(S)--N-{1-[6-ethyl-2-(4-fluorophenylamino)pyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide; [0442]
(S)-4-ethyl-N-(4-fluorophenyl)-6-(2-methoxymethylpyrrolidin-1-yl)pyrimidi-
n-2-amine; [0443]
4-ethyl-N-(4-fluorophenyl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;
[0444]
(S)-4-ethyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluorophenyl)py-
rimidin-2-amine; [0445]
(S)-3-[4-(3-phenoxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile; [0446]
(S)-2-amino-N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide; [0447]
(S)-{1-[2-(3-amino-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0448]
(S)-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0449]
(S)-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol; [0450]
(S)-3-[4-(2-formylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitri-
le; [0451]
(S)-3-(4-{2-[(methylamino)methyl]pyrrolidin-1-yl}-6-propylpyrim-
idin-2-ylamino)benzonitrile; [0452]
(S)-3-(4-{2-[(cyclobutylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidin-2-
-ylamino)benzonitrile; [0453]
(S)-3-(4-{2-[(4-fluorobenzylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile; [0454]
(S)-3-(4-propyl-6-{2-[(propylamino)methyl]pyrrolidin-1-yl}pyrimidin-2-yla-
mino)benzonitrile; [0455]
(S)-3-(4-{2-[(2-hydroxyethylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile; [0456]
(S)-2-methyl-5-{4-propyl-6-[3-(propylamino)pyrrolidin-1-yl]pyrimidin-2-yl-
amino}benzonitrile; [0457]
(S)-2-methyl-5-(4-{3-[3-(methylthio)propylamino]pyrrolidin-1-yl}-6-propyl-
pyrimidin-2-ylamino)benzonitrile; [0458]
(S)-5-(4-{3-[(1H-pyrrol-2-yl)methylamino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)-2-methylbenzonitrile; [0459]
(S)-5-{4-[3-(4-hydroxybenzylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}-2-methylbenzonitrile; [0460]
(S)-5-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
-2-methylbenzonitrile; [0461]
(S)-5-{4-[3-(cyclobutylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}-2-methylbenzonitrile; [0462]
(S)-5-{4-[3-(cyclopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamin-
o}-2-methylbenzonitrile; [0463]
(S)-5-{4-[3-(cyclohexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}-2-methylbenzonitrile; [0464]
(S)-2-methyl-5-{4-[3-(pentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
amino}benzonitrile; [0465]
(S)-2-methyl-5-{4-[3-(neopentylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-
-ylamino}benzonitrile; [0466]
(S)-5-(4-{3-[(4,5-dimethylfuran-2-yl)methylamino]pyrrolidin-1-yl}-6-propy-
lpyrimidin-2-ylamino)-2-methylbenzonitrile; [0467]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}propionamide; [0468]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-phenylacetamide; [0469]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(piperidin-1-yl)acetamide; [0470]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(pyridin-3-yl)acetamide; [0471]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(pyridin-4-yl)acetamide; [0472]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-(thiophen-2-yl)acetamide; [0473]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}methanesulfonamide; [0474]
(S)-1-(1-{2-[(3-cyano-4-methylphenyl)amino]-6-propylpyrimidin-4-yl}pyrrol-
idin-3-yl)-3-ethylurea; [0475]
(R)-3-(4-{3-[(diethylamino)methyl]pyrrolidin-1-yl}-6-propylpyrimidin-2-yl-
amino)benzonitrile; [0476]
(S)--N-{1-[6-butyl-2-(4-methyl-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0477]
(S)--N-{1-[6-butyl-2-(4-fluoro-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0478]
(S)--N-{1-[6-butyl-2-(4-chloro-3-nitrophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0479]
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide; [0480]
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-butylpyrimidin-4--
yl}pyrrolidin-3-yl)acetamide; [0481]
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-butylpyrimidin-4--
yl}pyrrolidin-3-yl)acetamide; [0482]
(S)--N-(1-{6-butyl-2-[4-fluoro-3-(trifluoromethyl)phenylamino]pyrimidin-4-
-yl}pyrrolidin-3-yl)acetamide; [0483]
(S)--N-{1-[6-butyl-2-(3-cyano-4-fluorophenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0484]
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-butylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0485]
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-butylpyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide; [0486]
(S)--N-{1-[2-(4-amino-3-cyanophenylamino)-6-butylpyrimidin-4-yl]pyrrolidi-
n-3-yl}acetamide; [0487]
(S)-2-amino-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylam-
ino}benzonitrile; [0488]
(S)-4-butyl-N-(4-methyl-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine; [0489]
(S)-4-butyl-N-(4-fluoro-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine; [0490]
(S)-4-butyl-N-(4-chloro-3-nitrophenyl)-6-[3-(methylamino)pyrrolidin-1-yl]-
pyrimidin-2-amine; [0491]
(S)-3-amino-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylam-
ino}benzonitrile; [0492]
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-5-
-(trifluoromethyl)benzene-1,3-diamine; [0493]
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3-
-(trifluoromethyl)benzene-1,4-diamine; [0494]
(S)-4-butyl-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-[3-(methylamino)pyrr-
olidin-1-yl]pyrimidin-2-amine; [0495]
(S)-5-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-f-
luorobenzonitrile; [0496]
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4-
-fluorobenzene-1,3-diamine; [0497]
(S)--N.sup.1-{4-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4-
-chlorobenzene-1,3-diamine; [0498]
(S)-2-amino-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}benzonitrile; [0499]
(S)-3-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}benzo-
nitrile; [0500]
(S)-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-me-
thylbenzonitrile; [0501]
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3--
nitrobenzene-1,4-diamine; [0502]
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophenyl)p-
yrimidin-2-amine; [0503]
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-(4-fluoro-3-nitrophenyl)p-
yrimidin-2-amine; [0504]
(S)-4-butyl-N-(4-chloro-3-nitrophenyl)-6-[3-(ethylamino)pyrrolidin-1-yl]p-
yrimidin-2-amine; [0505]
(S)-3-amino-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}benzonitrile; [0506]
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-5--
(trifluoromethyl)benzene-1,3-diamine; [0507]
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-3--
(trifluoromethyl)benzene-1,4-diamine; [0508]
(S)-4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluoromet-
hyl)phenyl]pyrimidin-2-amine; [0509]
(S)-5-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-fl-
uorobenzonitrile; [0510]
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4--
fluorobenzene-1,3-diamine; [0511]
(S)--N.sup.1-{4-butyl-6-[3-(ethylamino)pyrrolidin-1-yl]pyrimidin-2-yl}-4--
chlorobenzene-1,3-diamine; [0512]
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide; [0513]
(S)--N-{1-[2-(3-cyano-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide; [0514]
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}-2-hydroxyacetamide; [0515]
(S)--N-(1-{2-[3-amino-5-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)-2-hydroxyacetamide; [0516]
(S)--N-(1-{2-[4-amino-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin-4-
-yl}pyrrolidin-3-yl)-2-hydroxyacetamide; [0517]
(S)--N-(1-{2-[4-fluoro-3-(trifluoromethyl)phenylamino]-6-propylpyrimidin--
4-yl}pyrrolidin-3-yl)-2-hydroxyacetamide; [0518]
(S)--N-{1-[2-(3-amino-4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide; [0519]
(S)--N-{1-[2-(3-amino-4-chlorophenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}-2-hydroxyacetamide; [0520]
(S)--N-{1-[2-(3-chloro-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrrol-
idin-3-yl}-2-hydroxyacetamide; [0521]
(S)-2-hydroxy-N-(1-{2-[4-methyl-3-(trifluoromethyl)phenylamino]-6-propylp-
yrimidin-4-yl}pyrrolidin-3-yl)acetamide; [0522]
(S)-4-fluoro-N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidi-
n-2-yl}benzene-1,3-diamine; [0523]
(S)-3-amino-5-({4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}amino)benzonitrile; [0524]
(S)-2-amino-5-({4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl-
}amino)benzonitrile; [0525]
(S)--N.sup.1-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}--
5-(trifluoromethyl)benzene-1,3-diamine; [0526]
(S)--N.sup.1-{4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-3-
-(trifluoromethyl)benzene-1,4-diamine; [0527]
(S)-2-amino-5-({4-[3-(ethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yl}-
amino)benzonitrile; [0528]
(S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[3-(methylamino)pyrrolidin--
1-yl]-6-propylpyrimidin-2-amine; [0529]
(S)-4-[3-(ethylamino)pyrrolidin-1-yl]-N-[4-fluoro-3-(trifluoromethyl)phen-
yl]-6-propylpyrimidin-2-amine; and [0530]
(S)--N-(1-{2-[(3,4-diaminophenyl)amino]-6-propylpyrimidin-4-yl}pyrrolidin-
-3-yl)acetamide.
[0531] In the use, the pharmaceutical composition, the treatment
method, and the compound according to the present invention, still
more preferable compounds in terms of pharmacological activity
include the compound (or its pharmaceutically acceptable salt)
described in Table 2-1 to Table 2-3.
[0532] The present invention includes, within its scope, a process
for preparing a compound of Formula 1 or its pharmaceutically
acceptable salt, which comprises reacting a compound of Formula 2
with a compound of Formula 3 to obtain a compound of Formula 4;
performing a methylation of the compound of Formula 4 to obtain a
compound of Formula 5; reacting the compound of Formula 5 with
R.sub.1--NH.sub.2 to obtain a compound of Formula 6; performing a
halogenation of the compound of Formula 6 to obtain a compound of
Formula 7; and reacting the compound of Formula 7 with a compound
of Formula 8 to obtain a compound of Formula 1:
##STR00007##
[0533] wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
the same as defined in the above; and X is halogen.
[0534] The compounds of Formula 2 and 3 are commercially available.
The reaction between the compound of Formula 2 and the compound of
Formula 3 may be performed in the presence of a base and a solvent.
The base may be potassium carbonate, sodium carbonate, etc and the
solvent may be an aqueous solvent such as water. Typically, the
reaction may be carried out under heating.
[0535] The methylation of the compound of Formula 4 may be carried
out using a methylating agent such as iodomethane. The methylation
may be performed in the presence of a base and a solvent. The base
may be sodium hydroxide, potassium hydroxide, etc and the solvent
may be an aqueous solvent such as water. Typically, the methylation
may be carried out at room temperature or under heating.
[0536] The reaction between the compound of Formula 5 and
R.sub.1--NH.sub.2 may be performed in the absence of a solvent or
in the presence of a solvent such as diglyme. The reaction may be
carried out at a temperature ranging from 140.degree. C. to
180.degree. C.
[0537] The halogenation of the compound of Formula 6 may be carried
out using a halogenating agent such as phosphorus oxychloride. The
halogenation may be performed preferably at a temperature of about
100.degree. C. or higher. And also, for improving reaction rate
and/or yield, the halogenation may be performed in the presence of
N,N-dimethylaniline or N,N-dimethylformamide in a catalytic
amount.
[0538] The reaction between the compound of Formula 7 and the
compound of Formula 8 may be performed in the presence of an
organic solvent, such as anhydrous tetrahydrofuran, alcohol, and
1,4-dioxane. Typically, the reaction may be carried out under
heating. And also, for improving reaction rate and/or yield, the
reaction may be performed in the presence of a metallic catalyst
(e.g., palladium), a ligand, and a base such as cesium carbonate,
triethylamine and diisopropylethylamine; or performed under
microwave ranging from 300 W to 600 W.
[0539] The compound of Formula 5 may be also prepared by reacting a
compound of Formula 2 with a compound of Formula 9:
##STR00008##
[0540] wherein, R.sub.5 is the same as defined in the above.
[0541] The compound of Formula 9 is commercially available. The
reaction between the compound of Formula 2 and the compound of
Formula 9 may be performed in the presence of a base and a solvent.
The base may be potassium carbonate, sodium carbonate, etc and the
solvent may be an aqueous solvent such as water. Typically, the
reaction may be carried out at room temperature or under
heating.
[0542] The compound of Formula 6 may be also prepared by reacting a
compound of Formula 2 with a compound of Formula 10:
##STR00009##
[0543] wherein, R.sub.1 and R.sub.5 are the same as defined in the
above.
[0544] The compound of Formula 10 may be easily prepared by using
known methods, e.g., EP0560726. The reaction between the compound
of Formula 2 and the compound of Formula 10 may be performed in the
presence of a base and a solvent. The base may be sodium methoxide,
sodium ethoxide, etc and the solvent may be an alcohol. Typically,
the reaction may be carried out under heating.
[0545] The present invention also provides a process for preparing
a compound of Formula 1 or its pharmaceutically acceptable salt,
which comprises performing a halogenation of a compound of Formula
4 to obtain a compound of Formula 11; reacting the compound of
Formula 11 with a compound of Formula 8 to obtain a compound of
Formula 12; and reacting the compound of Formula 12 with
R.sub.1--NH.sub.2 to obtain a compound of Formula 1:
##STR00010##
[0546] wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
the same as defined in the above; and X is halogen.
[0547] The halogenation of the compound of Formula 4 may be carried
out using a halogenating agent such as phosphorus oxychloride. The
halogenation may be performed preferably at a temperature of about
100.degree. C. or higher. And also, for improving reaction rate
and/or yield, the halogenation may be performed in the presence of
N,N-dimethylaniline or N,N-dimethylformamide in a catalytic
amount.
[0548] The reaction between the compound of Formula 11 and the
compound of Formula 8 may be performed in the presence of an
organic solvent, such as anhydrous tetrahydrofuran, alcohol,
chloroform, and N,N-dimethylformamide. Typically, the reaction may
be carried out at room temperature or under heating. And also, for
improving reaction rate and/or yield, the reaction may be performed
in the presence of a base such as triethylamine and
diisopropylethylamine.
[0549] The reaction between the compound of Formula 12 and
R.sub.1--NH.sub.2 may be performed in the presence of a solvent
such as alcohol, toluene, 1,4-dioxane, and N,N-dimethylformamide.
The reaction may be carried out under heating. And also, for
improving reaction rate and/or yield, the reaction may be performed
in the presence of a metallic catalyst (e.g., palladium), a ligand,
and a base (e.g., cesium carbonate); or performed under microwave
ranging from 300 W to 600 W.
[0550] The compound of Formula 11 may be also prepared by reacting
a compound of Formula 5 with an acid to obtain a compound of
Formula 13; and then performing a halogenation of the compound of
Formula 13:
##STR00011##
[0551] wherein, R.sub.5 and X are the same as defined in the
above.
[0552] The reaction between the compound of Formula 5 and the acid
may be performed using an organic acid (e.g., acetic acid, etc) and
an inorganic acid (e.g. hydrochloric acid, etc). The reaction may
be performed in an aqueous solvent such as water. Typically, the
reaction may be carried out under heating.
[0553] The halogenation of the compound of Formula 13 may be
carried out using a halogenating agent such as phosphorus
oxychloride. The halogenation may be performed preferably at a
temperature of about 100.degree. C. or higher. And also, for
improving reaction rate and/or yield, the halogenation may be
performed in the presence of N,N-dimethylaniline or
N,N-dimethylformamide in a catalytic amount.
[0554] In accordance with an embodiment of the present invention,
there is provided a process for preparing a compound of Formula 1 b
or its pharmaceutically acceptable salt, which comprises reacting a
compound of Formula 1a with an organic acid or an acyl halide:
##STR00012##
[0555] wherein, R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are the same as defined in the above.
[0556] The reaction between the compound of Formula 1a and the
organic acid may be performed through amide coupling reaction,
using a coupling agent such as
(benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium
hexafluorophosphate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride, and 1-hydroxybenzotriazole hydrate; and a base such
as diisopropylethylamine and triethylamine. The coupling reaction
may be performed in an organic solvent such as dichloromethane, and
N,N-dimethylformamide. Typically, the coupling reaction is
performed at room temperature.
[0557] And also, the reaction between the compound of Formula 1a
and the acyl halide may be performed through amide coupling
reaction, using an organic base (e.g., diisopropylethylamine,
triethylamine, etc) or an inorganic base (e.g., sodium hydroxide,
etc). The coupling reaction may be performed in an organic solvent
such as dichloromethane or a mixed solvent of an organic solvent
and water. Typically, the coupling reaction is performed at room
temperature.
[0558] The compound of Formula 1 b or its pharmaceutically
acceptable salt may be also prepared by reacting a compound of
Formula 12a with an organic acid or an acyl halide to obtain a
compound of Formula 12b; and then reacting the compound of Formula
12b with R.sub.1--NH.sub.2 to obtain a compound of Formula 1 b:
##STR00013##
[0559] wherein, R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are the same as defined in the above; and X is halogen.
[0560] The reaction between the compound of Formula 12a and the
organic acid may be performed through amide coupling reaction,
using a coupling agent such as
(benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium
hexafluorophosphate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride, and 1-hydroxybenzotriazole hydrate; and a base such
as diisopropylethylamine or triethylamine. The coupling reaction
may be performed in an organic solvent such as dichloromethane, and
N,N-dimethylformamide. Typically, the coupling reaction is
performed at room temperature.
[0561] And also, the reaction between the compound of Formula 12a
and the acyl halide may be performed through amide coupling
reaction, using an organic base (e.g., diisopropylethylamine,
triethylamine, etc) or an inorganic base (e.g., sodium hydroxide,
etc). The coupling reaction may be performed in an organic solvent
such as dichloromethane or a mixed solvent of an organic solvent
and water. Typically, the coupling reaction is performed at room
temperature.
[0562] The reaction between the compound of Formula 12b and
R.sub.1--NH.sub.2 may be performed in an organic solvent such as
alcohol, toluene, 1,4-dioxane, and N,N-dimethylformamide, etc.
Typically, the reaction may be performed under heating. And also,
for improving reaction rate and/or yield, the reaction may be
performed in the presence of a metallic catalyst (e.g., palladium),
a ligand, and a base (e.g., cesium carbonate); or performed under
microwave ranging from 300 W to 600 W.
[0563] In accordance with another embodiment of the present
invention, there is provided a process for preparing a compound of
Formula 1c or its pharmaceutically acceptable salt, which comprises
performing a reductive amination using an aldehyde or a ketone with
respect to a compound of Formula 1a:
##STR00014##
[0564] wherein, R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.3, and
R.sub.9 are the same as defined in the above.
[0565] The reductive amination may be performed using a reducing
agent such as sodium borohydride, sodium triacetoxyborohydride, and
sodium cyanoborohydride. The reductive amination may be performed
in an organic solvent (e.g., alcohol) at room temperature or at low
temperature (e.g., at 0.degree. C. or less). And also, for
improving reaction rate and/or yield, the reaction may be performed
in the presence of acetic acid, etc.
[0566] The compound of Formula 1c or its pharmaceutically
acceptable salt may be prepared by introducing an amine-protecting
group to a compound of Formula 12a to obtain a compound of Formula
12c; performing an alkylation of the compound of Formula 12c to
obtain a compound of Formula 12d; and reacting a compound of
Formula 12d with R.sub.1--NH.sub.2, followed by removing the
amine-protecting group:
##STR00015##
[0567] wherein, R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.3 are
the same as defined in the above; X is halogen; and R.sub.9 is
hydrogen. P is an amine-protecting group such as
tert-butoxycarbonyl.
[0568] The reaction for introducing an amine-protecting group to
the compound of Formula 12a may be performed in an organic solvent
such as dichloromethane, chloroform, and 1,4-dioxane at room
temperature or at low temperature (e.g., at 0.degree. C. or less).
And also, the reaction may be performed in the presence of a base
such as triethylamine, diisopropylethylamine, and
4-dimethylaminopyridine.
[0569] The alkylation of the compound of Formula 12c may be
performed using an alkyl halide. The alkylation may be performed in
the presence of a base (e.g., sodium hydride) in an organic solvent
(e.g., N,N-dimethylformamide). The alkylation may be performed at
room temperature or under heating.
[0570] The reaction between the compounds of Formula 12d and
R.sub.1--NH.sub.2 may be performed in an organic solvent such as
alcohol, toluene, 1,4-dioxane, and N,N-dimethylformamide.
Typically, the reaction is performed under heating. And also, for
improving reaction rate and/or yield, the reaction may be performed
in the presence of a metallic catalyst (e.g., palladium), a ligand,
and a base (e.g., cesium carbonate); or performed under microwave
ranging from 300 W to 600 W. The reaction for removing the
amine-protecting group may be performed using an acid (e.g.,
hydrochloric acid, trifluoroacetic acid, etc) in an organic solvent
such as ethyl acetate and methanol. Typically, the reaction may be
performed at room temperature or at low temperature (e.g., at
0.degree. C. or less).
[0571] The compound of Formula 12d may be also prepared by
performing a reductive amination with respect to a compound of
Formula 12a to obtain a compound of Formula 12e; and then
introducing an amine-protecting group to the compound of Formula
12e:
##STR00016##
[0572] wherein, R.sub.2, R.sub.4, R.sub.5, and R.sub.3 are the same
as defined in the above; X is halogen; and R.sub.9 is hydrogen. P
is an amine-protecting group such as tert-butoxycarbonyl.
[0573] The reductive amination of the compound of Formula 12a may
be performed using a reducing agent such as sodium borohydride,
sodium triacetoxyborohydride, and sodium cyanoborohydride. The
reductive amination may be in an organic solvent (e.g., alcohol) at
room temperature or at low temperature (e.g., at 0.degree. C. or
less). And also, for improving reaction rate and/or yield, the
reaction may be performed in the presence of acetic acid, etc.
[0574] The reaction for introducing an amine-protecting group to
the compound of Formula 12e may be performed in an organic solvent
such as dichloromethane, chloroform and 1,4-dioxane at room
temperature or at low temperature (e.g., at 0.degree. C. or less).
And also, the reaction may be performed in the presence of a base
such as triethylamine, diisopropylethylamine, and
4-dimethylaminopyridine.
[0575] The following examples and experimental examples are
provided for illustration purposes only, and are not intended to
limit the scope of the invention.
Preparation 1.
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine
<Step 1> 2-(methylthio)-6-propylpyrimidin-4(3H)-one
[0576] A mixture of 6-n-propyl-2-thiouracil (25.0 g, 0.15 mol),
sodium hydroxide (5.9 g, 0.15 mol), iodomethane (10.2 ml, 0.17
mol), and water (300 ml) was stirred at room temperature overnight
and then filtered. The resulting solid was dried in vacuo to give
the titled compound (25.0 g) as a white solid. The product was used
in the subsequent reaction without further purification.
<Step 2>
2-(4-fluorophenylamino)-6-propylpyrimidin-4(3H)-one
[0577] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (3.7
g, 0.02 mol) prepared in Step 1 and 4-fluoroaniline (6.7 g, 0.06
mol) was stirred at 160.degree. C. overnight. The reaction mixture
was cooled to room temperature, and then ethanol (50 ml) and
charcoal (1 g) were added thereto. The reaction mixture was stirred
for 1 hour and then filtered. The filtrate was concentrated under
reduced pressure. Ethanol (20 ml) was added to the resulting
residue, which was then stirred for 1 hour. The reaction mixture
was filtered to give the titled compound as a gray solid.
[0578] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.70-7.50 (m, 2H),
7.07 (t, 2H), 5.75 (s, 1H), 2.43 (t, 2H), 1.70 (q, 2H), 0.98 (t,
3H)
<Step 3>
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine
[0579] 2-(4-Fluorophenylamino)-6-propylpyrimidin-4(3H)-one (2.2 g,
8.9 mmol) prepared in Step 2 was added to phosphorus oxychloride
(1.5 ml, 16.2 mmol), which was then stirred at 110.degree. C. for 5
hours. After cooling to room temperature, ice water was added to
the reaction mixture, which was then basified to pH 9 with sodium
hydroxide. The aqueous layer was extracted with ethyl acetate. The
resulting organic layer was dried on anhydrous sodium sulfate and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (ethyl acetate) to
give 2.2 g of the titled compound as a yellow solid.
[0580] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.50 (m, 2H),
7.03 (t, 2H), 6.63 (s, 1H), 2.60 (t, 2H), 1.75 (q, 2H), 0.99 (t,
3H)
Preparation 2.
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
<Step 1> 2,4-dichloro-6-propylpyrimidine
[0581] Phosphorus oxychloride (100 ml) was slowly added at room
temperature to 6-propyl-2-thiouracil (17.7 g, 0.1 mol), which was
then stirred at 110.degree. C. overnight. The reaction mixture was
added to ice water and then neutralized with a saturated aqueous
solution of sodium bicarbonate. The reaction mixture was extracted
with dichloromethane. The organic layer was dried on anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (n-hexane/ethyl acetate=50/1) to give 10.3 g of the
titled compound as pale yellow oil.
[0582] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.16 (s, 1H), 2.73
(t, 2H), 1.78 (m, 2H), 0.99 (t, 3H)
<Step 2>
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
[0583] 2,4-Dichloro-6-propylpyrimidine (1.4 g, 7.3 mmol) prepared
in Step 1 was dissolved in tetrahydrofuran (15 ml), and then
(S)-2-(methoxymethyl)pyrrolidine (1.2 g, 10.4 mmol) was added
thereto at room temperature. The reaction mixture was stirred at
60.degree. C. overnight and then cooled to room temperature. The
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (n-hexane/ethyl acetate=10/1) to give 1.5 g of the
titled compound as pale yellow oil. The product was used in the
subsequent reaction without further purification.
Preparation 3.
3-(4-chloro-6-propylpyrimidin-2-ylamino)benzonitrile
<Step 1>
3-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitrile
[0584] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (6.4
g, 34.7 mmol) prepared in Step 1 of Preparation 1 and
3-aminobenzonitrile (12.3 g, 104.1 mmol) was stirred at 160.degree.
C. overnight. The reaction mixture was cooled to room temperature
and then ethanol (50 ml) was added thereto. The reaction mixture
was stirred for 1 hour and then filtered to give 3.5 g of the
titled compound as a pale brown solid.
[0585] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.22 (s, 1H),
7.90-7.80 (m, 1H), 7.55-7.45 (m, 1H), 7.45-7.35 (m, 1H), 5.84 (s,
1H), 2.49 (t, 2H), 1.80-1.65 (m, 2H), 1.00 (t, 3H)
<Step 2> 3-(4-chloro-6-propyl
pyrimidin-2-ylamino)benzonitrile
[0586]
3-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitrile (3.3
g, 13.0 mmol) prepared in Step 1 was added to phosphorus
oxychloride (10 ml). The reaction mixture was stirred at
110.degree. C. for 2 hours and then cooled to room temperature. The
reaction mixture was added to ice water and then basified to pH 9
with sodium hydroxide. The aqueous layer was extracted with ethyl
acetate. The resulting organic layer was dried on anhydrous sodium
sulfate and then concentrated under reduced pressure. The resulting
residue was purified with silica gel column chromatography
(n-hexane/ethyl acetate=10/1) to give 3.2 g of the titled compound
as a yellow solid.
[0587] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (s, 1H),
7.75-7.65 (m, 1H), 7.50-7.20 (m, 3H), 6.72 (s, 1H), 2.65 (t, 2H),
1.78 (q, 2H), 1.01 (t, 3H)
Preparation 4.
N-(4-chloro-6-propylpyrimidin-2-yl)-1H-indol-6-amine
<Step 1>
2-(1H-indol-6-ylamino)-6-propylpyrimidin-4(3H)-one
[0588] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (1
g, 5.43 mmol) prepared in Step 1 of Preparation 1 and 6-aminoindole
(789 mg, 5.97 mmol) was stirred at 150.degree. C. overnight and
then cooled to room temperature. The resulting residue was purified
with silica gel column chromatography
(dichloromethane/methanol=40/1) to give 1.4 g of the titled
compound as a pale brown solid.
[0589] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.81 (s, 1H), 7.51
(d, 1H), 7.21 (d, 1H), 6.95 (dd, 1H), 6.42 (d, 1H), 5.70 (s, 1H),
2.44 (dd, 1H), 1.75-1.70 (m, 2H), 0.99 (t, 3H).
<Step 2>
N-(4-chloro-6-propylpyrimidin-2-yl)-1H-indol-6-amine
[0590] A solution of
2-(1H-indol-6-ylamino)-6-propylpyrimidin-4(3H)-one (1.2 g, 4.47
mmol) prepared in Step 1, phosphorus oxychloride (822 mg, 5.37
mmol), and diisopropylethylamine (1.9 ml, 10.7 mmol) in 1,4-dioxane
(45 ml) was refluxed under stirring for 30 minutes. The reaction
mixture was cooled to room temperature and then concentrated under
reduced pressure. The resulting residue was purified with silica
gel column chromatography (n-hexane/ethyl acetate=4/1) to give 1.1
g of the titled compound as a white solid.
[0591] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.17 (brs, 1H),
8.05 (s, 1H), 7.53 (d, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 6.98 (dd,
1H), 6.58 (s, 1H), 6.48 (s, 1H), 2.59 (dd, 2H), 1.81-1.71 (m, 2H),
0.99 (t, 3H).
Preparation 5.
(S)-1-(2-chloro-6-propylpyrimidin-4-yl)-N-methylpyrrolidin-3-amine
[0592] 2,4-Dichloro-6-propylpyrimidine (1 g, 5.2 mmol) prepared in
Step 1 of Preparation 2 was dissolved in ethanol (10 ml) and then
(3S)-(-)-3-(methylamino)pyrrolidine (1 g, 10 mmol) was slowly added
thereto at 0.degree. C. The reaction mixture was stirred at room
temperature overnight and then concentrated under reduced pressure.
The resulting residue was purified with silica gel column
chromatography (dichloromethane/methanol=40/1) to give 1 g of the
titled compound as pale yellow oil.
[0593] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.03 (s, 1H),
3.90-3.30 (m, 5H), 2.52 (t, 2H), 2.49 (s, 3H), 2.30-2.15 (m, 1H),
2.10-1.90 (m, 1H), 1.70 (q, 2H), 0.95 (t, 3H)
Preparation 6.
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-methylbenzonitrile
<Step 1>
2-methyl-5-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitrile
[0594] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (5
g, 27.1 mmol) prepared in Step 1 of Preparation 1 and
5-amino-2-methylbenzonitrile (7 g, 53 mmol) was stirred at
160.degree. C. overnight. The reaction mixture was cooled to room
temperature and then ethanol (30 ml) was added thereto. The
reaction mixture was stirred for 1 hour and then filtered to give
6.3 g of the titled compound as a pale yellow solid.
[0595] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.12 (d, 1H),
7.70-7.60 (m, 1H), 7.35 (d, 1H), 5.80 (s, 1H), 2.50-2.40 (m, 5H),
1.73 (q, 2H), 0.99 (t, 3H)
<Step 2> 5-(4-chloro-6-propyl
pyrimidin-2-ylamino)-2-methylbenzonitrile
[0596]
2-Methyl-5-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitr-
ile (6.3 g, 23.5 mmol) prepared in Step 1 was added to phosphorus
oxychloride (10 ml). The reaction mixture was stirred at
110.degree. C. for 2 hours and then cooled to room temperature. The
reaction mixture was added to ice water and then basified to pH 9
with sodium hydroxide. The aqueous layer was extracted with ethyl
acetate. The resulting organic layer was dried on anhydrous sodium
sulfate and then concentrated under reduced pressure to give 6 g of
the titled compound as a yellow solid. The product was used in the
subsequent reaction without further purification.
Preparation 7.
N.sup.1-(4-chloro-6-propylpyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
<Step 1>
2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4(3H)-one
[0597] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (3
g, 16.3 mmol) prepared in Step 1 of Preparation 1 and
2-nitrobenzene-1,4-diamine (5 g, 32.6 mmol) was stirred at
160.degree. C. overnight. The reaction mixture was cooled to
70.degree. C. and then ethanol (30 ml) was added thereto. The
reaction mixture was stirred for 1 hour and then filtered to give
4.5 g of the titled compound as a red solid.
[0598] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.42 (s, 1H),
7.55-7.45 (m, 1H), 6.96 (d, 1H), 5.73 (s, 1H), 2.43 (t, 2H), 1.73
(q, 2H), 0.98 (t, 3H)
<Step 2>
N.sup.1-(4-chloro-6-propylpyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
[0599] The titled compound (0.4 g) in the form of pale yellow solid
was prepared in accordance with the same procedures as in Step 3 of
Preparation 1, using
2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4(3H)-one (4.5 g,
15.5 mmol) prepared in Step 1.
[0600] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.65 (s, 1H), 7.78
(d, 1H), 7.40 (brs, 1H), 7.19 (d, 1H), 6.81 (s, 1H), 2.70 (t, 2H),
1.81 (q, 2H), 1.03 (t, 3H)
Preparation 8.
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-fluorobenzonitrile
<Step 1>
2-fluoro-5-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitrile
[0601] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (8.8
g, 47.8 mmol) prepared in Step 1 of Preparation 1 and
5-amino-2-fluorobenzonitrile (7.9 g, 57.2 mmol) was stirred at
160.degree. C. overnight. The reaction mixture was cooled to
70.degree. C. and then ethanol (50 ml) was added thereto. The
reaction mixture was stirred for 1 hour and then filtered to give
10 g of the titled compound as a pale brown solid. The product was
used in the subsequent reaction without further purification
<Step 2> 5-(4-chloro-6-propyl
pyrimidin-2-ylamino)-2-fluorobenzonitrile
[0602] The titled compound (10.8 g) in the form of pale brown solid
was prepared in accordance with the same procedures as in Step 3 of
Preparation 1, using
2-fluoro-5-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylamino)benzonitrile
(10 g, 36.7 mmol) prepared in Step 1.
[0603] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.20-8.10 (m, 1H),
7.75-7.65 (m, 1H), 7.30-7.10 (m, 2H), 6.72 (s, 1H), 2.64 (t, 2H),
1.77 (q, 2H), 1.00 (t, 3H)
Preparation 9.
4-chloro-6-ethyl-N-(4-fluorophenyl)pyrimidin-2-amine
<Step 1> 6-ethyl-2-(4-fluorophenylamino)pyrimidin-4-ol
[0604] A mixture of ethylpropionyl acetate (1.03 ml, 7.18 mmol),
N-(4-fluorophenyl)guanidine (1 g, 6.53 mmol), sodium methoxide
(0.39 g, 7.18 mmol), and ethanol (30 ml) was refluxed under
stirring overnight. The reaction mixture was cooled to room
temperature and then concentrated under reduced pressure. The
resulting residue was dissolved in water, acidified to pH 4 with a
1N hydrochloric acid solution, and then filtered. The resulting
white solid (0.82 g) was dried in vacuo and then used in the
subsequent reaction without further purification.
<Step 2>
4-chloro-6-ethyl-N-(4-fluorophenyl)pyrimidin-2-amine
[0605] 6-Ethyl-2-(4-fluorophenylamino)-pyrimidin-4-ol (0.82 g, 3.52
mmol) prepared in Step 1 was added to phosphorus oxychloride (1.5
ml, 16.2 mmol), which was then stirred at 110.degree. C. for 1
hour. After cooling to room temperature, the reaction mixture was
added to ice water and then basified to pH 9 with potassium
hydroxide. The aqueous layer was extracted with dichloromethane.
The resulting organic layer was dried on anhydrous sodium sulfate
and then concentrated under reduced pressure. The resulting residue
was purified with silica gel column chromatography (ethyl
acetate/n-hexane=2/1) to give 432.2 mg of the titled compound as a
white solid.
[0606] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.18 (m, 2H), 7.08
(m, 2H), 6.63 (s, 1H), 2.61 (m, 2H), 1.23 (t, 3H)
Preparation 10.
4-chloro-N-(4-fluorophenyl)-6-methylpyrimidin-2-amine
<Step 1> 2-(4-fluorophenylamino)-6-methylpyrimidin-4-ol
[0607] The titled compound (8.2 g) was prepared in accordance with
the same procedures as in Step 1 of Preparation 9, using ethyl
acetoacetate (10 g, 76.8 mmol), N-(4-fluorophenyl)guanidine (10.7
g, 69.8 mmol) and sodium methoxide (4.2 g, 71.8 mmol). The product
was used in the subsequent reaction without further
purification
<Step 2>
4-chloro-N-(4-fluorophenyl)-6-methylpyrimidin-2-amine
[0608] The titled compound (4.5 g) in the form of white solid was
prepared in accordance with the same procedures as in Step 2 of
Preparation 9, using 2-(4-fluorophenylamino)-6-methylpyrimidin-4-ol
(8.2 g, 37.4 mmol) prepared in Step 1 and phosphorus oxychloride
(15.9 ml, 172.0 mmol).
[0609] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.57-7.54 (m, 2H),
7.21 (brs, 1H), 7.05-7.01 (m, 2H), 6.64 (s, 1H), 2.39 (s, 3H)
Preparation 11.
3-(4-butyl-6-chloropyrimidin-2-ylamino)benzonitrile
<Step 1> 6-butyl-2-(methylthio)pyrimidin-4(3H)-one
[0610] A solution of ethyl 3-oxoheptanoate (10 g, 58.1 mmol),
2-methyl-2-thiopseudourea sulfate (11.7 g, 63.9 mmol), and sodium
carbonate (9.8 g, 92.9 mmol) in water (116 ml) was stirred at room
temperature for 2 days and then filtered. The resulting white solid
was dried in vacuo to give the titled compound (11 g). The product
was used in the subsequent step without further purification.
<Step 2>
3-(4-butyl-6-oxo-1,6-dihydropyrimidin-2-ylamino)benzonitrile
[0611] A solution of 6-butyl-2-(methylthio)pyrimidin-4(3H)-one (500
mg, 2.52 mmol) prepared in Step 1 and 3-aminobenzonitrile (298 mg,
2.52 mmol) in n-butanol (3 ml) was stirred at 170.degree. C.
overnight. The reaction mixture was cooled to room temperature and
then purified with silica gel column chromatography
(dichloromethane/methanol=50/1) to give 310 mg of the titled
compound as a brown solid.
[0612] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.47 (brs 1H),
8.27 (s, 1H), 7.80 (d, 1H), 7.37 (d, 1H), 5.88 (s, 1H), 2.58 (dd,
2H), 1.74-1.70 (m, 2H), 1.46-1.40 (m, 2H), 0.98 (t, 3H)
<Step 3>
3-(4-butyl-6-chloropyrimidin-2-ylamino)benzonitrile
[0613] The titled compound in the form of pale yellow solid was
prepared in accordance with the same procedures as in Step 2 of
Preparation 9, using
3-(4-butyl-6-oxo-1,6-dihydropyrimidin-2-ylamino)benzonitrile
prepared in Step 2 and phosphorus oxychloride.
[0614] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.69
(d, 1H), 7.42 (t, 1H), 7.33 (d, 1H), 7.26 (brs, 1H), 6.72 (s, 1H),
2.67 (t, 2H), 1.80-1.65 (m, 2H), 1.50-1.30 (m, 2H), 0.97 (t, 3H);
(Yield: 80%)
Preparation 12.
5-(4-butyl-6-chloropyrimidin-2-ylamino)-2-methylbenzonitrile
<Step 1>
5-(4-butyl-6-oxo-1,6-dihydropyrimidin-2-ylamino)-2-methylbenzonitrile
[0615] A mixture of 6-butyl-2-(methylthio)pyrimidin-4(3H)-one (800
mg, 4.03 mmol) prepared in Step 1 of Preparation 11 and
5-amino-2-methylbenzonitrile (586 mg, 4.44 mmol) was stirred at
170.degree. C. for 6 hours. The reaction mixture was cooled to room
temperature and then purified with silica gel column chromatography
(dichloromethane/methanol=100/1) to give 650 mg of the titled
compound as a brown solid.
[0616] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.45 (brs 1H),
8.10 (s, 1H), 7.63 (d, 1H), 7.25 (d, 1H), 5.78 (s, 1H), 2.55-2.48
(m, 5H), 1.70-1.65 (m, 2H), 1.44-1.37 (m, 2H), 0.98 (t, 3H)
<Step 2>
5-(4-butyl-6-chloropyrimidin-2-ylamino)-2-methylbenzonitrile
[0617] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Step 2 of Preparation
9, using
5-(4-butyl-6-oxo-1,6-dihydropyrimidin-2-ylamino)-2-methylbenzonitrile
prepared in Step 1 and phosphorus oxychloride.
[0618] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, 1H), 7.57
(dd, 1H), 7.25 (m, 2H), 6.69 (s, 1H), 2.65 (dd, 2H), 2.51 (s, 3H),
1.75-1.68 (m, 2H), 1.45-1.36 (m, 2H), 0.96 (t, 3H); (Yield:
85%)
Preparation 13.
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
[0619] A solution of 2,4-dichloro-6-propylpyrimidine (1 g, 5.23
mmol) prepared in Step 1 of Preparation 2,
(3S)-(-)-3-acetamidopyrrolidine (1 g, 7.85 mmol), and
diisopropylethylamine (1.8 ml, 10.46 mmol) in chloroform (52 ml)
was stirred at 60.degree. C. for 1 hour. The reaction mixture was
cooled to room temperature, washed by water, and then extracted
with dichloromethane. The organic layer was dried on anhydrous
sodium sulfate and then filtered. The filtrate was concentrated
under reduced pressure. The resulting residue was purified with
silica gel column chromatography (n-hexane/ethyl acetate=1/1) to
give 1.2 g of the titled compound as a white solid.
[0620] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.52 (brs, 1H),
6.02 (s, 1H), 4.59 (brs, 1H), 3.65-3.25 (m, 4H), 2.53 (dd, 2H),
2.28-2.24 (m, 1H), 2.02 (s, 3H), 2.02-1.98 (m, 1H), 1.74-1.65 (m,
2H), 0.96 (t, 3H)
Preparation 14.
N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
[0621] A solution of 2,4-dichloro-6-propylpyrimidine (200 mg, 1.05
mmol) prepared in Step 1 of Preparation 2, 3-acetamidopyrrolidine
(201 mg, 1.57 mmol), diisopropylethylamine (0.36 ml, 2.09 mmol) in
chloroform (10.5 ml) was stirred at 40.degree. C. for 1 hour. The
reaction mixture was cooled to room temperature, washed by water,
and then extracted with dichloromethane. The organic layer was
dried on anhydrous sodium sulfate and then filtered. The filtrate
was concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) to give 205 mg of the titled compound as a white
solid.
[0622] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.52 (brs, 1H),
6.02 (s, 1H), 4.59 (brs, 1H), 3.65-3.25 (m, 4H), 2.53 (dd, 2H),
2.28-2.24 (m, 1H), 2.02 (s, 3H), 2.02-1.98 (m, 1H), 1.74-1.65 (m,
2H), 0.96 (t, 3H)
Preparation 15.
(R)-2-chloro-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidine
[0623] A solution of 2,4-dichloro-6-propylpyrimidine (1 g, 5.23
mmol) prepared in Step 1 of Preparation 2, (R)-2-methylpyrrolidine
(668 mg, 7.85 mmol), diisopropylethylamine (1.8 ml, 10.46 mmol) in
chloroform (52 ml) was stirred at 60.degree. C. for 1 hour. The
reaction mixture was cooled to room temperature, washed by water,
and then extracted with dichloromethane. The organic layer was
dried on anhydrous sodium sulfate and then filtered. The filtrate
was concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=20/1) to give 910 mg of the titled compound as colorless
liquid.
[0624] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.00 (brs, 1H),
4.44-3.25 (m, 3H), 2.52 (dd, 2H), 2.12-1.95 (m, 3H), 1.75-1.66 (m,
3H), 1.22 (d, 3H), 0.96 (t, 3H)
[0625] Preparation 16.
N.sup.1-(4-butyl-6-chloropyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
<Step 1>
2-(4-amino-3-nitrophenylamino)-6-butylpyrimidin-4(3H)-one
[0626] The titled compound in the form of yellow solid was prepared
in accordance with the same procedures as in Step 2 of Preparation
11, using 6-butyl-2-(methylthio)pyrimidin-4(3H)-one prepared in
Step 1 of Preparation 11 and 2-nitrobenzene-1,4-diamine.
[0627] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.45 (s 1H), 7.47
(d, 1H), 6.96 (d, 1H), 5.73 (s, 1H), 4.61 (brs, 2H), 2.45 (d, 2H),
1.71-1.67 (m, 2H), 1.42-1.37 (m, 2H), 0.96 (t, 3H); (Yield:
85%)
<Step 2>
N.sup.1-(4-butyl-6-chloropyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
[0628] The titled compound in the form of pale yellow solid was
prepared in accordance with the same procedures as in Step 2 of
Preparation 9, using
2-(4-amino-3-nitrophenylamino)-6-butylpyrimidin-4(3H)-one prepared
in Step 1 and phosphorus oxychloride.
[0629] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.65 (s, 1H), 7.77
(d, 1H), 7.48 (brs, 1H), 7.20 (d, 1H), 6.80 (s, 1H), 2.72 (dd, 2H),
1.77-1.71 (m, 2H), 1.46-1.40 (m, 2H), 0.98 (t, 3H); (Yield:
37%)
Preparation 17. (R)-3-hydroxypyrrolidine hydrochloride
[0630] Hydrogen chloride gas was added at 0.degree. C. to a
solution of (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol (3 g, 16.0
mmol) in ethyl acetate (100 ml). The reaction mixture was stirred
at room temperature overnight and then filtered. The resulting
white solid was dried in vacuo to give 1.3 g of the titled
compound.
[0631] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.55 (m, 1H),
3.41-3.36 (m, 2H), 3.22 (m, 2H), 2.06-2.04 (m, 2H)
Preparation 18. (S)-3-methoxypyrrolidine
<Step 1> (S)-3-methoxypyrrolidin-1-carboxylic acid tert-butyl
ester
[0632] Sodium hydride (32 mg, 0.81 mmol, 60 wt %) was added at
0.degree. C. to a solution of
(S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol (100 mg, 0.53 mmol) in
N,N-dimethylformamide (2 ml). The reaction mixture was stirred for
30 minutes and iodomethane (99.7 .mu.l, 1.60 mmol) was added
thereto. The reaction mixture was stirred at room temperature
overnight and then water was added thereto. The reaction mixture
was concentrated under reduced pressure. The resulting residue was
dissolved in dichloromethane. The resulting solution was washed
with water, dried on anhydrous sodium sulfate, and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=5/2) to give 50 mg of the titled compound as colorless
oil.
[0633] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.55 (m, 1H),
3.41-3.36 (m, 2H), 3.22 (m, 2H), 2.06-2.04 (m, 2H)
<Step 2> (S)-3-methoxypyrrolidine
[0634] Trifluoroacetic acid (0.5 ml) was added to a solution of
(S)-3-methoxypyrrolidin-1-carboxylic acid tert-butyl ester (50 mg,
0.25 mmol) prepared in Step 1 in dichloromethane (5 ml). The
reaction mixture was stirred at room temperature for 1 hour and
then concentrated under reduced pressure. The resulting residue was
dissolved in dichloromethane and then basified with an aqueous
saturated solution of sodium bicarbonate. The resulting organic
layer was dried on anhydrous sodium sulfate and then concentrated
under reduced pressure to give 7.5 mg of the titled compound as
pale yellow oil. The product was used in the subsequent step
without further purification.
Preparation 19. 2,5-diaminobenzonitrile
[0635] A mixture of 5-nitroanthranilonitrile (200 mg, 1.23 mmol)
and palladium/charcoal (10 mg, 10 wt %) in methanol (3 ml) was
stirred at room temperature under hydrogen atmosphere overnight and
then filtered through a celite pad. The resulting filtrate was
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/2) to give 160.3 mg of the titled compound as a pale
yellow solid.
[0636] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.79 (d, 1H), 6.72
(s, 1H), 6.61 (d, 1H), 4.01 (brs, NH), 3.45 (brs, NH)
Preparation 20.
(S)-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-2-yl]methanol
[0637] The titled compound in the form of colorless oil was
prepared in accordance with the same procedures as Step 2 of
Preparation 2, using 2,4-dichloro-6-propylpyrimidine prepared in
Step 1 of Preparation 2 and (S)-(+)-2-pyrrolidinemethanol.
[0638] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.08 (s, 1H), 4.79
(br, 1H), 4.34 (br, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.47-3.39 (m,
2H), 2.54 (t, 2H), 2.11-2.01 (m, 3H), 1.99 (br, 1H), 1.76 (m, 2H),
1.62 (s, 1H), 0.92 (t, 3H); (Yield: 47%)
Preparation 21. (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate
[0639] 2,4-Dichloro-6-propylpyrimidine (1.5 g, 7.85 mmol) prepared
in Step 1 of Preparation 2 was dissolved in ethanol (10 ml) and
then (3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine (2.9 g, 15.7
mmol) was added thereto at 0.degree. C. The reaction mixture was
stirred at room temperature overnight and then concentrated under
reduced pressure. The resulting residue was purified with silica
gel column chromatography (n-hexane/ethyl acetate=1/1) to give 1.2
g of the titled compound as a white solid.
[0640] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.02 (s, 1H), 4.67
(br, 1H), 4.33 (br, 1H), 3.84 (br, 2H), 3.24 (br, 2H), 2.54 (t,
2H), 2.26 (m, 1H), 1.93 (br, 1H), 1.71 (m, 2H), 1.45 (s, 9H), 0.95
(t, 3H)
Preparation 22. 1H-benzo[d]imidazol-5-amine
[0641] 5-nitrobenzimidazole (200 mg, 1.2 mmol) was dissolved in a
mixed solvent of methanol and tetrahydrofuran (1:1, 10 ml) and then
palladium/charcoal (200 mg, 10 wt %) was added thereto. The
reaction mixture was stirred at room temperature under hydrogen
atmosphere (30 bar) for 3 hours and then filtered through a celite
pad. The resulting filtrate was concentrated under reduced pressure
to give 150 mg of the titled compound as a pale yellow solid. The
product was used in the subsequent reaction without further
purification.
Preparation 23. 2-methylbenzene-1,4-diamine
[0642] The titled compound (54 mg) in the form of pale yellow solid
was prepared in accordance with the same procedures as in
Preparation 22, using 2-methyl-4-nitroaniline. The product was used
in the subsequent reaction without further purification.
Preparation 24.
(S)--N-[1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl]acetamide
<Step 1> 6-butylpyrimidin-2,4-diol
[0643] A mixture of 6-butyl-2-(methylthio)pyrimidin-4(3H)-one (2.1
g, 10.6 mmol) prepared in Step 1 of Preparation 11, acetic acid (15
ml) and water (7 ml) was refluxed under stirring for 2 days. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
dried in vacuo to give 1.7 g of the titled compound as a pale
yellow solid.
[0644] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 10.87 (brs, OH),
10.78 (brs, OH), 5.31 (s, 1H), 2.27 (m, 2H), 1.50 (m, 2H), 1.27 (m,
2H), 0.88 (t, 3H)
<Step 2> 4-butyl-2,6-dichloropyrimidine
[0645] A mixture of 6-butylpyrimidin-2,4-diol (1.7 g, 10.2 mmol)
prepared in Step 1 and phosphorus oxychloride (5 ml) was refluxed
under stirring for 1 hour. The reaction mixture was cooled to room
temperature, added to ice water, and then basified to pH 8 with
sodium bicarbonate. The aqueous layer was extracted with ethyl
acetate. The resulting organic layer was dried on anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (ethyl acetate/n-hexane=1/50) to give 1.435 g of the
titled compound as brown oil.
[0646] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.16 (s, 1H), 2.75
(t, 2H), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H)
<Step 3>
(S)--N-[1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl]acetamide
[0647] The titled compound in the form of colorless oil was
prepared in accordance with the same procedures as in Preparation
13, using 4-butyl-2,6-dichloropyrimidine prepared in Step 2 and
(3S)-(-)-3-acetamidopyrrolidine.
[0648] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.25 (brs, NH),
6.02 (s, 1H), 4.54 (m, 1H), 3.64-3.41 (m, 4H), 2.54 (t, 2H), 2.24
(m, 1H), 2.04-2.01 (m, 1H+3H), 1.63 (m, 2H), 1.36 (m, 2H), 0.93 (t,
3H); (Yield: 56%)
Preparation 25. (S)-tert-butyl
1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
[0649] Diisopropylethylamine (4.46 ml, 25.6 mmol) was added to a
solution of 4-butyl-2,6-dichloropyrimidine (2.5 g, 12.1 mmol)
prepared in Step 2 of Preparation 24 and
(3S)-(-)-3-(methylamino)pyrrolidine (1.43 ml, 13.4 mmol) in
chloroform (50 ml). The reaction mixture was stirred at 50.degree.
C. for 3 hours and then di-tert-butyldicarbonate (2.66 g, 12.2
mmol) was added thereto. The reaction mixture was stirred at room
temperature overnight, washed with water, dried on anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The resulting residue was purified with silica gel column
chromatography (ethyl acetate/n-hexane=1/5) to give 3.29 g of the
titled compound as colorless oil.
[0650] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.02 (s, 1H), 4.81
(m, 1H), 3.50 (m, 4H), 2.80 (s, 3H), 2.56 (t, 2H), 2.17 (m, 1H),
1.67 (m, 2H), 1.48 (s, 9H+1H), 1.36 (m, 2H), 0.93 (t, 3H)
Preparation 26. (S)-tert-butyl
1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl(ethyl)carbamate
[0651] The titled compound in the form of pale yellow oil was
prepared in accordance with the same procedures as in Preparation
25, using 4-butyl-2,6-dichloropyrimidine prepared in Step 2 of
Preparation 24 and (3S)-(-)-3-(ethylamino)pyrrolidine.
[0652] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.00 (s, 1H), 4.64
(m, 1H), 3.91-3.14 (m, 6H), 2.55 (t, 2H), 2.18 (m, 1H), 1.65 (m,
2H), 1.47 (s, 9H+1H), 1.37 (m, 2H), 1.15 (t, 3H), 0.92 (t, 3H);
(Yield: 74%)
Preparation 27.
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]-2-hydroxyacet-
amide
<Step 1>
(S)-1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-amine
[0653] Diisopropylethylamine (1.09 ml, 6.28 mmol) was added to a
solution of 2,4-dichloro-6-propylpyrimidine (1 g, 5.23 mmol)
prepared in Step 1 of Preparation 2 and (S)-(-)-3-aminopyrrolidine
(0.55 ml, 6.28 mmol) in ethanol (30 ml), which was then stirred at
room temperature overnight. Dichloromethane was added to the
reaction mixture, which was then washed with water. The organic
layer was dried on anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The resulting residue was used
in the subsequent reaction without further purification.
<Step 2>
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]-2-hydroxyacet-
amide
[0654] A mixture of
(S)-1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-amine (1.25 g,
5.23 mmol) prepared in Step 1, glycolic acid (0.44 g, 5.79 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.1
g, 5.79 mmol), 1-hydroxybenzotriazole hydrate (0.78 g, 5.79 mmol),
diisopropylethylamine (1.8 ml, 10.3 mmol), and dichloromethane (30
ml) was stirred at room temperature for 3 days. The reaction
mixture was diluted with dichloromethane, washed with water and an
aqueous saturated solution of sodium bicarbonate, dried on
anhydrous sodium sulfate, and then concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (dichloromethane/methanol=20/1) to give 680 mg of
the titled compound as a white solid.
[0655] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.65 (s, NH), 6.03
(s, 1H), 4.65 (m, 1H), 4.14 (s, 2H), 3.80-3.41 (m, 4H), 2.54 (t,
2H), 2.39 (m, 1H), 2.10 (m, 1H), 1.72 (m, 2H), 0.96 (t, 3H)
Preparation 28. (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
[0656] 2,4-Dichloro-6-propylpyrimidine (2 g, 10.5 mmol) prepared in
Step 1 of Preparation 2 and diisopropylethylamine (4.6 ml, 26.3
mmol) were dissolved in chloroform (100 ml) and
(3S)-(-)-3-(methylamino)pyrrolidine (1.1 g, 10.5 mmol) was added
thereto at room temperature. The reaction mixture was then stirred
at 50.degree. C. for 1 hour and then cooled to room temperature.
Di-tert-butyl dicarbonate (2.5 g, 11.6 mmol) was added to the
reaction mixture, which was then was stirred at 50.degree. C. for 1
hour. Water was added to the reaction mixture, which was then
extracted with ethyl acetate. The organic layer was dried on
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The resulting residue was purified with silica
gel column chromatography (n-hexane/ethyl acetate=3/1) to give 2.1
g of the titled compound as pale yellow oil.
[0657] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.02 (s, 1H), 4.85
(brs, 1H), 4.00-3.10 (m, 4H), 2.80 (s, 3H), 2.54 (t, 2H), 2.30-2.00
(m, 2H), 1.80-1.60 (m, 2H), 1.48 (s, 9H), 0.96 (t, 3H)
Preparation 29. (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl(ethyl)carbamate
[0658] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Preparation 28, using
2,4-dichloro-6-propylpyrimidine prepared in Step 1 of Preparation 2
and (3S)-(-)-3-(ethylamino)pyrrolidine.
[0659] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.01 (s, 1H), 4.63
(brs, 1H), 3.91 (brs, 1H), 3.70-3.10 (m, 5H), 2.53 (t, 2H),
2.30-2.05 (m, 2H), 1.72 (q, 2H), 1.48 (s, 9H), 1.15 (t, 3H), 0.95
(t, 3H); (Yield: 65%)
Preparation 30.
4-chloro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-propylpyrimidin-2-amine
<Step 1>
2-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-6-propyl
pyrimidin-4(3H)-one
[0660] A mixture of 2-(methylthio)-6-propylpyrimidin-4(3H)-one (1.8
g, 9.8 mmol) prepared in Step 1 of Preparation 1 and
5-amino-2-fluorobenzotrifluoride (2 g, 11.2 mmol) was stirred at
160.degree. C. overnight. The reaction mixture was cooled to
80.degree. C. and then ethyl acetate (20 ml) was added thereto. The
reaction mixture was refluxed under stirring for 1 hour and then
filtered to give 2.2 g of the titled compound as a white solid.
[0661] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.20 (s, 1H),
7.80-7.70 (m, 1H), 7.29 (t, 1H), 5.81 (s, 1H), 2.46 (t, 2H), 1.73
(q, 2H), 0.98 (t, 3H)
<Step 2>
4-chloro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-propylpyrimidin-2-amine
[0662] A mixture of
2-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-6-propylpyrimidin-4(3H)-one
(2.2 g, 7.0 mmol) prepared in Step 1 and phosphorus oxychloride (10
ml) was stirred at 110.degree. C. overnight. The reaction mixture
was cooled to room temperature, added to ice water, and then
basified to pH 9 with sodium hydroxide. The aqueous layer was
extracted with ethyl acetate. The resulting organic layer was dried
on anhydrous sodium sulfate and then concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (n-hexane/ethyl acetate=4/1) to give 2 g of the
titled compound as a yellow solid.
[0663] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (brs, 1H),
8.09 (s, 1H), 7.71 (d, 1H), 7.16 (t, 1H), 6.69 (s, 1H), 2.64 (t,
2H), 1.76 (q, 2H), 0.98 (t, 3H)
[0664] The synthetic method for the compounds (including the salt
thereof) of the present invention is described in the following
working examples. And also, the compounds of the following working
examples and the NMR spectrum data are shown in the subsequent
Tables 1-1 to 1-51.
Example 1
[0665] A solution of
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine (20 mg, 0.08
mmol) prepared in Preparation 1 and pyrrolidine (25 mg, 0.35 mmol)
in isopropanol (1 ml) was stirred at 100.degree. C. overnight. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=4/1) to give 20 mg of the product as a pale yellow
solid.
Examples 2 to 24
[0666] The products of Examples 2 to 24 were prepared in accordance
with the same procedures as in Example 1, using
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine prepared in
Preparation 1; and (S)-2-pyrrolidinemethanol, 3-pyrrolidinol,
D-prolinol, DL-prolinol, 2-methylpyrrolidine,
(S)-2-(methoxymethyl)pyrrolidine, (R)-2-(methoxymethyl)pyrrolidine,
(S)-pyrrolidin-2-carboxamide, 3-acetamidopyrrolidine,
(3R)-(+)-3-acetamidopyrrolidine,
2,2,2-trifluoro-N-(pyrrolidin-3-yl)acetamide,
3-(ethylamino)pyrrolidine, 3-(dimethylamino)pyrrolidine,
(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine,
(S)-(+)-2-(anilinomethyl)pyrrolidine,
(3S)-(-)-3-acetamidopyrrolidine,
(3S)-(-)-3-(ethylamino)pyrrolidine,
(3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine,
3-aminopyrrolidine, 3-(diethylamino)pyrrolidine,
(3S)-(-)-3-(methylamino)pyrrolidine,
3-(N-acetyl-N-methylamino)pyrrolidine, or (S)-3-pyrrolidinol.
Example 25
[0667] A solution of
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine (20 mg, 0.08
mmol) prepared in Preparation 1 and 3-(ethylamino)pyrrolidine (0.25
g, 2.25 mmol) in isopropanol (3 ml) was stirred at 100.degree. C.
overnight. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/2) and then dissolved in ethyl acetate (2 ml). Hydrogen
chloride gas was added to the resulting solution and then filtered
to give 0.33 g of the product as a white solid.
Example 26
[0668] A mixture of
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
(0.4 g, 1.4 mmol) prepared in Preparation 2 and 6-aminoindole (0.28
g, 2.1 mmol) in n-butanol (1 ml) was refluxed under stirring
overnight. The reaction mixture was cooled to room temperature and
then filtered to give 0.25 g of the product as a pale yellow
solid.
Example 27
[0669] A mixture of
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
(20 mg, 0.07 mmol) prepared in Preparation 2 and 5-aminoindole (30
mg, 0.23 mmol) in n-butanol (1 ml) was refluxed under stirring
overnight. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) to give 5.2 mg of the product as a pale yellow
solid.
Examples 28 to 46
[0670] The products of Examples 28 to 46 were prepared in
accordance with the same procedures as in Example 27, using
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
prepared in Preparation 2; and 4-methoxyaniline, 3-methoxyaniline,
3-chloroaniline, 4-fluoro-3-nitroaniline, 3-nitroaniline,
4-chloro-3-nitroaniline, 3-aminobenzonitrile,
3-(methylthio)aniline, 3-(trifluoromethyl)aniline,
7-amino-4-methyl-2H-chromen-2-one, 5-chloro-2-methylaniline,
4-amino-2-chlorotoluene, 4-methyl-3-nitroaniline,
4-fluoro-3-(trifluoromethyl)aniline,
2-(trifluoromethyl)benzene-1,4-diamine,
5-amino-2-fluorobenzonitrile, 5-amino-2-methylbenzonitrile,
2,5-diaminobenzonitrile prepared in Preparation 19, or
2-nitro-1,4-phenylenediamine.
Example 47
[0671] (S)-tert-Butyl
1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamat-
e (10 mg, 0.02 mmol) prepared in Example 19 was dissolved in ethyl
acetate (1 ml) and then hydrogen chloride gas was added thereto.
The reaction mixture was stirred at room temperature for 1 hour and
then filtered to give 7 mg of the product as a white solid.
Examples 48 to 58
[0672] The products of Examples 48 to 58 were prepared in
accordance with the same procedures as in Example 1, using
3-(4-chloro-6-propylpyrimidin-2-ylamino)benzonitrile prepared in
Preparation 3; and
(3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine,
3-(diethylamino)pyrrolidine, (3S)-(-)-3-(methylamino)pyrrolidine,
3-(N-acetyl-N-methylamino)pyrrolidine, (S)-3-pyrrolidinol,
(R)-(-)-2-methylpyrrolidine, (3S)-(-)-3-acetamidopyrrolidine,
(3S)-(-)-3-(ethylamino)pyrrolidine,
(3S)-(-)-3-(N-tert-butoxycarbonylaminomethyl)pyrrolidine,
(R)-3-hydroxypyrrolidine hydrochloride prepared in Preparation 17,
or (S)-3-methoxypyrrolidine prepared in Preparation 18.
Example 59
[0673] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 25, using
3-(4-chloro-6-propylpyrimidin-2-ylamino)benzonitrile prepared in
Preparation 3 and 3-(methylamino)pyrrolidine.
Example 60
[0674] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 47, using
(S)-tert-Butyl
1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamate
prepared in Example 48.
Example 61
[0675] A mixture of
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride (20 mg, 0.05 mmol) prepared in Example 60,
butyric acid (7 mg, 0.08 mol),
(benzotriazole-1-yloxy)-tris-(dimethylamino)phosphonium
hexafluorophosphate (31.8 mg, 0.06 mmol), diisopropylethylamine
(25.9 mg, 0.2 mmol), and N,N-dimethylformamide (1 ml) was stirred
at room temperature overnight. Water was added to the reaction
mixture, which was then extracted with ethyl acetate. The organic
layer was washed with brine, dried on anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (n-hexane/ethyl acetate=1/1) to give 10.5 mg of the
product as a pale yellow solid.
Examples 62 to 82
[0676] The products of Examples 62 to 82 were prepared in
accordance with the same procedures as in Example 61, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride prepared in Example 60; and
cyclopentanecarboxylic acid, 1-piperidinepropionic acid, benzoic
acid, 4-fluorobenzoic acid, phenylacetic acid, 4-fluorophenylacetic
acid, 3-phenoxypropionic acid, 3-isobutoxypropanoic acid,
2-(4-benzylpiperazin-1-yl)acetic acid, 2-(piperidin-1-yl)acetic
acid, 3-benzoylpropionic acid, 4-aminophenylacetic acid,
cyclopentylacetic acid, methoxyacetic acid, 2-pyridylacetic acid,
3-pyridylacetic acid, 4-pyridylacetic acid, trans-styrylacetic
acid, 2-thiopheneacetic acid, isobutanoic acid or
3,3,3-trifluoropropanoic acid.
Example 83
[0677] A mixture of
3-(4-chloro-6-propylpyrimidin-2-ylamino)benzonitrile (20 mg, 0.07
mmol) prepared in Preparation 3, 2-pyrrolidone (9.4 mg, 0.11 mmol),
palladium acetate (0.16 mg, 0.7 .mu.mol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3 mg, 2.1
.mu.mol), cesium carbonate (71.4 mg, 0.22 mmol), and 1,4-dioxane (1
ml) was stirred at 110.degree. C. overnight and then concentrated
under reduced pressure. The resulting residue was purified with
silica gel column chromatography (n-hexane/ethyl acetate=4/1) to
give 5 mg of the product as a pale yellow solid.
Example 84
[0678]
(S)-3-[4-(3-Aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzo-
nitrile dihydrochloride (20 mg, 0.05 mmol) prepared in Example 60
and hexylaldehyde (5 mg, 0.05 mmol) in methanol (1 ml) was stirred
at room temperature for 30 minutes and sodium cyanoborohydride (9.4
mg, 0.15 mmol) was added thereto. The reaction mixture was stirred
at room temperature for 3 hours and then an aqueous saturated
solution of sodium bicarbonate was added thereto to terminate the
reaction. The reaction mixture was extracted with ethyl acetate.
The organic layer was dried on anhydrous sodium sulfate, filtered,
and then concentrated. The resulting residue was purified with
silica gel column chromatography (n-hexane/ethyl acetate=1/1) to
give 10 mg of the product as a pale yellow solid.
Examples 85 to 117
[0679] The products of Examples 85 to 117 were prepared in
accordance with the same procedures as in Example 84, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride prepared in Example 60; and propionaldehyde,
cyclohexanecarboxaldehyde, benzaldehyde, phenylacetaldehyde,
3-phenylpropionaldehyde, 3-fluorobenzaldehyde,
4-hydroxybenzaldehyde, 4-ethylbenzaldehyde, 3-methylbutanal,
pentanal, 2-methylbutanal, 2-methylpropanal, 4-methoxybenzaldehyde,
4-fluorobenzaldehyde, cyclopropanecarboxaldehyde,
cyclopropanecarboxaldehyde (2 eq.), 2-pyridinecarboxaldehyde,
3-pyridinecarboxaldehyde, 4-pyridinecarboxaldehyde, 2-ethylbutanal,
pivaldehyde, 2-fluorobenzaldehyde, 3-(trifluoromethyl)benzaldehyde,
4-(trifluoromethyl)benzaldehyde, 4-acetoxybenzaldehyde,
4-(dimethylamino)benzaldehyde, pyrrole-2-carboxaldehyde,
thiophene-2-carboxaldehyde, thiophene-3-carboxaldehyde, butanal (2
eq.), 3-(methylthio)propionaldehyde (2 eq.), butanal, or
3-(methylthio)propionaldehyde.
Example 118
[0680]
(S)-3-{4-Propyl-6-[3-(propylamino)pyrrolidin-1-yl]pyrimidin-2-ylami-
no}benzonitrile (20 mg, 0.05 mmol) prepared in Example 85 was
dissolved in ethyl acetate (1 ml) and hydrochloric acid was added
thereto. The reaction mixture was stirred at room temperature for 1
hour and then filtered to give 15.5 mg of the product as a white
solid.
Examples 119
[0681] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile prepared in Example 99.
Examples 120
[0682] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-{4-[3-(methylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile prepared in Example 50.
Example 121
[0683] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 1, using
N-(4-chloro-6-propylpyrimidin-2-yl)-1H-indol-6-amine prepared in
Preparation 4 and (3S)-(-)-3-(methylamino)pyrrolidine.
Example 122
[0684] A mixture of
(S)-1-(2-chloro-6-propylpyrimidin-4-yl)-N-methylpyrrolidin-3-amine
(0.4 g, 1.57 mmol) prepared in Preparation 5 and 6-aminoindole
(0.21 g, 1.57 mmol) in n-butanol (2 ml) was refluxed under stirring
overnight. The reaction mixture was cooled to room temperature and
then filtered. The resulting solid was dried to give 0.2 g of the
product as a pale yellow solid.
Example 123
[0685] A mixture of
(S)-1-(2-chloro-6-propylpyrimidin-4-yl)-N-methylpyrrolidin-3-amine
(1 g, 3.93 mmol) in prepared in Preparation 5 and
2-(trifluoromethyl)-1,4-phenylenediamine (0.7 g, 3.93 mmol) in
n-butanol (10 ml) was refluxed under stirring overnight. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
diluted with dichloromethane, washed with an aqueous saturated
solution of sodium bicarbonate, dried on anhydrous sodium sulfate,
and then concentrated under reduced pressure. The resulting residue
was purified with silica gel column chromatography
(dichloromethane/methanol=10/1) and then dissolved in ethyl acetate
(10 ml). Hydrogen chloride gas was added to the solution and then
filtered to give 0.4 g of the product as a white solid.
Example 124
[0686] A mixture of
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride (20 mg, 0.05 mmol) prepared in Example 60,
triethylamine (20 mg, 0.2 mmol), isopropylsulfonyl chloride (8 mg,
0.05 mmol), and N,N-dimethylformamide (1 ml) was stirred at room
temperature for 4 hours. Water was added to the reaction mixture,
which was then extracted with ethyl acetate. The organic layer was
washed with brine, dried on anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure. The resulting residue
was purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) to give 9.5 mg of the product as a pale yellow
solid.
Examples 125 and 126
[0687] The products of Examples 125 and 126 were prepared in
accordance with the same procedures as in Example 124, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride prepared in Example 60; and methanesulfonyl
chloride or 4-fluorobenzenesulfonyl chloride.
Example 127
[0688] A solution of
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride (30 mg, 0.08 mmol) prepared in Example 60 and
methyl ethyl ketone (18 mg, 0.25 mmol) in methanol (0.8 ml) was
stirred at room temperature for 30 minutes. Sodium
triacetoxyborohydride (71.2 mg, 0.34 mmol) and a catalytic amount
of acetic acid were added thereto. The reaction mixture was stirred
at room temperature overnight and then an aqueous saturated
solution of sodium bicarbonate was added thereto to terminate the
reaction. The reaction mixture was extracted with dichloromethane.
The organic layer was dried on anhydrous sodium sulfate, filtered,
and then concentrated. The resulting residue was purified with
silica gel column chromatography (dichloromethane/methanol=50/1) to
give 32 mg of the product as a white solid.
Examples 128 to 145
[0689] The products of Examples 128 to 145 were prepared in
accordance with the same procedures as in Example 127, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride prepared in Example 60; and 3-pentanone,
2,6-dimethyl-4-heptanone, 4,4-dimethyl-2-pentanone,
3-hydroxy-3-methyl-2-butanone, 4-heptanone, 2-hexanone,
5-methyl-2-hexanone, cyclohexanone, tert-butyl 2-oxoethylcarbamate,
1-benzyl-4-piperidinone, acetone, 1-benzoyl-4-piperidone,
1-acetyl-4-piperidone, cyclooctanone, cyclobutanone,
cyclopentanone, tert-butyl 3-oxoazetidine-1-carboxylate, or
2-benzyloxyacetaldehyde.
Example 146
[0690] A mixture of
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride (18 mg, 0.05 mmol) prepared in Example 60,
propionic acid (4.6, 0.06 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.8
mg, 0.06 mmol), 1-hydroxybenzotriazole hydrate (8.3 mg, 0.06 mmol),
diisopropylethylamine (19.4, 0.11 mmol), and dichloromethane (1 ml)
was stirred at room temperature overnight. The reaction mixture was
diluted with dichloromethane, washed with water and an aqueous
saturated solution of sodium bicarbonate, dried on anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (dichloromethane/methanol=70/1) to give 13.4 mg of
the product as a white solid.
Examples 147 to 167
[0691] The products of Examples 147 to 167 were prepared in
accordance with the same procedures as in Example 146, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitril-
e dihydrochloride prepared in Example 60; and pivalic acid,
2,2-dimethylbutyric acid, tiglic acid, hexanoic acid,
3-phenylpropionic acid, indole 3-acetic acid, 2-hydroxyisobutyric
acid, 3-(4-methoxyphenyl)propionic acid,
3-(4-hydroxyphenyl)propionic acid, levulinic acid, glycolic acid,
benzyloxyacetic acid, phenoxyacetic acid, N,N-dimethylglycine
hydrochloride, 3-(dimethylamino)propionic acid hydrochloride,
4-(dimethylamino)butyric acid hydrochloride, ethoxyacetic acid,
2-(2-methoxyethoxyl)acetic acid, benzyloxycarbonylaminoacetic acid,
N-(tert)-butoxycarbonyl-L-.gamma.-aminobutyric acid, or
piperidine-1,4-dicarboxylic acid mono tert-butyl ester.
Example 168
[0692] A solution of
(R)-2-chloro-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidine (20 mg,
0.083 mmol) prepared in Preparation 15 and
5-amino-2-methylbenzonitrile (12.6 mg, 0.091 mmol) in n-butanol
(0.5 ml) was reacted in a microwave reactor (450 W) for 40 minutes.
The reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=50/1) and then dissolved in ethyl acetate
(1 ml). Hydrogen chloride gas was added to the solution, which was
then stirred at room temperature for 1 hour. The reaction mixture
was filtered to give 9 mg of the product as a white solid.
Example 169
[0693] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 168, using
(R)-2-chloro-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidine
prepared in Preparation 15 and 2,5-diaminobenzonitrile prepared in
Preparation 19.
Examples 170 and 171
[0694] The products of Examples 170 and 171 were prepared in
accordance with the same procedures as in Example 1, using
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-methylbenzonitrile
prepared in Preparation 6; and (3S)-(-)-3-(methylamino)pyrrolidine
or (3S)-(-)-3-(ethylamino)pyrrolidine.
Example 172
[0695] A mixture of
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-methylbenzonitrile (20
mg, 0.07 mmol) prepared in Preparation 6 and
(3S)-(-)-3-(ethylamino)pyrrolidine (8 mg, 0.07 mmol) in isopropanol
(1 ml) was refluxed under stirring overnight. The reaction mixture
was cooled to room temperature and then filtered. The resulting
pale yellow solid was dried to give to 12 mg of the product.
Example 173
[0696] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 172, using
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-methylbenzonitrile
prepared in Preparation 6 and 3-(ethylamino)pyrrolidine.
Example 174
[0697] A solution of
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-methylbenzonitrile (200
mg, 0.7 mmol) prepared in Preparation 6 and
(3S)-(-)-3-(methylamino)pyrrolidine (69.9 mg, 0.7 mmol) in
isopropanol (1.4 ml) was reacted in a microwave reactor (450 W) for
30 minutes. The reaction mixture was cooled to room temperature and
then filtered to give 209 mg of the product as a pale gray
solid.
Examples 175 and 176
[0698] The products of Examples 175 and 176 were prepared in
accordance with the same procedures as in Example 1, using
N.sup.1-(4-chloro-6-propylpyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
prepared in Preparation 7; and (3S)-(-)-3-(methylamino)pyrrolidine
or (3S)-(-)-3-(ethylamino)pyrrolidine.
Example 177
[0699] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 172, using
N.sup.1-(4-chloro-6-propylpyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
prepared in Preparation 7 and
(3S)-(-)-3-(ethylamino)pyrrolidine.
Example 178
[0700] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 172, using
3-(4-chloro-6-propylpyrimidin-2-yl)benzonitrile prepared in
Preparation 3 and (3S)-(-)-3-(methylamino)pyrrolidine.
Example 179
[0701] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 47, using
(S)-tert-butyl
{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}methylc-
arbamate prepared in Example 56.
Examples 180 and 181
[0702] The products of Examples 180 and 181 were prepared in
accordance with the same procedures as in Example 172, using
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-fluorobenzonitrile
prepared in Preparation 8; and (3S)-(-)-3-(methylamino)pyrrolidine
or (3S)-(-)-3-(ethylamino)pyrrolidine.
Example 182
[0703] A solution of
5-(4-chloro-6-propylpyrimidin-2-ylamino)-2-fluorobenzonitrile (0.2
g, 0.67 mmol) prepared in Preparation 8 and
3-(tert-butoxycarbonylamino)pyrrolidine (0.2 g, 1.0 mmol) in
isopropanol (3 ml) was stirred at 100.degree. C. overnight. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) and then dissolved in ethyl acetate (1 ml). Hydrogen
chloride gas was added to the solution, which was then stirred at
room temperature for 1 hour. The reaction mixture was filtered to
give 0.1 g of the product as a white solid.
Example 183
[0704] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 1, using
4-chloro-N-(4-fluorophenyl)-6-methylpyrimidin-2-amine prepared in
Preparation 10 and pyrrolidine.
Example 184
<Step 1>
(2S,4R)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]-4-hydroxypyrro-
lidin-2-carboxylic acid
[0705] A solution of
4-chloro-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine (50 mg, 0.19
mmol) prepared in Preparation 1, trans-4-hydroxy-L-proline (27.3
mg, 0.21 mmol), and diisopropylethylamine (49 .mu.l, 0.38 mmol) in
isopropanol (1.0 ml) was reacted in a microwave reactor (500 W) for
30 minutes. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=30/1) to give 30 mg of the titled
compound.
<Step 2>
(2S,4R)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]-4-hydroxypyrro-
lidin-2-carboxylic acid methyl ester
[0706] A solution of
(2S,4R)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]-4-hydroxypyrro-
lidin-2-carboxylic acid (30 mg, 0.08 mmol) prepared in Step 1 and a
catalytic amount of sulfuric acid in methanol (3 ml) was refluxed
under stirring overnight. The reaction mixture was neutralized with
an aqueous saturated solution of sodium bicarbonate and then
extracted with dichloromethane. The organic layer was dried on
anhydrous sodium sulfate, filtered, and then concentrated to give
30 mg of the titled compound. The resulting product was used in the
subsequent reaction without further purification.
<Step 3> (3R,5S)-1-[2-(4-fluorophenyl)-6-propyl
pyrimidin-4-yl]-5-(hydroxymethyl)pyrrolidin-3-ol
[0707] A solution of
(2S,4R)-1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]-4-hydroxypyrro-
lidin-2-carboxylic acid methyl ester (20 mg, 0.05 mmol) prepared in
Step 2 and sodium borohydride (12.1 mg, 0.32 mmol) in ethanol (1
ml) was stirred for 3 hours and then an aqueous saturated solution
of ammonium chloride was added thereto to terminate the reaction.
The reaction mixture was extracted with dichloromethane. The
organic layer was dried on anhydrous sodium sulfate, filtered, and
then concentrated. The resulting residue was purified with silica
gel column chromatography (dichloromethane/methanol=30/1) to give
14 mg of the titled compound as a white solid.
Example 185
[0708] A mixture of
N-(4-chloro-6-propylpyrimidin-2-yl)-1H-indol-6-amine (13 mg, 0.05
mmol) prepared in Preparation 4, (S)-pyrrolidin-2-ylmethanol (9.1
mg, 0.09 mmol), diisopropylethylamine (17.6 mg, 14 mol) in
isopropanol (0.5 ml) was reacted in a microwave reactor (300 W) for
2 hours. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=2/1) to give 17.1 mg of the product as a yellow liquid.
Examples 186 to 192
[0709] The products of Examples 186 to 192 were prepared in
accordance with the same procedures as in Example 185, using
N-(4-chloro-6-propylpyrimidin-2-yl)-1H-indol-6-amine prepared in
Preparation 4; and (R)-pyrrolidin-2-ylmethanol,
pyrrolidin-2-ylmethanol, (R)-2-(methoxymethyl)pyrrolidine,
(S)-2-(methoxymethyl)pyrrolidine, 2-methylpyrrolidine,
(S)-methylpyrrolidine-2-carboxylate, or
N-(pyrrolidin-3-yl)acetamide.
Example 193
[0710] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 26, using
(S)-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-2-yl]methanol
prepared in Preparation 20 and 6-aminoindole.
Examples 194 to 215
[0711] The products of Examples 194 to 215 were prepared in
accordance with the same procedures as in Example 27, using
(S)-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-2-yl]methanol
prepared in Preparation 20; and 3-aminobenzonitrile,
3-(methylthio)aniline, 4-chloro-3-nitroaniline, 5-aminoindole,
1H-benzo[d]imidazol-5-amine prepared in Preparation 22,
5-amino-2-(trifluoromethyl)benzimidazole, 4-methoxyaniline,
3-chloroaniline, 3-methoxyaniline, 3-(trifluoromethyl)aniline,
5-chloro-2-methylaniline, 5-methoxy-2-methylaniline,
4-amino-2-chlorotoluene, 3-nitroaniline, 4-fluoro-3-nitroaniline,
6-aminoquinoline, 4-methyl-3-nitroaniline,
2-(trifluoromethyl)benzene-1,4-diamine,
3-nitro-1,4-phenylenediamine, 5-amino-2-methylbenzonitrile,
5-amino-2-fluorobenzonitrile, or 2,5-diaminobenzonitrile prepared
in Preparation 19.
Example 216
[0712] 3-Aminoquinoline (22 mg, 0.15 mmol) was added to a mixture
of (S)-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-2-yl]methanol
(30 mg, 0.12 mmol) prepared in Preparation 20, palladium acetate
(0.5 mg, 2 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(2.1 mg, 3 mol %), cesium carbonate (78 mg, 0.24 mmol), and
anhydrous 1,4-dioxane (1 ml). The reaction mixture was stirred in a
microwave reactor (600 W) for 1 hour. The reaction mixture was
cooled to room temperature, suspended in dichloromethane, and then
filtered through a celite pad. The resulting filtrate was
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) to give 29.8 mg of the product as a pale yellow
solid.
Example 217
<Step 1>
(S)-1-(6-{4-[2-(hydroxylmethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}indolin-1-yl)ethanone
[0713] The titled compound in the form of pale yellow oil was
prepared in accordance with the same procedures as in Example 27,
using
(S)-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-2-yl]methanol
prepared in Preparation 20 and 1-acetyl-6-aminoindoline. The
product was used in the subsequent reaction without further
purification.
<Step 2>
(S)-2-{1-[2-(indolin-6-ylamino)-6-propylpyrimidin-4-yl]pyrrolidin-2-yl}me-
thanol
[0714] A mixture of
(S)-1-(6-{4-[2-(hydroxylmethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylami-
no}indolin-1-yl)ethanone (45.7 mg, 0.12 mmol) prepared in Step 1
and 3N hydrochloric acid solution (1.5 ml) was refluxed under
stirring for 2 hours. The reaction mixture was cooled to room
temperature, basified to pH 8-9 with a 2N sodium hydroxide
solution, and then extracted with dichloromethane. The resulting
organic layer was dried on anhydrous sodium sulfate, and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=40/1) to give 19.2 mg of the titled
compound as colorless oil.
Example 218
[0715] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-{4-[3-(cyclohexylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino-
}benzonitrile prepared in Example 135.
Example 219
[0716] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}-
benzonitrile prepared in Example 138.
Example 220
[0717] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 47, using
(S)-tert-butyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
ethylcarbamate prepared in Example 136.
Example 221
[0718] A solution of
(S)-3-{4-[3-(1-benzylpiperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimid-
in-2-ylamino}benzonitrile (110 mg, 0.22 mmol) prepared in Example
137 and palladium/charcoal (11 mg, 10 wt %) in methanol (2.2 ml)
was stirred at room temperature under hydrogen atmosphere for 5
hours and then filtered through a celite pad. The resulting
filtrate was concentrated under reduced pressure. The resulting
residue was purified with silica gel column chromatography
(dichloromethane/methanol=10/1) to give 28 mg of the product as a
white solid.
Example 222
[0719] A solution of
(S)-3-{4-[3-(piperidin-4-ylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}benzonitrile (15 mg, 0.04 mmol) prepared in Example 221 and
butyraldehyde (2.7 mg, 0.04 mmol) in methanol (0.4 ml) was stirred
at room temperature for 30 minutes and then sodium
triacetoxyborohydride (15.7 mg, 0.08 mmol) was added thereto. The
reaction mixture was stirred at room temperature for 1 hour and
then an aqueous saturated solution of sodium bicarbonate was added
thereto to terminate the reaction. The reaction mixture was
extracted with dichloromethane. The resulting organic layer was
dried on anhydrous sodium sulfate, filtered, and then concentrated.
The resulting residue was purified with silica gel column
chromatography (dichloromethane/methanol=50/1) to give 4.0 mg of
the product as a white solid.
Example 223
[0720] A solution of
3-(4-butyl-6-chloropyrimidin-2-ylamino)benzonitrile (20 mg, 0.07
mmol) prepared in Preparation 11 and
(S)--N-(pyrrolidin-3-yl)acetamide (9.8 mg, 0.08 mmol) in
isopropanol (0.3 ml) was reacted in a microwave reactor (450 W) for
30 minutes. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=50/1) to give 26.7 mg of the product as a
white solid.
Examples 224 to 227
[0721] The products of Examples 224 to 227 were prepared in
accordance with the same procedures as in Example 223, using
3-(4-butyl-6-chloropyrimidin-2-ylamino)benzonitrile prepared in
Preparation 11; and (S)-pyrrolidin-2-ylmethanol,
(R)-2-methylpyrrolidine, (3S)-(-)-3-(methylamino)pyrrolidine, or
(S)-tert-butyl pyrrolidin-3-ylcarbamate.
Examples 228 to 232
[0722] The products of Examples 228 to 232 were prepared in
accordance with the same procedures as in Example 223, using
5-(4-butyl-6-chloropyrimidin-2-ylamino)-2-methylbenzonitrile
prepared in Preparation 12; and (S)--N-(pyrrolidin-3-yl)acetamide,
(S)-pyrrolidin-2-ylmethanol, (R)-2-methylpyrrolidine,
(3S)-(-)-3-(methylamino)pyrrolidine, or (S)-tert-butyl
pyrrolidin-3-ylcarbamate.
Example 233
[0723] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 47, using
(S)-tert-butyl
1-[6-butyl-2-(3-cyanophenylamino)pyrimidin-4-yl]pyrrolidin-3-ylcarbamate
prepared in Example 227.
Example 234
[0724] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 47, using
(S)-tert-butyl
1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]pyrrolidin-3-ylc-
arbamate prepared in Example 232.
Examples 235 to 237
[0725] The products of Examples 235 to 237 were prepared in
accordance with the same procedures as in Example 127, using
(S)-3-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]benzonitrile
dihydrochloride prepared in Example 233; and acetone, acetaldehyde
(2 eq.), or cyclopropanecarboxaldehyde.
Examples 238 to 240
[0726] The products of Examples 238 to 240 were prepared in
accordance with the same procedures as in Example 127, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-butylpyrimidin-2-ylamino]-2-methylben-
zonitrile dihydrochloride prepared in Example 234; and acetone,
acetaldehyde (2 eq.), or cyclopropanecarboxaldehyde.
Example 241
[0727] A solution of
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
(20 mg, 0.07 mmol) prepared in Preparation 13 and
4-chloro-3-nitroaniline (13.5 mg, 0.08 mmol) in n-butanol (0.5 ml)
was reacted in a microwave reactor (450 W) for 50 minutes. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=50/1) to give 26.1 mg of the product as a
pale yellow solid.
Examples 242 to 259
[0728] The products of Examples 242 to 259 were prepared in
accordance with the same procedures as in Example 241, using
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 13; and 3-(methylthio)aniline,
6-aminoindole, 3-(trifluoromethyl)aniline,
7-amino-4-methyl-2H-chromen-2-one, 2-chloro-4-aminotoluene,
3-nitroaniline, 4-fluoro-3-nitroaniline, 4-methyl-3-nitroaniline,
benzyl 5-amino-2-methoxyphenylcarbamate,
5-amino-2-fluorobenzonitrile, 5-amino-2-methylbenzonitrile,
4-fluoro-3-(trifluoromethyl)aniline, 2-nitrobenzene-1,4-diamine,
5-chloro-2-methylaniline, 3-aminobenzamide,
3-amino-N-methylbenzamide, 3-aminobenzylamine, or
3-amino-4-chlorobenzamide.
Example 260
[0729] A solution of
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
(20 mg, 0.08 mmol) prepared in Preparation 13 and
2,5-diaminobenzonitrile (9.5 mg, 0.07 mmol) prepared in Preparation
19 in n-butanol (0.5 ml) was reacted in a microwave reactor (450 W)
for 40 minutes. The reaction mixture was cooled to room temperature
and then filtered to give 17.1 mg of the product as a yellow
solid.
Examples 261 and 262
[0730] The products of Examples 261 and 262 were prepared in
accordance with the same procedures as in Example 260, using
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 13; and
2-(trifluoromethyl)-1,4-phenylenediamine or
3,5-diaminobenzonitrile.
Examples 263 to 273
[0731] The products of Examples 263 to 273 were prepared in
accordance with the same procedures as in Example 26, using
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 13; and 6-aminoindole,
5-chloro-2-methylaniline, 4-fluoro-3-(trifluoromethyl)aniline,
4-fluoro-1,3-diaminobenzene, 3-(trifluoromethyl)aniline,
5-(trifluoromethyl)-1,3-phenylenediamine, 3-nitroaniline,
1,4-phenylenediamine, 5-amino-2-chlorophenol, 4-aminosalicylic
acid, or 5-aminosalicylic acid.
Examples 274 to 282
[0732] The products of Examples 274 to 282 were prepared in
accordance with the same procedures as in Example 27, using
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 13; and 5-amino-o-cresol,
4-amino-2-chlorophenol, 4-amino-o-cresol, 4-amino-2-fluorophenol,
3-hydroxy-4-methoxyaniline, 3-methoxy-4-methylaniline,
4-methyl-3-(trifluoromethyl)aniline, 3,4-dimethylaniline, or
3-fluoro-4-methylaniline.
Example 283
[0733] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
248.
Example 284
[0734] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(4-methyl-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
249.
Example 285
[0735] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
252.
Example 286
[0736] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
254.
Example 287
[0737] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
acetamide prepared in Example 54.
Example 288
[0738] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
241.
Example 289
[0739] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 221, using
(S)-benzyl
5-[4-(3-acetamidopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methoxyp-
henylcarbamate prepared in Example 250.
Example 290
[0740] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(S)--N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
241.
Example 291
[0741] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(S)--N-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
248.
Example 292
[0742] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(S)--N-{1-[2-(4-methyl-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
249.
Example 293
[0743] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 260, using
N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 14 and 2-nitrobenzene-1,4-diamine.
Examples 294 to 309
[0744] The products of Examples 294 to 309 were prepared in
accordance with the same procedures as in Example 27, using
N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 14; and 3-aminobenzonitrile,
3-nitroaniline, 4-fluoro-3-nitroaniline, 4-chloro-3-nitroaniline,
3-methoxyaniline, 5-methoxy-2-methylaniline, 4-methoxyaniline,
3-(trifluoromethyl)aniline, 3-chloroaniline,
5-chloro-2-methylaniline, 2-chloro-4-aminotoluene,
3-(methylthio)aniline, 5-aminoindole,
5-amino-2-(trifluoromethyl)benzimidazole, 6-aminoquinoline, or
7-amino-4-methyl-2H-chromen-2-one.
Example 310
[0745] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 216, using
N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 14 and 3-aminoquinoline.
Examples 311 and 312
[0746] The products of Examples 311 and 312 were prepared in
accordance with the same procedures as in Example 26, using
N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 14 and 2,5-diaminobenzonitrile prepared in
Preparation 19 or 4-fluoro-1,3-phenylenediamine.
Examples 313 to 329
[0747] The products of Examples 313 to 329 were prepared in
accordance with the same procedures as in Example 241, using
(R)-2-chloro-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidine
prepared in Preparation 15; and 4-chloro-3-nitroaniline,
3-(methylthio)aniline, 6-aminoindole, 3-(trifluoromethyl)aniline,
7-amino-4-methyl-2H-chromen-2-one, 2-chloro-4-aminotoluene,
3-nitroaniline, 4-fluoro-3-nitroaniline, 4-methyl-3-nitroaniline,
4-fluoro-3-(trifluoromethyl)aniline,
2-(trifluoromethyl)-1,4-phenylenediamine, benzyl
5-amino-2-methoxyphenylcarbamate, 5-amino-2-fluorobenzonitrile,
5-amino-2-methylbenzonitrile, 2,5-diaminobenzonitrile prepared in
Preparation 19, 2-nitrobenzene-1,4-diamine, or
1-(6-aminoindolin-1-yl)ethanone.
Example 330
[0748] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 216, using
(R)-2-chloro-4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidine
prepared in Preparation 15 and 5-chloro-2-methylaniline.
Example 331
[0749] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(R)-benzyl
2-methoxy-5-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]phen-
ylcarbamate prepared in Example 324.
Example 332
[0750] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(R)--N-(4-chloro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine prepared in Example 313.
Example 333
[0751] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(R)--N-(4-fluoro-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine prepared in Example 320.
Example 334
[0752] The product in the form of pale yellow oil was prepared in
accordance with the same procedures as in Example 221, using
(R)--N-(4-methyl-3-nitrophenyl)-4-(2-methylpyrrolidin-1-yl)-6-propylpyrim-
idin-2-amine prepared in Example 321.
Example 335
[0753] A solution of
(S)-3-(4-{3-[2-(benzyloxy)ethylamino]pyrrolidin-1-yl}-6-propylpyrimidin-2-
-ylamino)benzonitrile (60 mg, 0.13 mmol) prepared in Example 145,
palladium/charcoal (12 mg, 10 wt %) and a catalytic amount of conc.
HCl in methanol (6.0 ml) was stirred at room temperature under
hydrogen atmosphere overnight and then filtered through a celite
pad. The resulting filtrate was concentrated under reduced
pressure. The resulting residue was dissolved in ethyl acetate (1
ml) and then hydrogen chloride gas was added thereto. The reaction
mixture was stirred at room temperature for 1 hour and then
filtered to give 39.0 mg of the product as a white solid.
Example 336
[0754] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-5-{4-butyl-6-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-2-ylamino}-2-
-methylbenzonitrile prepared in Example 229.
Examples 337 and 338
[0755] The products of Examples 337 and 338 were prepared in
accordance with the same procedures as in Example 223, using
N.sup.1-(4-butyl-6-chloropyrimidin-2-yl)-3-nitrobenzene-1,4-diamine
prepared in Preparation 16; and (S)--N-(pyrrolidin-3-yl)acetamide
or (3S)-(-)-3-(methylamino)pyrrolidine.
Example 339
[0756] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-(4-{3-[(1H-pyrrol-2-yl)methylamino]pyrrolidin-1-yl}-6-propylpyrimid-
in-2-ylamino)benzonitrile prepared in Example 111.
Example 340
[0757] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 168, using
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
prepared in Preparation 2 and 2-nitro-1,4-phenylenediamine.
Example 341
[0758] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol prepared in Example 208.
Example 342
[0759] A mixture of (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate (30 mg,
0.09 mmol) prepared in Preparation 21,
5-(trifluoromethyl)benzene-1,3-diamine (19.4 mg, 0.11 mmol), and
n-butanol (1 ml) was refluxed under stirring overnight. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=20/1) and then dissolved in ethyl acetate
(2 ml). Hydrogen chloride gas was added to the solution. The
reaction mixture was stirred at room temperature for 1 hour and
then filtered to give 11.1 mg of the product as a white solid.
Examples 343 to 361
[0760] The products of Examples 343 to 361 were prepared in
accordance with the same procedures as in Example 342, using
(S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate
prepared in Preparation 21; and 2-methylbenzene-1,4-diamine
prepared in Preparation 23, 4-chloro-3-nitroaniline,
3-(methylthio)aniline, 6-aminoindole, 3-(trifluoromethyl)aniline,
5-chloro-2-methylaniline, 4-amino-2-chlorotoluene, 3-nitroaniline,
4-methyl-3-nitroaniline, 2-(trifluoromethyl)benzene-1,4-diamine,
5-amino-2-fluorobenzonitrile, 5-amino-2-methylbenzonitrile,
2,5-diaminobenzonitrile prepared in Preparation 19,
(5-amino-2-methoxyphenyl)carbamic acid benzyl ester,
4-fluoro-3-(trifluoromethyl)aniline, 4-fluoro-3-nitroaniline,
2-nitro-1,4-phenylenediamine, 3,5-bis(trifluoromethyl)aniline or
3,5-dimethoxyaniline.
Example 362
[0761] A solution of (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate (30 mg,
0.09 mmol) prepared in Preparation 21, 3,5-diaminobenzonitrile
(14.6 mg, 0.11 mmol) in butanol (1 ml) was refluxed under stirring
overnight. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. Hydrochloric acid was
added at 0.degree. C. to the resulting residue. The suspension was
stirred at room temperature for 2 hours and then filtered. The
resulting solid was washed with ethyl acetate. The solid was
dissolved in dichloromethane (10 ml) and then an aqueous saturated
solution of sodium bicarbonate was added thereto. The solution was
stirred for 30 minutes and then extracted with dichloromethane. The
organic layer was dried on anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography (n-hexane/ethyl
acetate=1/1) to give 11.7 mg of the titled compound as a white
solid.
Example 363
[0762] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 362, using
(S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-ylcarbamate
prepared in Preparation 21 and 3-aminobenzenesulfonamide.
Example 364
[0763] Palladium/charcoal (25 mg, 10 wt %) was added to a solution
of
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-propylpyrimi-
din-2-amine (20 mg, 0.06 mmol) prepared in Example 32 in methanol
(2 ml). The reaction mixture was stirred at room temperature under
hydrogen atmosphere (30 bar) for 3 hours and then filtered through
a celite pad. The resulting filtrate was concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (n-hexane/ethyl acetate=1/1) to give 4.4 mg of the
product as a pale yellow solid.
Example 365
[0764] The product (4.4 mg) in the form of pale yellow solid was
prepared in accordance with the same procedures as in Example 364,
using
(S)--N-(4-fluoro-3-nitrophenyl)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-pr-
opylpyrimidin-2-amine prepared in Example 31.
Example 366
[0765] The product (7.2 mg) in the form of pale yellow solid was
prepared in accordance with the same procedures as in Example 364,
using
(S)-4-[2-(methoxymethyl)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine prepared in Example 40.
Example 367
<Step 1> (S)-benzyl
2-methoxy-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-yla-
mino}phenylcarbamate
[0766] The titled compound (15 mg) in the form of pale yellow oil
was prepared in accordance with the same procedures as in Example
27, using
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
prepared in Preparation 2 and (5-amino-2-methoxyphenyl)carbamic
acid benzyl ester.
<Step 2>
(S)-4-methoxy-N.sup.1-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrim-
idin-2-yl}benzene-1,3-diamine
[0767] The titled compound (7.8 mg) in the form of pale yellow
solid was prepared in accordance with the same procedures as in
Example 364, using (S)-benzyl
2-methoxy-5-{4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propyl
pyrimidin-2-ylamino}phenylcarbamate prepared in Step 1.
Example 368
[0768] The titled compound in the form of pale yellow oil was
prepared in accordance with the same procedures as in Example 217,
using
(S)-2-chloro-4-[2-(methoxymethyl)pyrrolidin-1-yl]-6-propylpyrimidine
prepared in Preparation 2 and 1-acetyl-6-aminoindoline.
Example 369
[0769] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 364, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-methyl-3-nitrophenyl)-6-propylpyrimid-
in-2-amine dihydrochloride prepared in Example 351.
Example 370
<Step 1>
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-fluoro-
benzene-1,3-diamine
[0770] The titled compound in the form of pale yellow solid was
prepared in accordance with the same procedures as in Example 364,
using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine dihydrochloride prepared in Example 358.
<Step 2>
(S)--N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-fluoro-
benzene-1,3-diamine dihydrochloride
[0771] The titled compound in the form of pale yellow solid was
prepared in accordance with the same procedures as in Example 118,
using
N.sup.1-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-4-fluorobenze-
ne-1,3-diamine prepared in Step 1.
Example 371
[0772] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-3-amino-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-amino]benzo-
nitrile prepared in Example 362.
Example 372
[0773] Cyclopropanecarboxaldehyde (6.51 ml, 0.09 mmol) was added to
a solution of
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-chloro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine dihydrochloride (30 mg, 0.07 mmol) prepared in Example
344 in methanol (1 ml). The reaction mixture was stirred at room
temperature for 30 minutes and then sodium cyanoborohydride (6.84
mg, 0.11 mmol) was added thereto. The reaction mixture was stirred
at room temperature overnight and then a 1N hydrochloric acid
solution was added thereto. The reaction mixture was stirred for 30
minutes, neutralized with a 1N sodium hydroxide solution, and then
extracted with ethyl acetate. The organic layer was dried on
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure. The resulting residue was purified with silica
gel column chromatography (ethyl acetate/methanol=20/1) to give 5.9
mg of the product as a pale yellow solid.
Example 373
[0774] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-propylpyrimid-
in-2-amine dihydrochloride prepared in Example 358.
Example 374
[0775] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4-methyl-3-nitrophenyl)-6-propylpyrimid-
in-2-amine dihydrochloride prepared in Example 351.
Example 375
[0776] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-amin-
e dihydrochloride prepared in Example 350.
Example 376
[0777] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-fluorobe-
nzonitrile dihydrochloride prepared in Example 353.
Example 377
[0778] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride prepared in Example 354.
Example 378
[0779] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidin-
-2-amine dihydrochloride prepared in Example 345.
Example 379
[0780] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl]pyri-
midin-2-amine dihydrochloride prepared in Example 347.
Example 380
[0781] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(5-chloro-2-methylphenyl)-6-propylpyrimi-
din-2-amine dihydrochloride prepared in Example 348.
Example 381
[0782] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-(3-chloro-4-methylphenyl)-6-propylpyrimi-
din-2-amine dihydrochloride prepared in Example 349.
Example 382
[0783] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 372, using
(S)-4-(3-aminopyrrolidin-1-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-p-
ropylpyrimidin-2-amine dihydrochloride prepared in Example 357.
Example 383
[0784] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 364, using
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophen-
yl)-6-propylpyrimidin-2-amine prepared in Example 374.
Example 384
[0785] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 364, using
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(3-nitrophenyl)-6-pro-
pylpyrimidin-2-amine prepared in Example 375.
Example 385
[0786] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-fluorobenzonitrile prepared in Example 376.
Example 386
[0787] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-N-(4-methyl-3-nitrophen-
yl)-6-propylpyrimidin-2-amine prepared in Example 374.
Example 387
<Step 1> tert-butyl
1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamate
[0788] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Example 1, using
3-(4-chloro-6-propylpyrimidin-2-ylamino)benzonitrile prepared in
Preparation 3 and 3-(tert-butoxycarbonylamino)pyrrolidine.
<Step 2>
3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile
dihydrochloride
[0789] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Example 47, using
tert-butyl
1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylcarbamate
prepared in Step 1.
<Step 3>
3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile
[0790] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Example 372, using
3-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile
dihydrochloride prepared in Step 2.
<Step 4>
3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile dihydrochloride
[0791] The titled compound in the form of white solid was prepared
in accordance with the same procedures as in Example 118, using
3-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylam-
ino}benzonitrile prepared in Step 3.
Examples 388 to 392
[0792] The products of Examples 388 to 392 were prepared in
accordance with the same procedures as in Example 1, using
4-chloro-6-ethyl-N-(4-fluorophenyl)pyrimidin-2-amine prepared in
Preparation 9; and L-prolinol, (3S)-(-)-3-acetamidopyrrolidine,
(S)-2-(methoxymethyl)pyrrolidine, 2-methylpyrrolidine, or
(3S)-(-)-3-(ethylamino)pyrrolidine.
Example 393
[0793] A solution of
(R)-3-[4-(3-hydroxypyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitr-
ile (30 mg, 0.09 mmol) prepared in Example 57, phenol (13.1 mg,
0.14 mmol), and cyanomethylenetributylphosphorane (37 .mu.l, 0.14
mmol) in toluene (0.5 mol) was stirred in a microwave reactor (400
W) for 1 hour. The reaction mixture was cooled to room temperature
and then concentrated under reduced pressure. The resulting residue
was purified with silica gel column chromatography
(dichloromethane/methanol=100/1) to give 4.0 mg of the product as
pale yellow oil.
Example 394
[0794] The product was prepared in accordance with the same
procedures as in Example 118, using
(S)--N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}-
-2-(pyridin-3-yl)acetamide prepared in Example 77.
Example 395
[0795] A catalytic amount of palladium/charcoal was added to a
solution of (S)-benzyl
2-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-ylamino}-
-2-oxoethylcarbamate (120 mg, 0.2 mmol) prepared in Example 165 in
methanol (3 ml). The reaction mixture was stirred under hydrogen
atmosphere at room temperature overnight. The reaction mixture was
filtered through a celite pad. The resulting filtrate was
concentrated under reduced pressure to give 21.2 mg of the product
as colorless oil.
Example 396
[0796] The product was prepared in accordance with the same
procedures as in Example 118, using
(S)-3-(4-{3-[4-(dimethylamino)benzylamino]pyrrolidin-1-yl}-6-propylpyrimi-
din-2-ylamino)benzonitrile prepared in Example 110.
Example 397
[0797] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-2-fluoro-5-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}benzonitrile prepared in Example 214.
Example 398
[0798] The product in the form of pale red solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-{1-[2-(4-amino-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin--
2-yl}methanol prepared in Example 212.
Example 399
[0799] The product in the form of pale red solid was prepared in
accordance with the same procedures as in Example 221, using
(S)-{1-[2-(4-methyl-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol prepared in Example 210.
Example 400
[0800] The product in the form of pale red solid was prepared in
accordance with the same procedures as in Example 221, using
(S)-{1-[2-(4-fluoro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol prepared in Example 208.
Example 401
[0801] The product in the form of pale red solid was prepared in
accordance with the same procedures as in Example 221, using
(S)-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-
-2-yl}methanol prepared in Example 196.
Example 402
[0802] Dess-Martin periodinane (449 mg, 1.06 mmol) was added at
room temperature to a solution of
(S)-3-{4-[2-(hydroxymethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}b-
enzonitrile (238 mg, 0.71 mmol) prepared in Example 194 in
dichloromethane (3.5 ml), and then stirred for 4 hours. Dess-Martin
periodinane (449 mg, 1.06 mmol) was further added at room
temperature to the reaction mixture, which was then stirred
overnight. The reaction mixture was diluted with ethyl ether,
washed with an aqueous saturated solution of sodium bicarbonate,
dried on anhydrous sodium sulfate, and then concentrated under
reduced pressure. The resulting residue was purified with silica
gel column chromatography (n-hexane/ethyl acetate=1/1) to give 154
mg of the product as pale yellow oil.
Example 403
[0803] A solution of
(S)-3-[4-(2-formylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitri-
le (20 mg, 0.06 mmol) prepared in Example 402 and methylamine
hydrochloride (4.8 mg, 0.07 mmol) in methanol (0.5 ml) was stirred
at room temperature for 30 minutes. Sodium triacetoxyborohydride
(25.3 mg, 0.12 mmol) and acetic acid (5.1 .mu.l, 0.09 mmol) were
added to the reaction mixture, which was then stirred at room
temperature overnight. An aqueous saturated solution of sodium
bicarbonate was added to the reaction mixture, which was then
extracted with dichloromethane. The organic layer was dried on
anhydrous sodium sulfate and then concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (ethyl acetate/methanol=1/1) to give 7 mg of the
product as colorless oil.
Examples 404 to 407
[0804] The products of Examples 404 to 407 were prepared in
accordance with the same procedures as in Example 403, using
(S)-3-[4-(2-formylpyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitri-
le prepared in Example 402; and cyclobutylamine hydrochloride,
4-fluorobenzylamine, n-propylamine, or ethanolamine.
Example 408
[0805] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
Example
N-{1-[2-(3-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide prepared in Example 294.
Example 409
[0806] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
N-{1-[2-(3-nitrophenylamino)-6-propylpyrimidin-4-yl]pyrrolidin-3-yl}aceta-
mide prepared in Example 295.
Example 410
[0807] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
N-{1-[2-(4-chloro-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
297.
Example 411
[0808] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-nitro-
benzene-1,4-diamine prepared in Example 328.
Example 412
[0809] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(R)--N.sup.1-[4-(2-methylpyrrolidin-1-yl)-6-propylpyrimidin-2-yl]-3-(trif-
luoromethyl)benzene-1,4-diamine prepared in Example 323.
Example 413
[0810] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-5-{4-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2--
ylamino}-2-methylbenzonitrile prepared in Example 377.
Examples 414 to 421
[0811] The products of Examples 414 to 421 were prepared in
accordance with the same procedures as in Example 84, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride prepared in Example 354; and
propionaldehyde, 3-(methylthio)propionaldehyde,
pyrrole-2-carboxaldehyde, 4-hydroxybenzaldehyde, acetone,
cyclobutanone, cyclopentanone, or cyclohexanone.
Example 422
[0812] A solution of
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride (20 mg, 0.05 mmol) prepared in Example
354 and pentanal (4.3 mg, 0.05 mmol) in methanol (1 ml) was stirred
at room temperature for 30 minutes and then sodium cyanoborohydride
(9.4 mg, 0.15 mmol) was added thereto. The reaction mixture was
stirred at room temperature for 3 hours and then an aqueous
saturated solution of sodium bicarbonate was added thereto to
terminate the reaction. The reaction mixture was extracted with
ethyl acetate. The resulting organic layer was dried on anhydrous
sodium sulfate, filtered, and then concentrated. The resulting
residue was purified with silica gel column chromatography
(n-hexane/ethyl acetate=1/1), and then dissolved in ethyl acetate
(1 ml). Hydrogen chloride gas was added to the solution. The
reaction mixture was stirred at room temperature for 1 hour and
then filtered to give 8 mg of the product as a white solid.
Examples 423 and 424
[0813] The products of Examples 423 and 424 were prepared in
accordance with the same procedures as in Example 422, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride prepared in Example 354; and pivaldehyde
or 4,5-dimethylfuran-2-carboxaldehyde.
Examples 425 to 430
[0814] The products of Examples 425 to 430 were prepared in
accordance with the same procedures as in Example 61, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride prepared in Example 354; and propionic
acid, 2-phenylacetic acid, 2-(piperidin-1-yl)acetic acid,
2-(pyridin-3-yl)acetic acid, 2-(pyridin-4-yl)acetic acid, or
2-(thiophene-2-yl)acetic acid.
Example 431
[0815] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 124, using
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride prepared in Example 354 and
methanesulfonyl chloride.
Example 432
[0816] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propylpyrimidin-4-yl]pyrroli-
din-3-yl}methanesulfonamide prepared in Example 431.
Example 433
[0817] Ethyl isocyanate (7.1 mg, 0.1 mmol) was slowly added at room
temperature to a solution of
(S)-5-[4-(3-aminopyrrolidin-1-yl)-6-propylpyrimidin-2-ylamino]-2-methylbe-
nzonitrile dihydrochloride (20 mg, 0.05 mmol) prepared in Example
354 and diisopropylethylamine (0.03 ml, 0.14 mmol) in
dichloromethane (1 ml). The reaction mixture was stirred at room
temperature for 30 minutes. Water was added to the reaction
mixture, which was then extracted with dichloromethane. The
separated organic layer was dried on anhydrous sodium sulfate,
filtered, and then concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (ethyl acetate) and then dissolved in ethyl acetate
(2 ml). Hydrogen chloride gas was added to the solution. The
reaction mixture was stirred at room temperature for 2 hours and
then filtered to give 6 mg of the product as a white solid.
Example 434
[0818] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 84, using
(R)-3-{4-[3-(aminomethyl)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino}ben-
zonitrile dihydrochloride prepared in Example 179 and
acetaldehyde.
Example 435
[0819] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)-5-{4-[3-(isopropylamino)pyrrolidin-1-yl]-6-propylpyrimidin-2-ylamino]-
-2-methylbenzonitrile prepared in Example 418.
Examples 436 to 446
[0820] The products of Examples 436 to 446 were prepared in
accordance with the same procedures as in Example 26, using
(S)--N-[1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl]acetamide
prepared in Preparation 24; and 4-methyl-3-nitroaniline,
4-fluoro-3-nitroaniline, 4-chloro-3-nitroaniline,
3,5-diaminobenzonitrile, 5-(trifluoromethyl)benzene-1,3-diamine,
2-(trifluoromethyl)benzene-1,4-diamine,
4-fluoro-3-trifluoromethylphenylamine,
5-amino-2-fluorobenzonitrile, 4-fluoro-1,3-phenylenediamine,
4-chloro-1,3-phenylenediamine, or 2,5-diaminobenzonitrile prepared
in Preparation 19.
Example 447
[0821] A solution of (S)-tert-butyl
1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
(85 mg, 0.23 mmol) prepared in Preparation 25 and
2,5-diaminobenzonitrile (34 mg, 0.25 mmol) prepared in Preparation
19 in n-butanol (0.5 ml) was stirred at 130.degree. C. for 3 hours.
The reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The resulting residue was
purified with silica gel column chromatography
(dichloromethane/methanol=20/1) and then dissolved in ethyl
acetate/methanol (1 ml/1 ml). The resulting solution was saturated
with hydrogen chloride gas and then filtered to give 46.7 mg of the
product as a white solid.
Examples 448 to 457
[0822] The products of Examples 448 to 457 were prepared in
accordance with the same procedures as in Example 447, using
(S)-tert-butyl
1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
prepared in Preparation 25; and 4-methyl-3-nitroaniline,
4-fluoro-3-nitroaniline, 4-chloro-3-nitroaniline,
3,5-diaminobenzonitrile, 5-(trifluoromethyl)benzene-1,3-diamine,
2-(trifluoromethyl)benzene-1,4-diamine,
4-fluoro-3-trifluoromethylphenylamine,
5-amino-2-fluorobenzonitrile, 4-fluoro-1,3-phenylenediamine, or
4-chloro-1,3-phenylenediamine.
Examples 458 to 471
[0823] The products of Examples 458 to 471 were prepared in
accordance with the same procedures as in Example 447, using
(S)-tert-butyl
1-(6-butyl-2-chloropyrimidin-4-yl)pyrrolidin-3-yl(ethyl)carbamate
prepared in Preparation 26; and 2,5-diaminobenzonitrile prepared in
Preparation 19, 3-aminobenzonitrile, 5-amino-2-methylbenzonitrile,
2-nitro-1,4-phenylenediamine, 4-methyl-3-nitroaniline,
4-fluoro-3-nitroaniline, 4-chloro-3-nitroaniline,
3,5-diaminobenzonitrile, 5-(trifluoromethyl)benzene-1,3-diamine,
2-(trifluoromethyl)benzene-1,4-diamine,
4-fluoro-3-trifluoromethylphenylamine,
5-amino-2-fluorobenzonitrile, 4-fluoro-1,3-phenylenediamine, or
4-chloro-1,3-phenylenediamine.
Example 472
[0824] A mixture of
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]-2-hydroxyacet-
amide (20 mg, 0.07 mmol) prepared in Preparation 27 and
5-amino-2-methylbenzonitrile (10.6 mg, 0.08 mmol) in n-butanol (0.5
ml) was stirred in a microwave reactor (600 W) for 1 hour. The
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified with silica gel column
chromatography (dichloromethane/methanol=20/1) to give 5.9 mg of
the product as yellow oil.
Examples 473 to 481
[0825] The products of Examples 473 to 481 were prepared in
accordance with the same procedures as in Example 472, using
(S)--N-[1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl]-2-hydroxyacet-
amide prepared in Preparation 27; and 5-amino-2-fluorobenzonitrile,
3,5-diaminobenzonitrile, 5-(trifluoromethyl)benzene-1,3-diamine,
2-(trifluoromethyl)benzene-1,4-diamine,
4-fluoro-3-trifluoromethylphenylamine,
4-fluoro-1,3-phenylenediamine, 4-chloro-1,3-phenylenediamine,
2-chloro-4-aminotoluene, or
4-methyl-3-(trifluoromethyl)aniline.
Example 482
[0826] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-amino-5-cyanophenylamino)-6-propylpyrimidin-4-yl]pyrrolid-
in-3-yl}-2-hydroxyacetamide prepared in Example 474.
Example 483
[0827] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-cyano-4-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}-2-hydroxyacetamide prepared in
Example 472.
Example 484
[0828] A solution of (S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
(0.2 g, 0.56 mmol) prepared in Preparation 28,
4-fluorobenzene-1,3-diamine (0.1 g, 0.61 mmol), and
diisopropylethylamine (0.2 ml, 1.12 mmol) in n-butanol (2 ml) was
stirred at 130.degree. C. overnight. The reaction mixture was
cooled to room temperature and then concentrated under reduced
pressure. The resulting residue was purified with silica gel column
chromatography (dichloromethane/ethyl acetate=20/1) and then
dissolved in ethyl acetate (2 ml). Hydrogen chloride gas was added
to the solution. The reaction mixture was stirred at room
temperature for 1 hour and then filtered to give 0.1 g of the
product as a white solid.
Examples 485 to 487
[0829] The products of Examples 485 to 487 were prepared in
accordance with the same procedures as in Example 484, using
(S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate
prepared in Preparation 28; and 3,5-diaminobenzonitrile,
2,5-diaminobenzonitrile prepared in Preparation 19, or
5-(trifluoromethyl)-1,3-phenylenediamine.
Examples 488 to 489
[0830] The products of Examples 488 to 489 was prepared in
accordance with the same procedures as in Example 484, using
(S)-tert-butyl
1-(2-chloro-6-propylpyrimidin-4-yl)pyrrolidin-3-yl(ethyl)carbamate
prepared in Preparation 29; and
2-(trifluoromethyl)-1,4-phenylenediamine or 2,5-diaminobenzonitrile
prepared in Preparation 19.
Examples 490 and 491
[0831] The products of Examples 490 and 491 were prepared in
accordance with the same procedures as in Example 172, using
4-chloro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-propylpyrimidin-2-amine
prepared in Preparation 30; and (3S)-(-)-3-(methylamino)pyrrolidine
or (3S)-(-)-3-(ethylamino)pyrrolidine.
Example 492
[0832] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[6-butyl-2-(3-cyano-4-methylphenylamino)pyrimidin-4-yl]pyrrolid-
in-3-yl}acetamide prepared in Example 228.
Example 493
[0833] The product in the form of white solid was prepared in
accordance with the same procedures as in Example 118, using
(S)--N-{1-[2-(3-amino-4-methylphenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide prepared in Example
292.
Example 494
[0834] The product in the form of pale yellow solid was prepared in
accordance with the same procedures as in Example 395, using
(S)--N-{1-[2-(4-amino-3-nitrophenylamino)-6-propyl
pyrimidin-4-yl]pyrrolidin-3-yl}acetamide hydrochloride prepared in
Example 286.
[0835] The compounds of Examples 1 to 494 and the NMR spectrum data
thereof are shown in Tables 1-1 to 1-51 below.
TABLE-US-00001 TABLE 1-1 Example Compound NMR Spectrum 1
N-(4-fluorophenyl)-4-propyl- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.70-7.60 (m, 2H), 6.97 (t, 6-(pyrrolidin-1-yl)pyrimidin-
2H), 5.68 (s, 1H), 3.70-3.20 (m, 4H), 2.46 (t, 2H), 2.10- 2-amine
1.90 (m, 4H), 1.80-1.60 (m, 2H), 0.97 (t, 3H) 2 (S)-{1-[2-(4-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60-7.50 (m, 2H), 6.99
(t, fluorophenylamino)-6- 2H), 6.75 (brs, 1H), 5.74 (s, 1H), 4.38
(brs, 1H), 3.80- propylpyrimidin-4- 3.60 (m, 2H), 3.50-3.40 (m,
1H), 3.40-3.30 (m, 1H), 2.48 yl]pyrrolidin-2-yl}methanol (t, 2H),
2.10-1.90 (m, 3H), 1.80-1.60 (m, 3H), 0.98 (t, 3H) 3
1-[2-(4-fluorophenylamino)- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.60-7.50 (m, 2H), 6.97 (t, 6-propylpyrimidin-4- 2H), 6.84
(brs, 1H), 5.70 (s, 1H), 4.62 (brs, 1H), 3.63 (brs,
yl]pyrrolidin-3-ol 4H), 2.46 (t, 2H), 2.20-2.00 (m, 2H), 1.71 (q,
2H), 0.98 (t, 3H) 4 (R)-[55142-(4- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.55-7.45 (m, 2H), 6.98 (t,
fluorophenylamino)-6- 2H), 6.83 (brs, 1H), 5.74 (s, 1H), 4.35 (brs,
1H), 3.70- propylpyrimidin-4- 3.55 (m, 2H), 3.50-3.40 (m, 1H),
3.40-3.30 (m, 1H), 2.47 yl]pyrrolidin-2-yl}methanol (t, 2H),
2.10-1.90 (m, 3H), 1.80-1.60 (m, 3H), 0.98 (t, 3H) 5
{1-[2-(4-fluorophenylamino)- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.55-7.45 (m, 2H), 6.98 (t, 6-propylpyrimidin-4- 2H), 6.83
(brs, 1H), 5.74 (s, 1H), 4.35 (brs, 1H), 3.70-
yl]pyrrolidin-2-yl}methanol 3.55 (m, 2H), 3.50-3.40 (m, 1H),
3.40-3.30 (m, 1H), 2.47 (t, 2H), 2.10-1.90 (m, 3H), 1.80-1.60 (m,
3H), 0.98 (t, 3H) 6 N-(4-fluorophenyl)-4-(-2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.65-7.55 (m, 2H), 6.97 (t,
methylpyrrolidin-1-yl)-6- 2H), 6.83 (brs, 1H), 5.68 (s, 1H), 4.20
(brs, 1H), 3.55 (brs, propylpyrimidin-2-amine 1H), 3.38 (brs, 1H),
2.45 (t, 2H), 2.10-1.90 (m, 3H), 1.80- 1.65 (m, 3H), 1.23 (d, 3H),
0.98 (t, 3H) 7 (S)-N-(4-fluorophenyl)-4-[2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.65-7.55 (m, 2H), 6.97 (t,
(methoxymethyl)pyrrolidin- 2H), 6.86 (brs, 1H), 5.73 (s, 1H),
4.30-4.10 (brs, 1H), 1-yl]-6-propylpyrimidin-2- 3.66 (brs, 1H),
3.49 (brs, 1H), 3.36 (s, 3H), 3.30-3.15 (m, amine 2H), 2.46 (t,
2H), 2.10-1.85 (m, 4H), 1.71 (q, 2H), 0.98 (t, 3H) 8
(R)-N-(4-fluorophenyl)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.65-7.55 (m, 2H), 6.97 (t, (methoxymethyl)pyrrolidin- 2H),
6.86 (brs, 1H), 5.73 (s, 1H), 4.30-4.10 (brs, 1H),
1-yl]-6-propylpyrimidin-2- 3.66 (brs, 1H), 3.49 (brs, 1H), 3.36 (s,
3H), 3.30-3.15 (m, amine 2H), 2.46 (t, 2H), 2.10-1.85 (m, 4H), 1.71
(q, 2H), 0.98 (t, 3H) 9 (S)-1-[2-(4- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.65-7.55 (m, 2H), 6.97 (t,
fluorophenylamino)-6- 2H), 5.90 (s, 1H), 4.60-4.40 (m, 1H),
3.75-3.60 (m, 1H), propylpyrimidin-4- 3.55-3.35 (m, 1H), 2.47 (t,
2H), 2.30-2.20 (m, 1H), 2.15- yl]pyrrolidin-2-carboxamide 1.95 (m,
3H), 1.72 (q, 2H), 0.98 (t, 3H) 10 N-{1-[2-(4- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 7.70-7.60 (m, 2H), 6.98 (t,
fluorophenylamino)-6- 2H), 5.81 (s, 1H), 4.44 (t, 1H), 3.80-3.30
(m, 4H), 2.45 (t, propylpyrimidin-4- 2H), 2.30-2.20 (m, 1H),
2.05-1.95 (m, 1H), 1.94 (s, 3H), yl]pyrrolidin-3-yl}acetamide 1.71
(q, 2H), 0.97 (t, 3H)
TABLE-US-00002 TABLE 1-2 Example Compound NMR Spectrum 11
(R)-N-{1-[2-(4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.70-7.60
(m, 2H), 6.98 (t, fluorophenylamino)-6- 2H), 5.79 (brs, 1H), 5.68
(s, 1H), 4.65-4.55 (m, 1H), 3.80- propylpyrimidin-4- 3.70 (m, 1H),
3.65-3.45 (m, 3H), 2.46 (t, 2H), 2.00 (s, 3H),
yl]pyrrolidin-3-yl}acetamide 1.80-1.60 (m, 2H), 0.97 (t, 3H) 12
2,2,2-trifluoro-N-{1-[2-(4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.60-7.50 (m, 2H), 6.99 (t, fluorophenylamino)-6- 2H), 6.80
(brs, 1H), 6.54 (brs, 1H), 5.70 (s, 1H), 4.70- propylpyrimidin-4-
4.60 (m, 1H), 3.85-3.75 (m, 1H), 3.70-3.30 (m, 3H), 2.48 (t,
yl]pyrrolidin-3-yl}acetamide 2H), 2.40-2.30 (m, 1H), 2.15-2.05 (m,
1H), 1.80-1.65 (m, 2H), 0.98 (t, 3H) 13
4-[3-(ethylamino)pyrrolidin- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.65-7.55 (m, 2H), 6.96 (t, 1-yl]-N-(4-fluorophenyl)-6-
2H), 6.92 (brs, 1 H), 5.67 (s, 1H), 3.47 (t, 2H), 2.72 (q, 2H),
propylpyrimidin-2-amine 2.45 (t, 2H), 2.25-2.10 (m, 1H), 1.90-1.80
(m, 1H), 1.71 (q, 2H), 1.15 (t, 3H), 0.99 (t, 3H) 14 4-[3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.55 (m, 2H), 6.96
(t, (dimethylamino)pyrrolidin-1- 2H), 6.88 (brs, 1H), 5.68 (s, 1H),
4.00-3.50 (m, 2H), 3.50- yl]-N-(4-fluorophenyl)-6- 3.30 (m, 1H),
3.30-3.10 (m, 1H), 2.85-2.70 (m, 1H), 2.46 (t,
propylpyrimidin-2-amine 2H), 2.31 (s, 6H), 2.20-2.10 (m, 1H),
1.90-1.80 (m, 1H), 1.72 (q, 2H), 0.97 (t, 3H) 15
(S)-N-(4-fluorophenyl)-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.70-7.60 (m, 2H), 6.97 (t, propyl-6-[2-(pyrrolidin-1- 2H), 5.72
(s, 1H), 3.60-3.20 (m, 2H), 3.10-2.60 (m, 6H),
ylmethyl)pyrrolidin-1- 2.51 (t, 2H), 2.40-2.20 (m, 1H), 2.10-2.00
(m, 4H), 2.00- yl]pyrimidin-2-amine 1.80 (m, 4H), 1.75 (q, 2H),
0.99 (t, 3H) 16 (S)-N-(4-fluorophenyl)-4-{2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.60-7.50 (m, 2H), 7.20-
[(phenylamino)methyl]pyrrolidin- 7.10 (m, 2H), 6.93 (t, 2H), 6.79
(brs, 1H), 6.65 (t, 1H), 6.50- 1-yl}-6-propylpyrimidin- 6.40 (m,
2H), 5.72 (s, 1H), 4.70-4.40 (m, 1H), 3.60-3.20 (m, 2-amine 3H),
3.20-3.10 (m, 1H), 2.46 (t, 2H), 2.20-1.90 (m, 4H), 1.71 (q, 2H),
0.98 (t, 3H) 17 (S)-N-{1-[2-(4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.60-7.50 (m, 2H), 7.05- fluorophenylamino)-6- 6.90 (m,
3H), 6.08 (brs, 1H), 5.66 (s, 1H), 4.56 (brs, 1H),
propylpyrimidin-4- 3.80-3.20 (m, 4H), 2.45 (t, 2H), 2.30-2.15 (m,
1H), 1.98 (s, yl]pyrrolidin-3-yl}acetamide 3H), 2.00-1.90 (m, 1H),
1.70 (q, 2H), 0.96 (t, 3H) 18 (S)-4-[3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.65-7.55 (m, 2H), 6.96 (t,
(ethylamino)pyrrolidin-1-yl]- 2H), 6.92 (brs, 1H), 5.67 (s, 1H),
3.47 (t, 2H), 2.72 (q, 2H), N-(4-fluorophenyl)-6- 2.45 (t, 2H),
2.25-2.10 (m, 1H), 1.90-1.80 (m, 1H), 1.71 (q,
propylpyrimidin-2-amine 2H), 1.14 (t, 3H), 0.97 (t, 3H) 19
(S)-tert-butyl 1-[2-(4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.65-7.55 (m, 2H), fluorophenylamino)-6- 6.97 (t, 2H), 6.86 (brs,
1H), 5.68 (s, 1H), 4.72 (brs, 1H), 4.34 propylpyrimidin-4- (brs,
1H), 3.80-3.20 (m, 4H), 2.46 (t, 2H), 2.30-2.20 (m, 1H),
yl]pyrrolidin-3-ylcarbamate 2.05-1.90 (m, 1H), 1.71 (q, 2H), 1.46
(s, 9H), 0.97 (t, 3H) 20 4-(3-aminopyrrolidin-1-yl)- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 7.70-7.60 (m, 2H), 6.98 (t,
N-(4-fluorophenyl)-6- 2H), 5.84 (s, 1H), 3.90-3.35 (m, 5H), 2.46
(t, 2H), 2.35- propylpyrimidin-2-amine 2.25 (m, 1H), 2.00-1.90 (m,
1H), 1.72 (q, 2H), 0.98 (t, 3H)
TABLE-US-00003 TABLE 1-3 Example Compound NMR Spectrum 21 4-[3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.55 (m, 2H), 7.05-
(diethylamino)pyrrolidin-1- 6.90 (m, 3H), 5.68 (s, 1H), 4.00-3.10
(m, 5H), 2.80-2.60 yl]-N-(4-fluorophenyl)-6- (m, 4H), 2.46 (t, 2H),
2.25-2.15 (m, 1H), 1.90- propylpyrimidin-2-amine 1.80 (m, 1 H),
1.72 (q, 2H), 1.06 (t, 6H), 0.98 (t, 3H) 22
(S)-N-(4-fluorophenyl)-4-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.70-7.60 (m, 2H), 7.20 (methylamino)pyrrolidin-1- (brs,
1H), 6.97 (t, 2H), 5.68 (s, 1H), 3.80-3.10 (m, 5H),
yl]-6-propylpyrimidin-2- 2.49 (s, 3H), 2.47 (t, 2H), 2.20-2.10 (m,
1H), 1.90-1.80 amine (m, 1 H), 1.71 (q, 2H), 0.98 (t, 3H) 23
N-{1-[2-(4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.55 (m,
2H), 6.98 (t, fluorophenylamino)-6- 2H), 6.88 (brs, 1H), 5.69 (s,
1H), 5.39 (t, 1H), 3.80-3.20 propylpyrimidin-4- (m, 4H), 2.94 (s,
3H), 2.47 (t, 2H), 2.30-2.20 (m, 2H), yl]pyrrolidin-3-yl)-N- 2.14
(s, 3H), 1.72 (q, 2H), 0.98 (t, 3H) methylacetamide 24 (S)-1-[2-
(4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.55 (m, 2H),
6.97 (t, fluorophenylamino)-6- 2H), 6.85 (brs, 1H), 5.68 (s, 1H),
4.62 (brs, 1H), 3.80- propylpyrimidin-4- 3.30 (m, 4H), 2.46 (t,
2H), 2.20-2.00 (m, 2H), 1.71 (q, 2H), yl]pyrrolidin-3-ol 0.97 (t,
3H) 25 4-[3-(ethylamino)pyrrolidin- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.65-7.55 (m, 2H), 7.17 (t,
1-yl]-N-(4-fluorophenyl)-6- 2H), 6.28 (s, 1H), 4.20-4.00 (m, 2H),
4.00-3.80 (m, 2H), propylpyrimidin-2-amine 3.80-3.70 (m, 1H),
3.25-3.10 (m, 2H), 2.68 (t, 2H), 2.60- dihydrochloride 2.45 (m,
1H), 2.40-2.20 (m, 1H), 1.79 (t, 2H), 1.45-1.30 (m, 3H), 1.07 (t,
3H) 26 (S)-N-{4-[2- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.61
(s, 1H), 7.55 (d, 1H), (methoxymethyl)pyrrolidin- 7.26 (s, 1H),
7.04 (d, 1H), 6.45 (s, 1H), 6.10 (s, 1H),
1-yl]-6-propylpyrimidin-2-yl}- 4.43 (brs, 1H), 3.60 (brs, 1H), 3.48
(brs, 1H), 3.50-3.40 (m, 1H-indol-6-amine 2H), 3.10 (s, 3H), 2.59
(t, 2H), 2.25-1.95 (m, 4H), 1.74 (q, hydrochloride 2H), 1.04 (t,
3H) 27 (S)-N-{4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.10-8.00 (m, 2H), 7.35- (methoxymethyl)pyrrolidin- 7.25 (m, 1H),
7.17 (s, 1H), 6.90-6.80 (m, 1H), 6.49 (s, 1H),
1-yl]-6-propylpyrimidin-2-yl}- 5.69 (brs, 1H), 3.80-3.60 (m, 2H),
3.60-3.40 (m, 2H), 1H-indol-5-amine 3.33 (s, 3H), 3.30-3.20 (m,
1H), 2.46 (t, 2H), 2.10-1.90 (m, 4H), 1.73 (q, 2H), 0.99 (t, 3H) 28
(S)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60-7.50 (m,
2H), 6.90- (methoxymethyl)pyrrolidin- 6.80 (m, 2H), 6.74 (brs, 1H),
5.70 (s, 1H), 4.35 (brs, 1H), 1-yl]-N-(4-methoxyphenyl)- 3.79 (s,
3H), 3.80-3.60 (m, 1H), 3.50-3.40 (m, 1H), 3.36 (s,
6-propylpyrimidin-2-amine 3H), 3.30-3.20 (m, 2H), 2.50-2.40 (m,
2H), 2.20-1.90 (m, 4H), 1.80-1.65 (m, 2H), 1.00-0.90 (m, 3H) 29
(S)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.50-7.40 (m,
1H), 7.20- (methoxymethyl)pyrrolidin- 7.10 (m, 2H), 6.87 (brs, 1H),
6.51 (d, 1H), 5.74 (s, 1H), 1-yl]-N-(3-methoxyphenyl)- 3.81 (s,
3H), 3.80-3.60 (m, 2H), 3.60-3.40 (m, 1H), 3.36 (s,
6-propylpyrimidin-2-amine 3H), 3.30-3.20 (m, 2H), 2.46 (t, 2H),
2.10-1.90 (m, 4H), 1.72 (q, 2H), 0.98 (t, 3H) 30
(S)-N-(3-chlorophenyl)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.95 (s, 1H), 7.34 (d, 1H), (methoxymethyl)pyrrolidin- 7.17
(t, 1H), 7.00-6.80 (m, 2H), 5.76 (brs, 1H), 4.50-
1-yl]-6-propylpyrimidin-2- 4.30 (m, 1H), 3.80-3.30 (m, 4H), 3.37
(s, 3H), 2.47 (t, 2H), amine 2.20-1.90 (m, 4H), 1.72 (q, 2H), 0.98
(t, 3H)
TABLE-US-00004 TABLE 1-4 Example Compound NMR Spectrum 31
(S)-N-(4-fluoro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
9.00-8.70 (m, 1H), 7.70- nitrophenyl)-4-[2- 7.40 (m, 1H), 7.16 (t,
1H), 7.11 (brs, 1H), 5.83 (brs, 1H), (methoxymethyl)pyrrolidin-
4.50-4.20 (m, 1H), 3.70-3.35 (m, 4H), 3.36 (s, 3H), 2.48 (t,
1-yl]-6-propylpyrimidin-2- 2H), 2.20-1.90 (m, 4H), 1.72 (q, 2H),
0.98 (t, 3H) amine 32 (S)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.75 (brs, 1H), 7.48 (brs, 2H), (methoxymethyl)pyrrolidin-
7.37 (d, 1H), 6.05 (brs, 1H), 5.83 (brs, 1H), 4.40 (brs, 1H),
1-yl]-N-(3-nitrophenyl)-6- 3.65-3.40 (m, 4H), 3.36 (s, 3H),
2.60-2.40 (m, 2H), 2.30- propylpyrimidin-2-amine 1.90 (m, 4H), 1.71
(q, 2H), 0.98 (t, 3H) 33 (S)-N-(4-chloro-3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.77 (dd, 1H), 7.64 (brs, 1H),
nitrophenyl)-4-[2- 7.38 (t, 1H), 7.19 (brs, 1H), 5.83 (brs, 1H),
4.60-4.30 (m, (methoxymethyl)pyrrolidin- 1H), 3.70-3.40 (m, 4H),
3.36 (s, 3H), 2.49 (t, 2H), 2.20- 1-yl]-6-propylpyrimidin-2- 1.90
(m, 4H), 1.73 (q, 2H), 0.99 (t, 3H) amine 34 (S)-3-{4-[2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.23 (brs, 1H), 7.66
(brs, 1H), (methoxymethyl)pyrrolidin- 7.34 (t, 1H), 7.21 (d, 1H),
7.08 (brs, 1H), 5.81 (brs, 1H), 1-yl]-6-propylpyrimidin-2-
4.50-4.30 (m, 1H), 3.70-3.40 (m, 4H), 3.31 (s, 3H), 2.48 (t,
ylamino}benzonitrile 2H), 2.20-1.90 (m, 4H), 1.72 (q, 2H), 0.99 (t,
3H) 35 (S)-4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.66
(br, 1H), 7.40 (br, 1H), methoxymethyl)pyrrolidin- 7.19 (t, 2H),
6.85 (d, 1H), 5.75 (br, 1H), 4.37 (br, 1H), 1-yl]-N-[3- 3.63 (br,
2H), 3.36 (s, 3H), 2.48 (m, 5H), 2.09 (m, 2H),
(methylthio)phenyl]-6- 2.00 (m, 2H), 1.74 (m, 2H), 0.98 (t, 3H)
propylpyrimidin-2-amine 36 (S)-4-[2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.89 (br, 1 H), 8.45-8.20 (br,
methoxymethyl)pyrrolidin- 1H), 7.65 (br, 1H), 7.39 (t, 1H), 7.25
(m, 1H), 5.78-5.62 (br, 1-yl]-6-propyl-N-[3- 2H), 4.49-4.05 (br,
1H), 3.54 (br, 3H), 3.33 (br, 4H), 2.55 (t,
(trifluoromethyl)phenyl] 2H), 2.04 (br, 2H), 1.81 (m, 2H), 1.00 (t,
3H) pyrimidin-2-amine 37 (S)-7-{4-[2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.03 (br, 1H), 7.69 (br, 1H),
(methoxymethyl)pyrrolidin- 7.46 (d, 1H), 7.35 (br, 1H), 6.12 (s,
1H), 5.80 (br, 1H), 4.53- 1-yl]-6-propylpyrimidin-2- 3.73 (br, 2H),
3.57-3.22 (br, 2H), 3.40 (s, 3H), 2.73 (br, 1H),
ylamino}-4-methyl-2H- 2.50 (t, 2H), 2.39 (s, 3H), 2.18 (m, 1H),
2.05 (m, 3H), chromen-2-one 1.76 (m, 2H), 0.97 (t, 3H) 38
(S)-N-(5-chloro-2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.24
(br, 1H), 8.05 (br, 1H), methylphenyl)-4-[2- 6.95 (d, 1H), 6.93 (d,
1H), 5.76 (br, 1H), 4.44 (br, 1H), (methoxymethyl)pyrrolidin- 3.53
(br, 3H), 3.31 (br, 4H), 2.55 (t, 2H), 2.40 (s, 3H), 2.10-
1-yl]-6-propylpyrimidin-2- 2.01 (m, 4H), 1.79 (m, 2H), 1.01 (t, 3H)
amine 39 (S)-N-(3-chloro-4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.56 (br, 1H), 7.89 (br, 1H), methylphenyl)-4-[2- 7.30 (m,
1H), 7.11 (d, 1H), 5.89-5.73 (br, 2H), 3.63-
(methoxymethyl)pyrrolidin- 3.48 (br, 3H), 3.35 (m, 4H), 2.53 (t,
2H), 2.30 (s, 3H), 2.10- 1-yl]-6-propylpyrimidin-2- 2.03 (m, 4H),
1.79 (m, 2H), 1.00 (t, 3H) amine 40 (S)-4-[2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 9.00-8.73 (br, 2H), 7.52 (br,
methoxymethyl)pyrrolidin- 1H), 7.22 (d, 1H), 5.96 (br, 1H), 5.55
(br, 1H), 4.55- 1-yl]-N-(4-methyl-3- 4.10 (br, 1H), 3.59 (br, 3H),
3.33 (m, 4H), 2.55 (m, 4H), nitrophenyl)-6- 2.60 (m, 4H), 1.79 (m,
2H), 1.00 (t, 3H) propylpyrimidin-2-amine
TABLE-US-00005 TABLE 1-5 Example Compound NMR Spectrum 41
(S)-N-[4-fluoro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.20
(br, 1H), 8.42-8.12 (br, (trifluoromethyl)phenyl]-4- 1H), 7.67 (br,
1H), 7.12 (t, 1H), 5.78 (br, 2H), 4.45-4.07 (br, [2- 1H), 3.50 (br,
3H), 3.32 (m, 4H), 2.56 (t, 2H), 2.06 (m, 4H),
(methoxymethyl)pyrrolidin- 1.81 (m, 2H), 1.00 (t, 3H)
1-yl]-6-propylpyrimidin-2- amine 42 (S)-N.sup.1-{4-[2- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.93 (br, 1H), 7.41 (br, 1H),
(methoxymethyl)pyrrolidin- 6.76 (br, 1H), 6.69 (d, 1H), 5.72 (br,
1H), 4.36 (br, 1H), 1-yl]-6-propylpyrimidin-2-yl}- 4.00 (s, 2H),
3.55 (br, 2H), 3.33 (m, 5H), 2.45 (t, 2H),
3-(trifluoromethyl)benzene- 2.09 (m, 2H), 2.00 (m, 2H), 1.72 (m,
2H), 0.97 (t, 3H) 1,4-diamine 43 (S)-2-fluoro-5-{4-[2- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.21 (br, 1H), 8.06 (br, 1H),
(methoxymethyl)pyrrolidin- 7.11 (t, 1H), 5.80 (br, 1H), 4.45 (br,
1H), 3.62 (m, 3H), 1-yl]-6-propylpyrimidin-2- 3.37 (m, 5H), 2.51
(t, 2H), 2.12-2.04 (m, 4H), 1.75 (m, 2H), ylamino}benzonitrile 0.99
(t, 3H) 44 (S)-5-{4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.58 (br, 1H), 8.17 (br, 1H), (methoxymethyl)pyrrolidin- 7.57 (br,
1H), 7.22 (d, 1H), 5.78 (br, 1H), 5.31 (br, 1H),
1-yl]-6-propylpyrimidin-2- 4.49-4.00 (br, 1H), 3.63 (m, 3H), 3.41
(m, 4H), 2.55 (t, 2H), ylamino}-2- 2.51 (s, 3H), 2.18-2.05 (m, 4H),
1.77 (m, 2H), 0.99 (t, 3H) methylbenzonitrile 45
(S)-2-amino-5-{4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.92
(br, 1H), 7.43 (m, 1H), (methoxymethyl)pyrrolidin- 7.12 (br, 1H),
6.71 (d, 1H), 5.75 (br, 1H), 4.40 (br, 1H),
1-yl]-6-propylpyrimidin-2- 4.19 (s, 2H), 3.53 (br, 3H), 3.36 (s,
5H), 2.47 (t, 2H), ylamino}benzonitrile 2.21 (br, 2H), 2.05 (m,
2H), 1.97 (m, 2H), 1.72 (m, 2H), 0.98 (t, 3H) 46 (S)-N.sup.1-{4-[2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (br, 1H), 8.35 (br,
1H), (methoxymethyl)pyrrolidin- 7.41 (br, 1H), 6.80 (d, 1H), 6.06
(s, 2H), 5.78 (br, 1H), 4.60- 1-yl]-6-propylpyrimidin-2-yl}- 4.10
(br, 3H), 3.54 (br, 3H), 3.32 (m, 3H), 2.52 (t, 2H), 2.18-
3-nitrobenzene-1,4-diamine 2.03 (m, 2H), 1.79 (m, 2H), 0.99 (t, 3H)
47 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 7.60-7.45 (m, 2H), 7.15 (t, yl)-N-(4-fluorophenyl)-6- 2H),
6.30-6.20 (m, 1H), 4.10-3.91 (m, 2H), 3.90-3.70 (m,
propylpyrimidin-2-amine 3H), 2.66 (t, 2H), 2.60-2.40 (m, 1H),
2.30-2.10 (m, 1H), dihydrochloride 1.80-1.65 (m, 2H), 1.05 (t, 3H)
48 (S)-tert-butyl 1-[2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.31 (brs, 1H), 7.62 (brs, 1H), cyanophenylamino)-6- 7.34
(t, 1H), 7.21 (d, 1H), 7.01 (brs, 1H), 5.75 (s, 1H),
propylpyrimidin-4- 4.71 (brs, 1H), 4.34 (brs, 1H), 3.80-3.20 (m,
4H), 2.48 (t, yl]pyrrolidin-3-ylcarbamate 2H), 2.40-2.20 (m, 1H),
2.10-1.90 (m, 1H), 1.72 (q, 2H), 1.46 (s, 9H), 0.98 (t, 3H) 49
3-{4-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.44 (brs, 1H),
7.55 (d, 1H), (diethylamino)pyrrolidin-1- 7.32 (t, 1H), 7.20 (d,
1H), 7.13 (brs, 1H), 5.74 (s, 1H), 4.00- yl]-6-propylpyrimidin-2-
3.80 (m, 1H), 3.70-3.10 (m, 4H), 2.71 (d, 4H), 2.48 (t, 2H),
ylamino}benzonitrile 2.25-2.15 (m, 1H), 2.00-1.85 (m, 1H), 1.72 (q,
2H), 1.05 (t, 6H), 0.98 (t, 3H) 50 (S)-3-{4-[3- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.40 (s, 1H), 7.57 (dd, 1H),
(methylamino)pyrrolidin-1- 7.32 (t, 1H), 7.19 (d, 1H), 7.17 (brs,
1H), 5.74 (s, 1H), 3.90- yl]-6-propylpyrimidin-2- 3.10 (m, 5H),
2.50 (s, 3H), 2.48 (t, 2H), 2.30-2.10 (m, 1H), ylamino}benzonitrile
1.90-1.85 (m, 1H), 1.72 (q, 2H), 0.98 (t, 3H)
TABLE-US-00006 TABLE 1-6 Example Compound NMR Spectrum 51
N-{1-[2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.32 (s, 1H),
7.61 (d, 1H), cyanophenylamino)-6- 7.34 (t, 1H), 7.21 (d, 1H), 7.02
(s, 1H), 5.75 (s, 1H), 5.37 (t, propylpyrimidin-4- 1H), 3.90-3.20
(m, 4H), 2.96 (s, 3H), 2.49 (t, 2H), 2.30- yl]pyrrolidin-3-yl}-N-
2.20 (m, 2H), 2.15 (s, 3H), 1.73 (q, 2H), 0.98 (t, 3H)
methylacetamide 52 (S)-3-[4-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.38 (s, 1H), 7.55 (dd, 1H), hydroxypyrrolidin-1-yl)-6-
7.32 (t, 1H), 7.20 (d, 1H), 7.00 (brs, 1H), 5.75 (s, 1H),
propylpyrimidin-2- 4.65 (brs, 1H), 3.90-3.30 (m, 4H), 2.48 (t, 2H),
2.20- ylamino]benzonitrile 2.00 (m, 2H), 1.72 (q, 2H), 0.98 (t, 3H)
53 (R)-3-[4-(2-methylpyrrolidin- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.46 (brs, 1H), 7.52 (d, 1H), 1-yl)-6-propylpyrimidin-2-
7.40-7.25 (m, 2H), 7.18 (d, 1H) 5.75 (s, 1H), 4.50-4.10 (m,
ylamino]benzonitrile 1H), 3.70-3.20 (m, 2H), 2.47 (t, 2H),
2.20-1.90 (m, 3H), 1.80-1.60 (m, 3H), 1.30-1.20 (m, 3H), 0.97 (t,
3H) 54 (S)-N-{1-[2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.31 (brs, 1H), 7.60 (brs, 1H), cyanophenylamino)-6- 7.33 (t, 1H),
7.20 (d, 1H), 7.06 (brs, 1H), 5.80 (d, 1H), propylpyrimidin-4- 5.75
(s, 1H), 4.60 (q, 1H), 3.90-3.20 (m, 4H), 2.48 (t, 2H),
yl]pyrrolidin-3-yl}acetamide 2.40-2.25 (m, 1H), 2.01 (s, 3H), 1.83
(brs, 1H), 1.72 (q, 2H), 0.98 (t, 3H) 55 (S)-3-{4-[3- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.39 (s, 1H), 7.58 (d, 1H),
(ethylamino)pyrrolidin-1-yl]- 7.32 (t, 1H), 7.19 (d, 1H), 7.15
(brs, 1H), 5.74 (s, 1H), 3.90- 6-propylpyrimidin-2- 3.10 (m, 5H),
2.74 (q, 2H), 2.48 (t, 2H), 2.25-2.15 (m, 1H), ylamino}benzonitrile
1.90-1.80 (m, 1H), 1.72 (q, 2H), 1.15 (t, 3H), 0.98 (t, 3H) 56
(R)-tert-butyl {1-[2- (3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.39 (s, 1H), 7.60 (d, 1H), cyanophenylamino)-6- 7.37 (brs, 1H),
7.33 (t, 1H), 7.21 (d, 1H), 5.74 (s, 1H), propylpyrimidin-4- 4.75
(brs, 1H), 3.90-3.00 (m, 6H), 2.53 (brs, 1H), 2.48 (t,
yl]pyrrolidin-3- 2H), 2.20-2.10 (m, 1H), 1.78 (brs, 1H), 1.72 (q,
2H), yl}methylcarbamate 1.46 (s, 9H), 0.98 (t, 3H) 57 (R)-3-[4-(3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.39 (s, 1H), 7.82 (d,
1H), hydroxypyrrolidin-1-yl)-6- 7.39 (t, 1H), 7.21 (d, 1H), 5.89
(s, 1H), 4.55 (s, 1H), propylpyrimidin-2- 3.62 (brs, 4H), 2.51 (t,
2H), 2.13 (m, 2H), 1.73 (m, 2H), ylamino]benzonitrile 0.97 (t, 3H)
58 (S)-3-[4-(3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.41 (s,
1H), 7.80 (d, 1H), methoxypyrrolidin-1-yl)-6- 7.39 (t, 1H), 7.21
(d, 1H), 5.89 (s, 1H), 4.14 (s, 1H), 3.60- propylpyrimidin-2- 3.55
(m, 4H), 3.48 (s, 3H), 2.49 (t, 2H), 2.19-2.11 (m, 2H),
ylamino]benzonitrile 1.75 (m, 2H), 0.98 (t, 3H) 59 3-{4-[3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.20-8.10 (m, 1H), 7.90-
(methylamino)pyrrolidin-1- 7.80 (m, 1H), 7.60-7.50 (m, 2H), 6.35
(s, 1H), 4.20-3.70 (m, yl]-6-propylpyrimidin-2- 5H), 2.81 (s, 3H),
2.69 (t, 2H), 2.60-2.45 (m, 1H), 2.45- ylamino}benzonitrile 2.25
(m, 1H), 1.80 (q, 2H), 1.06 (t, 3H) dihydrochloride 60
(S)-3-[4-(3-aminopyrrolidin- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 8.09 (d, 1H), 7.90-7.80 (m, 1-yl)-6-propylpyrimidin-2- 1H),
7.60-7.50 (m, 2H), 6.40-6.30 (m, 1H), 4.20-3.70 (m,
ylamino]benzonitrile 5H), 2.69 (t, 2H), 2.60-2.45 (m, 1H),
2.30-2.15 (m, 1H), dihydrochloride 1.80 (q, 2H), 1.06 (t, 3H)
TABLE-US-00007 TABLE 1-7 Example Compound NMR Spectrum 61
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.31(brs,
1H), 7.60(brs, 1H), cyanophenylamino)-6- 7.33(t, 1H), 7.20(d, 1H),
7.04(brs, 1H), 5.75(s, 1H), propylpyrimidin-4- 5.70(d, 1H), 4.61(q,
1H), 3.80-3.20(m, 4H), 2.48(t, 2H), yl]pyrrolidin-3-yl}butyramide
2.40-2.25(m, 1H), 2.17(t, 2H), 2.05-1.95(m, 1H), 1.80- 62
(S)-N-{1-[2-(3- 1.60(m, 4H), 1.00-0.90(m, 6H) cyanophenylamino)-6-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.31(brs, 1H), 7.60(brs,
1H), propylpyrimidin-4- 7.33(t, 1H), 7.20(d, 1H), 7.09(brs, 1H),
5.75(s, 1H), yl]pyrrolidin-3- 5.71(d, 1H), 4.65-4.55(m, 1H),
3.90-3.15(m, 4H), 2.50- yl}cyclopentanecarboxamide 2.40(m, 3H),
2.35-2.25(m, 1H), 1.90-1.65(m, 9H), 1.60- 1.50(m, 2H), 1.00(t, 3H)
63 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
9.53(brs, 1H), 8.38(brs, 1H), cyanophenylamino)-6- 7.62(brs, 1H),
7.34(t, 1H), 7.21(d, 1H), 7.02(brs, 1H), propylpyrimidin-4- 5.77(s,
1H), 4.59(brs, 1H), 3.90-3.20(m, 4H), 2.65(d, 1H)
yl]pyrrolidin-3-yl}-3- 2.60-2.15(m, 10H), 1.90-1.85(m, 1H), 1.72(q,
2H), (piperidin-1-yl)propanamide 1.50-1.25(m, 6H), 0.99(t, 3H) 64
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.35(brs,
1H), 8.16(d, 1H), cyanophenylamino)-6- 7.79(d, 1H), 7.72(brs, 1H),
7.60-7.30(m, 5H), 7.22(d, propylpyrimidin-4- 1H), 6.55(brs, 1H),
5.75(s, 1H), 4.80(q, 1H), yl]pyrrolidin-3-yl}benzamide 4.00-3.30(m,
4H), 2.53(t, 2H), 2.45-2.35(m, 1H), 2.25-2.15(m, 1H), 1.73(q, 2H),
1.00(t, 3H) 65 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.85-8.75(m, 2H), 8.31(brs, cyanophenylamino)-6- 1H),
7.60(brs, 1H), 7.33(t, 1H), 7.19(d, 1H), 7.15-7.00(m,
propylpyrimidin-4- 3H, 6.40(brs, 1H), 5.77(s, 1H), 4.78(q, 1H),
yl]pyrrolidin-3-yl}-4- 4.00-3.30(m, 4H), 2.48(t, 2H), 2.40-2.30(m,
1H), fluorobenzamide 2.20-2.10(m, 1H), 1.72(q, 2H), 0.98(t, 3H) 66
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.28(brs,
1H), 7.59(d, 1H), cyanophenylamino)-6- 7.48(brs, 1H), 7.40-7.20(m,
7H), 5.69(s, 1H), 5.66(d, propylpyrimidin-4- 1H), 4.57(q, 1H),
3.58(s, 2H), 3.85-3.10(m, 4H), 2.47(t, yl]pyrrolidin-3-yl}-2- 2H),
2.30-2.20(m, 1H), 1.90-1.80(m, 1H), 1.70(q, 2H), phenylacetamide
0.97(t, 3H) 67 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.31(brs, 1H), 7.57(d, 1H), cyanophenylamino)-6- 7.33(t,
1H), 7.30-7.20(m, 4H), 7.09(brs, 1H), 7.02(t, 2H),
propylpyrimidin-4- 5.72(s, 1H), 4.58(q, 1H), 3.53(s, 2H),
3.90-3.20(m, 4H), yl]pyrrolidin-3-yl}-2-(4- 2.48(t, 2H),
2.30-2.20(m, 1H), 1.90-1.85(m, 1H), 1.71(q, fluorophenyl)acetamide
1H), 0.97(t, 3H) 68 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.29(brs, 1H), 7.90-7.80(m,
cyanophenylamino)-6- 2H, 7.61(d, 1H), 7.33(t, 1H), 7.30-7.20(m,
3H), 7.00(brs, propylpyrimidin-4- 1H), 6.94(t, 1H), 6.22(d, 1H),
5.74(s, 1H), 4.62(q, 1H), yl]pyrrolidin-3-yl}-3 4.26(t, 2H),
3.90-3.20(m, 4H), 2.67(t, 2H), 2.49(t, 2H), phenoxypropanamide
2.35-2.25(m, 1H), 1.80-1.60(m, 3H), 0.98(t, 3H) 69 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.02(brs, 1H), 7.76(brs,
1H), cyanophenylamino)-6- 7.36(t, 1H), 7.30-7.20(m, 1H), 6.89(brs,
1H), 5.70(s, 1H), propylpyrimidin-4- 4.60(brs, 1H), 3.90-3.70(m,
3H), 3.65(t, 2H), 3.25-3.15(m, yl]pyrrolidin-3-yl}-3 3H), 2.63(t,
2H), 2.55-2.45(m, 3H), 2.40-2.30(m, 1H), isobutoxypropanamide
1.75-1.65 (m, 1H), 0.99(t, 3H), 0.86(d, 6H) 70
(S)-2-(4-benzylpiperazin-1- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.40(brs, 1H), 7.65(brs, 1H), yl)-N-{1-[2-(3- 7.40-7.15(m,
8H), 5.75(s, 1H), 5.30(s, 1H), 4.65-4.55(m, cyanophenylamino)-6-
1H), 3.90-3.30(m, 4H), 3.02(s, 2H), 2.60-2.30(m, 11H),
propylpyrimidin-4- 2.10-2.00(m, 1H), 1.72(q, 2H), 0.99(t, 3H)
yl]pyrrolidin-3-yl}acetamide
TABLE-US-00008 TABLE 1-8 Example Compound NMR Spectrum 71
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.38(brs,
1H), cyanophenylamino)-6- 7.68(brs, 1H), 7.48(d, 1H), 7.36(t, 1H),
7.24(d, 1H), propylpyrimidin-4- 5.75(s, 1H), 4.60(q, 1H),
3.90-3.30(m, 4H), yl]pyrrolidin-3-yl}-2- 3.01(s, 2H), 2.60-2.25(m,
7H), 2.10-2.00(m, 1H), (piperidin-1-yl)acetamide 1.71(q, 2H),
1.65-1.40(m, 6H), 0.98(t, 3H) 72 (S)-N-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.35(brs, 1H), 8.03(s, 1H),
cyanophenylamino)-6- 7.98{d, 2H), 7.90-7.85(m, 1H), 7.80{brs, 1H),
7.58(t, 1H), propylpyrimidin-4- 7.50-7.40{m, 3H), 7.33(t, 1H),
7.22(d, 1H), 7.12(brs, 1H), yl]pyrrolidin-3-yl}-4-oxo-4- 5.64(s,
1H), 4.63(brs, 1H), 3.90-3.20(m, 6H), 2.80- phenylbutanamide
2.60(m, 2H), 2.49(1, 2H), 2.30-2.20(m, 1H), 2.10-2.00{m, 1H),
1.67(q. 2H), 0.96(1. 3H) 73 (S)-2-(4-aminophenyl)-N-{1-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.32(brs, 1H), 7.60(brs,
1H), [2-(3-cyanophenylamino)-6- 7.34(t, 1H), 7.22(d, 1H), 7.02(d,
2H), 6.66(d, 2H), 5.70(s, propylpyrimidin-4- 2H), 3.30-310(m, 1H),
2.48(d, 2H), 2.30-2.20(m, 1H), yl]pyrrolidin-3-yl}acetamide
2.00-1.90(m, 1H), 1.71(q, 2H), 0.98(t, 3H) 74 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.33(brs, 1H), 7.61(brs,
1H), cyanophenylamino)-6- 7.34(t, 1H), 7.21(d, 1H), 5.75(s, 1H),
5.63(brs, 1H), 4.65- propylpyrimidin-4- 4.55(m, 1H), 3.90-3.20(m,
4H), 2.49(t, 2H), 2.30-2.10(m, yl]pyrrolidin-3-yl}-2- 3H),
2.00-1.90(m, 1H), 1.90-1.45(m, 9H), 1.20-1.05(m,
cyclopentylacetamide 2H), 0.98(t, 3H) 75 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.40(brs, 1H), 8.02(s,
1H), cyanophenylamino)-6- 7.78(d, 1H), 7.42(t, 1H), 7.40-7.25(m,
2H), 6.70(brs, 1H), propylpyrimidin-4- 5.77(s, 1H), 4.70-4.60(m,
1H), 3.91(s, 2H), 3.90-3.40(m, yl]pyrrolidin-3-yl}-2- 4H), 3.42(s,
3H), 2.60(t, 2H), 2.40-2.30(m, 1H), 2.10- methoxyacetamide 2,00(m,
1H), 1.72(q, 2H), 1.00(t, 3H) 76 (S)-N-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.49(s, 1H), 8.40(brs, 1H),
cyanophenylamino)-6- 8.05(brs, 1H), 7.80-7.60(m, 2H), 7.40-7.15(m,
5H), propylpyrimidin-4- 5.73(s, 1H), 4.60-450(m, 1H), 3.74(s, 2H),
3.90-3.20(m, yl]pyrrolidin-3-yl}-2-(pyridin- 4H), 2.55(t, 2H),
2.35-2.25(m, 1H), 2.10-2.00(m, 1H), 2-yl)acetamide 1.70(t, 2H),
0.98(t, 3H) 77 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.51(s, 2H), 8.32(brs, 1H), cyanophenylamino)-6- 7.71(t,
2H), 7.40-7.20(m, 4H), 6.45(brs, 1H), 5.70(s, 1H),
propylpyrimidin-4- 4.65-4.55(m, 1H), 3.57(s, 2H), 3.90-3.30(m, 4H),
2.55(t, yl]pyrrolidin-3-yl}-2-(pyridin- 2H), 2.30-2.20(m, 1H),
2.10-2.00(m, 1H), 1.69(q, 2H), 3-yl)acetamide 0.98(t, 3H) 78
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.80(brs,
1H), 8.52(d, 2H), cyanophenylamino)-6- 8.30(s, 1H), 7.70-765(m,
1H), 7.40-7.20(m, 5H), propylpyrimidin-4- 6.63(brs, 1H), 5.68(s,
1H), 4.62(q, 1H), 3.56(s, 2H), yl]pyrrolidin-3-yl}-2-(pyridin-
3.90-3.30(m, 4H), 2.53(t, 2H), 2.35-2.25(m, 1H), 2.10-
4-yl)acetamide 2.00(m, 1H), 1.68(q, 2H), 0.97(t, 3H) 79
(S,E)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.30(brs, 1H), 7.60(brs, 1H), cyanophenylamino)-6- 7.40-7.00(m,
8H), 6.53(d, 1H), 6.35-6.25(m, 1H), propylpyrimidin-4- 5.91(brs,
1H), 5.73(s, 1H), 4.65-455(m, 1H), 3.90- yl]pyrrolidin-3-yl}-4-
3.25(m, 4H), 3.17(d, 2H), 2.47(t, 2H), 2.35-2.25(m, 1H),
phenylbut-3-enamide 2.00-1.80(m, 2H), 1.71(q, 2H), 0.98(t, 3H) 80
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.30(s,
2H), 7.61(brs, 1H), cyanophenylamino)-6- 7.40-7.10(m, 4H),
7.00-6.85(m, 2H), 5.84(s, 1H), 5.69(s, propylpyrimidin-4- 1H),
4.60-450(m, 1H), 3.79(s, 2H), 3.80-320(m, 4H),
yl]pyrrolidin-3-yl}-2- 2.49(t, 2H), 2.30-2.20(m, 1H), 2.00-1.85(m,
1H), 1.80- (thiophen-2-yl)acetamide 1.60(m, 2H), 1.00-0.90(m,
3H)
TABLE-US-00009 TABLE 1-9 Example Compound NMR Spectrum 81
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.34(brs,
1H), 7.61(brs, 1H), cyanophenylamino)-6- 7.35(t, 1H), 7.22(d, 1H),
5.75(s, 1H), 5.67(d, 1H), 4.60(q, propylpyrimidin-4- 1H),
3.90-3.20(m, 4H), 2.49(t, 2H), 2.20-1.90(m, 2H), yl]pyrrolidin-3-
1.17(d, 6H), 0.98(t, 3H) yl}isobutyramide 82 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.29(brs, 1H), 7.64(d,
1H), cyanophenylamino)-6- 7.34(t, 1H), 7.22(d, 1H), 6.43(d, 1H),
5.73(s, 1H), 4.64(q, propylpyrimidin-4- 1H), 4.00-3.30(m, 4H),
3.20-3.00(m, 2H), 2.51(t, 2H), yl]pyrrolidin-3-yl}-3,3,3-
2.40-2.30(m, 1H), 2.15-2.05(m, 1H), 1.71(q, 2H), 0.99(t, 3H)
trifluoropropanamide 83 3-[4-(2-oxopyrrolidin-1-yl)-6-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.26(s, 1H), 7.79(s, 1H),
propylpyrimidin-2- 7.60(d, 1H), 7.38(t, 1H), 7.27(d, 1H), 7.13(s,
1H), 4.11(t, ylamino]benzonitrile 2H), 2.75-2.55(m, 4H), 2.18(t,
2H), 1.77(q, 2H), 0.99(t, 3H) 84 (S)-3-{4-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.38(s, 1H), 7.57(d, 1H),
(hexylamino)pyrrolidin-1-yl]- 7.33(t, 1H), 7.21(d, 1H), 5.74(s,
1H), 3.90-3.20(m, 5H), 6-propylpyrimidin-2- 2.67(t, 2H), 2.48(t,
2H), 2.25-2.15(m, 1H), 1.90-1.85(m, ylamino}benzonitrile 1H),
1.72(q, 2H), 1.55-1.45(m, 2H), 1.40-1.20(m, 6H), 0.98(t, 3H),
0.95-0.85(m, 3H) 85 (S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.39(s, 1H), 7.57(d, 1H),
(propylamino)pyrrolidin-1- 7.34(t, 1H), 7.22(d, 1H), 5.75(s, 1H),
4.00-3.20(m, 5H), yl]pyrimidin-2- 2.65(t, 2H), 2.48(t, 2H),
2.25-2.15(m, 1H), 1.90-1.80(m, ylamino}benzonitrile 1H),
1.80-1.50(m, 6H), 1.00-0.90(m, 6H) 86 (S)-3-{4[3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.40(s, 1H), 7.60(d, 1H),
(cyclohexylmethylamino) 7.50(t, 1H), 7.33(t, 1H), 7.21(d, 1H),
5.73(s, 1H), 4.00- pyrrolidin-1-y1]-6- 3.10(m, 5H), 2.50-2.40(m,
4H), 2.25-2.15(m, 1H), 2.00- propylpyrimidin-2- 1.60(m, 9H),
1.50-1.40(m, 1H), 1.30-1.10(m, 4H), 0.98(t, 3H)
ylamino}benzonltrile 87 (S)-3-{4-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.41(s, 1H), 7.59(d, 1H),
(benzylamino)pyrrolidin-1- 7.52(brs, 1H), 7.40-7.15(m, 7H), 5.72(s,
1H), 3.87(s, yl]-6-propylpyrimidin-2- 2H), 3.80-3.10(m, 5H),
2.49(t, 2H), 2.25-2.15(m, 1H), ylamino}benzonitrile 2.00-1.90(m,
1H), 1.80-1.60(m, 2H), 0.98(t, 3H) 88 (S)-3-{4-{3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.38(s, 1H), 7.56(d, 1H),
(phenethylamino)pyrrolidin-1- 7.50-7.00(m, 7H), 5.73(s, 1H),
3.95-3.75(m, 1H), 3.70- yl]-6-propylpyrimidin-2- 3.30(m, 3H),
3.25-3.10(m, 1H), 3.00-2.90(m, 2H), 2.84(t, ylamino}benzonitrile
2H), 2.48(t, 2H), 2.25-2.15(m, 1H), 1.90-1.85(m, 1H), 1.72(q, 2H),
0.98(t, 3H) 89 (S)-3-{4-[3-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.39(s, 1H), 7.63(d, 1H), 7.39(t, phenylpropylamino) 1H),
7.35-7.10(m, 6H), 5.75(s, 1H), 4.00-3.20(m, 5H), 2.80-
pyrrolidin-1-yl]-6- 2.60(m, 4H), 2.55(t, 2H), 2.30-2.00(m, 2H),
2.00-1.90(m, 2H), propylpyrimidin-2- 1.80-1.70(m, 2H), 1.01(t, 3H)
ylamino}benzonitrile 90 (S)-3-{4-[3-(3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.43(s, 1H), 7.53(d, 1H),
flourobenzylamino)pyrrolidin- 7.40-7.05(m, 6H), 6.95(t, 1H),
5.74(s, 1H), 3.87(s, 2H), 1-yl]-6-propylpyrimidin-2- 3.80-3.10(m,
5H), 2.48(t, 2H), 2.25-2.15(m, 1H), 2.00-1.90(m,
ylamino}benzonitrile 1H), 1.72(q, 2H), 0.98(t, 3H)
TABLE-US-00010 TABLE 1-10 Example Compound NMR Spectrum 91
(S)-3-{4-[3-(4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.37(s,
1H), 7.52(d, 1H), hydroxbenzylamino) 7.32(t, 1H), 7.25-7.15(m, 3H),
6.77(d, 2H), 5.73(s, 1H), pyrrolidin-1-yl]-6-pro- 3.78(s, 2H),
3.80-3.10(m, 5H), 2.48(t, 2H), 1.25-1.15(m, pylpyrimidin-2-ylamino}
1H), 2.00-1.90(m, 1H), 1.71(q, 2H), 0.97(t, 3H) benzonitrile 92
(S)-3-{4-[3-(4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.40(s,
1H), 7.59(d, 1H), ethylbenzylamino)pyrrolidin- 7.40-7.10(m, 6H),
5.72(s, 1H), 3.84(s, 2H), 3.80-3.10(m, 1-yl]-6-propylpyrimidin-2-
5H), 2.63(q, 2H), 2.48(t, 2H), 2.25-2.15(m, 1H), 2.00-
ylamino}benzonitrile 1.90(m, 1H), 1.72(q, 2H), 1.23(t, 3H), 0.98(t,
3H) 93 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.38(s, 1H), 7.58(d, 1H), (isopentylamino)pyrrolidin- 7.33(t, 1H),
7.20(d, 1H), 7.00(brs, 1H), 5.74(s, 1H), 3.90-
1-yl]-6-propylpyrimidin-2- 3.00(m, 5H), 2.68(t, 2H), 2.48(t, 2H),
2.25-2.15(m, 1H), ylamino}benzonitrile 1.90-1.80(m, 1H),
1.80-1.50(m, 3H), 1.40(q, 2H), 0.98(t, 3H), 0.92(d, 6H) 94
(S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.39(s, 1H),
7.56(d, 1H), (pentylamino)pyrrolidin- 7.34(t, 1H), 7.22(d, 1H),
7.00(brs, 1H), 5.75(s, 1H), 3.90- 1-yl]-6-propylpyrimidin-2-
3.30(m, 5H), 2.67(t, 2H), 2.48(t, 2H), 2.25-2.15(m, 1H),
ylamino}benzonitrile 2.00-1.60(m, 3H), 1.52(t, 2H), 1.40-1.20(m,
4H), 0.99(t, 3H), 0.92(t, 3H) 95 3-{4-[(3S)-3-(2- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.39(s, 1H), 7.58(d, 1H),
methylbutylamino)pyrrolidin- 7.33(t, 1H), 7.20(d, 1H), 7.03(brs,
1H), 5.74(s, 1H), 3.90- 1-yl]-6-propylpyrimidin-2- 3.10(m, 5H),
2.65-2.55(m, 1H), 2.50-2.40(m, 3H), 2.25- ylamino]benzonitrile
2.15(m, 1H), 1.90-1.80(m, 1H), 1.72(q, 2H), 1.50-1.35(m, 2H),
1.20-1.10(m, 1H), 0.98(t, 3H), 0.95-0.85(m, 6H) 96 (S)-3-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.39(s, 1H), 7.55(d, 1H),
(isobutylamino)pyrrolidin-1- 7.35(t, 1H), 7.23(d, 1H), 5.75(s, 1H),
3.90-3.10(m, 5H), yl]-6-propylpyrimidin-2- 2.55-2.45(m, 3H),
2.25-2.15(m, 1H), 1.90-1.85(m, 1H), ylamino}benzonitrile
1.80-1.60(m, 4H), 0.99(t, 3H), 0.94(d, 6H) 97 (S)-3-{4-[3-(4-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.40(s, 1H), 7.56(d, 1H),
methoxybenzylamino)pyrrolidin- 7.33(t, 1H), 7.26(t, 2H), 7.21(d,
1H), 6.87(d, 2H), 5.73(s, 1-yl]-6-propylpyrimidin- 1H), 3.81(s,
2H), 3.80(s, 3H), 3.80-3.10(m, 5H), 2.48(t, 2-ylamino}benzonitrile
2H), 2.25-2.15(m, 1H), 2.00-1.90(m, 1H), 1.80-160(m, 2H), 0.98(t,
3H) 98 (S)-3-{4-[3-(4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.44(s, 1H), 7.54(d, 1H), fluorobenzylamino)pyrrolidi 7.40-7.30(m,
3H), 7.21(d, 1H), 7.01(d, 2H), 5.73(s, 1H),
n-1-yl]-6-propylpyrimidin-2- 3.84(s, 2H), 3.80-3.10(m, 5H), 2.48(t,
2H), 2.25-2.15(m, ylamino}benzonitrile 1H), 2.00-1.90(m, 1H),
1.71(q, 2H), 0.98(t, 3H) 99 (S)-3-{4-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.39(s, 1H), 7.56(d, 1H),
(cyclopropylmethylamino) 7.35(t, 1H), 7.24(d, 1H), 5.75(s, 1H),
3.90-3.20(m, 5H), pyrrolidin-1-yl]-6- 2.56(d, 2H), 2.49(t, 2H),
2.25-2.15(m, 1H), 2.00-1.90(m, propylpyrimidin-2- 1H), 1.80-1.65(m,
2H), 1.00-0.90(m, 4H), 0.53(d, 2H), ylamino}benzonitrile 0.17(d,
2H) 100 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.39(s, 1H), 7.58(d, 1H), [bis(cyclopropylmethyl)amino] 7.32(t,
1H), 7.20(d, 1H), 7.08(brs, 1H), 5.73(s, 1H), 4.00-
pyrrolidin-1-yl}-6- 3.10(m, 5H), 2.70-2.55(m, 4H), 2.48(t, 2H),
2.25-2.15(m, propylpyrimidin-2-ylamino) 1H), 2.00-1.90(m, 1H),
1.80-1.65(m, 2H), 1.00-0.90(m, bezonitrile 5H), 0.55(d, 4H),
0.18(d, 4H)
TABLE-US-00011 TABLE 1-11 Example Compound NMR Spectrum 101
(S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.52(s, 1H), 7.70-7.60(m, (pyridin-2-ylmethylamino) 2H), 7.51(brs,
1H), 7.33(t, 1H), 7.21(d, 1H), 7.15(t, 2H),
pyrrolidin-1-yl]pyrimidin-2- 5.68(s, 1H), 3.95(s, 2H), 4.00-3.20(m,
5H), 2.48(t, 2H), ylamino}benzonitrile 2.50-2.20(m, 2H), 1.71(q,
2H), 0.98(t, 3H) 102 (S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.65-8.45(m, 3H), 7.70(t,
(pyridin-3-ylmethylamino) 1H), 7.55(d, 1H), 7.40-7.15(m, 3H),
5.73(s, 1H), 3.89(s, pyrrolidin-1-yl]pyrimidin-2- 2H), 3.90-3.20(m,
5H), 2.48(t, 2H), 2.25-2.15(m, 1H), ylamino}bezonitrile
2.00-1.90(m, 1H), 1.80-160(m, 2H), 0.98(t, 3H) 103
(S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.60-8.40(m, 3H), 8.10(brs, (pyridin-4-ylmethylamino) 1H),
7.60-7.50(m, 1H), 7.40-7.15(m, 4H), 5.73(s, 1H),
pyrrolidin-1-yl]pyrimidin- 3.90(s, 2H), 3.90-3.10(m, 5H), 2.48(t,
2H), 2.25-2.15(m, 2-ylamino}benzonitrile 1H), 2.00-1.90(m, 1H),
1.72(q, 2H), 0.99(t, 3H) 104 (S)-3-{4-[3-(2- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.41(s, 1H), 7.58(d, 1H),
ethylbutylamino)pyrrolidin- 7.33(1. 1H), 7.21(d, 1H), 5.74(s, 1H),
3.90-3.00(m, 5H), 1-yl]-6-propylpyrimidin-2- 2.48(1, 2H), 2.40(brs.
2H), 2.25-2.15(m, 1H), 1.88(brs, ylamino}benzonitrile 1H), 1.72(q,
2H), 0.98(t, 3H), 0.92(s, 9H) 105 (S)-3-{4-[3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.41(s, 1H), 7.58(d. 1H),
(neopentylamino)pyrrolidin- 7.33(1, 1H), 7.21(d, 1H), 5.74(s, 1H),
3.90-3.00(m, 5H), 1-yl]-6-propylpyrimidin-2- 2.48(1, 2H), 2.40(brs,
2H), 2.25-2.15(m, 1H), 1.88(brs, ylamino}benzonitrile 1H), 1.72(q,
2H), 0.98(t, 3H), 0.92(s, 9H) 106 (S)-3-{4-[3-(2- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.39(s, 1H), 7.60(d, 1H),
fluorobenzylamino)pyrrolidin- 7.50-7.20(m, 4H), 7.12(t, 1H),
7.05(1, 1H). 5.73(s, 1H), 1-yl]-6-propylpyrimidin-2- 3.92(s, 2H),
3.90-3.10(m, 5H), 2.48(t., 2H), 2.25-2.15(m, ylamino}benzonitrile
1H), 2.00-1.90(m, 1H), 1.72(q, 2H), 0.98(t, 3H) 107
(S)-3-(4-propyl-6-{3-[3- .sup.1H-NMR(400 MHz,, CDCl.sub.3) .delta.
8.45(S( 1H), 7.64(s( 1H), (trifluoromethyl)benzylamino]
7.60-7.40(m, 4H), 7.33(t, 1H), 7.21(d, 1H), 5.73(s, 1H),
pyrrolidin-1-yl}pyrimidin-2- 3.94(s, 2H), 3.90-3.10(m, 5H), 2.49(t,
2H), 2.25-2.15(m, ylamino)benzonitrile 1H), 2.00-1.90(m, 1H),
1.72(q, 2H), 0.98(t, 3H) 108 (S)-3-(4-propyl-6-{3-[4-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.48(s, 1H), 7.70-7.40(m,
(trifluoromethyl)benzylamino] 5H), 7.33(t, 1H), 7.21(d, 1H),
5.72(s, 1H), 3.94(8, 2H), pyrrolidin-1-yl}pyrimidin-2- 3.90-3.10(m,
5H), 2.48(t, 2H), 2.25-2.15(m, 1H), 2.00- ylamino)benzonitrile
1.90(m, 1H), 1.72(q, 2H), 0.98(t, 3H) 109 (S)-4({1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.39(s, 1H), 7.53(d, 1H),
cyanophenylamino)-6- 7.33(t, 1H), 7.25-7.15(m, 3H), 6.78(d, 2H),
5.74(s, 1H), propylpyrimidin-4- 3.79(s, 2H), 3.70-3.10(m, 5H),
2.49(s, 2H), 2.25-2.15(m, yl]pyrrolidin-3- 2H), 1.92(brs, 3H),
1.72(q, 2H), 0.98(t, 3H) ylamino}methyl)phenylacetate 110
(S)-3-(4-{3-[4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.36(s,
1H), 7.57(dd, 1H), (dimethylamino)benzylamino] 7.35(t, 1H),
7.30-7.15(m, 3H), 6.71(d, 2H), 5.74(s, 1H), pyrrolidin-1-yl}-6-
3.78(s, 2H), 3.80-3.30(m, 5H), 2.93(s, 6H), 2.50(t, 2H),
propylpyrimidin-2- 2.25-2.15(m, 1H), 2.00-1.90(m, 1H), 1.73(q, 2H),
0.99(t, ylamino)benzonitrile 3H)
TABLE-US-00012 TABLE 1-12 Example Compound NMR Spectrum 111
(S)-3-(4-{3-[(1H-pyrrol-2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.41(brs, 1H), 7.52(brs, 1H), yl)Methylamino]pyyrolidin- 7.34(t,
1H), 7.23(d, 1H), 6.74(s, 1H), 6.14(d, 1H), 6.08(s,
1-yl}-6-propylpyrimidin- 1H), 5.71(s, 1H), 3.90(s, 2H),
3.80-3.10(m, 5H), 2.49(t, 2-ylamino)benzonitrile 2H), 2.25-2.15(m,
1H), 1.90-1.85(m, 1H), 1.71(q, 2H), 0.99(t, 3H) 112
(S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.41(s, 1H), 7.59(d, 1H), (thiophen-2- 7.55(brs, 1H), 7.33(t, 1H),
7.30-7.20(m, 2H), 7.00- ylmethylamino)pyrrolidin- 6.90(m, 2H), 5
73(s, 1H), 4.08(s, 2H), 3.90-3.10(m, 5H), 1-yl]pyrimidin-2- 2.48(t,
2H). 2.25-2.15(m, 1H), 2.00-1.90(m, 1H), 1.72(q,
ylamino}benzonitrile 2H), 0.98(t, 3H) 113 (S)-3-{4-propyl-6-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.44(s, 1H), 7.57(d, 1H),
(thiophen-3- 7.50(brs, 1H), 7.40-7.25(m, 2H), 7.25-7.15{m, 2H),
ylmethylamino)pyrrolidin- 7.07(d, 1H), 5.73(s, 1H), 3.90(s, 2H),
3.90-3.10(m, 5H), 1-yl]pyrimidin-2-ylamino} 2.48(t, 2H),
2.25-2.15(m, 1H), 2.00-1.90(m, 1H), 1.72{q, benzonitrile 2H),
0.98{t, 3H) 114 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.37(s, 1H), 7.60(d, 1H), (dibutylamino)pyrrolidin- 7.32(t,
1H), 7.20(d, 1H), 7.13(brs, 1H), 5.74(s, 1H),
1-yl]-6-propylpyrimidin- 3.90(brs, 1H), 3.60-3.10(m, 4H),
2.75-2.40(m, 6H), 2.20- 2-ylamino}benzonitrile 2.10(m, 1H),
2.00-1.90(m, 1H), 1.73(q, 2H), 1.50-1.20(m, 8H), 1.00-0.90(m, 9H)
115 (S)-3-(4-{3-bis[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.42(brs, 1H), 7.57(d, 1H), (methylthio)propyl] 7.33(t, 1H),
7.20(d, 1H), 5.74(s, 1H), 3.90(brs, 1H), 3.65-
aminopyrrolidin-1-yl}- 3.10(m, 4H), 2.70-2.60(m, 4H), 2.54(t, 4H),
2.49(t, 2H), 6-propylpyrimidin-2- 2.25-2.15(m, 1H), 2.11(s, 6H),
2.00-1.90(m, 1H), 1.80- ylamino)benzonitirile 1.65(m, 6H), 0.98(t,
3H) 116 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.33(s, 1H), 7.58(d, 1H), (butylamino)pyrrolidin- 7.34(t, 1H),
7.22(d, 1H), 5.75(s, 1H), 3.90-3.10(m, 5H),
1-yl]-6-propylpyrimidin- 2.73(t, 2H), 2.49(t, 2H), 2.30-2.20(m,
1H), 2.10-1.95(m, 2-ylamino}benzonitrile 1H), 1.72(q, 2H),
1.55-1.45(m, 2H), 1.45-1.30(m, 2H), 1.00-0.85(m, 6H) 117
(S)-3-(4-{3-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.38(s,
1H), 7.57(d, 1H), (methylthio)propylamino] 7.37(t, 1H),
7.30-7.20(m, 1H), 5.77(s, 1H), 3.90-3.10(m, pyrrolidin-1-yl}-6-
5H), 2.90-2.70(m, 2H), 2.58(t, 2H), 2.51(t, 2H), 2.30-
propylpyrimidin-2- 2.20(m, 1H), 2.11(s, 3H), 2.00-1.90(m, 1H),
1.90-1.70(m, ylamino)benzonitrile 4H), 1.00(t, 3H) 118
(S)-3-{4-propyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.45(d, 1H), 7.77(t, 1H), (propylamino)pyrrolidin- 7.41(t, 1H),
7.25(d, 1H), 5.98(s, 1H), 4.10-3.90(m, 2H), 1-yl]pyrimidin-
385-3.50(m, 3H), 3.10-3.00(m, 2H), 2.60-2.40(m, 3H),
2-ylamino}benzonitrile 2.30-2.20(m, 1H), 1.80-1.65(m, 3H),
1.50-1.40(m, 1H), dihydrochloride 1.10-0.90(m, 6H) 119 (S)-3-{4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.15(d, 1H), 7.58(d, 1H),
(cyclopropylmethylamino) 1H), 7.60-7.45(m, 2H), 6.35(d, 1H),
4.25-365(m, 5H), pyrrolidin-1-yl]-6- 3.15-2.90(m, 2H), 2.70-2.50(m,
3H), 2.50-2.25(m, 1H), propylpyrimidin- 1.90-1.70(m, 2H),
1.20-1.10{m, 1H), 1.10-0.95{m, 3H), 2-ylamino}benzonitrile
0.80-0.65(m, 2H), 0.50-0.40(m, 2H) dihydrochloride 120 (S)-3-{4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.16(brs, 1H), 7.83(d,
1H), (methylamino)pyrrolidin- 7.61-7.53(m, 2H), 6.34(s, 1H),
4.12-3.79(m, 5H), 2.81(s, 1-yl]-6-propylpyrimidin- 3H), 2.69(dd,
2H), 2.58(brs, 1H), 2.38(brs, 1H), 1.85- 2-ylamino}benzonitrile
1.76(m, 2H), 1.06(dd, 3H) dihydrochloride
TABLE-US-00013 TABLE 1-13 Example Compound NMR Spectrum 121
(S)-N-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.03(s, 1H),
7.41(d, 1H), (methylamino)pyrrolidin-1- 7.12(d, 1H), 7.04(d, 1H),
6.35(d, 1H), 5.82(s, 1H), 3.90- yl]-6-propylpyrimidin-2-yl}-
3.30(m, 5H), 2.50-2.40(m, 5H), 2.30-2.20(m, 1H), 2.00-
1H-indol-6-amine 1.90(m, 1H), 1.73(q, 2H), 0.99(t, 3H) 122
(S)-N-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.66(s, 1H),
7.57(d, 1H), (methylamino)pyrrolidin-1- 7.27(d, 1H), 7.04(d, 1H),
6.46(d, 1H), 6.19(s, 1H), 4.10- yl]-6-propylpyrimidin-2-yl}-
3.60(m, 5H), 2.78(s, 3H), 2.62(t, 2H), 2.55(brs, 1H),
1H-indol-6-amine 2.31(brs, 1H), 1.75(q, 2H), 1.04(t, 3H) 123
(S)-N.sup.1-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.97(d,
1H), 7.65-7.55(m, (methylamino)pyrrolidin-1- 1H), 7.21(t, 1H),
6.30(d, 1H), 4.15-3.75(m, 5H), 2.79(d,
yl]-6-propylpyrimidin-2-yl}-3- 3H), 2.69(t, 2H), 2.65-2.50(m, 1H),
2.50-2.25(m, 1H), (trifluoromethyl)benzene-1,4- 1.90-1.70{m, 2H),
1.07(t, 3H) diamine dihydrochloride 124 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.45(s, 1H), 7.98(brs,
1H), cyanophenylamino)-6- 7.60-7.50(m, 1H), 7.34(t, 1H), 7.22(d(
1H), 6.27(brs, 1H), propylpyrimidin-4-yl] 5.53(s, 1H), 4.24(brs,
1H), 3.80-3.20(m, 5H), 2.50- pyrrolidin-3-yl}isopropane-2- 2.35(m,
2H), 2.30-2.00(m, 2H), 1.70-1.50(m, 2H), sulfonamide 1.46(d, 6H),
0.95(t, 3H) 125 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.43(s, 1H), 7.61(d, 1H), cyanophenylamino)-6- 7.35(t, 1H),
7.24(d, 1H), 5.66(s, 1H), 4.24(brs, 1H), 3.90-
propylpyrimidin-4-yl] 3.30(m, 5H), 3.08(s, 3H), 2.50-2.20(m, 4H),
1.67(q, 2H), pyrrolidin-3-yl} 0.98(t, 3H) methanesulfonamide 126
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.35(s,
1H), 8.00-7.90(m, cyanophenylamino)-6- 2H), 7.54(d, 1H), 7.33(t,
1H), 7.30-7.15(m, 3H), 5.54(s, propylpyrimidin-4-yl] 1H), 4.10(brs,
1H), 3.70-3.30(m, 4H), 2.50-2.25(m, 2H), pyrrolidin-3-yl}-4-
2.20-2.00(m, 2H), 1.58(q, 2H), 0.91(t, 3H) fluorobenzenesulfonamide
127 3-{4-[(3S)-3-(sec- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.36(s, 1H), 7.58{d, 1H), butylamino)pyrrolidin-1-yl]- 7.33(dd,
1H), 7.20(d, 1H), 7.10(s, 1H), 5.74(s, 1H), 6-propylpyrimidin-2-
4.10-3.10(m, 5H), 2.71-2.67(m, 1H), 2.48(dd, 2H),
ylamino}benzonitrile 2.26-2.21(m, 1H), 1.77-1.67(m, 3H),
1.52-1.46(m, 1H), 1.39-1.34(m, 1H), 1.10-1.07(m, 3H), 0.98(t, 3H),
0.94-0.90(m, 3H) 128 (S)-3-{4-[3-(pentan-3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 10.02(brs, 1H), 8.42(s, 1H),
ylamino)pyrrolidin-1-yl]- 7.70(d, 1H), 7.35(dd, 1H), 7.24(d, 1H),
5.71(s, 1H), 3.88- 6-propylpyrimidin-2- 3.12(m, 5H), 2.53-2.45(m,
3H), 2.26-2.18(m, 1H), 2.10(s, ylamino}benzonitrile 3H),
1.94-1.88(m, 1H), 1.76-1.67(m, 2H), 1.52-1.44(m, 4H), 0.98(t, 3H),
0.95-0.90(m, 6H) 129 (S)-3-[4-[3-(2,6- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.35(brs, 1H), 7.65(brs,
dimethylheptan-4-ylamino) 1H), 7.33(dd, 1H), 7.22-7.20(m, 2H),
5.74(s, 1H), 3.88- pyrrolidin-1-yl]-6- 3.12(m, 5H), 2.83-2.82(m,
1H), 2.48(dd, 2H), 2.24- propylpyrimdin-2-ylamino} 2.21(m, 1H),
1.84-1.62(m, 7H), 1.39-1.36(m, 1H). 1.26- benzonitrile 1.22(m, 1H),
1.14-1.02(m, 3H), 0.98(t, 3H), 0.88-0.81(m, 9H)
TABLE-US-00014 TABLE 1-14 Example Compound NMR Spectrum 130
(S)-3-{4-[3-(4,4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.36(brs, 1H), 7.62(brs, 2H), dimethylpentan-2- 7.33(dd, 1H),
7.21(d, 1H), 5.73(s, 1H), 3.84-3.07(m, 5H), ylamino)pyrrolidin-1-
2.85-2.81 (m, 1H), 2.49(dd, 2H), 2.27-2.20(m, 1H), 1.77-
yl]-6-propylpyrimdin-2- 1.70(m, 3H), 1.37-1.30{m, 2H), 1.12(d, 3H),
1.04-0.81(m, ylamino}benzonitrile 12H) 131
(S)-3-{4-[3-(3-hydroxy-3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.49-8.35(m, 1H), 7.68(brs, methylbutan-2-ylamino) 1H),
7.37-7.33(m, 1H), 7.25-7.23(m, 1H), 5.71(s, 1H),
pyrrolidin-1-yl]-6- 3.92-3.22(m, 5H), 2.54-2.49(m, 3H),
2.29-2.25(m, 1H), proylpyrimidin-2- 2.12-2.06(m, 1H), 1.75-1.66(m,
2H), 1.21(d, 3H), 1.16- ylamino}benzonitrile 1.13(m, 3H), 1.05(s,
3H), 1.00(t, 3H) 132 (S)-3-{4-[3-(heptan-4- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.36(brs, 1H), 7.62(brs, 1H),
ylamino)pyrrolidin-1-yl]- 7.47(brs, 1H), 7.33(m, 1H), 7.20(d, 1H),
5.71(s, 1H), 6-propylpyrimdin-2- 3.82-3.06(m, 5H), 2.58-2.56(m,
1H), 2.49(dd, 2H), 2.24- ylamino}bezonitrile 2.16(m, 1H),
1.94-1.90(m, 1H), 1.77-1.68(m, 2H), 1.43- 1.36(m, 8H), 1.00(t, 3H),
0.95-0.85(m, 6H) 133 (S)-3-{4-[3-(n-hexan-2- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 9.35(brs, 1H), 8.42(brs, 1H),
ylamino)pyrrolidin-1-yl]-6- 7.34(dd, 1H), 7.23(d, 1H), 5.71(s, 1H),
3.85-3.10(m, 5H), propylpyrimidin-2- 2.75-2.71(m, 1H), 2.50(dd,
2H), 2.26-2.22(m, 1H), 1.94- ylamino}benzonitrile 1.87(m, 1H),
1.74-1.69(m, 2H), 1.45-1.31(m, 6H), 1.11- 0.88(m, 9H) 134
(S)-3-[4-[3-(5-methylhexan- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.34(brs, 2H), 7.63(d, 1H), 2-ylamino)pyrrolidin-1-yl]-
7.33(dd, 1H), 7.21(d, 1H), 5.72(s, 1H), 3.85-3.10(m, 5H),
6-propylpyrimidin-2- 2.74-2.70(m, 1H), 2.49(dd, 2H), 2.26-2.21(m,
1H), 1.94- ylamino}benzonitrile 1.87(m, 1H), 1.74-1.69(m, 2H),
1.54-1.17(m, 5H), 1.10- 1.08(m, 3H), 0.98(t, 3H), 0.90-0.86(m, 6H)
135 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.45(s,
1H), 7.72(d, 1H), (cyclohexylamino(pyrrolidin- 7.35(dd, 1H),
7.25(d, 1H), 5.69(s, 1H), 3.95-3.15(m, 5H),
1-yl]-6-propylpyridin-2- 2.54-2.52(m, 3H), 2.27-2.23(m, 2H),
1.93(brs, 3H), 1.78- ylamino}bezonitrile 1.63(m, 5H), 1.32-1.15(m,
5H), 0.98(t, 3H) 136 (s)-tert-butyl 2-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.42(s, 1H), 7.58(d, 1H),
cyanophenylamino)-6- 7.33(dd, 1H), 7.20(d, 1H), 5.73(s, 1H),
4.97(brs, 1H), propylpyrimidin-4-yl] 3.72-3.25(m, 9H), 2.81(brs,
1H), 2.48(dd, 2H), 2.23- pyrrolidin-3-ylamino} 2.18(m, 1H),
1.88{brs, 1H), 1.76-1.71{m, 2H), 1.44(s, ethylcarbamate 9H),
0.98(t, 3H) 137 (S)-3-{4-[3-(1- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.39(s, 1H), 7.57(d, 1H), benzylpiperidin-4- 7.35-7.19(m,
6H), 7.09(brs, 1H), 5.73(s, 1H), 3.76- ylamino)pyrrolidin-1-yl]-6-
3.58(m, 3H), 3.51(s, 2H), 3.51-3.05(m, 2H), 2.87(d, 2H),
propylpyrimidin-2- 2.61-2.54(m, 1H), 2.47(dd, 2H), 2.23-2.19(m,
1H), ylamino}benzonitrile 2.05(dd, 2H), 1.89-1.85(m, 3H),
1.76-1.67(m, 2H), 1.46- 1.37(m, 2H), 0.97(t, 3H) 138 (S)-3-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.38(s, 1H), 7.59(d, 1H),
(isopropylamino)pyrrolidin- 7.32(dd. 1H), 7.20(d, 1H), 7.11(brs,
1H), 5.73(s, 1H), 1-yl]-6-propylpyrimidin-2- 4.10-2.99(m, 5H),
2.99-2.93(m, 1H), 2.48(dd, 2H), 2.28- ylamino}benzonitrile 2.21(m,
1H), 1.84(brs, 1H), 1.77-1.67(m, 2H), 1.11(dd, 6H), 0.97(t, 3H) 139
(S)-3-{4-[3-(1- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.54(brs,
1H), 7.47-7.40(m, benzoylpiperidin-4- 6H), 7.33(dd, 1H), 7.21(d,
1H), 5.73(s, 1H), 4.63{brs, ylamino)pyrrolidin-1-yl]-6- 1H),
4.23-2.90(m, 9H), 2.48(dd, 2H), 2.27-2.23(m, 1H),
propylpyrimidin-2- 2.11-1.69(m, 7H), 0.98(t, 3H)
ylamino}benzonitrile
TABLE-US-00015 TABLE 1-15 Example Compound NMR Spectrum 140
(S)-3-{4-[3-(1- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.50-8.37(m, 1H), 7.60- acetylpiperidin-4- 7.49(m, 1H), 7.32(dd,
1H), 7.20(d, 1H), 7.14(brs, 1H), ylamino)pyrrolidin-1-yl]- 5.74(s,
1H), 4.51(d, 1H), 3.89-3.38(m, 6H), 3.15(dd, 1H),
6-propylpyrimidin-2- 2.84(brs, 1H), 2.76(dd, 1H), 2.48(dd, 2H),
2.26-2.20(m, ylamino}benzonitrile 1H), 2.10(s, 3H), 1.97-1.89(m,
3H), 1.76-1.67(m, 2H), 1.30-1.25(m, 2H), 0.98(t, 3H) 141
(S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.38(brs,
1H), 7.56(brs, 1H), (cyclooctylamino)pyrrolidin- 7.33(dd, 1H),
7.20(d, 1H), 7.16(brs, 1H), 5.73(s, 1H), 1-yl]-6-propylpyrimidin-2-
3.89-3.38(m, 5H), 2.79(brs, 1H), 2.53-2.45(m, 4H), 2.23-
ylamino}benzonitrile 2.09(m, 3H), 2.01-1.50(m, 14H), 0.98(t, 3H)
142 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.37(brs,
1H), 7.59(d, 1H), (cyclobutylamino)pyrrolidin- 7.33(dd, 1H),
7.20(d, 1H), 7.00(brs, 1H), 5.73(s, 1H), 1-yl]-6-propylpyrimidin-2-
3.83-3.32(m, 6H), 2.47(dd, 2H), 2.29-2.15(m, 3H),
ylamino}benzonitrile 1.85(brs, 1H), 1.79-1.64(m, 6H), 0.98(t, 3H)
143 (S)-3-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.37(brs,
1H), 7.58(d, 1H), (cyclopentylamino)pyrrolidin- 7.32(dd, 1H),
7.19(d, 1H), 7.18(brs, 1H), 5.73(s, 1H), 1-yl]-6-propylpyrimidin-2-
3.99-3.14(m, 6H), 2.47(dd, 2H), 2.28-2.20(m, 1H), 1.93-
ylamino}benzonitrile 1.88(m, 3H), 1.76-1.67(m, 4H), 1.64-1.51(m,
2H), 1.38- 1.24(dd, 2H), 0.97(t, 3H) 144 (S)-tert-butyl 3-{1-{2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.36(brs, 1H), 7.59(d,
1H), cyanophenylamino)-6- 7.32(dd, 1H), 7.21(brs, 1H), 7.20(d, 1H),
5.76(brs, 1H), propylpyrimidin-4-yl] 4.65(d, 4H), 3.97-3.40(m, 6H),
2.48(dd, 2H), 2.26- pyrrolidin-3-ylamino} 2.05(m, 2H), 1.74-1.69(m,
2H), 1.49(8, 9H), 0.97(t, 3H) azetidine-1-carboxylate 145
(S)-3-(4-{3-[2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.44(s,
1H), 7.70(d, 1H), (benzyloxy)ethylamino] 7.37-7.23(m, 7H), 5.69(s,
1H), 4.53(s, 2H), 3.85-3.19(m, pyrrolidin-1-yl}-6- 7H), 2.89(brs,
2H), 2.52(dd, 2H), 2.25-2.17(m, 1H), propylpyrimidin-2-ylamino)
2.10(s, 3H), 1.94(brs, 1H), 1.76-1.67(m, 2H), 0.99(t, 3H)
benzonitrile 146 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.32(s, 1H), 7.61(s, 1H), cyanophenylamino)-6- 7.54(8, 1H)(
7.33(t, 1H), 7.19(d, 1H), 5.81(m, 1H), propylpyrimidin-4-yl]
5.80(s, 1H), 4.62(m, 1H), 3.78-3.01(m, 4H), 2.48(t, 2H),
pyrrolidin-3-yl}propionamide 2.32(m, 1H), 2.23(m, 2H), 2.01(m, 1H),
1.72(m, 2H), 1.17(t, 3H), 0.98(t, 3H) 147 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.45(s, 1H), 7.71(s, 1H),
cyanophenylamino)-6- 7.35(t, 1H), 7.23(d, 1H), 5.77(s, 1H), 5.71(s.
1H), propylpyrimidin-4-yl] 4.59(m, 1H). 3.81-3.22(m. 4H), 2.47(1,
2H), 2.34(m. 1H), pyrrolidin-3-yl}pivalamide 2.01(m, 1H), 1.67(q,
2H), 1.21(s, 9H), 0.98(t, 3H) 148 (S)-N-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.25(S, 1H), 7.53(s, 1H),
cyanophenylamino)-6- 7.26(t, 1H), 7.13(d, 1H), 7.09(brs, 1H),
5.69(s, 1H), propylpyrimidin-4-yl] 4.53(m, 1H), 3 75-3.21(m, 4H),
2.43(t, 2H), 2.25(m, 1H), pyrrolidin-3-yl}-2,2- 1.86(m, 1H),
1.66(m, 2H), 1.47(m, 2H), 1.09(s, 6H), dimethylbutanamide 0.91(t,
3H), 0.75(t, 3H)
TABLE-US-00016 TABLE 1-16 Example Compound NMR Spectrum 149
(S,E)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.34(s,
1H), 7.61 cyanophenylamino)-6- (s, 1H), 7.34(t, 1H), 7.22(d, 1H),
7.06(s, 1H), propylpyrimidin-4-yl] 6.45(m, 1H), 5.86(m, 1H),
5.76(s, 1H), 4.66(m, 1H), pyrrolidin-3-yl}-2- 3.81-3.37(m, 4H),
2.48(t, 2H), 2.34(m, 1H), methylbut-2-enamide 2.05(m, 1H), 1.85(s,
3H), 1.71(m. 5H), 0.98(t, 3H) 150 (S)-N-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.32(s, 1H), 7.60(s, 1H),
cyanophenylamino)- 7.34(t, 1H), 7.20(d, 1H), 7.06(s, 1H), 5.75(s,
1H), 6-propylpyrimidin- 5.67(m, 1H), 4.60(m, 1H), 3.77-3.34(m, 4H),
2.50(t, 2H), 4-yl]pyrrolidin- 2.31(m, 1H), 2.17(t, 2H), 2.02(m,
1H), 1.76-1.62(m, 4H), 3-yl}hexanamide 1.31(m, 6H), 0.98(t, 3H),
0.89(t, 3H) 151 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.30(s, 1H), 7.59{s, 1H), cyanophenylamino)-6- 7.35(t, 1H),
7.27-7.12(m, 7H), 5.70(s, 1H), 5.57(m, 1H), propylpyrimidin-4-yl]
4.55(m, 1H), 3.69(m, 4H), 2.97 pyrrolidin-3-yl}-3- (t, 2H), 2.49(m,
4H), 2.22(m, 1H), 1.73(m, 1H), phenylpropanamide 1.69(m, 2H),
0.98(t, 3H) 152 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.30 cyanophenylamino)-6- (s, 1H), 8.26(s, 1H), 7.52(m,
2H), propylpyrimidin-4-yl] 7.39-7.31(m, 2H), 7.22-7.16(m, 2H),
pyrrolidin-3-yl}-2- 7.09(m, 1H), 5.80(m, 1H), 5.65(s, 1H), 4.58(m,
1H), (1H-indol-3-yl) 3.76(s, 2H), 3.34-320(m, 4H), 2.46(t, 2H),
2.25(m, 1H), acetamide 1.71(m, 3H),0.97(t, 3H) 153 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.37 cyanophenylamino)-6-
(s, 1H), 7.58(d, 1H), 7.32(1, 1H), 7.20(d, 2H),
propylpyrimidin-4-yl] 6.97(m, 1H), 5.75(s, 1H), 4.59(m, 1H),
3.83-3.34 pyrrolidin-3-yl}-2- (m, 4H), 2.51(t, 2H), 2.31(m, 1H),
2.03(m, 1H), hydroxy-2- 1.71 (m, 2H), 1.47(s, 6H), 0.98(t, 3H)
methylpropanamide 154 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.28(s, 1H), 7.62(s, 1H), cyanophenylamino)-6-
7.48(s, 1H), 7.32(t, 1H), 7.18(d, 1H), 7.08(d, 1H), 6.80(d,
propylpyrimidin-4-yl] 1H), 5.70(s, 1H), 5.65(m, 1H), 4.56(m, 1H),
3.73(s, 3H), pyrrolidin-3-yl}-3-(4- 3.69-3.00(m, 4H), 2.90(t, 2H),
2.46(m, 4H), 2.21(m, 1H), methoxyphenyl) 1.90(m, 1H), 1.69(m, 2H),
0.98(t, 3H) propanamide 155 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.01(s, 1H), 7.50(s, 1H), cyanophenylamino)-6-
7.37(t, 1H), 7.20(d, 1H), 7.04(d. 2H), 6.78(d, 2H), 5.69
propylpyrimidin-4-yl] (s, 1H), 5.47(m, 1H), 4.55(m, 1H),
3.75-3.24(m, 4H), pyrrolidin-3-yl}-3-(4- 2.89(m, 2H), 2.49(m, 4H),
1.68(m, 2H), 0.96(t, 3H) hydroxyphenyl) propanamide 156
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.38(s,
1H), 7.78(s, 1H), cyanophenylamino)-6- 7.65(s, 1H), 7.33(t, 1H),
7.19(d, 1H), propylpyrimidin-4-yl] 5.59(s, 1H), 4.61(m, 1H),
3.65-3.00(m, 4H), pyrrolidin-3-yl}-4- 2.89(m, 2H), 2.48(m, 4H),
2.22(s, 3H + 1H), 2.06 oxopentanamide (m, 1H), 1.64(m, 2H), 0.95(t,
3H) 157 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.36(s, 1H), 7.59(d, 1H), cyanophenylamino)-6- 7.47(s, 1H), 7.33(t,
1H), 7.19(d, 1H), propylpyrimidin-4-yl] 6.83(d, 1H), 5.73(s, 1H),
4.65(m, 1H), 4.14(s, 2H), pyrrolidin-3-yl}-2- 3.81-3.43(m, 4H),
2.48(t, 2H), 2.33(m, 1H), hydroxyacetamide 2.05(m, 1H), 1.70(m,
2H), 0.98(t, 3H)
TABLE-US-00017 TABLE 1-17 Example Compound NMR Spectrum 158
(S)-2-benzyloxy-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.30(s, 1H), 7.64(s, 1H), cyanophenylamino)-6- 7.31(m, 5H),
7.20(m, 1H), 6.74(d, 1H), 5.75(8, 1H), 4.65 propylpyrimidin-4-yl]
(m, 1H), 4.57(s, 2H), 3.99(s, 2H), 3.79-3.37(m. 4H), 2.51
pyrrolidin-3-yl}acetamide (t, 2H), 2.32(m, 1H), 2.02(m, 1H),
1.70(m, 2H), 0.98(t, 3H) 159 (S)-N-{1-[2-3- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.30(s, 1H), cyanophenylamino)-6- 7.63(s, 1H),
7.36-7.20(m, 4H), 7.02(t, 1H), propylpyrimidin-4-yl] 6.90(d, 2H),
6.71 (m, 1H), 5.75(s, 1H), 4.69(m, 1H), pyrrolidin-3-yl}-2- 4.51(s,
2H), 3.83-3.42(m, 4H), 2.51(t, 2H), phenoxyacetamide 2.34(m, 1H),
2.04(m. 1H), 1.70(m, 2H), 0.98(t 3H) 160 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.35(s, 1H), 7.60(s, 1H),
cyanophenylamino)-6- 7.33(m, 2H), 7.21(d, 1H), 5.76(s, 1H),4.65(m,
1H), 3.93- propylpyrimidin-4-yl] 3.31(m, 4H), 2.96{s, 2H), 2.49(t,
2H), 2.34(m, 1H), pyrrolidin-3-yl}-2- 2.28(s, 6H), 2.03(m, 1H),
1.71(m, 2H), 0.97(t, 3H) (dimethylamino)acetamide 161
(S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.91(s,
1H), cyanophenylamino)-6- 8.37(s, 1H), 7.62(s, 1H), 7.35(t, 1H),
propylpyrimidin-4-yl] 7.23(d. 1H), 5.75(s, 1H), 4.57(m, 1H),
3.74(m, 2H), pyrrolidin-3-yl}-3- 2.96(m, 2H), 2.60(m, 2H), 2.50(m,
2H), 2.41(m, 2H), 2.28 (dimethylamino) (m, 7H), 2.00(m, 1H),
1.71(q, 2H), 0.98(t, 3H) propanamide 162 (S)-N-{1-[2-(3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.36(S, 1H),
cyanophenylamino)-6- 8.02(s, 1H), 7.60(d, 1H), 7.34(t, 2H), 7.20
propylpyrimidin-4-yl] (d, 1H), 5.75(s, 1H), 4.56(m, 1H),
pyrrolidin-3-yl}-4- 3.74-3.49(m, 4H), 2.55-2.41(m, 8H), 2.35(s,
6H), dimethylaminobutanamide 2.00(m, 1H), 1.86(m, 1H), 1.69(m, 2H),
0.96(t, 3H) 163 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.31(s, 1H), 7.63(s, 1H), cyanophenylamino)-6- 7.32(t, 1H),
7.22(m, 1H), 7.18(s, 1H), 6.72{m, 1H), propylpyrimidin-4-yl]
5.76(s, 1H), 4.68(m, 1H), 3.95(s, 2H), 3.81 (m, 2H),
pyrrolidin-3-yl}-2- 3.55(m, 2H), 3.41(m, 2H), 2.51(t, 2H), 2.34(m,
1H), ethoxyacetamide 2.06(m, 1H), 1.71(m, 2H), 1.23(t, 3H), 0.96(t,
3H) 164 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.35(s, 1H), 7.61(s, 1H), cyanophenylamino)-6- 7.40(s, 1H), 7.36(1,
1H), 7.20(d, 1H), 7.13{s, 1H), 5 76(s, propylpyrimidin-4-yl] 1H),
4.67(m, 1H), 4.01(s, 2H), 3.80(m, 2H), 3.76(d, 2H),
pyrrolidin-3-yl}-2-(2- 3.66(d, 2H), 3.50(m, 2H), 3.32(s, 3H),
2.49(t, 2H), methoxyethoxy)acetamide 2.33(m, 1H), 2.06(m, 1H),
1.71(m, 2H), 0.98(1, 3H) 165 (S)-benzyl 2-{1-[2-(3- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.35{s, 1H), cyanophenylamino)-6- 7.64(d,
1H), 7.34(m, 5H), 7.20(d, 1H), 6.58(s, 1H), propylpyrimidin-4-yl]
5.70(s, 1H), 5.46(m, 1H), 5.12(s, 2H), 4.61(m, 1H), 3.89
pyrrolidin-3-ylamino}-2- (m, 2H), 3.80-3.25(m, 4H), 2.48(t, 2H),
2.28(m, 1H), 2.01 oxoethylcarbamate (m, 1H), 1.70(m, 2H), 0.98(t,
3H) 166 (S)-tert-butyl 3-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.32(s, 1H), 7.64(s, 1H), cyanophenylamino)-6- 7.31(t, 1H),
7.20(d, 1H), 7.11(s, 1H), 5.75(s, 1H), propylpyrimidin-4-yl]
4.75(m, 1H), 4.61(m, 1H), 3.76-3.25(m, 4H), 3.18{m,
pyrrolidin-3-ylamino}-3- 2H), 2.50(m, 2HJ, 2.32(m, 1H), 2.27(m,
2H), 2.17(m, oxobutylcarbamate 1H), 1.81(m, 2H), 1.69(m, 2H),
1.37(s, 9H), 0.96(t, 3H)
TABLE-US-00018 TABLE 1-18 Example Compound NMR Spectrum 167
(S)-tert-butyl 4-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.30(s, 1H), 7.60(s, 1H), cyanophenylamino)-6- 7.34-7.27(m, 1H),
7.18{d, 1H), 5.90(m, 1H), 5.74 propylpyrimidin-4-yl] (s, 1H),
4.61(m, 1H), 4.14(m, 2H), 3.78-3.34(m, 4H), 2.72
pyrrolidin-3-ylcarbamoyl} (m, 2H), 2.23(t, 2H), 2.11(m, 2H),
2.01(m, 1H), 1.81-1.71 piperidine-1-carboxylate (m, 6H), 1.45{s,
9H),0.98(t, 3H) 168 (R)-2-methyl-5-[4-(2- .sup.1H-NMR(400 MHz,
CD.sub.3OD).delta. 8.80(dd, 1H), 7.65(dd, 1H),
methylpyrrolidin-1-yl)-6- 7.44(d, 1H). 6.24(d, 1H), 4.35(m, 1H),
3.90-3.45(m, 2H), propylpyrimidin-2- 2.70-2.60{m, 2H). 2.52(s, 3H),
2.30-2.00(m, 3H), 1.90- ylamino]benzonitrile 1.70(m, 3H),
1.40-1.20(m. 3H), 1.05(t, 3H) hydrochloride 169
(R)-2-amino-5-[4-(2- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.63(d, 1H), 7.35(dd, 1H), methylpyrrolidin-1-yl)-6- 6.85(d, 1H),
6.15{d, 1H), 4.30(m, 1H), 3.80-3.40(m, 2H), propylpyrimidin-2-
2.60(t, 2H), 2.30-2.00(m, 3H), 1.90-1 70(m, 3H), 1.30-
ylamino]benzonitrile 1.20(m, 3H), 1.04(t, 3H) hydrochloride 170
(R)-2-methyl-5-[4-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.31(s, 1H), 7.45(dd, 1H), (methylamino)pyrrolidin-1- 7.20-7.10(m,
2H), 5.72(s, 1H), 3.90-3.10(m, 5H), 2.50- yl)-6-propylpyrimidin-2-
2.40(m, 8H), 2.25-2.10(m, 1H), 1.90(brs, 1H), 1.71(q,
ylamino]benzonitrile 2H), 0.97(t, 3H) 171 (S)-5-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.32(s, 1H), 7.63(brs,
1H), (ethylamino)pyrrolidin-1- 7.48(d, 1H), 7.17(d, 1H), 5.71(s,
1H), 3.90-3.10(m, 5H), yl]-6-propylpyrimidin-2- 2.80-2.70(m, 2H),
2.60-2.40(m, 5H), 2.25-2.15(m, 1H), ylamino}-2- 2.00-1.80(m, 1H),
1.71(q, 2H), 1.15{t, 3H), 0.98{t, 3H) methylbenzonitrile 172
(S)-5-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.38(s, 1H),
7.63{dd, 1H), (ethylamino)pyrrolidin-1- 7.27(d, 1H), 5.96(s, 1H),
4.10-3.90(m, 2H), 3.85-3.50(m, yl]-6-propypyrimidin-2- 3H), 3.17(q,
2H), 2.60-2.45(m, 3H), 2.45(s, 3H), 2.30- ylamino}-2- 2.20(m, 1H),
1.74(q, 2H), 1.36(t, 3H), 0.98(t, 3H) methylbenzonitrile
hydrochloride 173 5-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.38(s, 1H), 7.63{dd, 1H), (ethylamino)pyrrolidin-1- 7.27(d, 1H),
5.96(s, 1H), 4.10-3.90(m, 2H), 3.85-3.50(m, yl]-6-propypyrimidin-2-
3H), 3.17(q, 2H), 2.60-2.45(m, 3H), 2.45(s, 3H), 2.30- ylamino}-2-
2.20(m, 1H), 1.74(q, 2H), 1.36(t, 3H), 0.98(t, 3H)
methylbenzonitrile hydrochloride 174 (S)-2-methyl-5-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.32(s, 1H), 7.63(dd, 1H),
(methylamino)pyrrolidin-1- 7.27(d, 2H), 5.97(s, 1H), 3.95-3.62(m,
5H), 2.78(s, 3H), yl)-6-propylpyrimidin-2- 2.54-2.49(m, 3H),
2.44(s, 3H), 2.28-2.23(m, 1H), 1.76- ylamino}benzonitrile
1.70(m,2H), 0.97(t, 3H) hydrochloride 175 (S)-N.sup.1-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.65(s, 1H), 7.70(d, 1H),
(methylamino)pyrrolidin-1- 7.37(d, 1H), 5.77(s. 1H), 4.00-3.30(m,
5H), 2.60-2.40(m, yl]-6-propypyrimidin-2- 5H), 2.25-2.15(m, 1H),
2.05-1.95(m, 1H), 1.70-1.60(m, yl}-3-nitrobenzene-1,4- 2H), 0.99(t,
3H) diamine
TABLE-US-00019 TABLE 1-19 Example Compound NMR Spectrum 176
(S)-N.sup.1-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.64(s,
1H), 7.70(d, 1H), (ethylamino)pyrrolidin-1- 7.28{d, 1H), 5.77(s,
1H), 4.00-3.30(m, 5H), 2.80-2.70(m, yl]-6-propypyrimidin-2- 2H),
2.51(t, 2H), 2.30-2.20(m, 1H), 2.00-1.90(m, 1H),
yl}-3-nitrobenzene-1,4- 1.72(q, 2H), 1.17(t, 3H), 0.99(t, 3H)
diamine 177 (S)-N.sup.1-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.66(s, 1H), 7.76(d, 1H), (ethylamino)pyrrolidin-1- 7.47(d,
1H). 6.05(s, 1H), 4.10-3.90(m, 2H), 3.80-3.50(m,
yl]-6-propypyrimidin-2- 3H), 3.25-3 10(m, 2H), 2.60-2.45(m, 3H),
2.30-2.20(m, yl}-3-nitrobenzene-1,4- 1H), 1.78(q, 2H), 1.37(t, 3H),
1.00(t, 3H) diamine hydrochloride 178 (S)-3-{4-[3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.44(s, 1H), 7.79{d, 1H),
(methylamino)pyrrolidin-1- 7.39(t, 1H), 7.24(d, 1H), 5.99(s, 1H),
3.96(m, 2H), 3.75- yl]-6-propypyrimidin-2- 3.65(m, 3H), 2.80(5,
3H), 2.53(m, 1H + 2H), 2.26(m, 1H), ylamino}benzonitrile 1.73(m,
2H), 0.99(s, 3H) hydrochloride 179 (R)-3-{4-[3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.13(d, 1H), 7.87(dd, 1H),
(aminomethyl)pyrrolidin-1- 7.60-7.45(m, 2H), 6.27(d, 1H),
4.20-3.60(m, 3H), 3.50- yl]-6-propylpyrimidin-2- 3.35(m, 1H),
3.20-3.00(m, 2H), 2.80-2.60(m, 3H), 2.45- ylamino}benzonitrile
2.25(m, 1H), 2.00-1.90(m, 1H), 1.79(q, 2H), 1.05(t, 3H)
dihydrochloride 180 (S)-2-fluoro-5-{4-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.90-8.80(m, 1H), 8.45-
(methylamino)pyrrolidin-1- 8.35(m, 1H), 7.24(t, 1H), 5.98(s, 1H),
4.00-3.80(m, 2H), yl]-6-propylpyrimidin-2- 3.80-3.55(m, 3H),
2.79{s, 3H), 2.55-2.45(m, 3H), 2.30- ylamino}benzonitrile 2.20(m,
1H), 1.74(q, 2H), 0.98(t, 3H) hydrochloride 181
(S)-2-fluoro-5-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.40(brs, 1H), 7.90-7.75(m, (ethylamino)pyrrolidin-1- 1H), 7.24(t,
1H), 5.98(s, 1H), 4.10-3.85(m, 2H), 3.85- yl]-6-propylpyrimidin-2-
3.50(m, 3H), 3.18(q, 2H), 2.60-2.40(m, 3H), 2.30-2.20(m,
ylamino}benzonitrile 1H), 1.74(q, 2H), 1.36(t, 3H), 0.98(t, 3H)
hydrochloride 182 5-[4-(3-aminopyrrolidin-1- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.20-8.00(m, 1H), 7.95-
yl)-6-propylpyrimidin-2- 7.85(m, 1H), 7.42{t, 1H), 6.32(s, 1H),
4.20-3.60(m, 5H), ylamino]-2- 2.68(t, 2H), 2.60-2.40(m, 1H),
2.30-2.15(m, 1H), 1.90- fluorobenzonitrile 1.70(m, 2H), 1.06(t, 3H)
dihydrochloride 183 N(4-flurophenyl)-4- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 7.63-7.58(m, 2H), 7.00- methyl-6-(pyrrolidin-1-
6.95(m, 3H), 5.59(s, 1H), 3.53-3.41(m, 4H), 2.25(s, 3H),
yl)pyrimidin-2-amine 1.99(brs, 4H) 184 (3R,5S)-1-[2-(4-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.48(dd, 2H), 6.97(dd,
2H), fluorophenyl)-6- 5.66(s, 1H), 4.56(s, 1H), 4.41(d, 1H),
3.78(d, 1H), 3.62- propylpyrimidin-4-yl]-5- 3.45(m, 4H), 2.43(dd,
2H), 2.13(brs, 1H), 1.97(brs, 1H), (hydroxymethyl)pyrrolidin-3
1.71-1.65(m, 2H), 0.96(t, 3H) ol 185 (S)-{1-[2-(1H-indol-6-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.40(brs, 1H), 8.05(s,
1H), ylamino)-6-propylpyrimidin- 7.49(d, 1H), 7.04(dd, 1H),
6.97(dd, 1H), 6.90{brs, 1H), 4-yl]pyrrolidin-2-yl}methanol 6.43(d,
1H), 5.70(s, 1H), 4.39(brs, 1H), 3.75(dd, 1H), 3.59(dd, 1H),
3.46(brs, 1H), 3.35-3.27(m, 1H), 2.48(dd, 2H), 2.04-1.96(m, 3H),
1.78-1.69(m, 3H), 0.97(t, 3H)
TABLE-US-00020 TABLE 1-20 Example Compound NMR Spectrum 186
(R)-{1-[2-(1H-indol-6- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.49(brs, 1H), 8.03(s, 1H), ylamino)-6-propylpyrimidin- 7.48(d,
1H), 7.01-6.80(m, 3H), 6.42(s, 1H), 569(s, 1H),
4-yl]pyrrolidin-2-yl}methanol 4.86(brs, 1H), 4.38(brs, 1H),
3.74(dd, 1H), 3.57(dd. 1H), 3.44(brs, 1H), 3.29(brs, 1H), 2.48(dd,
2H), 2.04-1.96(m, 3H), 1.77-1.68(m, 3H), 0.96(t, 3H) 187
{1-[2-(1H-indol-6-ylamino)- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.49(brs, 1H), 8.02(s, 1H), 6-propylpyrimidin-4-yl]
7.47(dd, 1H), 7.02-6.89(m, 3H), 6.42(d, 1H), 5.69(s, 1H),
pyrrolidin-2-yl}methanol 4.86(brs, 1H), 4.38(brs, 1H), 3.75(dd,
1H), 3.57(dd, 1H), 3.43(brs, 1H), 3.29(brs, 1H), 2.47(dd, 2H),
2.04-1.96(m, 3H), 1.77-1.68(m, 3H), 0.98(t, 3H) 188 (R)-N-{4-[2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.49(brs, 1H), 8.19(brs,
1H), (methoxymethyl)pyrrolidin- 7.48(d, 1H), 7.10(dd, 1H),
7.01-6.92(m, 2H), 6.45(d, 1H), 1-yl]-6-propylpyrimidin-2-yl}-
5.69(s, 1H), 4.53(brs, 1H), 3.94(brs, 1H), 3.47(d, 1H),
1H-indol-6-amine 3.37(s, 3H), 3.31-3.16(m, 2H), 2.47(dd, 2H), 2.11-
2.00(m, 4H), 1.76-1.69(m, 2H), 0.99(t, 3H) 189 (S)-N-{4-[2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.48(brs, 1H), 8.22(brs,
1H), (methoxymethyl)pyrrolidin- 7.48(d, 1H), 7.10(dd, 1H),
7.01-6.92(m. 2H), 6.46(d, 1H), 1-yl]-6-propylpyrimidin-2-yl}-
5.69(s, 1H), 4.53(brs, 1H), 3.94(brs. 1H), 3.47(d, 1H),
1H-indol-6-amine 3.36(s, 3H), 3.31-3.16(m, 2H), 2.47(dd, 2H), 2.11-
2.00(m, 4H), 1.76-1.69(m, 2H), 0.99(t, 3H) 190
N-{4-[2-methylpyrrolidin .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.14(brs, 1H), 8.04(brs, 1H), 7.49(d, 1H), 7.11-7.08(m, 3H),
6.47(dd, 1H), 5.67(s, 1H), 4.28(brs, 1H), 3 59(brs, 1H), 3.42(brs,
1H), 2.47(dd, 2H), 2.12-1.98(m, 4H), 1.79-1.72(m, 2H), 1.27(dd,
3H), 0.99(t, 3H) 191 (S)-methyl 1-[2-(1H-indol-6- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.56(brs, 1H), 8.31(brs, 1H),
ylamino)-6-propyIpyrimidin- 7.45(dd. 1H), 7.12(dd, 1H), 7.00(s,
1H), 6.45(dd, 1H), 4-yl]pyrrolidine-2- 5.74(brs, 1H), 4.75{brs,
1H), 3.63(s, 3H), 3.65-3.45(d, carboxylate 1H), 2.48(dd, 2H),
2.32-2.02(m, 4H), 1.75-1.70(m, 2H), 0.99(dd, 3H) 192
N-{1-[2-(1H-indol-6- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.68(brs, 1H), 8.10(brs, 1H), ylamino)-6-propylpyrimidin- 7.47(d,
1H), 7.11(s, 1H), 7.04(s, 1H), 6.46(s, 1H), 4-yl]pyrrolidin-3-
5.48(brs, 1H), 4.55(s, 1H), 3.82-3.44(m. 5H), 2.38- yl}acetamide
2.23(m, 3H), 2.03(s, 3H). 2.05-1.95(m, 1H), 1.75-1.68(m, 2H),
0.99(dd, 3H) 193 (S)-{1-[2-(1H-indol-6- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 12.25(brs, 1H), 9.81-9.78(m,
ylamino)-6-propylpyrimidin- 2H), 8.22(s, 1H), 7.37(d, 1H), 7.16(dd,
1H), 6.80(d, 1H), 4-yl]pyrrolidin-2-yl}methanol 6.37(s, 1H),
5.10(s, 1H), 4.70(brs, 1H), 4.50(brs, 1H), hydrochloride 4.06(d,
1H), 3.69(dd, 1H), 3.31(dd, 1H), 3.20-3.13(m, 1H), 2.30-1.98(m,
6H), 1.58-1.50(m, 2H), 0.93(t, 3H) 194 (S)-3-{4-[2- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.31{s, 1H), 7.58(dd, 1H),
(hydroxymethyl)pyrrolidin-1- 7.34(t, 1H), 7.24(d, 1H), 7.22(brs,
1H), 5.81(s, 1H), yl]-6-propylpyrimidin-2- 4.41 (br, 1H), 3.73(m,
2H), 3.52(br, 1H), 3.39(m, 1H), ylamino}benzonilrile 2.51(t, 2H),
2.11-2.00(m, 3H), 1.88(br, 1H), 1.75(m, 2H), 0.99(t, 3H) 195
(S)-(1-{2-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
10.30-10.13(br, 1H), 7.84(s, (methylthio)phenylamino]-6- 1H),
7.25(m, 2H), 6.98(s, 1H), 5.71(brs, 1H), 4.45(br,
propylpyrimidin-4- 1H), 3.89(br, 1H), 3.68(br, 2H), 3.43(br, 1H),
2.70(br, yl}pyrrolidin-2-yl)methanol 2H), 2.49(s, 3H), 2.18(br,
1H), 2.08(m, 3H), 1.77(m, 2H), 1.00(m, 3H)
TABLE-US-00021 TABLE 1-21 Example Compound NMR Spectrum 196
(S)-{1-[2-(4-chloro-3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.87(s, 1H), 7.37(m, 2H), nitrophenylamino)-6- 7.34(br, 1H),
5.82(s, 1H), 4.44(br, 1H), 3.77(m, 2H), propylpyrimidin-4- 3.52(br,
1H), 3.39{br, 1H), 2.50(t, 2H), 2.07(m, 3H),
yl]pyrrolidin-2-yl}methanol 1.94(m, 1H), 1.74(m, 2H), 1.00(t, 3H)
197 (S)-{1-[2-{1H-indol-5- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.29(brs, 1H), 7.80(s, 1H), ylamino)-6- 7.27(m, 3H), 7.13(m, 1H),
6.47(s, 1H), 5.69(s, 1H), propylpyrimidin-4-yl] 3.59(m, 2H),
3.48(br, 1H), 3.38(br, 1H), 2.49(t, 2H), pyrrolidin-2-yl}methanol
1.97(m, 3H), 1.75(m, 3H), 1.99(t, 3H) 198 (S)-{1-[2-(1H-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.84(s, 1H), 8.24(m, 2H),
benzo[o]irnidazol-5- 8.01(s, 1H), 7.56(d, 1H), 6.71(d, 1H), 6.06(s,
1H), ylamino)-6-propylpyrimidin- 4.57(br, 1H), 3.95(br, 1H),
3.72(m, 1H), 3.56(m, 1H), 4-yl]pyrrolidin-2-yl}methanol 3.40{br,
1H), 2.63(m, 2H), 2.10(m, 3H), 1.82{m, 3H), 1.03(t 3H) 199
(S)-(1-{6-propyl-2-[2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.42(brs, 1H), 7.59(d, 1H), (trifluoromethyl)-1H- 7.44(d, 1H),
7.38(d, 1H), 6.88(d, 1H), 6.84(s, 1H), benzo[d]irnidazol-5-
5.93(brs, 1H), 3.76(br, 1H), 3.55(br, 1H), 3.35(s, 2H),
ylamino]pyrimidin-4- 2.50(t, 2H), 2.11{m, 2H), 2.02(m, 2H), 1.77(m,
2H), yl}pyrrolidin-2-yl)methanol 1.02(t, 3H) 200 (S)-{1-[2-(4-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.98(br, 1H), 7.45(br,
2H), methoxyphenylamino)-6- 6.84(d, 2H), 6.10-5.67(br, 1H),
4.38(br, 1H), 3.78(s, 3H), propylpyrimidin-4- 3.73(m, 2H), 3.59(br,
1H). 3.42(br, 1H), 2.52(m, 2H), yl]pyrrolidin-2-yl}methanol
2.15(br, 1H), 2.05(m, 3H), 1.75(m, 2H), 0.97(t, 3H) 201
(S)-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 10.45(br,
1H), 7.92(s, 1H), chlorophenylamino)-6- 7.36(br, 1H), 7.22(m, 1H),
7.03(m, 1H), 5.73(br, 1H), propylpyrimidin-4- 4.47(br, 1H), 4.13(m,
2H), 3.83(br, 1H), 3.43(br, 1H), yl]pyrrolidin-2-yl}methanol
2.51(m, 2H), 2.09(m, 4H), 1.75(m, 2H), 0.97(t, 3H) 202
(S)-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3).delta. 10.17(br,
1H), 7.61{brs, 1H), methoxyphenylamino)-6- 7.21(m, 1H), 7.04(br,
1H), 6.63(m, 1H), 5.70(brs, 1H), propylpyrimidin-4- 4.42(br, 1H),
3.90(br, 1H), 3.81(s, 3H), 3.75(m, 2H), yl]pyrrolidin-2-yl}methanol
3.40(m, 1H), 2.53(m, 2H), 2.09(m, 4H), 1.76(m, 2H), 0.97(t. 3H) 203
(S)-(1-{6-propyl-2-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
10.62(br, 1H), 8.32(m, 1H), (trifluoromethyl)phenylamino] 7.57(d,
1H), 7.41(brs, 1H), 7.33(m, 1H), 6.22-5.78(br,
pyrimidin-4-yl}pyrrolidin-2- 1H)( 4.50(br, 1H), 4.13(m, 1H),
3.93(m, 2H), 3.46(br, yl)methanol 1H), 2.53(br, 2H), 2.28-2.05(m,
4H), 1.77(m, 2H), 0.97(t, 3H) 204 (S)-{1-[2-(5-chloro-2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.08(s, 1H), 7.09(d, 1H),
methylphenylamino)-6- 6.95(d, 1H), 5.76(s, 1H), 4.33(br, 1H),
3.71-3.61(m, 2H), propylpyrimidin-4- 3.40(br, 1H), 3.39(br, 1H),
2.52(m, 2H), 2.30(s, 3H), yl]pyrrolidin-2-yl}methanol 2.11-2.00(m,
4H), 1.77(m, 2H), 1.00(t, 3H) 205 (S)-{1-[2-(5-methoxy-2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.31(br, 1H), 7.64(s, 1H),
methylphenylamino)-6- 7.09{d, 1H), 6.62(m, 1H), 5.72{s, 1H),
4.27(br, 1H), propylpyrimidin-4- 3.82(s, 3H), 3.77(m, 1H), 3.46(m,
2H), 3.36(m, 1H), yl]pyrrolidin-2-yl}methanol 2.56(m, 2H), 2.31(s,
3H), 2.06-1.99(m, 4H), 1.80(m, 2H), 1.02(t, 3H)
TABLE-US-00022 TABLE 1-22 Example Compound NMR Spectrum 206
(S)-{1-[2-(3-chloro-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
10.11 (br, 1H), 7.91 (d, 1H), methylphenylamino)-6- 7.23 (br, 1H),
7.13 (m, 1H), 6.14-5.73 (br, 1H), 4.46 (br, propylpyrimidin-4- 1H),
3.81 (m, 2H), 3.63 (br, 1H), 3.38 (br, 1H), 2.52 (m,
yl]pyrrolidin-2-yl}methanol 2H), 2.32 (s, 3H), 2.10 (m, 4H), 1.78
(m, 2H), 0.98 (t, 3H) 207 (S)-{1-[2-(3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 9.15 (s, 1H), 8.37 (br, 1H),
nitrophenylamino)-6- 7.83 (d,1H), 7.81 (d, 1H), 7.41 (t, 1H), 5.83
(s, 1H), propylpyrimidin-4- 4.67 (br, 1H), 4.13 (m, 1H), 3.80 (m,
1H), 3.56 (br, 1H), yl]pyrrolidin-2-yl}methanol 3.42 (br, 1H), 2.53
(m, 2.17-2.05 (m, 4H), 1.79 (m, 2H), 1.00 (t, 3H) 208
(S)-{1-[2-(4-fluoro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.95 (s, 1H), 7.85 (br, 1H), nitrophenylamino)-6- 7.50 (m, 1H),
7.16 (t, 1H), 5.81 (s, 1H), 4.49 (br, 1H), propylpyrimidin-4- 4.45
(br, 1H), 3.76 (m, 2H), 3.53-3.39 (m, 2H), 2.48 (m,
yl]pyrrolidin-2-yl}methanol 2H), 2.13 (m, 3H), 1.75 (m, 2H), 0.97
(t, 3H) 209 (S)-{1-[6-propyl-2-(quinolin- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.75 (d, 1H), 8.38 (d, 1H),
6-ylamino)pyrimidin-4- 8.09 (d, 1H), 8.00 (d,1H), 7.72 (dd, 1H),
7.33 (m, 1H), yl]pyrrolidin-2-yl}methanol 5.81 (s, 1H), 4.49 (br,
1H), 3.75 (m, 2H), 3.55 (m, 1H), 3.42 (m, 1H), 2.54 (m, 2H), 2.07
(m, 3H), 1.91 (m, 1H), 1.78 (m, 2H), 1.02 (t, 3H) 210
(S)-{1-[2-(4-methyl-3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
8.65 (s, 1H), 7.56 (s, 1H), nitrophenylamino)-6- 7.28 (d, 1H), 6.01
(s, 1H), 4.43-3.50 (m, 5H), 2.53 (m, 5H), propylpyrimidin-4-
2.12-2.02 (m, 4H), 1.73 (m, 2H), 1.00 (t, 3H)
yl]pyrrolidin-2-yl}methanol 211 (S)-(1-{2[4-amino-3- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 7.77 (brs, 1H), 7.34 (d, 1H),
(trifluoromethyl)phenylamino]- 6.85 (d, 1H), 6.12 (brs, 1H), 4.13
(m, 1H), 3.93-3.50 (m, 6-propylpyrimidin-4- 4H), 2.57 (t, 2H),
2.09-1.98 (m, 4H), 1.74 (m, 2H), 1.03 (t,
yl}pyrrolidin-2-yl)methanol 3H) 212 (S)-{1-[2-(4-amino-3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.82 (s, 1H), 7.25 (m,
1H), nitrophenylamino)-6- 6.82 (brs, 1H), 6.74 (d,1H), 5.94 (s,
2H), 5.74 (s, 1H), propylpyrimidin-4- 4.52 (s, 1H), 3.75 (m, 1H),
3.63 (m, 1H), 3.49 (m, 1H), yl]pyrrolidin-2-yl}methanol 3.37 (s,
1H), 2.47 (t, 2H), 2.02 (m, 3H), 1.90 (m, 1H), 1.72 (m, 2H), 0.98
(t, 3H) 213 (S)-5-{4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.21 (s, 1H), 7.45 (d, 1H), (hydroxymethyl)pyrrolidin-1- 7.18 (d,
1H), 6.97 (brs, NH), 5.79 (s, 1H), 4.41 (s, 1H),
yl]-6-propylpyrimidin-2- 3.71 (m, 2H), 3.51 (m, 1H), 3.38 (s, 1H),
2.48 (m, 5H), ylamino}-2- 2.02 (m, 3H), 1.86 (s, 1H), 1.70 (m, 2H),
0.99 (t, 3H) methylbenzonitrile 214 (S)-2-fluoro-5-{4-[2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (m, 1H), 7.58 (m,
1H), (hydroxymethyl)pyrrolidin-1- 7.12 (s, 1H), 7.07 (t, 1H), 5.81
(s, 1H), 4.39 (s, 1H), 3.73 (m, yl]-6-propylpyrimidin-2- 2H), 3.51
(s, 1H), 3.38 (s, 1H), 2.52 (t, 2H), 2.02 (m, 3H),
ylamino}benzonitrile 1.84 (s, 1H), 1.74 (m, 2H), 0.99 (t, 3H) 215
(S)-2-amino-5-{4-[2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.83
(s, 1H), 7.33 (d, 1H), (hydroxymethyl)pyrrolidin-1- 6.76 (d, 1H),
5.80 (s, 1H), 4.42 (m, 3H), 3.75 (m, 3H), yl]-6-propylpyrimidin-2-
2.55 (m, 2H), 2.07 (m, 4H), 1.78 (m, 2H), 1.00 (t, 3H)
ylamino}benzonitrile
TABLE-US-00023 TABLE 1-23 Example Compound NMR Spectrum 216
(S)-{1-[6-propyl-2-(quinolin- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.94 (s, 1H), 8.66 (d, 1H), 3-ylamino)pyrimidin-4- 7.99 (d,
1H), 7.72 (d, 1H), 7.55-7.45 (m, 2H), 7.25 (br, 1H),
yl]pyrrolidin-2-yl}methanol 5.80 (s, 1H), 4.40 (br, 1H), 3.75 (m,
2H), 3.51 (m, 1H), 3.40 (m, 1H), 2.51 (m, 2H), 2.04 (m, 3H), 1.95
(m, 1H), 1.77 (m, 2H), 0.98 (t, 3H) 217 (S)-{1-[2-(indolin-6-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (s, 1H), 7.00 (d,
1H), ylamino)-6-propylpyrimidin- 6.83 (brs, 1H), 6.69 (d, 1H), 5.69
(s, 1H), 4.37 (s, 1H), 4-yl]pyrrolidin-2-yl}methanol 3.76 (m, 1H),
3.62 (m, 1H), 3.55 (m, 1H), 3.46 (m, 1H), 3.32 (m, 1H), 2.96 (t,
2H), 2.46 (t, 2H), 2.00 (m, 3H), 1.83 (m, 1H), 1.69 (m, 2H), 0.97
(t, 3H) 218 (S)-3-{4-[3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
8.19 (d, 1H), 7.82-7.75 (m, (cyclohexylamino)pyrrolidin- 1H),
7.61-7.54 (m, 2H), 6.35 (s, 1H), 4.23-3.74 (m, 5H),
1-yl]-6-propylpyrimidin-2- 3.23 (brs, 1H), 2.69 (dd, 2H), 2.60
(brs, 1H), 2.35-2.20 (m, ylamino}benzonitrile 1H), 1.90(d, 2H),
1.85-1.72 (m, 5H), 1.47-1.25 (m, 5H), dihydrochloride 1.06 (t, 3H)
219 (S)-3-{4-[3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.25
(brs, 1H), 7.79 (brs, (isopropylamino)pyrrolidin- 1H), 7.60-7.52
(m, 2H), 6.32 (s, 1H), 4.21-3.75 (m, 5H),
1-yl]-6-propylpyrimidin-2- 3.58-3.52 (m, 1H), 2.68 (dd, 2H), 2.60
(brs, 1H), 2.32 (brs, ylamino}benzonitrile 1H), 1.85-1.75 (m, 2H),
1.42 (dd, 6H), 1.06 (t, 3H) dihydrochloride 220 (S)-3-{4-[3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.15(d, 1H), 7.82 (s,
1H), (aminoethylamino)pyrrolidin- 7.60-7.54 (m, 2H), 6.35 (s, 1H),
4.18-3.75 (m, 5H), 3.44- 1-yl]-6-propylpyrimidin-2- 3.40 (m, 2H),
3.31-3.25 (m, 2H), 2.69 (dd, 2H), 2.67- ylamino}benzonitrile 2.49
(m, 1H), 2.40-2.25 (m, 1H), 1.83-1.76 (m, 2H), 1.06(t,
dihydrochloride 3H) 221 (S)-3-{443-(piperidin-4- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 8.20 (brs, 1H), 7.57 (brs,
ylamino)pyrrolidin-1-yl]-6- 1H), 7.38 (dd, 1H), 7.22 (d, 1H), 5.87
(s, 1H), 4.15-3.31 (m, propylpyrimidin-2- 7H), 3.01-2.94 (m, 3H),
2.48 (dd, 2H), 2.31-2.18 (m, 2H), ylamino}benzonitrile 2.11 (d,
1H), 1.91 (brs, 1H), 1.75-1.68 (m, 2H), 1.57- 1.46 (m, 2H), 0.97
(t, 3H) 222 (S)-3-{4[3-(1-butylpiperidin- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 8.55-8.45 (m, 1H), 7.32-
4-ylamino)pyrrolidin-1-yl]-6- 7.26 (m, 1H), 7.39 (dd, 1H), 7.23 (d,
1H), 5.89 (s, 1H), propylpyrimidin-2- 3.99-3.44 (m, 6H), 2.99 (d,
2H), 2.65 (brs, 1H), 2.49 (dd, ylamino}benzonitrile 2H), 2.39-2.28
(m, 3H), 2.10-1.94 (m, 4H), 1.85-1.69 (m, 2H), 1.55-1.28 (m, 6H),
1.00-0.87 (m, 6H) 223 (S)-N-{1-[6-butyl-2-(3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.25 (brs, 1H), 7.61 (brs, 1H),
cyanophenylamino)pyrimidin- 7.33-7.28 (m, 2H), 7.17 (d, 1H), 6.17
(brs, 1H), 5.73 (s, 4-yl]pyrrolidin-3- 1H), 4.58 (brs, 1H),
3.92-3.33 (m, 4H), 2.49 (dd, 2H), 2.30- yl}acetamide 2.25(m, 1H),
2.04-2.00 (m, 1H), 2.00 (s, 3H), 1.69-1.61 (m, 2H), 1.43-1.33 (m,
2H), 0.94 (t, 3H) 224 (S)-3-{4-butyl-6[2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.31 (s, 1H), 7.58 (dd, 1H),
(hydroxymethyl)pyrrolidin-1- 7.34 (dd, 1H), 7.22 (d, 1H), 7.17
(brs, 1H), 5.81 (s, 1H), yl]pyrimidin-2- 4.88-4.30 (m, 2H),
3.75-3.69 (m, 2H), 3.51 (brs, 1H), ylamino}benzonitrile 3.38 (brs,
1H), 2.53 (dd, 2H), 2.11-2.00 (m, 3H), 1.86 (brs, 1H), 1.73-1.65
(m, 2H), 1.45-1.37 (m, 2H), 0.94 (t, 3H) 225 (R)-3-[4-butyl-6-(2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.48 (brs, 1H), 7.51 (d,
1H), methylpyrrolidin-1- 7.33-7.25 (m, 2H), 7.19 (d, 1H), 5.74 (s,
1H), 4.37-3.38 (m, yl)pyrimidin-2- 3H), 2.49 (dd, 2H), 2.08-2.01
(m, 3H), 1.78-1.75 (m, 1H), ylamino]benzonitrile 1.71-1.63 (m, 2H),
1.44-1.36 (m, 2H), 1.29 (brs, 3H), 0.94 (t, 3H)
TABLE-US-00024 TABLE 1-24 Example Compound NMR Spectrum 226
(S)-3-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.40
(s, 1H), 7.56 (dd, 1H), (methylamino)pyrrolidin-1- 7.33-7.28 (m,
2H), 7.17 (d, 1H), 5.74 (s, 1H), 3.78-3.16 (m, yl]pyrimidin-2- 5H),
2.50 (s, 3H), 2.48 (dd, 2H), 2.22-2.17 (m, 1H),
ylamino}benzonitrile 1.91 (brs, 1H), 1.70-1.62 (m, 2H), 1.43-1.34
(m, 2H), 0.94 (t, 3H) 227 (S)-tert-butyl1-[6-butyl-2-(3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.30 (brs, 1H), 7.61
(brs, 1H), cyanophenylamino)pyrimidin- 7.33 (dd, 1H), 7.20 (d, 1H),
7.13 (brs, 1H), 5.74 (s, 1H), 4-yl]pyrrolidin-3- 4.80 (brs, 1H),
4.34 (brs, 1H), 3.82-3.33 (m, 4H), 2.50 (dd, ylcarbamate 2H),
2.29-2.23 (m, 1H), 1.99 (brs, 1H), 1.70-1.63 (m, 2H), 1.46 (s, 9H),
1.42-1.34 (m, 2H), 0.95 (t, 3H) 228 (S)-N-{1-[6-butyl-2-(3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (brs, 1H), 7.48
(brs, 1H), cyano-4- 7.16 (d, 1H), 7.06 (brs, 1H), 6.01 (brs, 1H),
5.71 (s, 1H), methylphenylamino)pyrimidi 4.60-4.56 (m, 1H),
3.75-3.38 (m, 4H), 2.48 (dd, 2H), n-4-yl]pyrrolidin-3- 2.45 (s,
3H), 2.32-2.24 (m, 1H), 2.04-2.00 (m, 1H), 2.00(s, yl}acetamide
3H), 1.69-1.61 (m, 2H), 1.43-1.34 (m, 2H), 0.94 (t, 3H) 229
(S)-5-{4-butyl-6-[2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.20
(dd, 1H), 7.45 (dd, 1H), (hydroxymethyl)pyrrolidin-1- 7.18 (d, 1H),
7.11 (brs, 1H), 5.78 (s, 1H), 4.40 (brs, 1H),
yl]pyrimidin-2-ylamino}-2- 3.74-3.69 (m, 2H), 3.50 (brs, 1H), 3.37
(brs, 1H), 2.51 (dd, methylbenzonitrile 2H), 2.47 (s, 3H),
2.08-1.99 (m, 3H), 1.86 (brs, 1H), 1.72- 1.64 (m, 2H), 1.42-1.37
(m, 2H), 0.94 (t, 3H) 230 (R)-5-[4-butyl-6-(2- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.40 (brs, 1H), 7.40 (brs, 1H),
methylpyrrolidin-1- 7.16 (d, 1H), 7.03 (brs, 1H), 5.72 (s, 1H),
4.40-3.36 (m, yl)pyrimidin-2-ylamino]-2- 3H), 2.48 (dd, 2H), 2.47
(s, 3H), 2.12-2.00 (m, 3H), 1.77- methylbenzonitrile 1.75 (m, 1H),
1.70-1.62 (m, 2H), 1.44-1.36 (m, 2H), 1.29 (brs, 3H), 0.94 (t, 3H)
231 (S)-5-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.32 (d, 1H), 7.44 (dd, 1H), (methylamino)pyrrolidin-1- 7.16 (d,
1H), 7.11 (brs, 1H), 5.72 (s, 1H), 3.78-3.16 (m,
yl]pyrimidin-2-ylamino}-2- 5H), 2.50 (s, 3H), 2.48 (dd, 2H), 2.47
(s, 3H), 2.22-2.16 (m, methylbenzonitrile 1H), 1.90 (brs, 1H),
1.70-1.62 (m, 2H), 1.43-1.34 (m, 2H), 0.94 (t, 3H) 232
(S)-tert-butyl 1-[6-butyl-2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.20 (brs, 1H), 7.50 (brs, 1H), cyano-4- 7.17 (d, 1H), 7.16
(brs, 1H), 5.70 (s, 1H), 4.90 (brs, 1H), methylphenylamino)pyrimidi
4.33 (brs, 1H), 3.82-3.33 (m, 4H), 2.49 (dd, 2H), 2.47 (s,
n-4-yl]pyrrolidin-3- 3H), 2.27-2.23 (m, 1H), 1.99 (brs, 1H),
1.69-1.62 (m, 2H), ylcarbamate 1.46 (s, 9H), 1.43-1.33 (m, 2H),
0.95 (t, 3H) 233 (S)-3-[4-(3-aminopyrrolidin- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.19 (brs, 1H), 7.48 (brs, 1H),
1-yl)-6-butylpyrimidin-2- 7.16 (d, 1H), 7.06 (brs, 1H), 6.01 (brs,
1H), 5.71 (s, 1H), ylamino]benzonitrile 4.60-4.56 (m, 1H),
3.75-3.38 (m, 4H), 2.48 (dd, 2H), dihydrochloride 2.45 (s, 3H),
2.32-2.24 (m, 1H), 2.04-2.00 (m, 1H), 2.00 (s, 3H), 1.69-1.61 (m,
2H), 1.43-1.34 (m, 2H), 0.94 (t, 3H) 234
(S)-5-[4-(3-aminopyrrolidin- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.19 (brs, 1H), 7.48 (brs, 1H), 1-yl)-6-butylpyrimidin-2-
7.16 (d, 1H), 7.06 (brs, 1H), 6.01 (brs, 1H), 5.71 (s, 1H),
ylamino]-2- 4.60-4.56 (m, 1H), 3.75-3.38 (m, 4H), 2.48 (dd, 2H),
methylbenzonitrile 2.45 (s, 3H), 2.32-2.24 (m, 1H), 2.04-2.00 (m,
1H), 2.00 (s, dihydrochloride 3H), 1.69-1.61 (m, 2H), 1.43-1.34 (m,
2H), 0.94 (t, 3H) 235 (S)-3-{4-butyl-6-[3- .sup.1H-NMR (400 MHz,
CDC13) .delta. 8.38 (s, 1H), 7.58 (d, 1H),
(isopropylamino)pyrrolidin- 7.33 (dd, 1H), 7.20 (d, 1H), 7.17 (brs,
1H), 5.73 (s, 1H), 1-yl]pyrimidin-2- 3.90-3.38 (m, 5H), 2.99-2.93
(m, 1H), 2.50 (dd, 2H), 2.28- ylamino}benzonitrile 2.21 (m, 1H),
1.85 (brs, 1H), 1.71-1.63 (m, 2H), 1.44- 1.37 (m, 2H), 1.11 (t,
6H), 0.97 (t, 3H)
TABLE-US-00025 TABLE 1-25 Example Compound NMR Spectrum 236
(S)-3-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.45
(brs, 1H), 7.53 (brs, 1H), (diethylamino)pyrrolidin-1- 7.32 (dd,
1H), 7.21 (d, 1H), 7.09 (brs, 1H), 5.74 (s, 1H), yl]pyrimidin-2-
4.04-3.35 (m, 5H), 2.72 (brs, 4H), 2.51 (dd, 2H), 2.24 (brs,
ylamino}benzonitrile 1H), 1.93 (brs, 1H), 1.71-1.64 (m, 2H),
1.44-1.35 (m, 2H), 1.05 (t, 3H), 1.11 (t, 6H), 0.97 (t, 3H) 237
(S)-3-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.40
(s, 1H), 7.57 (d, 1H), (cyclopropylmethylamino)pyrrolidin- 7.33
(dd, 1H), 7.21 (d, 1H), 7.11 (brs, 1H), 5.74 (s, 1H),
1-yl]pyrimidin-2- 3.91-3.14 (m, 6H), 2.63-2.48 (m. 4H), 2.26-2.18
(m, 1H), ylamino}benzonitrile 1.90 (brs, 1H), 1.71-1.63 (m, 2H),
1.44-1.35 (m, 2H), 1.25- 0.93 (m, 4H), 0.53 (dd, 2H), 0.15 (d, 2H)
238 (S)-5-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.30 (s, 1H), 7.47 (d, 1H), (isopropylamino)pyrrolidin- 7.17 (d,
1H), 7.08 (brs, 1H), 5.71 (s, 1H), 3.90-3.05 (m,
1-yl]pyrimidin-2-ylamino}-2- 5H), 2.99-2.93 (m, 1H), 2.49 (dd, 2H),
2.47 (s, 3H), 2.28- methylbenzonitrile 2.20 (m, 1H), 1.84 (brs,
1H), 1.70-1.63 (m, 2H), 1.44- 1.34 (m, 2H), 1.11 (dd, 6H), 0.97 (t,
3H) 239 (S)-5-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.36 (brs, 1H), 7.42 (brs, 1H), (diethylamino)pyrrolidin-1-
7.16 (d, 1H), 7.05 (brs, 1H), 5.71 (s, 1H), 4.04-3.18 (m,
yl]pyrimidin-2-ylamino}-2- 5H), 2.71 (brs, 4H), 2.49 (dd, 2H), 2.47
(s, 3H), 2.23- methylbenzonitrile 1.92 (m, 2H), 1.71-1.63 (m, 2H),
1.44-1.35 (m, 2H), 1.07 (dd, 6H), H), 0.97 (t, 3H) 240
(S)-5-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.32
(s, 1H), 7.45 (d, 1H), (cyclopropylmethylamino) 7.17 (d, 1H), 7.09
(brs, 1H), 5.71 (s, 1H), 3.90-3.05 (m, pyrrolidin-1-yl]pyrimidin-2-
5H), 2.56-2.48 (m, 7H), 2.25-2.18 (m, 1H), 1.89 (brs, 1H),
ylamino}-2- 1.70-1.63 (m, 2H), 1.44-1.36 (m, 2H), 1.25-0.93 (m,
4H), methylbenzonitrile 0.53 (dd, 2H), 0.15 (d, 2H) 241
(S)-N-{1-[2-(4-chloro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.89 (brs, 1H), 8.10 (brs, 1H), nitrophenylamino)-6- 7.35 (s, 2H),
6.21 (brs, 1H), 5.74 (s, 1H), 4.63-4.59 (m, propylpyrimidin-4- 1H),
4.10-3.38 (m, 4H), 2.47 (dd, 2H), 2.34-2.28 (m, 1H),
yl]pyrrolidin-3-yl}acetamide 2.09-2.04 (m, 1H), 2.03 (s, 3H),
1.74-1.68 (m, 2H), 0.97 (t, 3H) 242 (S)-N-(1-{2-[3- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.78 (s, 1H), 7.29 (dd, 1H),
(methylthio)phenylamino]-6- 7.18 (dd, 1H), 7.01 (brs, 1H), 6.84 (d,
1H), 5.96 (d, 1H), propylpyrimidin-4- 5.67 (s, 1H), 4.59-4.56 (m,
1H), 4.73-3.48 (m, 4H), 2.68 (s, yl}pyrrolidin-3-yl)acetamide 3H),
2.46 (dd, 2H), 2.44-2.21 (m, 1H), 2.06-2.00 (m, 1H), 2.03 (s, 3H),
1.76-1.66 (m, 2H), 0.97 (t, 3H) 243 (S)-N-{1-[2-(1H-indol-6-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H), 7.49 (d,
1H), ylamino)-6-propylpyrimidin- 7.11 (dd, 1H), 7.00 (d, 1H), 6.47
(s, 1H), 5.95 (brs, 1H), 4-yl]pyrrolidin-3- 5.62 (s, 1H), 4.55
(brs, 1H), 3.75-3.49 (m, 4H), 2.45 (dd, yl}acetamide 2H), 2.29-2.23
(m, 1H), 2.06-2.00 (m, 1H), 2.03 (s, 3H), 1.75-1.66 (m, 2H), 0.96
(t, 3H) 244 (S)-N-(1-{6-propyl-2-[3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.44 (brs, 1H), 7.46 (d, 1H),
(trifluoromethyl)phenylamino] 7.35 (dd, 1H), 7.19 (d, 2H), 5.88 (d,
1H), 5.72 (s, 1H), 4.62- pyrimidin-4-yl}pyrrolidin-3- 4.58 (m, 1H),
3.75-3.49 (m, 4H), 2.47 (dd, 2H), 2.24- yl)acetamide 2.33 (m, 1H),
2.06-2.00 (m, 1H), 2.00 (s, 3H), 1.76-1.67 (m, 2H), 0.95 (t, 3H)
245 (S)-N-{142-(4-methyl-2-oxo- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.08 (brs, 1H), 7.38 (d, 1H), 2H-chromen-7-ylamino)-6- 7.35
(dd, 1H), 6.99 (brs, 1H), 6.98 (d, 1H), 5.94 (brs, 1H),
propylpyrimidin-4- 5.72 (s, 1H), 4.69 (brs, 1H), 3.72-3.49 (m, 4H),
2.45 (dd, yl]pyrrolidin-3-yl}acetamide 2H), 2.33 (s, 3H), 2.33-2.24
(m, 1H), 2.06-2.00 (m, 1H), 2.03 (s, 3H), 1.75-1.67 (m, 2H), 0.99
(t, 3H)
TABLE-US-00026 TABLE 1-26 Example Compound NMR Spectrum 246
(S)-N-{1-[2-(3-chloro-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.97 (brs, 1H), 7.20 (d, 1H), methylphenylamino)-6- 7.09 (d, 1H),
7.00 (brs, 1H), 6.15 (d, 1H), 5.65 (s, 1H), propylpyrimidin-4- 4.59
(brs, 1H), 3.70-3.48 (m, 4H), 2.45 (dd, 2H), 2.30 (s,
yl]pyrrolidin-3-yl}acetamide 3H), 2.28-2.23 (m, 2H), 2.00 (s, 3H),
1.72-1.66 (m, 2H), 0.96 (t, 3H) 247 (S)-N-{1-[2-(3- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 9.27 (brs, 1H), 7.76 (dd, 1H),
nitrophenylamino)-6- 7.45 (brs, 1H), 7.37 (brs, 1H), 7.24 (brs,
1H), 5.89 (s, 1H), propylpyrimidin-4- 5.76 (s, 1H), 4.64-4.60 (m,
1H), 3.86-3.32 (m, 4H), yl]pyrrolidin-3-yl}acetamide 2.48 (dd,
2H),2.36-2.28 (m, 1H), 2.08-2.02 (m, 1H), 2.02 (s, 3H), 1.75-1.68
(m, 2H), 0.98 (t, 3H) 248 (S)-N-{1-[2-(4-fluoro-3- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 9.05 (brs, 1H), 7.43 (brs, 1H),
nitrophenylamino)-6- 7.13 (dd, 1H), 6.56 (brs, 1H), 5.74 (s, 1H),
4.64-4.61 (m, propylpyrimidin-4- 1H), 3.83-3.43 (m, 4H), 2.47 (dd,
2H), 2.32 (brs, 1H), 2.12- yl]pyrrolidin-3-yl}acetamide 2.05 (m,
1H), 2.05 (s, 3H), 1.75-1.67 (m, 2H), 0.98 (t, 3H) 249
(S)-N-{1-[2-(4-methyl-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.93 (brs, 1H), 7.82 (brs, 1H), nitrophenylamino)-6- 7.33 (d, 1H),
7.17 (d, 1H), 6.38 (brs, 1H), 5.69 (s, 1H), propylpyrimidin-4-
4.62-4.58 (m, 1H), 3.76-3.48 (m, 4H), 2.51 (s, 3H),
yl]pyrrolidin-3-yl}acetamide 2.45 (dd, 2H), 2.32-2.26 (m, 1H),
2.08-2.02 (m, 1H), 2.02 (s, 3H), 1.73-1.67 (m, 2H), 0.96 (t, 3H)
250 (S)-benzyl 5-[4-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.52 (brs, 1H), 7.41-7.33 (m, acetamidopyrrolidin-1-yl)-6- 5H),
7.18 (d, 1H), 7.10 (brs, 1H), 6.78 (d, 1H), 5.93 (s, 1H),
propylpyrimidin-2-ylamino]- 5.64 (s, 1H), 5.18 (s, 2H), 4.55 (brs,
1H), 3.82 (s, 3H), 3.76- 2-methoxyphenylcarbamate 3.48 (m, 4H),
2.45 (dd, 2H), 2.26-2.20 (m, 1H), 2.04- 1.96 (m, 1H), 1.97 (s, 3H),
1.73-1.66 (m, 2H), 0.97 (t, 3H) 251 (S)-N-{1-[2-(3-cyano-4-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.21 (brs, 1H), 7.61
(brs, 2H), fluorophenylamino)-6- 7.09 (dd, 1H), 6.07 (brs, 1H),
5.74 (s, 1H), 4.60 (d, 1H), propylpyrimidin-4- 3.76-3.39 (m, 4H),
2.48 (dd, 2H), 2.33-2.28 (m, 1H), 2.08-
yl]pyrrolidin-3-yl}acetamide 2.02 (m, 1H), 2.02 (s, 3H), 1.76-1.67
(m, 2H), 0.98 (t, 3H) 252 (S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.20 (brs, 1H), 7.49 (brs, 2H),
methylphenylamino)-6- 7.27 (brs, 1H), 7.18 (d, 1H), 5.99 (d, 1H),
5.71 (s, 1H), propylpyrimidin-4- 4.62-4.58 (m, 1H), 3.75-3.41 (m,
4H), 2.47 (dd, 2H), yl]pyrrolidin-3-yl}acetamide 2.46 (s, 3H),
2.32-2.27 (m, 1H), 2.08-2.02 (m, 1H), 2.01 (s, 3H), 1.74-1.68 (m,
2H), 0.97 (t, 3H) 253 (S)-N-(1-{2-[4-fluoro-3- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.40 (brs, 1H), 7.44 (brs, 2H),
(trifluoromethyl)phenylamino]- 7.08 (dd, 1H), 5.91 (brs, 1H), 5.72
(s, 1H), 4.62-4.58 (m, 6-propylpyrimidin-4- 1H), 3.75-3.39 (m, 4H),
2.47 (dd, 2H), 2.32-2.25 (m, 1H), yl}pyrrolidin-3-yl)acetamide
2.08-2.01 (m, 1H), 2.01 (s, 3H), 1.76-1.66 (m, 2H), 0.97 (t, 3H)
254 (S)-N-{1-[2-(4-amino-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.97 (brs, 1H), 7.24 (brs, 1H), nitrophenylamino)-6- 6.98
(brs, 1H), 6.73 (d, 1H), 6.06 (d, 1H), 5.92 (brs, 2H),
propylpyrimidin-4- 5.67 (s, 1H), 4.61-4.57 (m, 1H), 3.79-3.44 (m,
4H), yl]pyrrolidin-3-yl}acetamide 2.44 (dd, 2H), 2.32-2.27 (m, 1H),
2.08-2.01 (m, 1H), 2.00 (s, 3H), 1.75-1.65 (m, 2H), 0.97 (t, 3H)
255 (S)-N-{1-[2-(5-chloro-2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.59 (brs, 1H), 7.07 (d, 1H), methylphenylamino)-6- 6.86
(dd, 1H), 6.68 (brs, 1H), 6.22 (s, 1H), 5.68 (s, 1H),
propylpyrimidin-4- 4.58 (s, 1H), 3.71-3.33 (m, 5H), 2.47 (dd, 2H),
2.30- yl]pyrrolidin-3-yl}acetamide 2.20 (m, 2H), 2.27 (s, 3H), 2.00
(s, 3H), 1.73-1.68 (m, 2H), 0.98 (t, 3H)
TABLE-US-00027 TABLE 1-27 Example Compound NMR Spectrum 256
(S)-3-[4-(3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (s,
1H), 7.82 (d, 1H), acetamidopyrrolidin-1-yl)-6- 7.42 (d, 1H), 7.35
(t, 1H), 5.89 (s, 1H), 4.50-4.40 (m, 1H), propylpyrimidin-2-
3.90-3.30 (m, 4H), 2.49 (t, 2H), 2.30-2.20 (m, 1H), 2.10-
ylamino]benzamide 1.90 (m, 4H), 1.73 (q, 2H), 0.99 (t, 3H) 257
(S)-3-{[4-(3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.29 (s,
1H), 7.80 (s, 1H), acetamidopyrrolidin-1-yl)-6- 7.33 (d, 2H), 5.87
(s, 1H), 4.47 (t, 1H), 3.90-3.30 (m, 4H),
propylpyrimidin-2-yl]amino}- 2.91 (s, 3H), 2.48 (t, 2H), 2.35-2.20
(m, 1H), 2.10-2.00 (m, N-methylbenzamide 1H), 1.95 (s, 3H), 1.72
(q, 2H), 1.00 (t, 3H) 258 (S)-N-M-(2-{[3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.03 (t, 1H), 6.80-6.55 (m,
(aminomethyl)phenyl]amino}- 3H), 5.85 (s, 1H), 4.50-4.35 (m, 3H),
3.80-3.40 (m, 4H), 6-propylpyrimidin-4- 2.47 (t, 2H), 2.30-2.15 (m,
1H), 2.05-1.95 (m, 1H), 1.94 (s, yl)pyrrolidin-3-yl]acetamide 3H),
1.68 (q, 2H), 0.98 (t, 3H) 259 (S)-3-{[4-(3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.35-7.20 (m, 2H), 7.07 (d,
acetamidopyrrolidin-1-yl)-6- 1H), 6.28 (brs, 1H), 4.55-4.35 (m,
1H), 3.85-3.40 (m, 4H), propylpyrimidin-2-yl]amino}- 2.51 (t, 2H),
2.40-2.15 (m, 1H), 2.15-1.90 (m, 1H), 1.94 (s, 4-chlorobenzamide
3H), 1.68 (q, 2H), 0.95 (t, 3H) 260 (S)-N-{1-[2-(4-amino-3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.48 (d, 1H), 7.44-7.40
(m, cyanophenylamino)-6- 1H), 6.84 (d, 1H), 6.13 (d, 1H), 4.52-4.43
(m, 1H), 3.86- propylpyrimidin-4- 3.44 (m, 4H), 2.63-2.59 (m, 2H),
2.33-2.25 (m, 1H), 2.10- yl]pyrrolidin-3-yl}acetamide 2.02 (m, 1H),
1.96 (d, 3H), 1.78-1.73 (m, 2H), 1.03 (t, 3H) hydrochloride 261
(S)-N-(1-{2-[4-amino-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.05-7.91 (m, 2H), 7.33 (dd, (trifluoromethyl)phenylamino]- 1H),
6.72 (dd, 1H), 5.53 (d, 1H), 4.72 (brs, 1H), 4.19 (brs,
6-propylpyrimidin-4- 2H), 4.03-3.50 (m, 4H), 2.37-2.23 (m, 4H),
2.11 (s, 3H), yl}pyrrolidin-3-yl)acetamide 1.68-1.53 (m, 2H), 0.98
(t, 3H) hydrochloride 262 (S)-N-{1-[2-(3-amino-5- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 7.15 (d, 1H), 7.13 (s, 1H),
cyanophenylamino)-6- 6.67 (s, 1H), 6.15 (d, 1H), 4.54-4.47 (m, 1H),
3.97-3.46 (m, propylpyrimidin-4- 4H), 2.65-2.60 (m, 2H), 2.41-2.30
(m, 1H), 2.16-2.08 (m, yl]pyrrolidin-3-yl}acetamide 1H), 1.97 (s,
3H), 1.81-1.74 (m, 2H), 1.04 (t, 3H) hydrochloride 263
(S)-N-{1-[2-(1H-indol-6- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
7.75 (s, 1H), 7.54 (d, 1H), ylamino)-6-propylpyrimidin- 7.26 (s,
1H), 7.01 (t, 1H), 6.45 (s, 1H), 6.09 (d, 1H), 4.47 (d,
4-yl]pyrrolidin-3- 1H), 4.00-3.50 (m, 4H), 2.59 (q, 2H), 2.40-2.20
(m, 1H), yl}acetamide hydrochloride 2.20-2.00 (m, 1H), 1.96 (s,
3H), 1.80-1.60 (m, 2H), 1.03 (t, 3H) 264 (S)-N-{1-[2-(5-chloro-2-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.76 (d, 1H), 7.35-7.15
(m, methylphenylamino)-6- 2H), 6.21 (d, 1H), 4.45 (d, 1H),
3.90-3.50 (m, 4H), 2.62 (t, propylpyrimidin-4- 2H), 2.40-2.15 (m,
4H), 2.15-1.85 (m, 4H), 1.76 (q, 2H), yl]pyrrolidin-3-yl}acetamide
1.05 (t, 3H) hydrochloride 265 (S)-N-(1-{2-[4-fluoro-3- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 8.16 (d, 1H), 7.77 (brs, 1H),
(trifluoromethyl)phenylamino]- 7.38 (t, 1H), 6.26 (d, 1H), 4.48 (d,
1H), 3.90-3.45 (m, 4H), 6-propylpyrimidin-4- 2.65 (t, 2H),
2.40-2.20 (m, 1H), 2.20-2.00 (m, 1H), 1.95 (s,
yl}pyrrolidin-3-yl)acetamide 3H), 1.76 (q, 2H), 1.05 (t, 3H)
hydrochloride
TABLE-US-00028 TABLE 1-28 Example Compound NMR Spectrum 266
(S)-N-{1-[2-(3-amino-4- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
7.05 (brs, 1H), 6.94 (t, 1H), fluorophenylamino)-6- 6.76 (t, 1H),
6.13 (d, 1H), 4.47 (d, 1H), 4.00-3.40 (m, 4H), propylpyrimidin-4-
2.65-2.50 (m, 2H), 2.40-2.20 (m, 1H), 2.20-2.00 (m, 1H),
yl]pyrrolidin-3-yl}acetamide 1.95 (s, 3H), 1.75 (q, 2H), 1.03 (t,
3H) hydrochloride 267 (S)-N-(1-{6-propyl-2-[3- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 8.17 (d, 1H), 7.80-7.70 (m,
(trifluoromethyl)phenylamino] 1H), 7.59 (t, 1H), 7.47 (d, 1H), 6.26
(d, 1H), 4.60-4.40 (m, pyrimidin-4-yl}pyrrolidin-3- 1H), 4.00-3.40
(m, 4H), 2.66 (t, 2H), 2.40-2.20 (m, 1H), yl)acetamide
hydrochloride 2.20-2.00 (m, 1H), 1.95 (s, 3H), 1.78 (q, 2H), 1.05
(t, 3H) 268 (S)-N-(1-{2-[3-amino-5- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.29 (d, 1H), 7.01 (d, 1H),
(trifluoromethyl)phenylamino]- 6.74 (s, 1H), 6.21 (d, 1H),
4.60-4.40 (m, 1H), 4.00-3.40 (m, 6-propylpyrimidin-4- 4H), 2.63 (t,
2H), 2.40-2.20 (m, 1H), 2.20-2.00 (m, 1H),
yl}pyrrolidin-3-yl)acetamide 1.95 (s, 3H), 1.77 (q, 2H), 1.04 (t,
3H) hydrochloride 269 (S)-N-{1-[2-(3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 8.92 (d, 1H), 8.04 (d, 1H),
nitrophenylamino)-6- 7.81 (t, 1H), 7.63 (t, 1H), 6.30 (d, 1H),
4.60-4.45 (m, 1H), propylpyrimidin-4- 4.10-3.40 (m, 4H), 2.75-2.60
(m, 2H), 2.45-2.25 (m, 1H), yl]pyrrolidin-3-yl}acetamide 2.20-2.00
(m, 1H), 1.96 (s, 3H), 1.90-1.70 (m, 2H), 1.06 (t, hydrochloride
3H) 270 (S)-N-(1-{2-[(4- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
7.90-7.75 (m, 2H), 7.50- aminophenyl)amino]-6- 7.40 (m, 2H), 6.26
(d, 1H), 4.50-4.35 (m, 1H), 4.00-3.40 (m, propylpyrimidin-4- 4H),
2.66 (q, 2H), 2.40-2.20 (m, 1H), 2.20-2.00 (m, 1H),
yl}pyrrolidin-3-yl)acetamide 1.96 (s, 3H), 1.90-1.70 (m, 2H), 1.05
(t, 3H) hydrochloride 271 (S)-N-(1-{2-[(4-chloro-3- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 7.28 (d, 1H), 7.24 (d, 1H),
hydroxyphenyl)amino]-6- 7.01 (s, 1H), 6.20 (d, 1H), 4.49 (d, 1H),
4.00-3.40 (m, 4H), propylpyrimidin-4- 2.63 (t, 2H), 2.40-2.20 (m,
1H), 2.20-2.00 (m, 1H), 1.96 (s, yl}pyrrolidin-3-yl)acetamide 3H),
1.76 (q, 2H), 1.03 (t, 3H) hydrochloride 272 (S)-4-{[4-(3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.18 (t, 1H), 6.98 (d,
1H), acetamidopyrrolidin-1-yl)-6- 6.62 (d, 1H) 6.17 (d, 1H) 4.49
(d, 1H), 4.00-3.40 (m, 4H), propylpyrimidin-2-yliaminol- 2.62 (t,
2H), 2.40-2.20 (m, 1H) 2.20-2.00 (m, 1H) 1.95 (s, 2-hydroxybenzoic
acid 3H), 1.76 (q, 2H), 1.04 (t, 3H) hydrochloride 273
(S)-5-{[4-(3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.15 (d,
1H), 7.71 (s, 1H), acetamidopyrrolidin-1-yl)-6- 6.93 (d, 1H), 6.14
(d, 1H), 4.47 (d, 1H), 4.10-3.40 (m, 4H),
propylpyrimidin-2-yliaminol- 2.62 (t, 2H), 2.55-2.30 (m 1H)
2.30-2.00 (m 1H) 1.95 (s, 2-hydroxybenzoic acid 3H), 1.04 (q, 3H)
hydrochloride 274 (S)-N-(1-{2-[(3-hydroxy-4- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.50 (s, 1H), 7.10 (brs, 1H),
methylphenyl)amino]-6- 6.95 (d, 1H), 6.70 (brs, 1H), 6.61 (s, 1H),
5.59 (s, 1H), propylpyrimidin-4- 4.12 (brs, 1H), 3.80-3.30 (m, 4H),
2.44 (t, 2H), 2.18 (s, 3H), yl}pyrrolidin-3-yl)acetamide 2.15-1.95
(m, 2H), 1.91 (s, 3H), 1.66 (q, 2H), 0.92 (t, 3H) 275
(S)-N-(1-{2-[(3-chloro-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.96 (s, 1H), 7.21 (d, 1H), hydroxyphenyl)amino]-6- 6.92 (d, 1H),
5.72 (brs, 1H), 5.68 (s, 1H), 4.12 (d, 1H), propylpyrimidin-4-
3.80-3.20 (m, 4H), 2.46 (t, 2H), 2.35-2.20 (m, 1H), 2.00-
yl}pyrrolidin-3-yl)acetamide 1.90 (m, 4H), 1.70 (q, 2H), 0.97 (t,
3H)
TABLE-US-00029 TABLE 1-29 Example Compound NMR Spectrum 276
(S)-N-(1-{2-[(4-hydroxy-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.24 (s, 1H), 6.85 (brs, 1H), methylphenyl)amino]-6- 6.70
(d, 1H), 6.26 (d, 1H), 5.59 (s, 1H), 4.52 (brs, 1H),
propylpyrimidin-4- 3.80-3.20 (m, 4H), 2.43 (t, 2H), 2.25-2.10 (m, 1
+ 3H), 2.00- yl}pyrrolidin-3-yl)acetamide 1.85 (m, 1 + 3H), 1.67
(q, 2H), 0.94 (t, 3H) 277 (S)-N-(1-{2-[(3-fluoro-4- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.75 (d, 1H), 6.95 (d, 1H),
hydroxyphenyl)amino]-6- 6.89 (t, 1H), 6.10 (brs, 1H), 5.63(s, 1H),
4.59(brs, 1H), propylpyrimidin-4- 3.90-3.30 (m, 4H), 2.45 (t, 2H),
2.35-2.15 (m, 1H), 2.10- yl}pyrrolidin-3-yl)acetamide 2.00 (m, 1H),
1.99 (s, 3H), 1.68 (q, 2H), 0.96 (t, 3H) 278
(S)-N-(1-{2-[(3-hydroxy-4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.43 (s, 1H), 7.10-7.00 (m, methoxyphenyl)amino]-6- 1H),
6.78 (d, 1H), 5.62 (s, 1H), 4.59 (s, 1H), 3.86 (s, 3H),
propylpyrimidin-4- 3.80-3.20 (m, 4H), 2.45 (t, 2H), 2.35-2.20 (m,
1H), 2.10- yl}pyrrolidin-3-yl)acetamide 2.00 (m, 1H), 2.01 (s, 3H),
1.67 (q, 2H), 0.96 (t, 3H) 279 (S)-N-(1-{2-[(3-methoxy-4-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.56 (s, 1H), 7.38 (brs,
1H), methylphenyl)amino]-6- 7.00 (d, 1H), 6.89 (d, 1H), 5.78 (brs,
1H), 5.65 (s, 1H), propylpyrimidin-4- 4.59 (brs, 1H), 3.83 (s, 3H),
3.80-3.20 (m, 4H), 2.46 (t, 2H), yl}pyrrolidin-3-yl)acetamide
2.40-2.20 (m, 2H), 2.16 (s, 3H), 1.99 (s, 3H), 1.71 (q, 2H), 0.97
(t, 3H) 280 (S)-N-[1-(2-{[4-methyl-3-amin .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.40 (brs, 1H), 7.37 (d, 1H),
(trifluoromethyl)phenyl]amino}- 7.21 (brs, 1H), 7.16 (d, 1H), 5.70
(s, 1H), 4.60 (brs, 1H), 6-propylpyrimidin-4- 3.85-3.20 (m, 4H),
2.46 (t, 2H), 2.41 (s, 3H), 2.35-2.20 (m,
yl)pyrrolidin-3-yl}acetamide 1H), 2.15-2.00 (m, 1H), 1.98 (s, 3H),
1.71 (q, 2H), 0.97 (t, 3H) 281 (S)-N-(1-{2-[(3,4- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 7.50-7.40 (m, 2H), 7.04 (d,
dimethylphenyl)amino}-6- 1H), 5.73 (brs, 1H), 5.65 (s, 1H), 4.62
(brs, 1H), 3.85- propylpyrimidin-4- 3.20 (m, 4H), 2.46 (t, 2H),
2.40-2.25 (m, 1H), 2.24 (s, 3H), yl}pyrrolidin-3-yl)acetamide 2.21
(s, 3H), 2.15-2.00 (m, 1H), 2.00 (s, 3H), 1.71 (q, 2H), 0.97 (t,
3H) 282 (S)-N-(1-{2-[(3-fluoro-4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.73 (d, 1H), 7.16 (brs, 1H), methylphenyl)amino]-6-
7.10-7.00 (m, 2H), 5.74 (brs, 1H), 5.68 (s, 1H), 4.61 (brs,
propylpyrimidin-4- 1H), 3.85-3.20 (m, 4H), 2.47 (t, 2H), 2.40-2.25
(m, 1H), yl}pyrrolidin-3-yl)acetamide 2.21 (s, 3H), 2.10-1.90 (m,
4H), 1.71 (q, 2H), 0.97 (t, 3H) 283 (S)-N-{1-[2-(4-fluoro-3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 11.06 (d, 1H), 8.98 (d,
1H), nitrophenylamino)-6- 7.55 (d, 1H), 7.22 (d, 1H), 6.78 (s, 1H),
5.79 (s, 1H), 4.68 (s, propylpyrimidin-4- 1H), 4.05-3.59 (m, 4H),
2.56-2.51 (m, 2H), 2.40-2.21 (m, yl]pyrrolidin-3-yl}acetamide 2H),
2.05 (s, 3H), 1.82-1.76 (m, 2H), 0.98-0.94 (m, 3H) hydrochloride
284 (S)-N-{1-[2-(4-methyl-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.78 (d, 1H), 7.70-7.60 (m, nitrophenylamino)-6- 1H),
7.38-7.34 (m, 1H), 7.24-7.21(m, 1H), 5.73(d, 1H),
propylpyrimidin-4- 4.73 (brs, 1H), 4.08-3.70 (m, 4H), 2.53 (s, 3H),
2.46- yl]pyrrolidin-3-yl}acetamide 2.27 (m, 4H), 2.11 (s, 3H),
1.78-1.68 (m, 2H), 0.98-0.94 (m, hydrochloride 3H) 285
(S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
12.85 (d, 1H), 10.66 (d, 1H), methylphenylamino)-6- 8.10-7.88 (m,
2H), 7.61-7.54 (m, 1H), 7.29-7.24 (m, 1H), propylpyrimidin-4- 5.73
(s, 1H), 4.73(s, 1H), 4.06-3.73(m, 4H), 2.63(brs,
yl]pyrrolidin-3-yl}acetamide 1H), 2.48 (s, 3H), 2.44-2.28 (m, 4H),
2.12 (s, 3H), 1.73- hydrochloride 1.65 (m, 2H), 0.97-0.93 (m,
3H)
TABLE-US-00030 TABLE 1-30 Example Compound NMR Spectrum 286
(S)-N-{1-[2-(4-amino-3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
8.66 (s, 0.5H), 8.57 (s, nitrophenylamino)-6- 0.5H), 7.46-7.42 (m,
1H), 7.03 (d, 1H), 6.18 (s, 0.5H), propylpyrimidin-4- 6.14 (s,
0.5H), 4.54-4.48 (m, 1H), 3.92-3.60 (m, 4H), 2.65-
yl]pyrrolidin-3-yl}acetamide 2.60 (m, 2H), 2.30-2.22 (m, 1H),
2.13-2.05 (m, 1H), 2.00 (s, hydrochloride 1.5H), 1.99 (s, 1.5H),
1.80-1.74 (m, 2H), 1.07-1.02 (m, 3H) 287 (S)-N-{1-[2-(3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.34 (brs, 1H), 7.59
(brs, 1H), cyanophenylamino)-6- 7.34 (dd, 1H), 7.22 (d, 1H), 6.98
(brs, 1H), 5.76 (s, 1H), propylpyrimidin-4- 5.66 (d, 1H), 4.64-4.57
(m, 1H), 3.77-3.35 (m, 4H), yl]pyrrolidin-3-yl}acetamide 2.48 (dd,
2H), 2.36-2.29 (m, 1H), 2.05-2.01 (m, 1H), hydrochloride 2.01 (s,
3H), 1.75-1.69 (m, 2H), 0.98 (t, 3H) 288 (S)-N-{1-[2-(4-chloro-3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.66 (s, 0.5H), 8.55 (s,
nitrophenylamino)-6- 0.5H), 7.73-7.64 (m, 2H), 6.32 (s, 0.5H), 6.28
(s, 0.5H), propylpyrimidin-4- 4.53-4.50 (m, 1H), 3.90-3.52 (m, 4H),
2.70-2.65 (m, 2H), yl]pyrrolidin-3-yl}acetamide 2.33-2.25 (m, 1H),
2.15-2.07 (m, 1H), 1.97 (s, 3H), 1.82- hydrochloride 1.76 (m, 2H),
1.07-1.03 (m, 3H) 289 (S)-N-{1-[2-(3-amino-4- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.10 (d, 1H), 6.97 (dd, 1H),
methoxyphenylamino)-6- 6.72 (d, 1H), 5.95 (brs, 1H), 5.62 (s, 1H),
4.58 (brs, 1H), propylpyrimidin-4- 3.82 (s, 3H), 3.84-3.60 (m, 6H),
2.44 (dd, 2H), 2.28- yl]pyrrolidin-3-yl}acetamide 2.23 (m, 1H),
2.02-1.95 (m, 1H), 2.00 (s, 3H), 1.74-1.65 (m, 2H), 0.97 (t, 3H)
290 (S)-N-{1-[2-(3-amino-4- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.24 (d, 1H), 7.12-7.04 (m, chlorophenylamino)-6- 2H),
6.93-6.89 (m, 1H), 5.98 (brs, 1H), 5.69 (s, 1H), propylpyrimidin-4-
4.58 (brs, 1H), 3.97 (s, 2H), 3.75-3.36 (m, 4H), 2.46 (dd,
yl]pyrrolidin-3-yl}acetamide 2H), 2.30-2.24 (m, 1H), 2.06-1.96 (m,
1H), 1.99 (s, 3H), 1.74-1.68 (m, 2H), 1.00 (t, 3H) 291
(S)-N-{1-[2-(3-amino-4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.25 (d, 1H), 6.91-6.87 (m, fluorophenylamino)-6- 2H), 5.72 (d,
1H), 5.67 (s, 1H), 5.60-4.55 (m, 1H), 3.72 (s, propylpyrimidin-4-
2H), 3.84-3.36 (m, 4H), 2.46 (dd, 2H), 2.31-2.26 (m, 1H),
yl]pyrrolidin-3-yl}acetamide 2.06-1.96 (m, 1H), 2.00 (s, 3H),
1.75-1.66 (m, 2H), 0.97 (t, 3H) 292 (S)-N-{1-[2-(3-amino-4-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.14 (d, 1H), 6.95-6.89
(m, methylphenylamino-6- 3H), 5.96 (d, 1H), 5.63 (s, 1H), 5.60-4.55
(m, 1H), 3.84- propylpyrimidin-4- 3.36 (m, 6H), 2.44 (dd, 2H),
2.28-2.23 (m, 1H), 2.12 (s, yl]pyrrolidin-3-yl}acetamide 3H),
2.02-1.95 (m, 1H), 2.00 (s, 3H), 1.72-1.67 (m, 2H), 0.97 (t, 3H)
293 N-{1-[2-(4-amino-3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
8.62 (s, 0.5H), 8.51 (s, nitrophenylamino)-6- 0.5H), 7.41 (brs,
1H), 6.99 (d, 1H), 6.16 (s, 1H), 4.49 (d, propylpyrimidin-4- 1H),
3.83-3.44 (m, 4H), 2.62 (brs, 2H), 2.34-2.27 (m, 1H),
yl]pyrrolidin-3-yl}acetamide 2.11-2.01 (m, 1H), 1.96 (s, 3H),
1.78-1.74 (m, 2H), 1.04 (t, hydrochloride 3H) 294 N-{1-[2-(3-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.73 (brs, NH), 8.32 (s,
1H), cyanophenylamino)-6- 7.65 (m, 1H), 7.33 (m, 1H), 7.20 (m, 1H),
6.14 (brs, NH), propylpyrimidin-4- 5.70 (s, 1H), 4.61 (m, 1H), 3.76
(m, 4H), 2.47 (t, 2H), yl]pyrrolidin-3-yl}acetamide 2.30 (m, 1H),
2.02 (m, 4H), 1.69 (m, 2H), 0.98 (t, 3H) 295 N-{1-[2-(3-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.18 (s, 1H), 8.10 (brs,
NH), nitrophenylamino)-6- 7.76 (d, 1H), 7.47 (m, 1H), 7.34 (m, 1H),
6.24 (brs, NH), propylpyrimidin-4- 5.72 (s, 1H), 4.63 (m, 1H),
3.80-3.64 (m, 4H), 2.47 (t, 2H), yl]pyrrolidin-3-yl}acetamide 2.33
(m, 1H), 2.03 (m, 4H), 1.71 (m, 2H), 0.98 (t, 3H)
TABLE-US-00031 TABLE 1-31 Example Compound NMR Spectrum 296
N-{1-[2-(4-fluoro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.08
(s, 1H), 8.10 (brs, NH), nitrophenylamino)-6- 7.45 (m, 1H), 7.13
(m, 1H), 5.98 (brs, NH), 5.75 (s, 1H), propylpyrimidin-4- 4.62 (m,
1H), 3.79-3.44 (m, 4H), 2.49 (t, 2H), 2.33 (m, 1H),
yl]pyrrolidin-3-yl} 2.03 (m, 4H), 1.70 (m, 2H), 0.98 (t, 3H)
acetamide 297 N-{1-[2-(4-chloro-3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.95 (s, 1H), 7.81 (brs, NH),
nitrophenylamino)-6- 7.35 (m, 2H), 5.94 (brs, NH), 5.74 (s, 1H),
4.60 (m, 1H), propylpyrimidin-4- 3.76-3.40 (m, 4H), 2.47 (t, 2H),
2.31 (m, 1H), 2.06 (m, 4H), yl]pyrrolidin-3-yl} 1.70 (m, 2H), 0.95
(t, 3H) acetamide 298 N-{1-[2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.15 (brs, NH), 7.51 (s, 1H), methoxyphenylamino)-6- 7.16
(t, 1H), 7.02 (d, 1H), 6.72 (brs, NH), 6.53 (d, 1H),
propylpyrimidin-4- 5.53 (s, 1H), 4.63 (m, 1H), 3.80 (s, 3H), 3.70
(m, 4H), yl]pyrrolidin-3-yl} 2.39 (t, 2H), 2.25 (m, 1H), 2.04 (m,
4H), 1.65 (m, 2H), acetamide 0.95 (t, 3H) 299 N-{1-[2-(5-methoxy-2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.91 (s, 1H), 7.05 (d,
1H), methylphenylamino)-6- 6.54 (d, 1H), 5.63 (s, 1H), 4.62 (m,
1H), 3.78 (s, 3H), 3.72- propylpyrimidin-4- 3.60 (m, 4H), 2.46 (4t,
2H), 2.30 (s, 3H), 2.21 (m, 1H), yl]pyrrolidin-3-yl} 2.05 (m, 4H),
1.67 (m, 2H), 0.95 (t, 3H) acetamide 300 N-{1-[2-(4- .sup.1H-NMR
(400 MHz, CDCl.sub.3).delta. 8.29 (brs, NH), 7.53 (d, 2H),
methoxyphenylamino)-6- 6.85 (m, 2H + NH), 5.53 (s, 1H), 4.66 (m,
1H), 3.77 (s, propylpyrimidin-4- 3H), 3.71-3.51 (m, 4H), 2.39 (t,
2H), 2.25 (m, 1H), yl]pyrrolidin-3-yl}acetamide 2.05 (m, 4H), 1.62
(m, 2H), 0.94 (t, 3H) 301 N-(1-{6-propyl-2-[3- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.60 (brs, NH), 8.37 (s,
(trifluoromethyl)phenylamino] 1H), 7.50 (m, 1H), 7.37 (t, 1H), 7.22
(m, 1H), pyrimidin-4-yl}pyrrolidin-3- 6.85 (brs, NH), 5.65 (s, 1H),
4.66 (m, 1H), 3.75-3.60 yl)acetamide (m, 4H), 2.39 (t, 2H), 2.26
(m, 1H), 2.11 (m, 1H), 2.04 (s, 3H), 1.66 (m, 2H), 0.94 (t, 3H) 302
N-{1-[2-(3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.42 (brs,
NH), 7.91 chlorophenylamino)-6- (s, 1H), 7.33 (d, 1H), 7.18 (t,
1H), 6.94 (d, 1H), propylpyrimidin-4- 6.74 (brs, NH), 5.58 (s, 1H),
4.66 (m, 1H), 3.73- yl]pyrrolidin-3-yl}acetamide 3.70 (m, 4H), 2.42
(t, 2H), 2.29 (m, 1H), 2.11 (m, 1H), 2.06 (s, 3H), 1.64 (m, 2H),
0.96 (t, 3H) 303 N-{1-[2-(5-chloro-2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.43 (s, 1H), 7.06 (d, 1H),
methylphenylamino)-6- 6.90 (d, 1H), 6.31 (brs, NH), 5.68 (s, 1H),
4.62 (m, 1H), propylpyrimidin-4- 3.73-3.44 (m, 4H), 2.48 (t, 2H),
2.31 (s, 3H), 2.24 (m, 1H), yl]pyrrolidin-3-yl}acetamide 2.01 (m,
4H), 1.70 (m, 2H), 0.98 (t, 3H) 304 N-{1-[2-(3-chloro-4-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.52 (brs, NH), 7.86
methylphenylamino)-6- (s, 1H), 7.27 (m, 1H), 7.10 (d, 1H), 7.05
propylpyrimidin-4- (brs, NH), 5.52 (s, 1H), 4.65 (m, 1H), 3.70 (m,
4H), yl]pyrrolidin-3-yl}acetamide 2.37 (m, 2H), 2.28 (s, 3H), 2.26
(m, 1H), 2.13 (m, 1H), 2.07 (s, 3H), 1.63 (m, 2H), 0.95 (t, 3H) 305
N-(1-{2-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (brs,
NH), 7.73 (methylthio)phenylamino]-6- (s, 1H), 7.30 (d, 1H), 7.18
(t, 1H), 6.85 (d, 1H), 6.57 propylpyrimidin-4- (brs, NH), 5.57 (s,
1H), 4.63 (m, 1H), 3.72 (m, 4H), yl}pyrrolidin-3-yl)acetamide 2.48
(s, 3H), 2.39 (t, 2H), 2.26 (m, 1H), 2.04 (m, 4H), 1.64 (m, 2H),
0.94 (t, 3H)
TABLE-US-00032 TABLE 1-32 Example Compound NMR Spectrum 306
N-{1-[2-(1H-indol-5- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.11
(s, NH), 7.98 (s, 1H), ylamino)-6-propylpyrimidin- 7.37 (d, 1H),
7.35 (m, 1H), 7.30 (m, 1H), 7.17 (m, 1H), 4-yl]pyrrolidin-3- 6.99
(brs, NH), 6.49 (s, 1H), 5.75 (brs, NH), 5.64 (s, 1H), yl}acetamide
4.60 (m, 1H), 3.81-3.43 (m, 4H), 2.48 (t, 2H), 2.25 (m, 1H), 1.98
(m, 4H), 1.71 (m, 2H), 0.98 (t, 3H) 307 N-(1-{6-propyl-2-[2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (brs, 1H), 7.64 (s,
1H), (trifluoromethyl)-1H- 7.53 (brs, 1H), 7.10 (s, 1H), 6.12 (s,
1H), 5.68 (s, 1H), benzo[d]imidazol-5- 4.47 (m, 1H), 3.92-3.54 (m,
4H), 2.48 (m, 2H), 2.27 (m, ylamino]pyrimidin-4- 1H), 2.01 (m, 4H),
1.71 (m, 2H), 0.98 (t, 3H) yl}pyrrolidin-3-yl)acetamide 308
N-{1-[6-propyl-2-(quinolin-6- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.67 (s, 1H), 8.28 (s, 1H), ylamino)pyrimidin-4- 7.91 (m,
2H), 7.64 (m, 1H), 7.31 (brs, NH), 7.24 (m, 1H),
yl]pyrrolidin-3-yl}acetamide 6.80 (brs, NH), 5.65 (s, 1H), 4.63 (m,
1H), 3.71-3.54 (m, 4H), 2.50 (t, 2H), 2.23 (m, 1H), 2.04 (m, 4H),
1.70 (m, 2H), 0.98 (t, 3H) 309 N-{1-[2-(4-methyl-2-oxo-2H-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.22 (m, 1H), 7.65 (d,
1H), chromen-7-ylamino)-6- 7.46 (m, 1H), 6.13 (s, 1H), 5.93 (s,
1H), 4.49 (m, 1H), 3.80- propylpyrimidin-4- 3.55 (m, 4H), 2.53 (t,
2H), 2.49 (s, 3H), 2.29 (m, 1H), yl]pyrrolidin-3-yl}acetamide 2.10
(m, 1H), 1.96 (s, 3H), 1.73 (m, 2H), 0.99 (t, 3H) 310
N-{1-[6-propyl-2-(quinolin-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.98 (s, 1H), 8.58 (s, 1H), ylamino)pyrimidin-4- 7.97 (d,
1H), 7.66 (m, 2H), 7.52-7.46 (m, 2H), 5.80 (brs,
yl]pyrrolidin-3-yl}acetamide NH), 5.53 (s, 1H), 4.63 (m, 1H),
3.71-3.57 (m, 4H), 2.44 (t, 2H), 2.27 (m, 1H), 2.05 (m, 4H), 1.68
(m, 2H), 0.97 (t, 3H) 311 N-{1-[2-(4-amino-3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 8.33 (m, 1H), 7.59-7.50 (d,
cyanophenylamino)-6- 1H), 7.39 (m, 1H), 6.84 (d, 1H), 6.13 (d, 1H),
4.49 (m, 1H), propylpyrimidin-4- 3.86 (m, 1H), 3.68 (m, 2H), 3.45
(m, 1H), 2.61 (m, 2H), yl]pyrrolidin-3-yl}acetamide 2.27 (m, 1H),
2.04 (m, 1H), 1.94 (s, 3H), 1.73 (m, 2H), hydrochloride 1.05 (m,
3H) 312 N-{1-[2-(3-amino-4- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 7.04 (m, 1H), 6.96 (t, 1H), fluorophenylamino)-6- 6.75 (m,
1H), 6.17 (d, 1H), 4.51-4.43 (m, 1H), 3.92-3.40 (m,
propylpyrimidin-4- 4H), 2.60 (m, 2H), 2.37 (m, 1H), 2.10 (m, 1H),
1.95 (s, 3H), yl]pyrrolidin-3-yl}acetamide 1.75 (q, 2H), 1.03 (t,
3H) hydrochloride 313 (R)-N-(4-chloro-3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.91 (s, 1H), 7.54 (d, 1H), nitrophenyl)-4-(2-
7.44 (d, 1H), 5.83 (brs, 1H), 4.56-3.44 (m, 3H), 2.62 (dd,
methylpyrrolidin-1-yl)-6- 2H), 2.26-2.03 (m, 3H), 1.88-1.79 (m,
3H), 1.31 (brs, 3H), propylpyrimidin-2-amine 1.02 (t, 3H) 314
(R)-4-(2-methylpyrrolidin-1- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.57 (s, 1H), 7.80 (s, 1H), yl)-N-[3-(methylthio)phenyl}-
7.34 (dd, 1H), 7.20 (dd, 1H), 6.89 (d, 1H), 5.70 (brs, 1H),
6-propylpyrimidin-2-ylamine 4.56-3 37 (m, 3H), 2.53 (dd, 2H), 2.48
(s, 3H), 2.10- 2.04 (m, 3H), 1.82-1.73 (m, 3H), 1.28 (d, 3H), 0.99
(t, 3H) 315 (R)-N-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
9.16 (brs, 1H), 8.96 (brs, 1H), methylpyrrolidin-1-yl)-6- 8.02 (s,
1H), 7.44 (d, 1H), 7.13-7.11 (m, 1H), 6.41 (s, 1H),
propylpyrimidin-2-yl]-1H- 5.46 (s, 1H), 4.56-3.29 (m, 3H), 2.39
(dd, 2H), 2.10- indol-6-amine 2.04 (m, 3H), 1.72-1.66 (m, 3H), 1.21
(brs, 3H), 0.93 (t, 3H)
TABLE-US-00033 TABLE 1-33 Example Compound NMR Spectrum 316
(R)-4-(2-methylpyrrolidin-1- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.03 (brs, 1H), 8.48 (s, 1H), yl)-6-propyl-N-[3- 7.51 (d,
1H), 7.38 (dd, 1H), 7.26 (d, 1H), 5.75 (s, 1H), 4.48-
(trifluoromethyl)phenyl]pyrimidin- 3.43 (m, 3H), 2.55 (dd, 2H),
2.18-2.04 (m, 3H), 1.84- 2-amine 1.74 (m, 3H), 1.28 (d, 3H), 1.00
(t, 3H) 317 (R)-4-methyl-7-[4-(2- .sup.1H-NMR (400 MHz, CDCl3)
.delta. 8.20 (s, 1H), 7.69 (brs, 1H), methylpyrrolidin-1-yl)-6-
7.46 (d, 1H), 7.21 (dd, 1H), 6.11 (s, 1H), 5.77 (s, 1H), 4.14-
propylpyrimidin-2-ylamino}- 3.32 (m, 3H), 2.50 (dd, 2H), 2.39 (s,
3H), 2.12-2.03 (m, 2H-chromen-2-one 3H), 1.79-1.71 (m, 3H), 1.30
(brs, 3H), 1.00 (t, 3H) 318 (R)-N-(3-chloro-4- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 8.78 (brs, 1H), 8.06 (s, 1H),
methylphenyl)-4-(2- 7.23 (d, 1H), 7.11 (d, 1H), 5.70 (s, 1H),
4.52-3.35 (m, 3H), methylpyrrolidin-1-yl)-6- 2.53 (dd, 2H), 2.31
(s, 3H), 2.12-2.03 (m, 3H), 1.81- propylpyrimidin-2-amine 1.75 (m,
3H), 1.30 (brs, 3H), 1.00 (t, 3H) 319 (R)-4-(2-methylpyrrolidin-1-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.23 (dd, 1H), 7.85 (dd,
1H), yl)-N-(3-nitrophenyl)-6- 7.58 (dd, 1H), 7.41 (dd, 1H), 5.78
(s, 1H), 4.67-3.40 (m, propylpyrimidin-2-ylamine 3H), 2.56 (dd,
2H), 2.12-2.03 (m, 3H), 1.85-1.75 (m, 3H), 1.32(brs, 3H), 1.01(t,
3H) 320 (R)-N-(4-fluoro-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.08 (d, 1H), 7.61-7.57 (m, nitrophenyl)-4-(2- 1H), 7.22
(dd, 1H), 5.81 (s, 1H), 4.63-3.44 (m, 3H),
methylpyrrolidin-1-yl)-6- 2.60 (dd, 2H), 2.22-2.08 (m, 3H),
1.88-1.78 (m, 3H), propylpyrimidin-2-amine 1.32 (brs, 3H), 1.02 (t,
3H) 321 (R)-N-(4-methyl-3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.39 (brs, 1H), 8.99 (d, 1H), nitrophenyl)-4-(2- 7.43 (dd,
1H), 7.23 (d, 1H), 5.77 (s, 1H), 4.60-3.38 (m, 3H),
methylpyrrolidin-1-yl)-6- 2.56 (dd, 2H), 2.55 (s, 3H), 2.17-2.03
(m, 3H), 1.85- propylpyrimidin-2-amine 1.77 (m, 3H), 1.30 (brs,
3H), 1.01 (t, 3H) 322 (R)-N44-fluoro-3- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 9.02 (brs, 1H), 8.42 (dd, 1H),
(trifluoromethyl)phenyl]-4- 7.53-7.50 (m, 1H), 7.11 (dd,1H), 5.75
(s, 1H), 4.47- (2-methylpyrrolidin-1-yl)-6- 3.34 (m, 3H), 2.55 (dd,
2H), 2.55 (s, 3H), 2.17-2.03 (m, propylpyrimidin-2-ylamine 3H),
1.83-1.76 (m, 3H), 1.26 (d, 3H), 1.00 (t, 3H) 323
(R)-N.sup.1-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.72
(brs, 1H), 8.14 (s, 1H), methylpyrrolidin-1-yl)-6- 7.30-7.27 (m,
1H), 6.72 (d, 1H), 5.68 (s, 1H), 4.33-3.38 (m,
propylpyrimidin-2-yl]-3- 3H), 4.09 (s, 2H), 2.52 (dd, 2H),
2.17-2.03 (m, 3H), 1.82- (trifluoromethyl)benzene- 1.72 (m, 3H),
1.23 (d, 3H), 0.99 (t, 3H) 1,4-diamine 324 (R)-benzyl
2-methoxy-5-[4- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.32
(brs, 1H), 7.46-7.26 (m, (2-methylpyrrolidin-1-yl)-6- 6H), 6.78 (d,
1H), 5.65 (s, 1H), 5.19 (s, 2H), 3.81 (s, 3H), propylpyrimidin-2-
4.44-3.34 (m, 3H), 2.46 (dd, 2H), 2.10-1.95 (m, 3H), 1.76-
ylamino]phenylcarbamate 1.68 (m, 3H), 1.21 (d, 3H), 0.98 (t, 3H)
325 (R)-2-fluoro-5-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.36 (brs, 1H), 7.60 (brs, 1H), methylpyrrolidin-1-yl)-6- 7.12 (dd,
1H), 5.77 (s, 1H), 4.45-3.36 (m, 3H), 2.54 (dd, propylpyrimidin-2-
2H), 2.18-2.03 (m, 3H), 1.83-1.73 (m, 3H), 1.31 (brs, 3H),
ylamino]benzonitrile 1.00 (t, 3H)
TABLE-US-00034 TABLE 1-34 Example Compound NMR Spectrum 326
(R)-2-methyl-5-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.91 (brs, 1H), 8.37 (brs, 1H), methylpyrrolidin-1-yl)-6- 7.48 (d,
1H), 7.21 (d, 1H), 5.75 (s, 1H), 4.45-3.41 (m, 3H),
propylpyrimidin-2- 2.54 (dd, 2H), 2.49 (s, 3H), 2.18-2.03 (m, 3H),
1.83- ylamino}benzonitrile 1.75 (m, 3H), 1.32 (brs, 3H), 1.00 (t,
3H) 327 (R)-2-amino-5-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.12 (brs, 1H), 7.31 (d, 1H), methylpyrrolidin-1-yl)-6-
7.16 (brs, 1H), 6.69 (d, 1H), 4.20 (s, 2H), 4.45-3.54 (m,
propylpyrimidin-2- 3H), 2.45 (dd, 2H), 2.09-2.01 (m, 3H), 1.76-1.66
(m, 3H), ylamino]benzonitrile 1.26 (d, 3H), 0.98 (t, 3H) 328
(R)-N.sup.1-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.97
(s, 1H), 8.87 (brs, 1H), methylpyrrolidin-1-yl)-6- 7.29 (dd, 1H),
6.73 (d, 1H), 6.23 (s, 2H), 5.71 (s, 1H), 4.63-
propylpyrimidin-2-yl]-3- 3.33 (m, 3H), 2.53 (dd, 2H), 2.09-2.01 (m,
3H), 1.82- nitrobenzene-1,4-diamine 1.73 (m, 3H), 1.28 (brs, 3H),
0.99 (t, 3H) 329 (R)-1-{6-[4-(2- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.65 (brs, 1H), 7.44 (brs, 1H), methylpyrrolidin-1-yl)-6-
7.07 (d, 1H), 5.68 (s, 1H), 4.04 (dd, 2H), 4.63-3.33 (m, 3H),
propylpyrimidin-2- 3.13 (dd, 2H), 2.50 (dd, 2H), 2.20 (s, 3H),
2.10-2.01 (m, ylamino]indolin-1- 3H), 1.79-1.73 (m, 3H), 1.22 (d,
3H), 0.99 (t, 3H) yl}ethanone 330 (R)-N-(5-chloro-2- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.69 (s, 1H), 7.04 (d, 1H),
methylphenyl)-4-(2- 6.84 (dd, 1H), 6.68 (brs, 1H), 5.71 (s, 1H),
4.46-3.27 (m, methylpyrrolidin-1-yl)-6- 3H), 2.46 (dd, 2H), 2.28
(s, 3H), 2.20-2.03 (m, 3H), 1.75- propylpyrimidin-2-amine 1.67 (m,
3H), 1.28 (brs, 3H), 0.99 (t, 3H) 331 (R)-4-methoxy-N.sup.1-[4-(2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.18 (s, 1H), 6.96 (dd,
1H), methylpyrrolidin-1-yl)-6- 6.71 (d, 1H), 5.64 (s, 1H),
4.56-3.33 (m, 3H), 3.82 (s, 3H), propylpyrimidin-2- 3.76 (s, 2H),
2.46 (dd, 2H), 2.09-1.99 (m, 3H), 1.77- yl]benzene-1,3-diamine 1.66
(m, 3H), 1.26 (d, 3H), 0.98 (t, 3H) 332 (R)-4-chloro-N.sup.1-[4-(2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (s, 1H), 7.10 (d,
1H), methylpyrrolidin-1-yl)-6- 6.90 (dd, 1H), 5.68 (s, 1H),
4.56-3.33 (m, 3H), 3.96 (s, 2H), propylpyrimidin-2- 2.45 (dd, 2H),
2.07-2.00 (m, 3H), 1.76-1.66 (m, 3H), yl]benzene-1,3-diamine 1.26
(d, 3H), 0.99 (t, 3H) 333 (R)-4-fluoro-N.sup.1-[4-(2- .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.31 (d, 1H), 6.97 (s, 1H),
methylpyrrolidin-1-yl)-6- 6.87 (d, 2H), 5.67 (s, 1H), 4.56-3.33 (m,
3H), 3.67 (s, 2H), propylpyrimidin-2- 2.45 (dd, 2H), 2.12-1.98 (m,
3H), 1.75-1.68 (m, 3H), yl]benzene-1,3-diamine 1.26 (d, 3H), 0.98
(t, 3H) 334 (R)-4-methyl-N.sup.1-[4-(2- .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 9.56 (s, 1H), 7.08 (d, 1H),
methylpyrrolidin-1-yl)-6- 7.02 (s, 1H), 6.96 (d, 3H), 5.66 (s, 1H),
4.55-3.36 (m, 5H), propylpyrimidin-2- 2.56 (dd, 2H), 2.15-2.07 (m,
2H), 2.12 (s, 3H), 1.85- yl]benzene-1,3-diamine 1.76 (m, 2H), 1.29
(brs, 3H), 1.00 (t, 3H) 335 (S)-3-{4-[3-(2- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.81-7.70 (m, 2H), 7.49 (d,
hydroxyethylamino)pyrrolidi 1H), 7.30 (d, 1H), 6.30 (s, 1H),
4.21-3.77 (m, 9H), 2.69- n-1-yl]-6-propylpyrimidin-2- 2.30 (m, 4H),
1.82 (brs, 2H), 1.05 (t, 3H) ylamino}benzonitrile
dihydrochloride
TABLE-US-00035 TABLE 1-35 Example Compound NMR Spectrum 336
(S)-5-{4-butyl-6-[2- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.99
(d, 1H), 7.70 (d, 1H), (hydroxymethyl)pyrrolidin-1- 7.44 (d, 1H),
6.31 (d, 1H), 4.28 (d, 1H), 3.84-3.56 (m, 4H),
yl]pyrimidin-2-ylamino}-2- 2.66 (dd, 2H), 2.51 (s, 3H), 2.12-2.02
(m, 4H), 1.76- methylbenzonitrile 1.68 (m, 2H), 1.48-1.43 (m, 2H),
1.03 (t, 3H) hydrochloride 337 (S)-N-{1-[2-(4-amino-3- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 8.86 (brs, 1H), 7.42 (d, 1H),
nitrophenylamino)-6- 6.90 (d, 1H), 5.83 (s, 1H), 4.48 (s, 1H),
3.78-3.40 (m, 4H), butylpyrimidin-4- 2.49 (dd, 2H), 2.28-2.23 (m,
1H), 2.04-1.99 (m, 1H), yl]pyrrolidin-3-yl}acetamide 1.95 (s, 3H),
1.71-1.64 (m, 2H), 1.45-1.35 (m, 2H), 0.98 (t, 3H) 338
(S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.06 (brs, 1H), 7.34 (d, 1H), (methylamino)pyrrolidin-1-
6.90 (d, 1H), 5.85 (s, 1H), 3.96-3.44 (m, 5H), 2.64 (s, 3H),
yl]pyrimidin-2-yl}-3- 2.49 (dd, 2H), 2.39 (brs, 1H), 2.08 (brs,
1H), 1.71-1.64 (m, nitrobenzene-1,4-diamine 2H), 1.44-1.36 (m, 2H),
0.96 (t, 3H) 339 (S)-3-(4-{3-[(1H-pyrrol-2- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 10.59-10.51 (m, 1H),
yl)methylamino]pyrrolidin-1- 8.12 (s, 1H), 7.83 (d, 1H), 7.60-7.56
(m, 2H), 6.87-6.83 (m, yl}-6-propylpyrimidin-2- 1H), 6.36-6.30 (m,
2H), 6.16-6.12 (m, 1H), 4.36-4.33 (m, ylamino)benzonitrile 2H),
4.12-3.75 (m, 5H), 2.71-2.58 (m, 3H), 2.41-2.30 (m, dihydrochloride
1H), 1.83-1.77 (m, 2H), 1.06 (dd, 3H) 340 (S)-N.sup.1-{4-[2-
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 10.71 (s, 1H), 8.96 (d,
1H), (methoxymethyl)pyrrolidin- 7.38 (s, 1H), 6.85 (s, 1H),
6.15-6.13 (m, 2H), 5.89 (d, 1H), 1-yl]-6-propylpyrimidin-2-yl}-
4.68-3.43 (m, 5H), 3.31 (d, 3H), 2.62 (brs, 2H), 2.33-
3-nitrobenzene-1,4-diamine 2.05 (m, 4H), 1.88-1.84 (m, 2H), 1.00
(m, 3H) hydrochloride 341 (S)-{1-[2-(4-fluoro-3- .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 13.50 (s, 1H), 13.18 (s, 1H),
nitrophenylamino)-6- 11.25 (s, 1H), 11.04 (s, 1H), 9.05 (m, 1H),
8.97 (m, 1H), propylpyrimidin-4- 7.63 (m, 2H), 7.26 (m, 2H), 6.34
(s, 1H), 5.84 (s, 1H), yl]pyrrolidin-2-yl}methanol 4.62 (m, 1H),
4.20 (m, 1H), 3.83 (m, 2H), 3.81 (m, 3H), hydrochloride 3.76 (m,
3H), 3.47 (m, 2H), 2.65 (m, 3H), 2.31 (m, 3H), 2.13 (m, 4H), 1.86
(m, 4H), 1.01 (m, 6H) 342 (S)-N.sup.1-[4-(3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.97 (d, 1H), 7.75 (d, 1H),
aminopyrrolidin-1-yl)-6- 7.30 (d, 1H), 6.37 (s, 1H), 4.17-3.75 (m,
5H), 2.71 (t, 2H), propylpyrimidin-2-yl]-5- 2.58 (m, 1H), 2.33 (m,
1H), 1.82 (m, 2H), 1.06 (t, 3H) (trifluoromethyl)benzene-
1,3-diamine dihydrochloride 343 (S)-N.sup.1-[4-(3- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 7.63 (br, 1H), 7.60 (s, 1H),
aminopyrrolidin-1-yl)-6- 7.38 (m, 1H), 6.31 (d, 1H), 4.15-3.75 (m,
5H), 2.68 (t, 2H), propylpyrimidin-2-yl]-3- 2.53 (m, 1H), 2.43 (d,
3H), 2.29 (m, 1H), 1.82 (m, 2H), methylbenzene-1,4-diamine 1.07 (t,
3H) dihydrochloride 344 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 8.59 (d, 1H), 7.75-7.64 (m,
yl)-N-(4-chloro-3- 2H), 7.41 (d, 1H), 6.57 (d, 1H), 4.11-3.78 (m,
5H), nitrophenyl)-6- 2.72 (m, 2H), 2.65 (m, 1H), 2.04 (m, 1H), 1.78
(m, 2H), propylpyrimidin-2-amine 1.06 (m, 3H) dihydrochloride 345
(S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 7.51 (d, 1H), 7.33 (m, 2H), yl)-N-[3-(methylthio)phenyl]-
7.01 (m, 1H), 6.28 (brs, 1H), 4.15-3.75 (m, 5H), 2.67 (m,
6-propylpyrimidin-2-amine 2H), 2.56 (m, 1H), 2.50 (s, 3H), 2.24 (m,
1H), 1.79 (m, 2H), dihydrochloride 1.29 (m, 3H)
TABLE-US-00036 TABLE 1-36 Example Compound NMR Spectrum 346
(S)-N-[4-(3-aminopyrrolidin- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 7.67 (d, 1H), 7.56 (d, 1H), 1-yl)-6-propylpyrimidin-2-yl]-
7.28 (s, 2H), 7.05 (d, 1H), 6.17 (d, 1H), 4.14-3.71 (m, 5H),
1H-indol-6-amine 2.62 (m, 2H), 2.57 (m, 1H), 2.29 (m, 1H), 1.78 (m,
2H), dihydrochloride 1.04 (t, 3H) 347 (S)-4-(3-aminopyrrolidin-1-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.20-8.05 (d, 1H), 7.81-
yl)-6-propyl-N-[3- 7.30 (dd, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 6.34
(d, 1H), (trifluoromethyl)phenyl]pyrimidin- 4.17-3.74 (m, 5H), 2.70
(m, 2H), 2.57 (m, 1H), 2.25 (m, 2-amine dihydrochloride 1H), 1.83
(m, 2H), 1.06 (t, 3H) 348 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. 7.77-7.67 (d, 1H), 7.29 (d,
yl)-N-(5-chloro-2- 1H), 7.21 (m, 1H), 6.28 (d, 1H), 4.11-3.70 (m,
5H), 2.67 (m, methylphenyl)-6- 2H), 2.55 (m, 1H), 2.30 (d, 3H),
2.20 (m, 1H), 1.79 (m, 2H), propylpyrimidin-2-amine 1.05 (t, 3H)
dihydrochloride 349 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 7.78-7.71 (d, 1H), 7.37-
yl)-N-(3-chloro-4- 7.30 (m, 2H), 6.28 (s, 1H), 4.08-3.81 (m, 5H),
2.66 (m, 2H), methylphenyl)-6- 2.52 (m, 1H), 2.35 (s, 3H), 2.20 (m,
1H), 1.80 (m, 2H), propylpyrimidin-2-amine 1.05 (t, 3H)
dihydrochloride 350 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 8.94 (d, 1H), 8.05 (m, 1H),
yl)-N-(3-nitrophenyl)-6- 7.82 (m, 1H), 7.64 (m, 1H), 6.60 (d, 1H),
4.16-3.76 (m, 5H), propylpyrimidin-2-amine 2.71 (m, 2H), 2.55 (m,
1H), 2.30 (m, 1H), 1.84 (m, 2H), dihydrochloride 1.07 (t, 3H) 351
(S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 8.64 (d, 1H), 7.64 (m, 1H), yl)-N-(4-methyl-3- 7.47 (m,
1H), 6.64 (d, 1H), 4.16-3.71 (m, 5H), 2.70 (m, 2H), nitrophenyl)-6-
2.56 (s, 3H), 2.54 (m, 1H), 2.31 (m, 1H), 1.81 (m, 2H),
propylpyrimidin-2-amine 1.06 (t, 3H) dihydrochloride 352
(S)-N.sup.1-[-(3- .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.18
(d, 1H), 7.92-7.85 (dd, aminopyrrolidin-1-yl)-6- 1H), 7.52 (m, 1H),
6.35 (s, 1H), 6.78-4.18 (m, 5H), 2.68 (m, propylpyrimidin-2-yl]-3-
2H), 2.58 (m, 1H), 2.35 (m, 1H), 1.82 (m, 2H), 1.05 (t, 3H)
(trifluoromethyl)benzene- 1,4-diamine dihydrochloride 353
(S)-5-[-(3-aminopyrrolidin- .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 8.07 (d, 1H), 7.87 (m, 1H), 1-yl)-6-propylpyrimidin-2- 7.43
(t, 1H), 6.33 (s, 1H), 4.14-3.84 (m, 5H), 2.69 (m, 2H), ylamino]-2-
2.56 (m, 1H), 2.23 (m, 1H), 1.80 (m, 2H), 1.06 (t, 3H)
fluorobenzonitrile dihydrochloride 354 (S)-5-[4-(3-aminopyrrolidin-
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.02 (d, H), 7.68 (d,
1H), 1-yl)-6-propylpyrimidin-2- 7.45 (d, 1H), 6.31 (s, 1H),
4.08-3.82 (m, 5H), 2.68 (m, 2H), ylamino]-2- 2.58 (m, 1H), 2.52 (s,
3H), 2.28 (m, 1H), 1.80 (m, 2H), methylbenzonitrile 1.06 (t, 3H)
dihydrochloride 355 (S)-2-amino-5-[-(3- .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 7.64 (d, 1H), 7.45 (m, 1H),
aminopyrrolidin-1-yl)-6- 6.94 (m, 1H), 6.25 (s, 1H), 4.13-3.70 (m,
5H), 2.65 (m, 2H), propylpyrimidin-2- 2.55 (m, 1H), 2.28 (m, 1H),
1.78 (m, 2H), 1.05 (t, 3H) ylamino]benzonitrile dihydrochloride
TABLE-US-00037 TABLE 1-37 Example Compound NMR Spectrum 356
(S)-benzyl 5-[4-(3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.34(d, 1H), 7.44-7.31(m, aminopyrrolidin-1-yl)-6- 5H),
7.09-7.00(dd, 2H), 6.21(d, 1H), 5.20(d, 2H), 4.01-
propylpyrimidin-2-ylamino]- 3.72(m, 5H), 3.80(s, 3H), 2.64(m, 2H),
2.62(m, 1H), 2-methoxyphenylcarbamate 2.54-2.29(m, 1H), 1.78(m,
2H), 1.04(t, 3H) dihydrochloride 357 (S)-4-(3-aminopyrrolidin-1-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.12(d, 1H), 7.85(m, 1H),
yl)-N-[4-fluoro-3- 7.41(m, 1H), 6.30(s, 1H), 4.09-3.88(m, 5H),
2.71(m, 2H), (trifluoromethyl)phenyl]-6- 2.64(m, 1H), 2.30(m, 1H),
1.82(m, 2H), 1.07(m, 3H) propylpyrimidin-2-amine dihydrochloride
358 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.81-8.68(m, 1H), 7.83(m, yl)-N-(4-fluoro-3- 1H), 7.49(m,
1H), 6.36(s, 1H), 4.18-3.76(m, 5H), 2.70(m, nitrophenyl)-6- 2H),
2.58(m, 1H), 2.32(m, 1H), 1.82(m, 2H), 1.06(t, 3H)
propylpyrimidin-2-amine dihydrochloride 359 (S)-N.sup.1-[4-(3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.54(m, 1H), 7.43(m, 1H),
aminopyrrolidin-1-yl)-6- 7.02(m, 1H), 6.25(d, 1H), 4.15-3.71(m,
5H), 2.66(m, 2H), propylpyrimidin-2-yl]-3- 2.57(m, 1H), 2.30(m,
1H), 1.79(m, 2H), 1.05(t, 3H) nitrobenzene-1,4-diamine
dihydrochloride 360 (S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.34-8.30(d, 2H), 7.78(s,
yl)-N-[3,5-bis(trifluoromethyl) 1H), 6.40(s, 1H), 4.16-3.77(m, 5H),
2.73(t, 2H), 2.54(m, phenyl]-6-propylpyrimidin-2- 1H), 2.26(m, 1H),
1.82(m, 2H), 0.90(t, 3H) amine dihydrochloride 361
(S)-4-(3-aminopyrrolidin-1- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 6.81-6.78(m, 2H), 6.35(s, yl)-N-(3,5-dimethoxyphenyl)- 1H),
6.28(s, 1H), 4.15-3.99(m, 4H), 3.85(s, 6H), 3.84-
6-propylpyrimidin-2-amine 3.79(m, 1H), 2.66(t, 2H), 2.59(m, 1H),
2.50(m, 1H), dihydrochloride 1.81(m, 2H), 1.05(t, 3H) 362
(S)-3-amino-5-{[4-(3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
6.53(s, 1H), 6.26(m, 2H), aminopyrrolidin-1-yl)-6- 5.83(s, 1H),
3.82(br, 1H), 3.65(m, 2H), 3.48(br, 1H), propylpyrimidin-2-
3.30(br, 1H), 2.46(m, 2H), 2.21(m, 1H), 1.89(m, 1H),
yliamino}benzonitrile 1.71(m, 2H), 0.97(t, 3H) 363
(S)-3-[4-(3-aminopyrrolidin- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.76(s, 1H), 7.62(m, 1H), 1-yl)-6-propylpyrimidin-2-
7.41(m, 2H), 5.86(s, 1H), 3.88-3.77(br, 1H), 3.65(m, 2H),
ylamino]benzenesulfonamide 3.53(br, 2H), 2.48(m, 2H), 2.21(m, 1H),
1.87(m, 1H), 1.74(m, 2H), 0.98(t, 3H) 364 (S)-N.sup.1-{4-[2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.73(br, 1H), 7.04(t, 1H),
(methoxymethyl)pyrrolidin- 6.97(br, 1H), 6.63(br, 1H), 6.30(m, 1H),
5.68(br, 1H), 1-yl]-6-propylpyrimidin-2- 4.63(br, 1H), 3.92(m, 3H),
3.45(br, 1H), 3.39(s, 3H), yl}benzene-1,3-diamine 3.18(br, 1H),
3.14(m, 1H), 2.45(t, 2H), 2.10-1.96(m, 4H), 1.68(m, 3H), 0.99(t,
3H) 365 (S)-4-fluoro-N.sup.1-{4-[2- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 7.82(br, 1H), 6.97(br, 1H),
(methoxymethyl)pyrrolidin- 6.85(m, 1H), 6.51(br, 1H), 5.68(s, 1H),
4.46(br, 1H), 1-yl]-6-propylpyrimidin-2- 3.89(br, 2H), 3.45(br,
1H), 3.39(s, 3H), 3.34(m, 1H), yl}benzene-1,3-diamine 3.12(m, 1H),
2.45(t, 2H), 2.09-1.98(m, 4H), 1.68(m, 3H), 0.97(t, 3H)
TABLE-US-00038 TABLE 1-38 Example Compound NMR Spectrum 366
(S)-N.sup.1-{4-[2- .sup.1H-NMR(400 MHz, CDCl3) .delta. 7.72(br,
1H), 6.90(m, 2H), (methoxymethyl)pyrrolidin- 6.57(br, 1H), 5.67(s,
1H), 4.51(br, 1H), 3.93-3.78(br, 2H),
1-yl]-6-propylpyrimidin-2-yl}- 3.45(br, 1H), 3.40(s, 3H), 3.22(m,
1H), 3.13(m, 1H), 4-methylbenzene-1,3-diamine 2.45(m, 2H), 2.11(s,
3H), 1.99(m, 4H), 1.69(m, 3H), 0.98(t, 3H) 367
(S)-4-methoxy-N.sup.1-{4-[2- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 7.62(br, 1H), 7.00(br, 1H), (methoxymethyl)pyrrolidin-
6.70(m, 2H), 5.66(s, 1H), 4.72(br, 1H), 3.92(br, 2H),
1-yl]-6-propylpyrimidin-2- 3.81(s, 3H), 3.40(m , 1H), 3.39(s, 3H),
3.29(m, 1H), yl}benzene-1,3-diamine 3.17(m, 1H), 2.44(t, 2H),
2.02(m, 4H), 1.71(m, 2H), 0.97(t, 3H) 368 (S)-N-{4-[2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.40(br, 1H), 6.99(m, 1H),
(methoxymethyl)pyrrolidin- 6.78(m, 1H), 6.68(s, 1H), 4.40(br, 1H),
3.75(br, 1H), 1-yl]-6-propylpyrimidin-2- 3.59(t, 2H), 3.53(br, 1H),
3.38(s, 3H), 3.36(m, 1H), yl}indolin-6-amine 3.26(t, 1H), 2.99(t,
2H), 2.46(t, 2H), 2.09-1.95(m, 4H), 1.72(m, 2H), 0.96(t, 3H) 369
(S)-N.sup.1-[4-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.17(s,
1H), 6.94(s, 1H), aminopyrrolidin-1-yl)-6- 6.81(br, 1H), 5.65(s,
1H), 3.71(m, 2H), 3.56(br, 1H), propylpyrimidin-2-yl]-4- 2.45(m,
2H), 2.19(m, 1H), 2.12(s, 3H), 1.81(m, 1H),
methylbenzene-1,3-diamine 1.70(m, 2H), 1.26(br, 2H), 0.97(t, 3H)
370 (S)-N.sup.1-[4-(3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.90(m, 1H), 7.65(m, 1H), aminopyrrolidin-1-yl)-6- 7.41(t, 1H),
6.32(s, 1H), 4.16-3.77(m, 5H), 2.69(m, 2H),
propylpyrimidin-2-yl]-4- 2.57(m, 1H), 2.51(m, 1H), 1.81(m, 2H),
1.00(t, 3H) fluorobenzene-1,3-diamine dihydrochloride 371
(S)-3-amino-5-{[4-(3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.85(d, 1H), 7.78(s, 1H), aminopyrrolidin-1-yl)-6- 7.28(m, 1H),
6.36(s, 1H), 4.17-3.76(m, 5H), 2.70(m, 2H), propylpyrimidin-2-
2.60(m, 1H), 2.33(m, 1H), 1.82(m, 2H), 1.06(t, 3H)
yl]amino}benzonitrile dihydrochloride 372 (S)-N-(4-chloro-3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.05(brs, 1H), 7.37(d,
1H), nitrophenyl)-4-[3- 7.30(br, 1H), 7.15(br, 1H), 5.75(s, 1H),
3.86-3.30(m, 5H), (cyclopropylmethylamino)pyrrolidin- 2.55(d, 2H),
2.47(t, 2H), 2.23(m, 1H), 1.90(br, 1H),
1-yl]-6-propylpyrimidin-2-amine 1.72(m, 3H), 1.00(t, 4H), 0.55(d,
2H), 0.15(m, 2H) 373 ((S)-4-[3-(cyclopropylmethylamino)
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.16(brs, 1H), 7.40(br,
1H), pyrrolidin-1-yl]-N-(4-fluoro-3- 7.17(br, 1H) 7.12(t, 2H),
5.74(s, 1H), 3.90-3.15(m, 5H), nitrophenyl)-6-propylpyrimidin-2-
2.56(d, 2H), 2.47(t, 2H), 2.23(m, 1H), 1.90(br, 1H), amine 1.74(m,
3H), 0.97(t, 4H), 0.51(d, 2H), 0.16(d, 2H) 374
(S)-4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 9.06(brs, 1H), 7.30(m, 1H), pyrrolidin-1-yl]-N-(4-methyl-3-
7.17(d, 1H), 7.10(br, 1H), 5.72(s, 1H), 3.91-3.40(m, 5H),
nitrophenyl)-6-propylpyrimidin-2- 2.57(m, 2H), 2.54(s, 3H), 2.47(t,
2H), 2.23(m, 1H), amine 1.90(br, 1H), 1.75(m, 3H), 0.98(t, 3H),
0.52(d, 2H), 0.15(m, 2H) 375 ((S)-4-[3-cyclopropylmethylamino)
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.26(brs, 1H), 7.77(d,
1H), pyrrolidin-1-yl]-N-(3-nitrophenyl)-6- 7.44(m, 1H), 7.37(m,
1H), 5.74(s, 1H), 3.92-3.60(m, 5H), propylpyrimidin-2-amine 2.64(m,
2H), 2.48(t, 2H), 2.29(m, 1H), 2.02(m, 1H), 1.72(m, 2H), 1.00(m,
4H), 0.56(m, 4H), 0.22(m, 2H)
TABLE-US-00039 TABLE 1-39 Example Compound NMR Spectrum 376
(S)-5-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.34(m, 1H),
7.56(m, 1H), (cyclopropylmethylamino) 7.09(m, 2H), 5.73(s, 1H),
3.84-3.16(m, 5H), 2.60(m, 2H), pyrrolidin-1-yl]-6- 2.47(t, 2H),
2.22(m, 1H), 1.88(br, 1H), 1.70(m, 3H), propylpyrimidin-2-ylamino}-
0.99(m, 4H), 0.50(m, 2H), 0.15(m, 2H) 2-fluorobenzonitrile 377
(S)-5-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.32(d, 1H),
7.46(d, 1H), (cyclopropylmethylamino) 7.18(d, 1H), 7.02(br, 1H),
5.71(s, 1H), 3.80-3.00(m, 5H), pyrrolidin-1-yl]-6- 2.54(d, 2H),
2.48-2.45(m, 5H), 2.21(m, 1H), 1.88(br, 1H),
propylpyrimidin-2-ylamino}- 1.74(m, 3H), 0.98(t, 4H), 0.54(m, 2H),
0.17(m, 2H) 2-methylbenzonitrile 378
(S)-4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 7.86(s, 1H), 7.28(d, 1H), pyrrolidin-1-yl]-N[3- 7.17(t,
1H), 6.96(br, 1H), 6.84(d, 1H), 5.69(s, 1H), 4.00-
(methylthio)phenyl]-6- 3.20(m, 5H), 2.54(d, 2H), 2.49(s, 3H),
2.44(m,2H), propylpyrimidin-2-amine 2.20(m,1H), 1.86(br, 1H),
1.73(m, 3H), 0.97(m, 4H), 0.50(m, 2H), 0.15(m, 2H) 379
((S)-4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.54(s, 1H), 7.40(m, 1H), pyrrolidin-1-yl]-6-propyl-N-[3-
7.33(m, 1H), 7.18(m, 2H), 5.71(s, 1H), 4.10-3.00(m, 5H),
(trifluoromethyl)phenyl] 2.53(m, 2H), 2.46(t, 2H), 2.21(m, 1H),
1.88(br, 1H), pyrimidin-2-amine 1.72(m, 3H), 0.97(t, 4H), 0.50(m,
2H), 0.15(m, 2H) 380 (S)-N-(5-chloro-2- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 8.64(s, 1H), 7.03(d, 1H), methylphenyl)-4-[3-
6.86(d, 1H), 6.70(brs, 1H), 5.71(s, 1H), 3.84-3.15(m,
(cyclopropylmethylamino) 5H), 2.55(m, 2H), 2.47(t, 2H), 2.27(s,
3H), 2.23(m, 1H), pyrrolidin-1-yl]-6- 1.87(br, 1H), 1.71(m, 3H),
0.98(m, 4H), 0.50(m, 2H), propylpyrimidin-2-amine 0.15(m, 2H) 381
(S)-N-(3-chloro-4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.03(s,
1H), 7.27(br, 1H), methylphenyl)-4-[3- 7.18(m, 1H), 7.09(m, 1H),
5.68(s, 1H), 4.00-3.15(m, 5H), (cyclopropylmethylamino) 2.55(m,2H),
2.47(m, 2H), 2.31(s, 3H), 2.23(m, 1H), pyrrolidin-1-yl]-6- 1.91(br,
1H), 1.68(m, 3H), 0.98(m, 4H), 0.52(m, 2H), propylpyrimidin-2-amine
0.15(m, 2H) 382 (S)-4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.48(brs, 1H), 7.39(brs, 1H),
pyrrolidin-1-yl]-N-[4-fluoro-3- 7.06(m, 2H), 5.71(s, 1H),
4.00-3.00(m, 5H), 2.53(m, 2H), (trifluoromethyl)phenyl]-6- 2.46(m,
2H), 2.21(m, 1H), 1.88(m, 1H), 1.72(m, 3H), propylpyrimidin-2-amine
0.97(m, 4H), 0.52(m, 2H), 0.14(m, 2H) 383 (S)-N.sup.1-{4-[3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.16(s, 1H), 6.96(m, 2H),
(cyclopropylmethylamino) 5.64(s, 1H), 3.71-3.31(m, 7H), 2.54(dd,
2H), 2.46(m, pyrrolidin-1-yl]-6- 2H), 2.19(m, 1H), 2.12(s, 3H),
1.87(br, 1H), 1.71(m, 3H), propylpyrimidin-2-yl}-4- 0.98(t, 4H),
0.51(m, 2H), 0.14(m, 2H) methylbenzene-1,3-diamine 384
(S)-N.sup.1-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 7.17(s,
1H), 7.09-6.99(m, (cyclopropylmethylamino) 2H), 6.32(d, 1H),
5.66(s, 1H), 3.59-3.41(m, 7H), 2.53(m, pyrrolidin-1-yl]-6- 2H),
2.32(m, 2H), 2.20(m, 1H), 1.87(br, 1H), 1.68(m, propylpyrimidin-2-
3H), 0.96(m, 4H), 0.51(m, 2H), 0.14(m, 2H) yl}benzene-1,3-diamine
385 (S)-5-{4-[3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.16(br,
1H), 7.85(br, 1H), (cyclopropylmethylamino) 7.42(t, 1H), 6.31(s,
1H), 4.12-3.74(m, 5H), 3.05(m, 2H), pyrrolidin-1-yl]-6- 2.69(t,
2H), 2.58(br, 1H), 2.35(br, 1H), 1.80(m, 2H),
propylpyrimidin-2-ylamino}- 1.14(m, 1H), 1.05(t, 3H), 0.75(m, 2H),
0.48(m, 2H) 2-fluorobenzonitrile dihydrochloride
TABLE-US-00040 TABLE 1-40 Example Compound NMR Spectrum 386
(S)-4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.77(d, 1H), 7.60(m, 1H), pyrrolidin-1-yl]-N-(4-methyl-3-
7.46(d, 1H), 6.33(s, 1H), 4.24-3.93(m, 5H), 3.05(m, 2H),
nitrophenyl)-6-propylpyrimidin-2- 2.70(t, 2H), 2.63(m, 1H), 2.57(s,
3H), 2.37(br, 1H), amine dihydrochloride 1.79(m, 2H), 1.22(m, 1H),
1.18(t, 3H), 0.76(m, 2H), 0.46(m, 2H) 387
3-{4-[3-(cyclopropylmethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.16(d, 1 H), 7.85-7.78 pyrrolidin-1-yl]-6-propylpyrimidin-
(m, 1H), 7.59(m, 2H), 6.35(s, 1H), 4.19-3.73(m, 5H),
2-ylamino}benzonitrile 3.07-3.00(m, 2H), 2.67(t, 2H), 2.63-2.60(m,
2H), 1.79 dihydrochioride (m, 2H), 1.22(m, 1H), 1.16(t, 3H),
0.74(m, 2H), 0.48(m, 2H) 388 (S)-{1-[6-ethyl-2-(4- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 7.45(t, 2H), 7.18(t, 2H),
fluorophenylamino)pyrimidin- 6.28-6.11(m, 1H), 4.35-4.09(d, 1H),
3.70-3.45(m, 4H), 4-yl]pyrrolidin-2-yl}methanol 2.60(q, 2H),
2.10(m, 4H), 1.27(t, 3H) 389 (S)-N-{1-[6-ethyl-2-(4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.42(m, 2H), 7.19(t, 2H),
fluorophenylamino)pyrimidin- 6.14-6.10(m, 1H), 4.50(m, 1H),
3.86-3.40(m, 4H), 4-yl]pyrrolidin-3-yl} 2.60(m, 2H), 2.31(m, 1H),
2.10(m, 1H), 1.95(s, 3H), acetamide 1.27(t, 3H) 390
(S)-4-ethyl-N-(4-fluorophenyl)- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 7.43(m, 2H), 7.19(t, 2H), 6-(2-methoxymethylpyrrolidin-
6.28-6.11(m, 1H), 4.44-4.21(d, 1H), 3.59-3.54(m, 4H),
1-yl)pyrimidin-2-amine 3.24(d, 3H), 2.61(q, 2H), 2.04(m, 4H),
1.26(t, 3H) 391 4-ethyl-N-(4-fluorophenyl)- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.43(t, 2H), 7.16(t, 2H),
6-(2-methylpyrrolidin-1-yl) 6.13-6.07(m, 1 H), 4.37-4.18(d, 1H),
3.69-3.44(m, 2H), pyrimidin-2-amine 3.35(s, 3H), 2.63(q, 2H),
2.14(m, 3H), 1.82(m, 1H), 1.27(t, 3H) 392
(S)-4-ethyl-6-[3-(ethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 7.45(m, 2H), 7.19(m, 2H),
pyrrolidin-1-yl]-N-(4-fluorophenyl) 6.14(s, 1H), 3.87-3.58(m, 5H),
2.84(m, 2H), 2.63(m, 2H), pyrimidin-2-amine 2.36(m, 1 H), 2.06(m, 1
H), 1.27-1 .22(m, 6H) 393 (S)-3-[4-(3-phenoxypyrrolidin-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.40(s, 1H), 7.58(m, 1H),
1-yl)-6-propylpyrimidin-2- 7.38(brs, 1H), 7.20(m, 3H), 7.20(d, 1H),
7.00(t, 1H), ylamino]benzonitrile 6.90(m, 2H), 5.77(s, 1H), 5.08(s,
1H), 3.77(m, 4H), 2.51(t, 2H), 2.40(m, 1H), 2.27(m, 1H), 1.73(q,
2H), 0.98(t, 3H) 394 (S)-N-{1-[2-(3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.80(s, 1H), 8.77(t, 1H), cyanophenylamino)-6-
8.58(d, 1H), 8.17(d, 1H), 8.07(m, 1H), 7.82-7.75(m, 1H),
propylpyrimidin-4-yl] 7.59-7.51(m, 2H), 6.32(d, 1H), 4.58-4.50(m,
1H), 3.99(m, pyrrolidin-3-yl}-2-(pyridin-3-yl) 1H), 3.82(m, 3H),
3.78-3.56(m, 3H), 2.66(m, 2H), acetamide dihydrochioride 2.39(m,
1H), 2.14(m, 1H), 1.80(m, 2H), 1.06(t, 3H)
TABLE-US-00041 TABLE 1-41 Example Compound NMR Spectrum 395
(S)-2-amino-N-{1-[2-(3- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.33(s, 1H), 7.61(m, 2H), cyanophenylamino)-6- 7.34(t, 1H), 7.20(d,
1H), 5.75(s, 1H), 4.63(m, 1H), propylpyrimidin-4- 3.81(m, 3H),
3.38(s, 4H), 2.51(t, 2H), 2.33(m, 1H), yl]pyrrolidin-3-yl}acetamide
2.05(m, 1H), 1.71(m, 2H), 0.98(t, 3H) 396 (S)-3-(4-{3-[4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.38(s, 1H), 7.77(d, 1H),
(dimethylamino)benzylamino] 7.45(t, 1H), 7.34(m, 3H), 6.81(d, 2H),
6.06(s, 1H), pyrrolidin-1-yl}-6- 4.21(s, 2H), 4.04(m, 2H),
3.81-3.64(m, 3H), 2.96(s, 6H), propylpyrimidin-2-ylamino) 2.56(t,
3H), 2.31(m, 1H), 1.77(q, 2H), 1.00(t, 3H) benzonitrile
dihydrochloride 397 (S)-2-fluoro-5-{4-[2- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.08-8.01(d, 1H), 7.86
(hydroxymethyl)pyrrolidin-1- (m, 1H), 7.41(m, 1H), 6.41-6.23(d,
1H), 4.34-4.18 yl]-6-propylpyrimidin-2- (d, 1H), 3.71-3.55(m, 4H),
2.63(t, 2H), 2.11(m, 4H), ylamino}benzonitrile 1.77(m, 2H), 1.05(t,
3H) hydrochloride 398 (S)-{1-[2-(4-amino-3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.58-8.38(d, 1H), 7.41 nitrophenylamino)-6- (m,
1H), 7.03(m, 1H), 6.34-7.17(d, 1H), 4.40-4.17 propylpyrimidin-4-yl]
(d, 1H), 3.88-3.62(m, 4H), 2.61(t, 2H), 2.25-2.01(m,
pyrrolidin-2-yl}methanol 4H), 1.76(m, 2H), 1.04(t, 3H)
hydrochloride 399 (S)-{1-[2-(3-amino-4- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 7.32(s, 1H), 6.92(d, 1H), methylphenylamino)-6-
6.78(brs, NH), 6.67(d, 1H), 5.69(s, 1H), 4.41(brs, 1H),
propylpyrimidin-4-yl] 3.80(m, 1H), 3.70(brs, 1H), 3.59(m, 1H),
3.46(m, 1H), pyrrolidin-2-yl}methanol 3.30(m, 1H), 2.44(t, 2H),
2.11(s, 3H), 2.02(m, 3H), 1.85(m, 1H), 1.71(m, 2H), 0.98(t, 3H) 400
(S)-{1-[2-(3-amino-4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
7.43(d, 1H), 6.86(m, 2H), fluorophenylamino)-6- 6.63(brs, 1H),
5.70(s, 1H), 4.38(s, 1H), 3.86(s, 1H), propylpyrimidin-4-yl]
3.76(m, 1H), 3.58(m, 1H), 3.45(m, 1H), 3.29(brs, 1H),
pyrrolidin-2-yl}methanol 2.45(t, 3H), 2.01(m, 3H), 1.85(m, 1H),
1.70(m, 2H), 0.97(t, 3H) 401 (S)-{1-[2-(3-amino-4- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 7.52(s, 1H), 7.00(d, 1H),
chlorophenylamino)-6- 6.68(m, 1H), 5.73(s, 1H), 4.43(m, 1H),
4.22(m, 1H), propylpyrimidin-4-yl] 3.82(m, 1H), 3.62(m, 1H),
3.49(m, 1H), 3.34(m, 1H), pyrrolidin-2-yl}methanol 2.49(t, 2H),
2.05(m, 2H), 1.63(m, 4H), 0.98(t, 3H) 402
(S)-3-(4-{2-formylpyrrolidin- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 9.61(s, 1H), 8.12(s, 1H), 1-yl)-6-propylpyrimidin-2-
7.57(d, 1H), 7.34(t, 1H), 7.24(t, 1H), 7.13(s, 1H), 5.84(s,
ylamino]benzonitrile 1H), 4.54(s, 1H), 3.62-3.52(m, 2H), 2.53(t,
2H), 2.22(s, 403 (S)-3-(4-{2-[(methylamino) 1H), 2.09(m, 3H),
1.73(m, 2H), 0.99(t, 3H) methyl]pyrrolidin-1-yl}-6- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.32(s, 1H), 7.83(d, 1H), propylpyrimidin-
7.41(t, 1H), 7.22(d, 1H), 5.94(s, 1H), 4.30(brs, 1H),
2-ylamino)benzonitrile 3.56-3.38(m, 2H), 2.86(s, 1H), 2.62(m, 1H),
2.48(t, 2H), 2.40(s, 3H), 2.04(m, 4H), 1.74(m, 2H), 0.99(t, 3H)
TABLE-US-00042 TABLE 1-42 Example Compound NMR Spectrum 404
(S)-3-(4-{2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.75(s, 1H),
8.45(s, 1H), [(cyclobutylamino)methyl] 7.87(s, 1H), 7.31(m, 1H),
7.19(d, 1H), 5.80(s, 1H), pyrrolidin-1-yl}-6- 4.52(s, 1H),
3.45-3.31(m, 2H), 2.92-2.81(m, 2H), 2.53(m, propylpyrimidin-2- 2H),
2.23-2.01(m, 7H), 1.75(m, 4H), 0.88(t, 3H) ylamino)benzonitrile 405
(S)-3-(4-{2-[(4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.37(s,
1H), 7.64(s, 1H), fluorobenzylamino)methyl] 7.33-7.19(m, 4H),
6.94(m, 2H), 5.75(s, 1H), 4.44(s, 1H), pyrrolidin-1-yl}-6- 3.85(s,
2H), 3.45-3.31(m, 2H), 2.87-2.76(m, 2H), 2.48(m, propylpyrimidin-2-
2H), 2.02(m, 4H), 1.71(m, 2H), 0.98(t, 3H) ylamino)benzonitrile 406
(S)-3-(4-propyl-6-{2- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
9.44(s, 1H), 8.56(s, 1H), [(propylamino)methyl] 7.99(m, 1H),
7.30(m, 1H), 7.18(d, 1H), 5.80(s, 1H), pyrrolidin-1-yl}pyrimidin-2-
4.69(s, 1H), 3.48-3.32(m, 3H), 3.02(m, 1H), 2.82(m, 2H),
ylamino)benzonitrile 2.54(t, 2H), 2.16(m, 1H), 1.98(m, 2H),
1.88-1.75(m, 5H), 0.98(t, 3H), 0.89(t, 3H) 407 (S)-3-(4-{2-[(2-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 9.11(s, 1H), 8.48(s, 1H),
hydroxyethylamino)methyl] 7.89(d, 1H), 7.31(m, 1H), 7.17(d, 1H),
5.78(s, 1H), pyrrolidin-1-yl}-6- 4.30(m, 1H), 4.10(m, 1H), 3.92(m,
1H), 3.45(m, 1H), propylpyrimidin-2- 3.37(m, 2H), 3.14-3.04(m, 2H),
2.92(m, 1H), 2.55(t, 2H), ylamino)benzonitrile 2.23(m, 1H), 1.97(m,
2H), 1.80-1.75(m, 3H), 1.01(t, 3H) 408 N{1-[2-(3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.14-8.02(d, 1H), 7.85(m,
cyanophenylamino)-6- 1H), 7.58-7.52(m, 2H), 6.29(d, 1H), 4.52(m,
1H), 3.95- propylpyrimidin-4-yl] 3.48(m, 4H), 2.66(m, 2H), 2.33(m,
1H), 2.10(m, 1H), pyrrolidin-3-yl}acetamide 1.95(s, 3H), 1.77(m,
2H), 1.05(m, 3H) hydrochloride 409 N-{1-[2-(3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.97(d, 1H), 8.03(m, 1H), nitrophenylamino)-6-
7.79(m, 1H), 7.60(m, 1H), 6.27(m, 1H), 4.53(m, 1H),
propylpyrimidin-4-yl] 3.99-3.48(m, 4H), 2.66(m, 2H), 2.33(m, 1H),
2.10(m, pyrrolidin-3-yl}acetamide 1H), 1.96(s, 3H), 1.78(m, 2H),
1.06(m, 3H) hydrochloride 410 N-{1-[2-(4-chloro-3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.64-8.52(d, 1H), 7.71-
nitrophenylamino)-6- 7.66(m, 2H), 6.32(d, 1H), 4.52(m, 1H),
4.10-3.62(m, 4H), propylpyrimidin-4-yl] 2.69(m, 2H), 2.34(m, 1H),
2.13(m, 1H), 1.99(s, 3H), pyrrolidin-3-yl}acetamide 1.77(m, 2H),
1.04(m, 3H) hydrochloride 411 (R)-N.sup.1-[4-(2- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.56(s, 1H), 7.41(m, 1H),
methylpyrrolidin-1-yl)-6- 6.99(d, 1H), 6.21(m, 1H), 4.52-4.23(m,
2H), 3.81-3.48(m, propylpyrimidin-2-yl]-3- 2H), 2.63(t, 2H),
2.15(m, 3H), 1.74(m, 2H), 1.25(m, 3H), nitrobenzene-1,4-diamine
1.03(t, 3H) hydrochloride 412 (R)-N.sup.1-[4-(2- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.15-8.10(m, 1H), 7.66-
methylpyrrolidin-1-yl)-6- 7.65(m, 1H), 7.30-7.25(m, 1H),
6.29-6.17(d, 1H), 4.45- propylpyrimidin-2-yl]-3- 4.24(m, 1H),
3.78-3.47(m, 2H), 2.63(m, 2H), 2.21- (trifluoromethyl)benzene-
2.07(m 3H), 1.78(m, 3H), 1.27(m, 3H), 1.05(t, 3H) 1,4-diamine
hydrochloride 413 (S)-5-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.12-8.03(d, 1H), 7.65(m, (cyclopropylmethylamino) 1H),
7.44(d, 1H), 6.32(s, 1H), 4.14(m, 2H), 3.94-3.75(m,
pyrrolidin-1-yl]-6- 3H), 3.06-3.00(m, 2H), 2.68(t, 2H), 2.61(m,
1H), 2.52(s, propylpyrimidin-2- 3H), 2.38-2.36(m, 1H), 1.82-1.76(m,
2H), 1.15(m, 1H), ylamino}-2- 1.05(t, 3H), 0.74(m, 2H), 0.48(m, 2H)
methylbenzonitrile dihydrochloride
TABLE-US-00043 TABLE 1-43 Example Compound NMR Spectrum 414
(S)-2-methyl-5-{4-propyl-6- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.37(d, 1 H), 7.64(d, 1 H), [3-(propylamino)pyrrolidin-
7.26(d, 1H), 5.87(d, 1H), 4.00-3.30(m, 5H), 2.90-2.60(m,
1-yl]pyrimidin-2- 2H), 2.48(t, 2H), 2.44(s, 3H), 2.40-2.25(m, 1H),
2.05- ylamino}benzonitrile 1.90(m, 1H), 1.80-1.50(m, 4H),
1.00-0.90(m, 6H) 415 (S)-2-methyl-5-(4-{3-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.36(s, 1H), 7.66(d, 1H),
(methylthio)propylamino] 7.26(d, 1H), 5.87(s, 1H), 3.90-3.30(m,
5H), 2.81(t, 2H), pyrrolidin-1-yl}-6- 2.57(t, 2H), 2.48(t, 2H),
2.45(s, 3H), 2.30-2.20(m, 1H), propylpyrimidin-2- 2.09(s, 3H),
2.00-1.90(m, 1H), 1.84(t, 2H), 1.75(q, 2H), ylamino)benzonitrile
0.98(t, 3H) 416 (S)-5-(4-{3-[(1H-pyrrol-2- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.35(s, 1H), 7.66(dd, 1H),
yl)methylamino]pyrrolidin-1- 7.26(d, 1H), 6.69(s, 1H), 6.10-6.00(m,
2H), 5.84(s, 1H), yl}-6-propylpyrimidin-2- 3.86(s, 2H),
3.80-3.30(m, 5H), 2.47(t, 2H), 2.45(s, 3H), ylamino)-2-
2.25-2.15(m, 1H), 2.00-1.90(m, 1H), 1.72(q, 2H), 0.98(t,
methylbenzonitrile 3H) 417 (S)-5-{4-[3-(4- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.36(s, 1H), 7.65(d, 1H), hydroxybenzylamino)
7.30-7.20(m, 3H), 6.77(d, 1H), 5.85(s, 1H), 3.82(s, 2H),
pyrrolidin-1-yl]-6- 3.80-3.30(m, 5H), 2.48(t, 2H), 2.44(s, 3H),
2.30-2.20(m, propylpyrimidin-2-ylamino}- 1H), 2.00-1.90(m, 1H),
1.72(q, 2H), 0.98(t, 3H) 2-methylbenzonitrile 418 (S)-5-{4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.35(s, 1H), 7.66(d, 1H),
(isopropylamino)pyrrolidin- 7.25(d, 1H), 5.86(s, 1H), 4.00-3.35(m,
5H), 3.01(t, 1H), 1-yl]-6-propylpyrimidin-2- 2.47(t, 2H), 2.44(s,
3H), 2.35-2.25(m, 1H), 1.90-1.85(m, ylamino}-2- 1H), 1.73(q, 2H),
1.20-1.10(m, 6H), 0.98(t, 3H) methylbenzonitrile 419 (S)-5-{4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.33(s, 1H), 7.67(d, 1H),
(cyclobutylamino)pyrrolidin- 7.25(d, 1H), 5.84(s, 1H), 3.90-3.30(m,
6H), 2.47(t, 2H), 1-yl]-6-propylpyrimidin-2- 2.44(s, 3H),
2.30-2.15(m, 3H), 2.00-1.60(m, 7H), 0.98(t, ylamino}-2- 3H)
methylbenzonitrile 420 (S)-5-{4-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.36(s, 1H), 7.64(d, 1H),
(cyclopentylamino)pyrrolidin- 7.25(d, 1H), 5.85(s, 1H),
4.00-3.35(m, 5H), 3.21(t, 1H), 1-yl]-6-propylpyrimidin-2- 2.47(t,
2H), 2.44(s, 3H), 2.35-2.25(m, 1H), 2.05-1.80(m, ylamino}-2- 3H),
1.80-1.50(m, 6H), 1.40-1.30(m, 2H), 0.99(t, 3H) methylbenzonitrile
421 (S)-5-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.35(s,
1H), 7.63(d, 1H), (cyclohexylamino)pyrrolidin- 7.23(d, 1H), 5.83(s,
1H), 4.00-3.10(m, 5H), 2.60(t, 1H), 1-yl]-6-propylpyrimidin-2-
2.46(t, 2H), 2.43(s, 3H), 2.30-2.20(m, 1H), 2.00-1.60(m,
ylamino}-2- 7H), 1.45-1.05(m, 6H), 0.98(t, 3H) methylbenzonitrile
422 (S)-2-methyl-5-{4-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.20-8.00(m, 1H), 7.70- (pentylamino)pyrrolidin-1- 7.61(m, 1H),
7.45(d, 1H), 6.32(s, 1H), 4.20-3.60(m, 5H),
yl]-6-propylpyrimidin-2- 3.20-3.00(m, 2H), 2.68(t, 2H),
2.65-2.55(m, 1H), 2.52(s, ylamino}benzonitrile 3H), 2.40-2.25(m,
1H), 1.90-1.70(m, 4H), 1.50-1.30(m, dihydrochloride 4H), 1.05(t,
3H), 1.00-0.90(m, 3H) 423 (S)-2-methyl-5-{4-[3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.08(d, 1H), 7.75-7.55(m,
(neopentylamino)pyrrolidin- 1H), 7.50-7.40(m, 1H), 6.32(s, 1H),
4.30-3.60(m, 5H), 1-yl]-6-propylpyrimidin-2- 3.10-2.90(m, 2H),
2.80-2.60(m, 3H), 2.52(s, 3H), 2.50- ylamino}benzonitrile 2.30(m,
1H), 1.80(q, 2H), 1.12(s, 9H), 1.05(t, 3H) dihydrochloride
TABLE-US-00044 TABLE 1-44 Example Compound NMR Spectrum 424
(S)-5-(4-{3-[(4,5- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.10-8.00(m, 1H), 7.73(d, dimethylfuran-2-yl) 1H), 7.45(d, 1H),
6.48(s, 1H), 6.31(s, 1H), 4.40-4.20(m, methylamino]pyrrolidin-1-
2H), 4.20-3.60(m, 5H), 2.68(t, 2H), 2.60-2.50(m, 1 H),
yl}-6-propylpyrimidin-2- 2.52(s, 3H), 2.40-2.30(m, 1H),
2.25-2.15(m, 3H), 1.93(s, ylamino)-2- 3H), 1.80(q, 2H), 1.05(t, 3H)
methylbenzonitrile dihydrochloride 425 (S)-N-{1-[2-(3-cyano-4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.24(brs, 1H), 7.71(d,
1H), methylphenylamino)-6- 7.27(d, 1H), 5.89(s, 1H), 4.47(t, 1H),
3.90-3.30(m, 4H), propylpyrimidin-4-yl] 2.49(t, 2H), 2.44(s, 3H),
2.30-2.15(m, 3H), 2.10-2.00(m, pyrrolidin-3-yl} 1H), 1.73(q, 2H),
1.12(t, 3H), 0.98(t, 3H) propionamide 426 (S)-N-{1-[2-(3-cyano-4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.97(brs, 1H), 7.72(d,
1H), methylphenylamino)-6- 7.35-7.15(m, 6H), 5.92(s, 1H),
4.50-4.40(m, 1H), 3.90- propylpyrimidin-4-yl] 3.40(m, 6H), 2.50(t,
2H), 2.46(s, 3H), 2.30-2.20(m, 1H), pyrrolidin-3-yl}-2-
2.10-2.00(m, 1H), 1.73(q, 2H), 0.99(t, 3H) phenylacetamide 427
(S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.28(s, 1H), 7.69(dd, 1H), methylphenylamino)-6- 7.25(d, 1H),
5.88(s, 1H), 4.51(t, 1H), 3.90-3.35(m, 4H), propylpyrimidin-4-yl]
3.09(s, 2H), 2.60-2.45(m, 6H), 2.44(s, 3H), 2.35-2.25(m,
pyrrolidin-3-yl}-2- 1H), 2.10-2.00(m, 1H), 1.80-1.65(m, 2H),
1.60-1.50(m, (piperidin-1-yl)acetamide 4H), 1.50-1.40(m, 2H),
0.98(t, 3H) 428 (S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.84(s, 1H), 8.80-8.70(m, methylphenylamino)-6-
1H), 8.56(d, 1H), 8.10-8.00(m, 2H), 7.70-7.60(m, 1H),
propylpyrimidin-4-yl] 7.43(t, 1H), 6.25(d, 1H), 4.55-4.45(m, 1H),
4.10-3.50(m, pyrrolidin-3-yl}-2- 6H), 2.70-2.60(m, 2H), 2.51(d,
3H), 2.40-2.25(m, 1H), (pyridin-3-yl)acetamide 2.20-2.05(m, 1H),
1.80-1.65(m, 2H), 1.10-1.00(m, 3H) 429 (S)-N-{1-[2-(3-cyano-4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.50-8.40(m, 2H), 8.29(s,
methylphenylamino)-6- 1H), 7.70(dd, 1H), 7.36(d, 2H), 7.26(d, 1H),
5.87(s, 1H), propylpyrimidin-4-yl] 4.48(t, 1H), 3.90-3.30(m, 6H),
2.50-2.40(m, 5H), 2.30- pyrrolidin-3-yl}-2- 2.20(m, 1H),
2.10-2.00(m, 1H), 1.73(q, 2H), 0.98(t, 3H) (pyridin-4-yl)acetamide
430 (S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.24(brs, 1H), 7.72(d, 1H), methylphenylamino)-6-
7.30-7.20(m, 2H), 7.00-6.90(m, 2H), 5.86(s, 1H), 4.47(t,
propylpyrimidin-4-yl] 1H), 3.90-3.30(m, 6H), 2.48(t, 2H), 2.44(s,
3H), 2.20(m, pyrrolidin-3-yl}-2- 1H), 2.10-2.00(m, 1H), 1.73(q,
2H), 0.98(t, 3H) (thiophen-2-yl)acetamide 431
(S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.29(s, 1H), 7.70(dd, 1H), methylphenylamino)-6- 5.88(s, 1H),
4.15(t, 1H), 3.90-3.30(m, 4H), 3.02(s, 3H), propylpyrimidin-4-yl]
2.49(t, 2H), 2.44(s, 3H), 2.35-2.25(m, 1H), 2.10-2.00(m,
pyrrolidin-3-yl} 1H), 1.73(q, 2H), 0.98(t, 3H) methanesulfonamide
432 (S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.02(d, 1H), 7.70(d, 1H), methylphenylamino)-6- 7.44(d,
1H), 6.26(s, 1H), 4.30-4.10(m, 1H), 4.00-3.40(m,
propylpyrimidin-4-yl] 4H), 3.03(s, 3H), 2.65(t, 2H), 2.52(s, 3H),
2.45-2.30(m, pyrrolidin-3-yl} 1H), 2.20-2.00(m, 1H), 1.77(q, 2H),
1.05(t, 3H) methanesulfonamide hydrochloride
TABLE-US-00045 TABLE 1-45 Example Compound NMR Spectrum 433
(S)-1-(1-{2-[(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.00(d, 1H), 7.80-7.60(m, methylphenyl)amino]-6- 1H), 7.44(d, 1H),
6.24(d, 1H), 4.45-4.30(m, 1H), 4.00- propylpyrimidin-4-yl} 3.30(m,
4H), 3.20-3.00(m, 2H), 2.70-2.60(m, 2H), 2.51(s,
pyrrolidin-3-yl)-3- 3H), 2.40-2.20(m, 1H), 2.15-2.00(m, 1H),
1.90-1.70(m, ethylurea hydrochloride 2H), 1.20-1.00(m, 6H) 434
(R)-3-(4-{3-[(diethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.40(s, 1H), 7.81(d, 1H), methyl]pyrrolidin-1-yl}-6-
7.39(t, 1H), 7.22(d, 1H), 5.87(s, 1H), 3.90-3.20(m, 4H),
propylpyrimidin-2-ylamino) 2.80-2.50(m, 6H), 2.48(t, 2H),
2.20-2.10(m, 1H), 1.80- benzonitrile 1.65(m, 3H), 1.10(t, 6H),
0.98(t, 3H) 435 (S)-5-{4-[3-(isopropylamino) .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.03(d, 1H), 7.64(brs, 1H), pyrrolidin-1-yl]-6-
7.45(d, 1H), 6.32(s, 1H), 4.20-3.74(m, 5H), 3.56-3.51(m,
propylpyrimidin-2-ylamino}- 1H), 2.67(dd, 2H), 2.60(brs, 1H),
2.36-2.31(m, 1H), 1.84- 2-methylbenzonitrile 1.74(m, 2H), 1.42(dd,
6H), 1.05(t, 3H) dihydrochloride 436 (S)-N-{1-[6-butyl-2-(4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.68-8.56(d, 1H), 7.60(t,
methyl-3-nitrophenylamino) 1H), 7.44(d, 1H), 6.24(d, 1H), 4.49(m,
1H), 4.00-3.48(m, pyrimidin-4-yl]-3-yl} 4H), 2.68(m, 2H), 2.56(s,
3H), 2.33(m, 1H), 2.11(m, 1H), acetamide hydrochloride 1.96(s, 3H),
1.73(m, 2H), 1.45(m, 2H), 0.98(t, 3H) 437 (S)-N-{1-[6-butyl-2-(4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.78-8.66(d, 1H), 7.79(m,
fluoro-3-nitrophenylamino) 1H), 7.47(t, 1H), 6.30-6.27(d, 1H),
4.52(m, 1H), 4.48- pyrimidin-4-yl]pyrrolidin- 3.48(m, 4H), 2.69(m,
2H), 2.36(m, 1H), 2.10(m, 1H), 3-yl}acetamide 1.95(s, 3H), 1.73(s,
3H), 1.45(m, 2H), 0.98(t, 3H) hydrochloride 438
(S)-N-{1-[6-butyl-2-(4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.65-8.54(d, 1H), 8.40- chloro-3-nitrophenylamino) 8.37(m, 1H),
7.72-7.65(m, 2H), 6.31-6.28(d, 1H), 4.51(m,
pyrimidin-4-yl]pyrrolidin-3-yl} 1H), 3.96-3.48(m, 4H), 2.69(m, 2H),
2.32(m, 1H), acetamide hydrochloride 2.13(m, 1H), 1.96(s, 3H),
1.72(m, 2H), 1.45(m, 2H), 1.00(t, 3H) 439 (S)-N-{1-[2-(3-amino-5-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.06-7.83(m, 2H), 7.36(d,
cyanophenylamino)-6- 1H), 6.33(d, 1H), 4.53-4.47(m, 1H),
4.00-3.49(m, 4H), butylpyrimidin-4-yl] 2.70(m, 2H), 2.40(m, 1H),
2.16(m, 1H), 1.97(s, 3H), pyrrolidin-3-yl}acetamide 1.73(m, 2H),
1.44(m, 2H), 1.02(t, 3H) hydrochloride 440 (S)-N-(1-{2-[3-amino-5-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.14-8.02(d, 1H), 7.30(d,
(trifluoromethyl)phenylamino]- 1H), 6.33(d, 1H), 4.53-4.47(m, 1H),
3.97-3.49(m, 4H), 6-butylpyrimidin-4-yl] 2.71(m, 2H), 2.31(m, 1H),
2.15(m, 1H), 1.96(s, 3H), pyrrolidin-3-yl)acetamide 1.74(m, 2H),
1.47(m, 2H), 0.99(t, 3H) hydrochloride 441 (S)-N-(1-{2-[4-amino-3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.74-7.65(d, 1H), 7.34(d,
(trifluoromethyl)phenylamino]- 1H), 6.86(d, 1H), 6.13(d, 1H),
4.49(m, 1H), 3.83-3.43(m, 6-butylpyrimidin-4-yl] 4H), 2.63(m, 2H),
2.30(m, 1H), 2.08(m, 1H), 1.94(s, 3H), pyrrolidin-3-yl)acetamide
1.69(m 2H), 1.45(m, 2H), 0.99(t, 3H) hydrochloride 442
(S)-N-(1-{6-butyl-2[4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.19-8.10(d, 1H), 7.76(m, fluoro-3-(trifluoromethyl) 1H), 7.38(t,
1H), 6.27(d, 1H), 4.51(m, 1H), 3.89-3.48(m,
phenylamino]pyrimidin-4-yl} 4H), 2.68(m, 2H), 2.31(m, 1H), 2.11(m,
1H), 1.95(s, 3H), pyrrolidin-3-yl) 1.72(m, 2H), 1.45(m, 2H),
1.00(t, 3H) acetamide hydrochloride
TABLE-US-00046 TABLE 1-46 Example Compound NMR Spectrum 443
(S)-N-{1-[6-butyl-2-(3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.09-7.99(d, 1H), 7.87(m, cyano-4-fluorophenylamino) 1H), 7.41(t,
1H), 6.24(d, 1H), 4.51-4.45(m, 1H), 3.89-
pyrimidin-4-yl]pyrrolidin-3- 3.48(m, 4H), 2.69(m, 2H), 2.28(m, 1H),
2.11(m, 1H), yl}acetamide hydrochloride 1.95(s, 3H), 1.72(m, 2H),
1.45(m, 2H), 1.00(t, 3H) 444 (S)-N-{1-[2-(3-amino-4-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.03(m, 1H), 6.98(t, 1H),
fluorophenylamino)-6- 6.74(m, 1H), 6.17(d, 1H), 4.50-4.44(m, 1H),
2.63(m, 2H), butylpyrimidin-4-yl] 2.33(m, 1H), 2.09(m, 1H), 1.95(s,
3H), 1.67(m, 2H), pyrrolidin-3-yl}acetamide 1.43(m, 2H), 0.99(t,
3H) hydrochloride 445 (S)-N-{1-[2-(3-amino-4- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.18(d, 1H), 7.07(s, 1H), chlorophenylamino)-6-
6.79(m, 1H), 6.16(d, 1H), 4.51-4.45(m, 1H), 3.93-3.47(m,
butylpyrimidin-4-yl] 4H), 2.64(m, 2H), 2.34(m, 1H), 2.10(m, 1H),
1.95(s, 3H), pyrrolidin-3-yl}acetamide 1.69(m, 2H), 1.45(m, 2H),
0.99(t, 3H) hydrochloride 446 (S)-N-{1-[2-(4-amino-3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.59(d, 1H), 7.40(s, 1H),
cyanophenylamino)-6- 6.84(m, 1H), 6.13(m, 1H), 4.49(m, 1H),
3.84-3.44(m, butylpyrimidin-4-yl] 4H), 2.63(m, 2H), 2.32(m, 1H),
2.25(m, 1H), 1.94(s, 3H), pyrrolidin-3-yl}acetamide 1.69(m, 2H),
1.44(m, 2H), 0.99(m, 3H) hydrochloride 447
(S)-2-amino-5-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 7.65(s, 1H), 7.42(t, 1H), (methylamino)pyrrolidin-1-
6.94(d, 1H), 6.25(d, 1H), 4.04-3.73(m, 5H), 2.78(d, 3H),
yl]pyrimidin-2-ylamino} 2.59(t, 2H), 2.49(m, 1H), 2.36(m, 1H),
1.71(m, 2H), benzonitrile 1.45(m, 2H), 1.00(t, 3H) dihydrochloride
448 (S)-4-butyl-N-(4-methyl-3- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.81-8.79(m, 1H), 7.56(m, nitrophenyl)-6-[3- 1H), 7.46(m,
1H), 6.33(s, 1H), 4.19-3.81(m, 5H), 2.84(s,
(methylamino)pyrrolidin-1- 3H), 2.71(t, 2H), 2.57(s, 3H + 1H),
2.34(m, 1H), 1.75(m, yl]pyrimidin-2-amine 2H), 1.46(m, 2H), 1.01(t,
3H) dihydrochloride 449 (S)-4-butyl-N-(4-fluoro-3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.88(m, 1H), 7.72(m,1H),
nitrophenyl)-6-[3- 7.48(m, 1H), 6.36(s, 1H), 4.16-3.78(m, 5H),
2.83(s, 3H), (methylamino)pyrrolidin-1- 2.70(m, 2H), 2.59(m, 1H),
2.33(m, 1H), 1.75(m, 2H), yl]pyrimidin-2-amine 1.46(m, 2H), 1.01(m,
3H) dihydrochloride 450 (S)-4-butyl-N-(4-chloro-3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 8.73-8.63(m, 1H), 7.68(m,
nitrophenyl)-6-[3- 2H), 6.38(s, 1H), 4.19-3.74(m, 5H), 2.84(s, 3H),
2.75(m, (methylamino)pyrrolidin-1- 2H), 2.60(m, 1H), 2.36(m, 1H),
1.73(m, 2H), 1.46(m, yl]pyrimidin-2-amine 2H), 1.01(m, 3H)
dihydrochloride 451 (S)-3-amino-5-{4-butyl-6-[3- .sup.1H-NMR(400
MHz, CD.sub.3OD) .delta. 7.77-7.74(d, 1H), 7.58(s,
(methylamino)pyrrolidin-1- 1H), 7.16(s, 1H), 6.35(s, 1H),
4.09-3.77(m, 5H), 2.83(d, yl]pyrimidin-2-ylamino} 3H), 2.72(t, 2H),
2.41(m, 1H), 2.36(m, 1H), 1.74(m, 2H), benzonitrile 1.02(m, 2H),
0.99(t, 3H) dihydrochloride 452 (S)-N.sup.1-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.89-7.78(d, 1H), 7.54(m,
(methylamino)pyrrolidin-1- 1H), 7.17(m, 1H), 6.36(s, 1H),
4.14-3.79(m, 5H), 2.83(d, yl]pyrimidin-2-yl}-5- 3H), 2.65(t, 2H),
2.54(m, 1H), 2.37(m, 1H), 1.75(m, 2H), (trifluoromethyl)benzene-
1.46(m, 2H), 0.99(t, 3H) 1,3-diamine dihydrochloride
TABLE-US-00047 TABLE 1-47 Example Compound NMR Spectrum 453
(S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.77(d, 1H), 7.47(m, 1H), (methylamino)pyrrolidin-1- 7.02(t, 1H),
6.27(d, 1H), 4.04-3.75(m, 5H), 2.81(d, 3H), yl]pyrimidin-2-yl}-3-
2.58(t, 2H), 2.38(m, 1H), 2.35(m, 1H), 1.70(m, 2H),
(trifluoromethyl)benzene- 1.45(m 2H), 0.98(t, 3H) 1,4-diamine
dihydrochloride 454 (S)-4-butyl-N-[4-fluoro-3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.13(s, 1H), 7.79(m, 1H),
(trifluoromethyl)phenyl]-6- 7.40(t, 1H), 6.33(s, 1H), 5.06-3.79(m,
5H), 2.78(s, 3H), [3-(methylamino)pyrrolidin- 2.69(t, 2H), 2.34(m,
1H), 2.27(m, 1H), 1.74(m, 2H), 1-yl]pyrimidin-2-amine 1.46(m, 2H),
1.00(t, 3H) dihydrochloride 455 (S)-5-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.12(s, 1H), 7.83(m, 1H),
(methylamino)pyrrolidin-1- 7.42(t , 1H), 4.04-3.82(m, 5H), 2.81(s,
3H), 2.68(t, 2H), yl]pyrimidin-2-ylamino}-2- 2.35(m, 1H), 2.32(m,
1H), 1.73(m, 2H), 1.46(m, 2H), fluorobenzonitrile 1.00(t, 3H)
dihydrochloride 456 (S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.49(s, 1H), 7.34(m, 2H),
(methylamino)pyrrolidin-1- 6.29(d, 1H), 4.11-3.76(m, 5H), 2.82(d,
3H), 2.69(t, 2H), yl]pyrimidin-2-yl}-4- 2.60(m, 1H), 2.38(m, 1H),
1.73(m, 2H), 1.45(m, 2H), fluorobenzene-1,3-diamine 0.98(t, 3H)
dihydrochloride 457 (S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.67(m, 1H), 7.50(m, 1H),
(methylamino)pyrrolidin-1- 7.38(m, 1H), 6.33(d, 1H), 4.16-3.77(m,
5H), 2.81(d, 3H), yl]pyrimidin-2-yl}-4- 2.69(t, 2H), 2.52(m, 1H),
2.31(m, 1H), 1.74(m, 2H), chlorobenzene-1,3-diamine 1.48(m, 2H),
1.00(t, 3H) dihydrochloride 458 (S)-2-amino-5-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.66(d, 1H), 7.40(m, 1H),
(ethylamino)pyrrolidin-1- 6.91(d, 1H), 6.24(s, 1H), 4.06-3.70(m,
5H), 3.14(m, 2H), yl]pyrimidin-2- 2.69(m, 2H), 2.59-2.56(m, 1H),
2.36(m, 1H), 1.69(m, ylamino}benzonitrile 2H), 1.48(m, 2H), 1.37(t,
3H), 0.98(t, 3H) dihydrochloride 459 (S)-3-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.19-8.13(m, 1H), 7.80(m,
(ethylamino)pyrrolidin-1- 1H), 7.56(m, 2H), 6.35(s, 1H),
4.07-3.77(m, 5H), 3.19(m, yl]pyrimidin-2- 2H), 2.73(t, 2H), 2.60(m,
1H), 2.36(m, 1H), 1.75(m, 2H), ylamino}benzonitrile 1.48(m, 2H),
1.37(m, 3H), 0.99(t, 3H) dihydrochloride 460 (S)-5-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, DMSO-d.sub.6) .delta. 13.30(brs, 1H),
10.6(brs, (ethylamino)pyrrolidin-1- 1H), 9.53-9.36(m, 2H), 8.09(m,
1H), 7.76(m, 1H), yl]pyrimidin-2-ylamino}-2- 7.48(m, 1H), 6.34(s,
1H), 3.94(m, 7H), 3.04(m, 2H), methylbenzonitrile 2.62(m, 3H),
2.38(m, 2H), 1.70(m, 2H), 1.35(m, 2H), dihydrochloride 0.95(m, 3H),
0.91(m, 3H) 461 (S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 8.76-8.60(m, 1H), 7.38(m,
(ethylamino)pyrrolidin-1- 1H), 7.02(m, 1H), 6.28(s, 1H),
4.20-3.73(m, 5H), 3.21(m, yl]pyrimidin-2-yl}-3- 2H), 2.62(m, 2H),
2.60(m, 1H), 2.25(m, 1H), 1.47(m, nitrobenzene-1,4-diamine 2H),
1.40(m, 2H), 1.36(m, 3H), 1.00(m, 3H) dihydrochloride 462
(S)-4-butyl-6-[3- .sup.1H-NMR(400 MHz, DMSO-d.sub.6) .delta.
13.19(brs, 1H), (ethylamino)pyrrolidin- 10.79(brs, 1H),
9.52-9.38(m, 2H), 8.68(s, 1H), 7.67(s, 1-yl]-N-(4-methyl-3- 1H),
7.51(m, 1H), 6.35(s, 1H), 3.99-3.63(m, 5H), 3.05(m,
nitrophenyl)pyrimidin-2- 2H), 2.65(m, 2H), 2.39(m, 2H), 1.71(m,
2H), 1.36(m, amine dihydrochloride 2H), 1.27(m, 3H), 0.94(m,
3H)
TABLE-US-00048 TABLE 1-48 Example Compound NMR Spectrum 463
(S)-4-butyl-6-[3- .sup.1H-NMR(400 MHz, DMSO-d.sub.6) .delta.
13.00(brs, 1 H), (ethylamino)pyrrolidin-1-yl]- 10.77(brs, 1H),
9.34(m, 2H), 8.82(s, 1H), 7.83(s, 1H), N-(4-fluoro-3- 7.62(m, 1H),
6.35(s, 1H), 3.93(m, 5H), 3.05(m, 2H), nitrophenyl)pyrimidin-2-
2.65(m, 2H), 2.34(m, 2H), 1.71(m, 2H), 1.37(m, 2H), amine
dihydrochloride 1.25(m, 3H), 0.94(m, 3H) 464
(S)-4-butyl-N-(4-chloro-3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.74-8.64(m, 1H), 7.68(m, nitrophenyl)-6-[3- 2H), 6.38(s, 1H),
4.18-3.77(m, 5H), 3.22(m, 2H), 2.73(m, (ethylamino)pyrrolidin-1-
2H), 2.61(m, 1H), 2.35(m, 1H), 1.75(m, 2H), 1.40(m,
yl]pyrimidin-2-amine 2H), 1.39(m, 3H), 1.00(m, 3H) dihydrochloride
465 (S)-3-amino-5-{4-buty1-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.17-7.87(m, 2H), 7.39(s, (ethylamino)pyrrolidin-1- 1H),
6.38(d, 1H), 4.21-3.78(m, 5H), 3.19(m, 2H), 2.75(m, yl]pyrimidin-2-
2H), 2.59(m, 1H), 1.34(m, 1H), 1.76(m, 2H), 1.40(m,
ylamino}benzonitrile 2H), 1.39(m, 3H), 1.01(m, 3H) dihydrochloride
466 (S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 8.18-8.03(m, 1H), 7.98- (ethylamino)pyrrolidin-1- 7.88(m,
1H), 7.40(m, 1H), 6.40(m, 1H), 4.20-3.78(m, yl]pyrimidin-2-yl}-5-
5H), 3.20(m, 2H), 2.71(m, 2H), 2.62(m, 1H), 2.31(m,
(trifluoromethyl)benzene- 1H), 1.75(m, 2H), 1.46(m, 2H), 1.37(m,
3H), 0.99(m, 3H) 1,3-diamine dihydrochloride 467
(S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.01-7.89(m, 1H), 7.59(m, (ethylamino)pyrrolidin-1- 1H), 7.20(t,
1H), 6.28(d, 1H), 4.08-3.75(m, 5H), 3.21- yl]pyrimidin-2-yl}-3-
3.11(m, 2H), 2.69(m, 2H), 2.58-2.52(m, 1H), 2.38-
(trifluoromethyl)benzene- 2.27(m, 1H), 1.73(m, 2H), 1.45(m, 2H),
1.37(m, 3H), 1,4-diamine dihydrochloride 1.00(m, 3H) 468
(S)-4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.16-8.10(m, 1H), 7.78(m, (ethylamino)pyrrolidin-1-yl]- 1H),
7.41(m, 1H), 6.33(s, 1H), 4.07-3.76(m, 5H), 3.21- N-[4-fluoro-3-
3.19(m, 2H), 2.73(m, 2H), 2.56(m, 1H), 2.28(m, 1H),
(trifluoromethyl)phenyl] 1.72(m, 2H), 1.44(m, 2H), 1.36(m, 3H),
1.00(m, 3H) pyrimidin-2-amine dihydrochloride 469
(S)-5-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.14(m, 1H), 7.87(m, 1H), (ethylamino)pyrrolidin-1- 7.44(m, 1H),
6.34(s, 1H), 4.08(m, 2H), 3.90-3.76(m, 3H),
yl]pyrimidin-2-ylamino}-2- 3.19(m, 2H), 2.71(m, 2H), 2.59(m, 1H),
2.30(m, 1H), fluorobenzonitrile 1.74(m, 2H), 1.48(m, 2H), 1.37(m,
3H), 1.00(m, 3H) dihydrochloride 470 (S)-N.sup.1-{4-butyl-6-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.78-7.72(m, 1H), 7.45(m,
(ethylamino)pyrrolidin-1- 1H), 7.35-7.32(m, 1H), 6.31(s, 1H),
4.12-3.76(m, 5H), yl]pyrimidin-2-yl}-4- 3.20(m, 2H), 2.72(m, 2H),
2.52(m, 1H), 2.30(m, 1H), fluorobenzene-1,3-diamine 1.74(m, 2H),
1.39(m, 2H), 1.37(m, 3H), 1.00(m, 3H) dihydrochloride 471
(S)-N.sup.1-{4-butyl-6-[3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.62(m, 1H), 7.47(m, 1H), (ethylamino)pyrrolidin-1- 7.33(m, 1H),
6.30(s, 1H), 4.17-3.76(m, 5H), 3.20(m, 2H), yl]pyrimidin-2-yl}-4-
2.70(m, 2H), 2.40(m, 1H), 2.30(m, 1H), 1.74(m, 2H),
chlorobenzene-1,3-diamine 1.47(m, 2H), 1.39(m, 3H), 1.00(m, 3H)
dihydrochloride 472 (S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 9.25(brs, NH), 8.27(s, 1 H),
methylphenylamino)-6- 7.51(d, 1H), 7.16(d, 1H), 6.94(brs, NH),
5.67(s, 1H), propylpyrimidin-4- 4.66(m, 1H), 4.14(s, 2H),
3.81-3.44(m, 4H), 2.47(m, 5H), yl]pyrrolidin-3-yl}-2- 2.33(m, 1H),
2.10(m, 1H), 1.68(m, 2H), 0.98(t, 3H) hydroxyacetamide
TABLE-US-00049 TABLE 1-49 Example Compound NMR Spectrum 473
(S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
8.29(s, 1H), 7.58(d, 1H), fluorophenylamino)-6- 7.10(m, 1H),
6.76(brs, NH), 5.74(s, 1H), 4.67(m, 1H), propylpyrimidin-4-yl]
4.14(s, 2H), 3.81-3.42(m, 4H), 2.47(t, 2H), 2.34(m, 1H),
pyrrolidin-3-yl}-2- 2.04(m, 1H), 1.72(m, 2H), 0.98(t, 3H)
hydroxyacetamide 474 (S)-N-{1-[2-(3-amino-5- .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. 7.56(s, NH), 7.10-7.02(m, cyanophenylamino)-6-
2H), 6.69(m, 1H), 6.51(s, 1H), 5.73(s, 1H), 4.64(m, 1H),
propylpyrimidin-4-yl] 4.14(s, 2H), 3.85(brs, 2NH), 3.81-3.49(m,
4H), 2.49(t, pyrrolidin-3-yl}-2- 2H), 2.35(m, 1H), 2.06(m, 1H),
1.72(m, 2H), 0.98(t, 3H) hydroxyacetamide 475
(S)-N-(1-{2-[3-amino-5- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
7.63(s, NH), 7.10-6.98(m, (trifluoromethyl)phenylamino]- 2H),
6.78(m, 1H), 6.51(s, 1H), 5.68(s, 1H), 4.64(m, 1H),
6-propylpyrimidin-4-yl} 4.13(s, 2H), 3.83(brs, 2NH), 3.49(m, 4H),
2.45(t, 2H), pyrrolidin-3-yl)-2- 2.30(m, 1H), 2.04(m, 1H), 1.68(m,
2H), 0.96(t, 3H) hydroxyacetamide 476 (S)-N-(1-{2-[4-amino-3-
.sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 8.11(brs, NH), 7.26(m,
2H), (trifluoromethyl)phenylamino]- 6.94(brs, NH), 6.68(m, 1H),
5.63(s, 1H), 4.66(m, 1H), 6-propylpyrimidin-4-yl} 4.15(s, 2H),
4.00(brs, 2NH), 3.76-3.63(m, 4H), 2.43(t, pyrrolidin-3-yl)-2- 2H),
2.31(m, 1H), 2.08(m, 1H), 1.70(m, 2H), 0.96(t, 3H) hydroxyacetamide
477 (S)-N-(1-{2-[4-fluoro-3- .sup.1H-NMR(400 MHz, CDCl.sub.3)
.delta. 8.40(brs, NH), 7.45(m, 1 H), (trifluoromethyl)phenylamino]-
7.08(m, 2H), 6.70(m, 1H), 5.72(s, 1H), 4.66(m, 1H),
6-propylpyrimidin-4-yl} 4.15(s, 2H), 3.78-3.41(m, 4H), 2.46(t, 2H),
2.34(m, 1H), pyrrolidin-3-yl)-2- 2.04(m, 1H), 1.70(m, 2H), 0.97(t,
3H) hydroxyacetamide 478 (S)-N-{1-[2-(3-amino-4- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 7.21(m, 1H), 6.86(m, 2H),
fluorophenylamino)-6- 6.80(brs, NH), 5.64(s, 1H), 4.64(m, 1H),
4.15(s, 2H), propylpyrimidin-4-yl] 3.76(brs, 2NH), 3.63-3.59(m,
4H), 2.44(t, 2H), 2.31(m, pyrrolidin-3-yl}-2- 1H), 2.05(m, 1H),
1.70(m, 2H), 0.97(t, 3H) hydroxyacetamide 479
(S)-N-{1-[2-(3-amino-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.25(s, 1H), 7.06(m, 1H), chlorophenylamino)-6- 6.92(m, 1H),
5.89(s, 1H), 4.55(m, 1H), 3.99(s, 2H), 3.87- propylpyrimidin-4-yl]
3.62(m, 4H), 2.49(t, 2H), 2.31(m, 1H), 2.10(m, 1H),
pyrrolidin-3-yl}-2- 1.71(m, 2H), 0.99(t, 3H) hydroxyacetamide 480
(S)-N-{1-[2-(3-chloro-4- .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.
7.96(brs, NH), 7.21(m, 1H), methylphenylamino)-6- 7.09(m, 1H),
6.92(brs, NH), 6.76(m, 1H), 5.67(s, 1H), propylpyrimidin-4-yl]
4.67(m, 1H), 4.14(s, 2H), 3.77-3.43(m, 4H), 2.45(t, 2H),
pyrrolidin-3-yl}-2- 2.31(m, 4H), 2.04(m, 1H), 1.69(m, 2H), 0.97(t,
3H) hydroxyacetamide 481 (S)-2-hydroxy-N-(1-{2-[4- .sup.1H-NMR(400
MHz, CDCl.sub.3) .delta. 8.36(brs, NH), 7.38(m, 1H),
methyl-3-(trifluoromethyl) 7.16(m, 2H), 6.78(m, 1H), 5.67(s, 1H),
4.66(m, 1H), phenylamino]-6- 4.14(s, 2H), 3.76-3.61(m, 4H), 2.47(m,
5H), 2.30(m, 1H), propylpyrimidin-4-yl} 2.04(m, 1H), 1.70(m, 2H),
0.96(t, 3H) pyrrolidin-3-yl)acetamide
TABLE-US-00050 TABLE 1-50 Example Compound NMR Spectrum 482
(S)-N-{1-[2-(3-amino-5- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.73(m, 2H), 7.22(d, 1 H), cyanophenylamino)-6- 6.31(d, 1H),
4.57(m, 1H), 4.05(s, 2H), 3.95-3.54(m, 4H), propylpyrimidin-4-yl]
2.67(m, 2H), 2.38(m, 1H), 2.19(m, 2H), 1.80(m, 2H),
pyrrolidin-3-yl}-2- 1.05(m, 3H) hydroxyacetamide hydrochloride 483
(S)-N-{1-[2-(3-cyano-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.02(d, 1H), 7.71(m, 1H), methylphenylamino)-6- 7.43(d, 1H),
6.27(d, 1H), 4.56(m, 1H), 3.99(s, 2H), 3.90- propylpyrimidin-4-yl]
3.47(m, 4H), 2.64(m, 2H), 2.52(s, 3H), 2.17(m, 1H),
pyrrolidin-3-yl}-2- 2.01(m, 1H), 1.78(m, 2H), 1.05(m, 3H)
hydroxyacetamide hydrochloride 484 (S)-4-fluoro-N.sup.1-{4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.67-7.62(m, 1H), 7.44-
(methylamino)pyrrolidin-1- 7.28(m, 2H), 6.30(d, 1H), 4.12-3.76(m,
5H), 2.81(d, 3H), yl]-6-propylpyrimidin-2-yl} 2.67(dd, 2H),
2.60-2.01(m, 2H), 1.82-1.62(m, 2H), 1.05 benzene-1,3-diamine (t,
3H) dihydrochloride 485 (S)-3-amino-5-({4-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.79(d, 1H), 7.67(d, 1H),
(methylamino)pyrrolidin-1- 7.21(s, 1H), 6.36(d, 1H), 4.19-3.77(m,
5H), 2.82(d, 3H), yl]-6-propylpyrimidin-2- 2.70(dd, 2H),
2.64-2.36(m, 2H), 1.84-1.77(m, 2H), 1.05 yl}amino)benzonitrile (t,
3H) dihydrochloride 486 (S)-2-amino-5-({4-[3- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 7.63-7.62 (m, 1H), 7.43-
(methylamino)pyrrolidin-1- 7.39(m, 1H), 6.90(d, 1H), 6.24(d, 1H),
4.12-3.73(m, 5H), yl]-6-propylpyrimidin-2-yl} 2.79(d, 3H), 2.64(dd,
2H), 2.59-2.25(m, 2H), 1.79-1.73 amino)benzonitrile (m, 2H),
1.04(t, 3H) dihydrochloride 487 (S)-N.sup.1-{4-[3-(methylamino)
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.74(d, 1H), 7.47(d, 1H),
pyrrolidin-1-yl]-6- 7.10(s, 1H), 6.35(s, 1H), 4.20-3.70(m, 5H),
2.81(d, 3H), propylpyrimidin-2-yl}- 2.69(t 2H), 2.69-2.50(m, 1H),
2.45-2.25(m, 1H), 1.90- 5-(trifluoromethyl)benzene- 1.70(m, 2H),
1.06(t, 3H) 1,3-diamine dihydrochloride 488
(S)-N.sup.1-{4-[3-(ethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD)
.delta. 7.79(d, 1H), 7.50-7.40(m, pyrrolidin-1-yl]- 1H), 7.02(t,
1H), 6.30-6.20(m, 1H), 4.20-3.60(m, 5H), 6-propylpyrimidin-2-yl}-3-
3.25-3.00(m, 2H), 2.65(t, 2H), 2.60-2.40(m, 1H), 2.40-
(trifluoromethyl)benzene- 220(m, 1H) 1.78(q, 2H), 1.40-1.30(m, 3H),
1.05(t, 3H) 1,4-diamine dihydrochloride 489 (S)-2-amino-5-({4-[3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.69(d, 1H), 7.55-7.45(m,
(ethylamino)pyrrolidin-1-yl]- 1H), 6.96(d, 1H), 6.25(d, 1H),
4.15-3.60(m, 5H), 3.25- 6-propylpyrimidin-2-yl} 3.05(m, 2H),
2.65(t, 2H), 2.65-2.45(m, 1H), 2.40-2.20(m, amino)benzonitrile 1H),
1.75(q, 2H), 1.37(t, 3H), 1.04(t, 3H) dihydrochloride 490
(S)-N-[4-fluoro-3- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 8.47(d,
1H), 7.75-7.65(m, (trifluoromethyl)phenyl]-4- 1H), 7.20(t, 1H),
5.97(s, 1H), 4.00-3.85(m, 2H), 3.85- [3-(methylamino)pyrrolidin-
3.50(m, 3H), 2.78(s, 3H), 2.60-2.40(m, 3H), 2.30-2.20(m,
1-yl]-6-propylpyrimidin-2- 1H), 1.74(q, 2H), 0.98(t, 3H) amine
hydrochloride
TABLE-US-00051 TABLE 1-51 Example Compound NMR Spectrum 491
(S)-4-[3-(ethylamino) .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
8.45(d, 1H), 7.71(d, 1H), pyrrolidin-1-yl]-N-[4-fluoro-3- 7.20(t,
1H), 5.97(s, 1H), 4.10-3.85(m, 2H), 3.85-3.50(m,
(trifluoromethyl)phenyl]-6- 3H), 3.16(t, 2H), 2.60-2.40(m, 3H),
2.30-2.15(m, 1 H), propylpyrimidin-2-amine 1.75(q, 2H), 1.36(t,
3H), 0.98(t, 3H) hydrochloride 492 (S)-N-{1-[6-butyl-2-(3-
.sup.1H-NMR(400 MHz, CD.sub.3OD) .delta. 7.97(d, 1H), 7.71(t, 1H),
cyano-4-methylphenylamino) 7.44(d, 1H), 6.24(d, 1H), 4.48(d, 1H),
4.00-3.40(m, 4H), pyrimidin-4-yl]pyrrolidin-3- 2.67(t, 2H), 2.52(s,
3H), 2.40-2.20(m, 1H), 2.15-2.00(m, yl}acetamide hydrochloride 1H),
1.95(s, 3H), 1.80-1.60(m, 2H), 1.45(q, 2H), 0.98(t, 3H) 493
(S)-N-{1-[2-(3-amino-4- .sup.1H-NMR(400 MHz, CD.sub.3OD) .delta.
7.00(d, 1H), 6.92(s, 1H), methylphenylamino)-6- 6.76(t, 1H),
6.14(d, 1H), 4.47(d, 1H), 4.00-3.35(m, 4H), propylpyrimidin-4-yl]
2.60(t, 2H), 2.40-2.20(m, 1H), 2.13(s, 3H), 2.15-2.00(m,
pyrrolidin-3-yl}acetamide 1H), 1.95(s, 3H), 1.74(q, 2H), 1.03(t,
3H) hydrochloride 494 (S)-N-(1-{2-[(3,4- .sup.1H-NMR(400 MHz,
CD.sub.3OD) .delta. 6.88(s, 1H), 6.70(m, 2H),
diaminophenyl)amino]-6- 6.02(s, 1H), 4.45(brs, 1H), 3.83-3.63(m,
3H), 2.55(m, propylpyrimidin-4-yl} 2H), 2.28(br, 1H), 2.03(br, 1H),
1.97(s, 3H), 1.72(m, 2H), pyrrolidin-3-yl)acetamide 1.01(t, 3H)
Test Example 1
Evaluation of Agonistic Activity in CHO-K1 Cells Expressing Human
5-HT.sub.4(a)
[0836] As CHO-K1 cells stably expressing human 5-HT.sub.4(a), we
used the GeneBlAzer HTR4-CRE-bla CHO-K1 cells (Invitrogen Corp.).
The cells were cultured, under the condition of 37 .quadrature. and
5% CO.sub.2, in a DMEM supplemented with 10% fetal bovine serum
(FBS), 25 mM HEPES (pH7.4), 600 .mu.g/ml hygromycin B, 0.1 mM
non-essential amino acids, 100 unit/ml penicillin and 100 .mu.g/ml
streptomycin. Subcultures were performed three times per one week,
each being at less than 80% confluence. At the previous day before
treating test compounds, the cells were collected using 0.5%
trypsin/EDTA and then diluted with a DMEM supplemented with 1% FBS,
25 mM HEPES, and 0.1 mM non-essential amino acids into
3.125.times.10.sup.5 cells/ml. 32 .mu.l of the diluted cells were
added into 384-well plate (10.sup.4 cells per well) and then
incubated overnight. After the overnight culture, 8 .mu.l of the
medium having 1% of DMSO was added into the cell-free control well
and the non-stimulating control well, respectively. 8 .mu.l of the
respective test compound dilutions (which had been prepared by
diluting by 100-times with the medium as mentioned in the above)
having 1% of DMSO were added to the respective remaining wells.
After being cultured in the incubator for 5 hours, the wells of the
384-plate were treated with the substrate solution (8 .mu.l per
well) prepared according to the vendor's instruction (i.e.,
Invitrogen's instruction), and then incubated in the dark room for
additional two hours. Agonistic activities on 5-HT.sub.4 receptor
were evaluated, on the basis of fluorescence values of the
cleavage-products by beta-lactamase. After exciting to 410 nm of
wavelength using a fluorescence detector (Genios Pro), we measured
the fluorescence values at two emission wavelengths (first
wavelength: 465 nm, second wavelength: 535 nm). Data were analyzed
on the basis of the ratio of fluorescence intensities of each well
at the respective wavelengths. Each EC.sub.50 value was calculated
by non-linear regression analysis using the "GraphPad Prism"
program, based on the activities according to 8-different
concentrations of the test compounds. The results are shown in
Table 2-1 to 2-3 below.
TABLE-US-00052 TABLE 2-1 Example EC.sub.50 (nM) 13 0.12 17 0.35 18
0.14 22 0.33 31 0.13 32 0.23 33 0.059 34 0.16 36 0.243 40 0.03 41
0.15 42 0.033 43 0.178 44 0.022 45 0.036 46 0.0097 47 0.38 50 0.012
52 0.33 53 0.098 54 0.032 55 0.016 56 0.312 57 0.389 59 0.028 60
0.047 61 0.15 62 0.36 63 0.13 66 0.1 67 0.19 71 0.25 73 0.27 75
0.22 77 0.15 78 0.28 79 0.44 80 0.17 81 0.205 82 0.048 84 0.031 85
0.003 86 0.039 87 0.048 88 0.041 89 0.08 90 0.091 91 0.014 92 0.057
93 0.01 94 0.041 95 0.081 96 0.017 97 0.046 98 0.094 99 0.0015 100
0.31 102 0.39 103 0.067 104 0.073 105 0.005 106 0.13 107 0.42 108
0.21 109 0.012 110 0.018 111 0.008 112 0.045 113 0.016 116 0.0035
117 0.014 121 0.005 123 0.0019 125 0.159 127 0.0062 128 0.039 129
0.323 131 0.091 133 0.039 134 0.214 135 0.011 136 0.045 137 0.072
138 0.012 139 0.034 140 0.028 141 0.085 142 0.01 143 0.0066 144
0.036 145 0.046 146 0.084 149 0.277 150 0.41 151 0.334 153 0.228
155 0.417 156 0.219 157 0.044 158 0.436 160 0.121 161 0.119 162
0.193 165 0.2 166 0.103 170 0.0013 171 0.00064 173 0.004 175 0.229
176 0.018 177 0.02 180 0.0087 181 0.00088 182 0.036 185 0.015 186
0.382 187 0.037 189 0.028 190 0.05 191 0.29 192 0.02 194 0.2 195
0.25 196 0.1 203 0.3 204 0.47 206 0.16 207 0.083 208 0.06 210 0.016
211 0.019 212 0.0089 213 0.017 214 0.029 215 0.018 217 0.23 220
0.07 221 0.149 222 0.082 223 0.011 224 0.0043 225 0.052 226 0.052
228 0.014
TABLE-US-00053 TABLE 2-2 Example EC.sub.50 (nM) 229 0.00098 230
0.047 231 0.0067 232 0.13 233 0.019 234 0.0012 235 0.0023 236 0.209
237 0.0013 238 0.00039 239 0.115 240 0.0025 241 0.012 242 0.058 243
0.011 244 0.028 245 0.053 246 0.04 247 0.012 248 0.016 249 0.0018
251 0.01 252 0.0052 253 0.014 254 0.0015 255 0.023 260 0.015 261
0.0071 262 0.0039 268 0.011 270 0.204 274 0.087 279 0.078 280 0.026
281 0.196 282 0.103 286 0.0047 289 0.062 290 0.013 291 0.0074 292
0.038 293 0.0043 294 0.076 295 0.048 296 0.039 297 0.028 301 0.11
302 0.42 303 0.12 304 0.07 305 0.18 307 0.24 309 0.076 310 0.37 311
0.019 312 0.023 313 0.078 314 0.18 315 0.028 316 0.21 317 0.14 318
0.16 319 0.08 320 0.041 321 0.044 322 0.15 323 0.027 325 0.085 326
0.028 327 0.025 328 0.017 329 0.18 331 0.138 332 0.046 333 0.024
334 0.085 337 0.0026 338 0.0032 342 0.0055 344 0.0092 345 0.062 346
0.014 347 0.03 348 0.019 349 0.016 350 0.012 351 0.0035 352 0.0027
353 0.01 354 0.003 355 0.007 357 0.0065 358 0.014 359 0.0021 362
0.0021 364 0.122 365 0.027 366 0.078 367 0.153 368 0.182 369 0.049
370 0.015 372 0.0046 373 0.0043 374 0.0027 375 0.0033 376 0.0037
377 0.0013 378 0.015 379 0.0098 380 0.009 381 0.0043 382 0.0051 383
0.0057 384 0.077 387 0.007 395 0.082 399 0.13 400 0.033 401 0.073
402 0.236 403 0.414 405 0.399 406 0.402 407 0.254 414 0.0034 415
0.015 416 0.0074 417 0.0051 418 0.0022 419 0.0032 420 0.0029 421
0.0079 422 0.011 423 0.0084 424 0.02 425 0.056 426 0.079 427 0.024
428 0.066 429 0.025 430 0.027 431 0.029 433 0.055
TABLE-US-00054 TABLE 2-3 Example EC.sub.50(nM) 434 0.111 436 0.01
437 0.02 438 0.015 439 0.0075 440 0.017 441 0.0095 442 0.041 443
0.0099 444 0.012 445 0.0098 446 0.0077 447 0.0023 448 0.0025 449
0.0044 450 0.0078 451 0.003 452 0.0033 453 0.0016 454 0.014 455
0.0038 456 0.0026 457 0.003 458 0.0017 459 0.0034 460 0.0019 461
0.0019 462 0.0026 463 0.0021 464 0.0039 465 0.0022 466 0.0058 467
0.0014 468 0.0062 469 0.0021 470 0.0025 471 0.0033 472 0.0075 473
0.022 474 0.0066 475 0.011 476 0.014 477 0.0096 478 0.024 479
0.0064 480 0.032 481 0.0093 484 0.0058 485 0.0024 486 0.0014 487
0.0021 488 0.00077 489 0.0015 490 0.0048 491 0.0029 492 0.019 493
0.024
[0837] As shown in Table 2-1 to 2-3, the compounds of the present
invention have excellent activities as a 5-HT.sub.4 receptor
agonist, and therefore they can be usefully applied for preventing
or treating the dysfunction in gastrointestinal motility.
* * * * *