U.S. patent application number 13/851542 was filed with the patent office on 2013-10-10 for novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection.
The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Lei Guo, Xianfeng Lin, Haixia Liu, Zongxing Qiu, Hong Sheng, Guozhi Tang, Guolong Wu, Weixing Zhang, Wei Zhu.
Application Number | 20130267517 13/851542 |
Document ID | / |
Family ID | 49292800 |
Filed Date | 2013-10-10 |
United States Patent
Application |
20130267517 |
Kind Code |
A1 |
Guo; Lei ; et al. |
October 10, 2013 |
NOVEL 4-METHYL-DIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS
OF HEPATITIS B VIRUS INFECTION
Abstract
The invention provides novel compounds having the general
formula: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, M and X are as described herein, compositions including
the compounds and methods of using the compounds.
Inventors: |
Guo; Lei; (Shanghai, CN)
; Lin; Xianfeng; (Shanghai, CN) ; Liu; Haixia;
(Shanghai, CN) ; Qiu; Zongxing; (Shanghai, CN)
; Sheng; Hong; (Shanghai, CN) ; Tang; Guozhi;
(Shanghai, CN) ; Wu; Guolong; (Shanghai, CN)
; Zhang; Weixing; (Shanghai, CN) ; Zhu; Wei;
(Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Nutley |
NJ |
US |
|
|
Family ID: |
49292800 |
Appl. No.: |
13/851542 |
Filed: |
March 27, 2013 |
Current U.S.
Class: |
514/235.8 ;
514/256; 544/122; 544/333 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 417/14 20130101; C07D 413/14 20130101; C07D 417/04 20130101;
C07D 405/14 20130101 |
Class at
Publication: |
514/235.8 ;
544/333; 514/256; 544/122 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 417/04 20060101 C07D417/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2012 |
CN |
PCT/CN2012/073388 |
Claims
1. A compound of formula (I) ##STR00106## wherein: R.sup.1 is
C.sub.1-2 alkoxycarbonyl or cyano; R.sup.2 is phenyl, which is
substituted by halogen; R.sup.3 is thiazolyl, thienyl, imidazolyl,
isoxazolyl or pyridinyl; which is unsubstituted or substituted by
halogen or C.sub.1-6alkyl; X is oxygen or --NR.sup.7; R.sup.4 and
R.sup.5 are independently selected from hydrogen, C.sub.1-6alkyl
and trifluoroC.sub.1-6alkyl; or R.sup.4 and R.sup.5, together with
the carbon atom to which they are attached, form a 3 to 7 membered
cycloalkyl; or when X is --NR.sup.7, one of R.sup.4 and R.sup.5 is
hydrogen or C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5
along with R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and
R.sup.7 are attached form a pyrrolidinyl, morpholinyl or
piperidinyl ring, which pyrrolidinyl, morpholinyl or piperidinyl
ring is unsubstituted or substituted by fluoro; M is C.sub.1-6
alkoxycarbonyl, carboxy,
di-C.sub.1-6alkylaminoC.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, di-C.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--, ##STR00107## R.sup.7 is C.sub.1-6alkyl
or trifluoroC.sub.1-6alkyl; y is 1-6; or pharmaceutically
acceptable salts, or tautomerism isomers thereof.
2. A compound according to claim 1, wherein, R.sup.1 is
C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is phenyl, which is once
or twice substituted by halogen; R.sup.3 is (i) 2-thiazolyl which
is unsubstituted or once substituted by C.sub.1-6alkyl or halogen,
(ii) 2-thienyl, (iii) 2-pyridinyl, which 2-thienyl or 2-pyridinyl
are once substituted by halogen, (iv) 2-imidazolyl substituted by
one C.sub.1-6alkyl; or (v) 3-isoxazolyl which is unsubstituted or
substituted by one C.sub.1-6alkyl; X is oxygen or --NR.sup.7;
R.sup.4 and R.sup.5 are independently selected from hydrogen,
C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl; or R.sup.4 and R.sup.5,
together with the carbon atom to which they are attached, form a 3
to 7 membered cycloalkyl ring; or when X is --NR.sup.7, one of
R.sup.4 and R.sup.5 is hydrogen or C.sub.1-6alkyl, and the other of
R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to which
R.sup.4 or R.sup.5 and R.sup.7 are attached form a morpholinyl,
pyrrolidinyl or piperidinyl each substituted by fluoro; M is
C.sub.1-6alkoxycarbonyl, carboxy,
diC.sub.1-6alkylamino-C.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, diC.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--, ##STR00108## R.sup.7 is C.sub.1-6alkyl
or trifluoroC.sub.1-6alkyl; y is 1-6; or pharmaceutically
acceptable salts, or tautomerism isomers thereof.
3. A compound according to claim 2, wherein R.sup.2 is phenyl
substituted by one or two fluorine atoms; R.sup.3 is ##STR00109##
R.sup.4 and R.sup.5 are independently selected from hydrogen,
methyl and trifluoromethyl; or R.sup.4 and R.sup.5 together with
the carbon atom to which they are attached are cyclopropyl; or when
X is --NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen or methyl,
and the other of R.sup.4 and R.sup.5 along with R.sup.7 and the
atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached form:
##STR00110## M is methoxycarbonyl, carboxy,
dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl,
methylaminocarbonyl, methylsulfonylaminocarbonyl,
2-thiazolylaminocarbonyl, hydroxymethyl, hydroxypropyl,
--C(Me).sub.2OH, ##STR00111## R.sup.7 is methyl or trifluoroethyl;
or pharmaceutically acceptable salts, or tautomerism isomers
thereof.
4. A compound according to claim 1 wherein. R.sup.1 is
C.sub.1-2alkoxycarbonyl; R.sup.2 is phenyl substituted by one
halogen; R.sup.3 is thiazol-2-yl; X is oxygen; R.sup.4 and R.sup.5
are independently selected from hydrogen, C.sub.1-6alkyl and
trifluoroC.sub.1-6alkyl; M is C.sub.1-6alkoxycarbonyl or
carboxy.
5. A compound according to any one of claim 4, wherein; R.sup.1 is
methoxycarbonyl; R.sup.2 is 4-fluorophenyl; R.sup.3 is
thiazol-2-yl; X is oxygen; R.sup.4 and R.sup.5 are independently
selected from hydrogen, methyl and trifluoromethyl; M is
methoxycarbonyl or carboxy.
6. A compound according to claim 1 wherein; R.sup.1 is
C.sub.1-2alkoxycarbonyl; R.sup.2 is phenyl substituted by one
halogen; R.sup.3 is 2-thiazolyl; X is --N(C.sub.1-6alkyl) or
--N(trifluoroC.sub.1-6alkyl); R.sup.4 is hydrogen; R.sup.5 is
hydrogen; or R.sup.4 and R.sup.5, together with the carbon atom to
which they are attached, form a 3 to 7 membered cycloalkyl; M is
carboxy.
7. A compound according to any one of claim 6, wherein: R.sup.1 is
methoxycarbonyl; R.sup.2 is 4-fluorophenyl; R.sup.3 is
thiazol-2-yl; X is --NCH.sub.3 or --NCH.sub.2CF.sub.3; R.sup.4 is
hydrogen; R.sup.5 is hydrogen; or R.sup.4 and R.sup.5, together
with the carbon atom to which they are attached, form cyclopropyl;
M is carboxy.
8. A compound according to claim 1 wherein R.sup.1 is
C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is phenyl substituted by
one kor two halogen; R.sup.3 isthiazol-2-yl; 2-pyridin-2-yl
substituted by one halogen; or imidazol-2-yl substituted by one
C.sub.1-6alkyl; X is --NR.sup.7; one of R.sup.4 and R.sup.5 is
hydrogen, and the other of R.sup.4 and R.sup.5 along with R.sup.7
and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached
form a morpholinyl; M is C.sub.1-6alkoxycarbonyl, carboxy or
hydroxy-C.sub.yH.sub.2y--; y is 1-6.
9. A compound according to any one of claim 8, wherein R.sup.1 is
methoxycarbonyl, ethoxycarbonyl or cyano; R.sup.2 is 4-fluorophenyl
or 3,4-difluorophenyl; R.sup.3 is thiazol-2-yl,
5-fluoro-pyridin-2-yl or 1-methyl-imidiazolid-2-yl; one of R.sup.4
and R.sup.5 is hydrogen, and the other of R.sup.4 and R.sup.5 along
with R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7
are attached form: ##STR00112## M is methoxycarbonyl, carboxy or
hydroxymethyl-.
10. A compound according to claim 1 or 2, wherein R.sup.1 is
C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is phenyl substituted by
one or two halogen; R.sup.3 is thiazol-2-yl optionally substituted
by one C.sub.1-6alkyl or one halogen; thien-2-yl or -pyridin-2-yl
said thien-2-yl or -pyridin-2-yl substituted by one halogen;
-imidazol-2-yl, which substituted by one C.sub.1-6alkyl; or
isoxazol-3-yl optionally substituted by one C.sub.1-6alkyl; X is
--NR.sup.7; one of R.sup.4 and R.sup.5 is hydrogen or
C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5 along with
R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are
attached form a pyrrolidinyl or piperidinyl substituted by fluoro;
M is C.sub.1-6alkoxycarbonyl, carboxy,
di-C.sub.1-6alkylaminoC.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, di-C.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--, ##STR00113## y is 1-6.
11. A compound according to any one of claim 1, 2, 3 or 10, wherein
R.sup.1 is methoxycarbonyl, ethoxycarbonyl or cyano; R.sup.2 is
4-fluorophenyl or 3,4-difluorophenyl; R.sup.3 is ##STR00114## X is
--NR.sup.7; one of R.sup.4 and R.sup.5 is hydrogen or methyl, and
the other of R.sup.4 and R.sup.5 along with R.sup.7 and the atoms
to which R.sup.4 or R.sup.5 and R.sup.7 are attached form:
##STR00115## M is methoxycarbonyl, carboxy,
dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl,
methylaminocarbonyl, methylsulfonylaminocarbonyl,
2-thiazolylaminocarbonyl, hydroxymethyl, hydroxypropyl,
--C(Me).sub.2OH, ##STR00116##
12. A compound according to claim 1 of formula (I') ##STR00117##
wherein, R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is
phenyl, which is substituted by halogen; R.sup.3 is 2-thiazolyl
which is unsubstituted or substituted by C.sub.1-6alkyl or
2-pyridinyl, which is substituted by halogen; X is oxygen or
--NR.sup.7; R.sup.4 and R.sup.5 are independently selected from
hydrogen, C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl; or R.sup.4
and R.sup.5, together with the carbon atom to which they are
attached, form a 3 to 7 membered cycloalkyl; or when X is
--NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen or
C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5 along with
R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are
attached form a morpholinyl; or pyrrolidinyl substituted by fluoro;
R.sup.6 is hydrogen or C.sub.1-6alkyl; R.sup.7 is C.sub.1-6alkyl;
or pharmaceutically acceptable salts, or tautomerism isomers
thereof.
13. A compound according to claim 12, wherein R.sup.1 is
methoxycarbonyl or cyano; R.sup.2 is phenyl substituted once or
twice by fluoro; R.sup.3 is thiazol-2-yl, 5-methyl-thiazol-2-yl or
5-fluoro-pyridin-2-yl; or; X is oxygen or --NR.sup.7; R.sup.4 and
R.sup.5 are independently selected from hydrogen, methyl and
trifluoromethyl; or R.sup.4 and R.sup.5 together with the carbon
atom to which they are attached form cyclopropyl; or when X is
--NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen or methyl, and
the other of R.sup.4 and R.sup.5 along with R.sup.7 and the atoms
to which R.sup.4 or R.sup.5 and R.sup.7 are attached form:
##STR00118## R.sup.6 is hydrogen or methyl; R.sup.7 is methyl; or
pharmaceutically acceptable salts, or tautomerism isomers
thereof.
14. A compound according to claim 12, wherein R.sup.1 is
C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is phenyl which is
substituted by halogen; R.sup.3 is thiazol-2-yl or pyridin-2-yl,
which is substituted by halogen; X is --NR.sup.7; one of R.sup.4
and R.sup.5 is hydrogen or C.sub.1-6alkyl, and the other of R.sup.4
and R.sup.5 along with R.sup.7 and the atoms to which R.sup.4 or
R.sup.5 and R.sup.7 are attached form a morpholinyl; R.sup.6 is
hydrogen or C.sub.1-6alkyl.
15. A compound according to any one of claim 14, wherein R.sup.1 is
methoxycarbonyl or cyano; R.sup.2 is 4-fluorophenyl or
3,4-difluorophenyl; R.sup.3 is thiazol-2-yl or
5-fluoro-pyridin-2-yl; one of R.sup.4 and R.sup.5 is hydrogen or
methyl, and the other of R.sup.4 and R.sup.5 along with R.sup.7 and
the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached
formform ##STR00119## R.sup.6 is hydrogen or methyl.
16. A compound according to claim 12, wherein R.sup.1 is
C.sub.1-2alkoxycarbonyl or cyano; R.sup.2 is phenyl which is
substituted by halogen; R.sup.3 is 2-thiazolyl optionally
substituted by C.sub.1-6alkyl or 2-pyridinylsaid pyridinyl
substituted by halogen; X is --NR.sup.7; one of R.sup.4 and R.sup.5
is hydrogen or C.sub.1-6alkyl, and the other and the other of
R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to which
R.sup.4 or R.sup.5 and R.sup.7 are attached form a pyrrolidinyl
substituted by fluoro; R.sup.6 is hydrogen or C.sub.1-6alkyl.
17. A compound according to any one of claims 16, wherein R.sup.1
is methoxycarbonyl or cyano; R.sup.2 is 4-fluorophenyl or
3,4-difluorophenyl; R.sup.3 is thiazol-2-yl, 5-methyl-thiazol-2-yl
or 5-fluoro-pyridin-2-yl; X is --NR.sup.7; one of R.sup.4 and
R.sup.5 is hydrogen or methyl, and the other of R.sup.4 and R.sup.5
along with R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and
R.sup.7 are attached form ##STR00120## R.sup.6 is hydrogen or
methyl.
18. A compound according to any one of claims 1 selected from
4-(4-fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl--
2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester;
6-(1-carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2-
-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester;
6-{[(1-carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-m-
ethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3-
,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihy-
dro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid methyl
ester;
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihy-
dro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid;
(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6--
dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid;
(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6--
dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid;
4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-meth-
yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic
acid;
4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-meth-
yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic
acid;
6-(2-(S)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-p-
henyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
4-[(S)-6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl--
3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
methyl ester;
4-[6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2--
yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-(2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-
-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phe-
nyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-1-[(S)-5-cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydr-
o-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid;
(S)-4-[5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydr-
o-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(S)-1-[(S)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-di-
hydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic
acid;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid ethyl ester;
(S)-6-(2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
(S)-6-(2-carboxy-4,4-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-ph-
enyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carbox-
ylic acid methyl ester;
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid ethyl ester;
(S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-2-thiazol-2-yl-3-
,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(S)-4-[(S)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-(1-methyl-1H--
imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic
acid;
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluor-
o-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carb-
oxylic acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thia-
zol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((2S,4R)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
2-isoxazol-3-yl-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
(R)-6-((S)-2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)--
4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carbo-
xylic acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester;
(S)-6-((2S,4S)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-(5-methyl-isoxazol-3-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester;
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester;
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester;
(S)-6-{[carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-(4-fluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-flu-
oro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-[(S)-2-(2-dimethylamino-ethoxycarbonyl)-4,4-difluoro-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester;
(S)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl-
)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
(S)-6-((S)-2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fl-
uoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-2-dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-f-
luoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
6-((S)-4,4-difluoro-2-methylcarbamoyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl-pyrrolidin-1-ylmet-
hyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5--
carboxylic acid methyl ester;
(S)-6-[(S)-4,4-difluoro-2-(thiazol-2-ylcarbamoyl)-pyrrolidin-1-ylmethyl]--
4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carbo-
xylic acid methyl ester;
4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4-ylmethyl)-4-methyl-
-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester;
(S)-6-[(S)-4,4-difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethy-
l]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-ca-
rboxylic acid methyl ester;
(S)-6-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluor-
o-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-[4,4-difluoro-2-(3-hydroxy-propyl)-pyrrolidin-1-ylmethyl]-4-(4-fluo-
ro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester;
(S)-6-[(S)-4,4-difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester;
(S)-6-[(S)-4,4-difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4--
fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; and
(S)-6-[(S)-4,4-difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester.
19. A process for the preparation of a compound according to claim
1 comprising the reaction of (a) a compound of formula (A)
##STR00121## in the presence of an acid; wherein R.sup.1 to
R.sup.5, M and X are defined as in claim 1.
20. A compound according to any one of claim 1 for use as
therapeutically active substance.
21. A pharmaceutical composition comprising a compound in
accordance with any one of claim 1 and at least one carrier,
diluent or excipient.
22. The use of a compound according to any one of claim 1 for the
treatment or prophylaxis of hepatitis B virus infection.
23. The use of a compound according to any one of claim 1 for the
preparation of a medicament for the treatment or prophylaxis of
hepatitis B virus infection.
24. A compound according to any one of claim 1 for the treatment or
prophylaxis of hepatitis B virus infection.
25. A compound according to any one of claims 1 when manufactured
according to a process of claim 19.
26. A method for the treatment or prophylaxis of hepatitis B virus
infection, which method comprises administering an effective amount
of a compound as defined in any one of claim 1.
Description
CROSS-REFERENCE TO PRIOR APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn.119(a) to PCT/CN2012/073388 filed Mar. 31, 2012 the
contents of which is herein incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to organic compounds useful
for therapy and/or prophylaxis in a human, and in particular to
Hepatitis B virus (HBV) inhibitors by targeting on HBV capsid
useful for treating HBV infection.
[0003] HBV is a species of the hepadnaviridae family of viruses.
HBV is a serious public health problem worldwide, with more than
400 million people especially in Asia-pacific regions chronically
infected by this small enveloped DNA virus. Although most
individuals seem to resolve the infection following acute symptoms,
15-40% of HBV patients will finally develop clinical diseases
during their lifespan, most notably, hepatitis, liver cirrhosis,
and hepatocellular carcinoma. Every year 500,000 to 1 million
people die from the end stage of liver diseases caused by HBV
infection.
[0004] HBV lifecycle begins with the binding of the "Dane" particle
with an unidentified receptor on the surface of hepatocyte.
Following entry, viral genome is delivered into nucleus where a
covalently closed circular DNA (cccDNA) is formed through DNA
repair of viral relaxed circular DNA. Unlike the mechanisms of most
other DNA viruses, HBV cccDNA replicates through the
retrotranscription of a 1.1-genome unit-length RNA copy (pregenomic
RNA). Viral pregenomic RNA interacts with other two viral
components, capsid protein and polymerase, as well as some host
factors, to form capsid particles where viral DNA replication
occurs. Most copies of the encapsidated genome then efficiently
associate with the envelope proteins for virion assembly and
secretion; a minority of these genomes are shunted to the nucleus,
where they are converted to cccDNA.
[0005] Currently, there are two types of anti-HBV agents on the
market, nucleoside (tide) analogs targeting viral polymerase
(lamivudine, adefovir, tenofovir, telbivudine and entecavir) and
interferon modulating host immune functions. Mutations in the
primary sequence of the polymerase that confer resistance to
lamivudine and adefovir have been identified clinically and
underlie a rebound of serum virus titers that 70% of treated
patients experience within 3 years of the start of lamivudine
therapy. Although resistance to telbivudine, adefovir, and
entecavir occurs more rarely, it has been recorded. Interferon
alpha is the other major therapy available for hepatitis B, but it
is limited by a poor long-term response and debilitating side
effects. Some viral genotypes do not show good responses to
interferon therapy. Now, the standard of clinic cure of HBV
infection is the loss and/or seroconversion of HBsAg. The majority
(around or more than 90%) of treated patients fail to achieve this
goal. This drawback is mainly due to the presence of a stable pool
of viral cccDNA in nucleus that doesn't replicate itself,
therefore, shows no accessibility to nucleoside (tide) analogs.
[0006] Hence, there is certainly a medical need for treatments with
improved characteristics, and for a diversity of approaches in the
development of therapies for HBV infection.
[0007] HBV capsid protein plays essential roles in HBV replication.
HBV has an icosahedral core comprising of 240 copies of the capsid
(or core) protein. The predominant biological function of capsid
protein is to act as a structural protein to encapsidate
pre-genomic RNA and form immature capsid particles in the
cytoplasm. This step is prerequisite for viral DNA replication. The
HBV capsid spontaneously self-assembles from many copies of core
dimers present in the cytoplasm. It has been shown that the
formation of a trimeric nucleus and the subsequent elongation
reactions occur by adding one dimeric subunit at a time until it is
complete. Besides this function, capsid protein regulates viral DNA
synthesis through different phosphorylation status of its
C-terminal phosphorylation sites. When a near full-length relaxed
circular DNA is formed through reverse-transcription of viral
pregenomic RNA, an immature capsid becomes a mature capsid. On one
hand, capsid protein might facilitate the nuclear translocation of
viral relaxed circular genome by means of the nuclear localization
signals located in the Arginine-rich domain of the C-terminal
region of capsid protein. In nucleus, as a component of viral
cccDNA minichromosome, capsid protein could play a structural and
regulatory role in the functionality of cccDNA minichromosomes.
Capsid protein also interacts with viral large envelope protein in
endoplasmic reticulum and triggers the release of intact viral
particles from hepatocytes.
[0008] There have been a couple of capsid related anti-HBV
inhibitors reported. For example, phenylpropenamide derivatives,
including compounds named AT-61 and AT-130 (Feld J. et al.
Antiviral Research 2007, 168-177), and a class of
thiazolidin-4-ones from Valeant R&D (WO2006/033995), have been
shown to inhibit pgRNA packaging. A recent study suggested that
phenylpropenamides are, in fact, accelerators of HBV capsid
assembly, and their actions result in the formation of empty
capsids. These very interesting results illustrate the importance
of the kinetic pathway in successful virus assembly.
[0009] Heteroaryldihydropyrimidines or HAP, including compounds
named Bay 41-4109, Bay 38-7690 and Bay 39-5493, were discovered in
a tissue culture-based screening (Deres K. et al. Science 2003,
893). These HAP analogs act as synthetic allosteric activators and
are able to induce aberrant capsid formation that leads to
degradation of the core protein. HAP analogs also reorganized core
protein from preassembled capsids into noncapsid polymers,
presumably by interaction of HAP with dimers freed during capsid
`breathing`, the transitory breaking of individual intersubunit
bonds. Bay 41-4109 was administered to HBV infected transgenic
mouse or humanized mouse models and demonstrated in vivo efficacy
with HBV DNA reduction (Deres K. et al. Science 2003, 893;
Brezillon N. et al. PLoS ONE 2011, e25096.). It was also shown that
bis-ANS, a small molecule that acts as a molecular `wedge` and
interferes with normal capsid-protein geometry and capsid formation
(Zlotnick A. et al. J. Virol. 2002, 4848-4854).
SUMMARY OF THE INVENTION
[0010] Objects of the present invention are novel compounds of
formula I, their manufacture, medicaments based on a compound in
accordance with the invention and their production as well as the
use of compounds of formula I for the treatment or prophylaxis of
HBV infection.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1. Bay 41-4109 was converted to XLVI in human liver
microsomes.
[0012] FIG. 2. Mean.+-.SD Plasma Concentration-Time Curve of
Bay41-4109 in Male ICR Mice Following Intravenous and Oral
Administration* *Drug exposure in liver is not available due to
instability of Bay 41-4109 in liver homogenate.
[0013] FIG. 3. Mean.+-.SD Plasma and Tissue Concentration-Time
Curve of Example 6 in Male ICR Mice Following Intravenous and Oral
Administration
[0014] FIG. 4. Mean.+-.SD Plasma and Tissue Concentration-Time
Curve of Example 11 in Male ICR Mice Following Intravenous and Oral
Administration
[0015] FIG. 5. Mean.+-.SD Plasma and Tissue Concentration-Time
Curve of Example 13 in Male ICR Mice Following Intravenous and Oral
Administration
[0016] FIG. 6. Mean.+-.SD Plasma and Tissue Concentration-Time
Curve of Example 19 in Male ICR Mice Following Intravenous and Oral
Administration
[0017] FIG. 7. X-ray structure of compound XXVII
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0018] As used herein, the term "C.sub.1-6alkyl" alone or in
combination signifies a saturated, linear- or branched chain alkyl
group containing 1 to 6, particularly 1 to 4 carbon atoms, for
example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl,
tert-butyl and the like. Particular "C.sub.1-6alkyl" groups are
methyl, ethyl, isopropyl, tert-butyl.
[0019] The term "cycloalkyl", alone or in combination, refers to a
saturated carbon ring containing from 3 to 7 carbon atoms,
particularly from 3 to 6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Particular cycloalkyl groups are cyclopropyl, cyclopentyl and
cyclohexyl.
[0020] The term "C.sub.1-6alkoxy" alone or in combination signifies
a group C.sub.1-6alkyl-O--, wherein the "C.sub.1-6alkyl" is as
defined above; for example methoxy, ethoxy, propoxy, isopropoxy,
n-butoxy, i-butoxy, 2-butoxy, t-butoxy and the like. Particular
C.sub.1-6alkoxy groups are methoxy and ethoxy and more particularly
methoxy.
[0021] The term "C.sub.2-6alkoxy" alone or in combination signifies
a group C.sub.2-6alkyl-O--, wherein the "C.sub.2-6alkyl" alone or
in combination signifies a saturated, linear- or branched chain
alkyl group containing 2 to 6, particularly 2 to 4 carbon atoms;
for example ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy,
2-butoxy, t-butoxy and the like.
[0022] The term "C.sub.1-2alkoxy" alone or in combination refers to
methoxy or ethoxy.
[0023] The term "C.sub.yH.sub.2y" alone or in combination signifies
a saturated, linear- or branched chain alkyl group containing 1 to
6, particularly 1 to 4 carbon atoms.
[0024] The term "amino", alone or in combination, refers to primary
(--NH.sub.2), secondary (--NH--) or tertiary amino
##STR00002##
[0025] The term "carbonyl" alone or in combination refers to the
group --C(O)--.
[0026] The term "carboxy" alone or in combination refers to the
group --COOH.
[0027] The term "cyano" alone or in combination refers to the group
--CN.
[0028] The term "halogen" means fluorine, chlorine, bromine or
iodine. Halogen is particularly fluorine or chlorine, more
particularly fluorine.
[0029] The term "hydroxy" alone or in combination refers to the
group --OH.
[0030] The term "sulfonyl" alone or in combination refers to the
group --S(O).sub.2--.
[0031] The term "morpholinyl" alone or in combination refers to the
group (i). When morpholine is formed between either of R.sup.4 or
R.sup.5 and R.sup.7 along with the atoms to which they are attached
it represents the group (ii):
##STR00003##
[0032] The term "pyrrolidinyl" alone or in combination refers to
the group (iii). When pyrrolidinyl is formed between either of
R.sup.4 or R.sup.5 and R.sup.7 along with the atoms to which they
are attached it represents the group (iv):
##STR00004##
[0033] The term "piperidinyl" alone or in combination refers to the
group (v). When piperidinyl is formed between either of R.sup.4 or
R.sup.5 and R.sup.7 along with the atoms to which they are attached
it represents the group (vi):
##STR00005##
[0034] The term "tautomers isomers" refers to constitutional
isomers of organic compounds that readily interconvert by a
chemical reaction called tautomerization. This reaction commonly
results in the formal migration of a hydrogen atom or proton,
accompanied by a switch of a single bond and adjacent double bond.
For example, compounds of general formular (I)
##STR00006##
and its tautomers isomer
##STR00007##
[0035] The term "pharmaceutically acceptable salt" refers to
conventional acid-addition salts or base-addition salts that retain
the biological effectiveness and properties of the compounds of
formula I and are formed from suitable non-toxic organic or
inorganic acids or organic or inorganic bases. Acid-addition salts
include for example those derived from inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, sulfamic acid, phosphoric acid and nitric acid, and those
derived from organic acids such as p-toluenesulfonic acid,
salicylic acid, methanesulfonic acid, oxalic acid, succinic acid,
citric acid, malic acid, lactic acid, fumaric acid, and the like.
Base-addition salts include those derived from ammonium, potassium,
sodium and, quaternary ammonium hydroxides, such as for example,
tetramethyl ammonium hydroxide. The chemical modification of a
pharmaceutical compound into a salt is a technique well known to
pharmaceutical chemists in order to obtain improved physical and
chemical stability, hygroscopicity, flowability and solubility of
compounds. It is for example described in Bastin R. J., et. al.,
Organic Process Research & Development 2000, 4, 427-435; or in
Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug
Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular
are the sodium salts of the compounds of formula I.
[0036] Compounds of the general formula I which contain one or
several chiral centers can either be present as racemates,
diastereomeric mixtures, or optically active single isomers. The
racemates can be separated according to known methods into the
enantiomers. Particularly, diastereomeric salts which can be
separated by crystallization are formed from the racemic mixtures
by reaction with an optically active acid such as e.g. D- or
L-tartaric acid, mandelic acid, malic acid, lactic acid or
camphorsulfonic acid.
Inhibitors of Hepatitis B Virus
[0037] The present invention provides (i) novel compounds having
the general formula I:
##STR00008##
wherein
[0038] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0039] R.sup.2 is phenyl, which is substituted by halogen;
[0040] R.sup.3 is thiazolyl, thienyl, imidazolyl, isoxazolyl or
pyridinyl; which is unsubstituted or substituted by halogen or
C.sub.1-6alkyl;
[0041] X is oxygen or --NR.sup.7;
[0042] R.sup.4 and R.sup.5 independently selected from hydrogen,
C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl; or
[0043] R.sup.4 and R.sup.5, together with the carbon atom to which
they are attached, form a 3 to 7 membered cycloalkyl; or
[0044] when X is --NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen
or C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5 along with
R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are
attached form a pyrrolidinyl, morpholinyl or piperidinyl ring,
which ring is unsubstituted or substituted by fluoro;
[0045] M is C.sub.1-6alkoxycarbonyl, carboxy,
diC.sub.1-6alkylaminoC.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, diC.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--,
##STR00009##
[0046] R.sup.7 is C.sub.1-6alkyl or trifluoroC.sub.1-6alkyl;
[0047] y is 1-6;
or pharmaceutically acceptable salts, or tautomerism isomers
thereof.
[0048] Another embodiment of present invention is (ii) a compound
of formula I, wherein
[0049] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0050] R.sup.2 is phenyl, which is once or twice substituted by
halogen;
[0051] R.sup.3 is 2-thiazolyl, which is unsubstituted or once
substituted by C.sub.1-6alkyl or halogen; or 2-thienyl or
2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl,
which is once substituted by C.sub.1-6alkyl; or 3-isoxazolyl, which
is unsubstituted or once substituted by C.sub.1-6alkyl;
[0052] X is oxygen or --NR.sup.7;
[0053] R.sup.4 and R.sup.5 are independently selected from
hydrogen, C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl; or
[0054] R.sup.4 and R.sup.5, together with the carbon atom to which
they are attached, form a 3 to 7 membered cycloalkyl; or
[0055] when X is --NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen
or C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5 along with
R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are
attached form a morpholinyl; or pyrrolidinyl or piperidinyl, which
is substituted by fluoro;
[0056] M is C.sub.1-6alkoxycarbonyl, carboxy,
diC.sub.1-6alkylamino-C.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, diC.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--,
##STR00010##
[0057] R.sup.7 is C.sub.1-6alkyl or trifluoroC.sub.1-6alkyl;
[0058] y is 1-6;
or pharmaceutically acceptable salts, or tautomerism isomers
thereof.
[0059] Further embodiment of present invention is (iii) a compound
of formula I, wherein
[0060] R.sup.1 is methoxycarbonyl, ethoxycarbonyl or cyano;
[0061] R.sup.2 is phenyl substituted once or twice by fluoro;
[0062] R.sup.3 is
##STR00011##
[0063] X is oxygen or --NR.sup.7;
[0064] R.sup.4 and R.sup.5 are independently selected from
hydrogen, methyl and trifluoromethyl; or
[0065] R.sup.4 and R.sup.5 together with the carbon atom to which
they are attached form cyclopropyl; or when X is --NR.sup.7, one of
R.sup.4 and R.sup.5 is hydrogen or methyl, and the other of R.sup.4
and R.sup.5 along with R.sup.7 and the atoms to which R.sup.4 or
R.sup.5 and R.sup.7 are attached form:
##STR00012##
[0066] M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,
aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,
methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxymethyl, hydroxypropyl, --C(Me).sub.2OH,
##STR00013##
[0067] R.sup.7 is methyl or trifluoroethyl;
or pharmaceutically acceptable salts, or tautomerism isomers
thereof.
[0068] Another embodiment of present invention is (iv) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0069] R.sup.1 is C.sub.1-2alkoxycarbonyl;
[0070] R.sup.2 is phenyl which is once substituted by halogen;
[0071] R.sup.3 is 2-thiazolyl;
[0072] X is oxygen;
[0073] R.sup.4 and R.sup.5 are independently selected from
hydrogen, C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl;
[0074] M is C.sub.1-6alkoxycarbonyl or carboxy.
[0075] Further embodiment of present invention is (v) a compound of
formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0076] R.sup.1 is methyoxycarbonyl;
[0077] R.sup.2 is 4-fluorophenyl;
[0078] R.sup.3 is thiazol-2-yl;
[0079] X is oxygen;
[0080] R.sup.4 and R.sup.5 are independently selected from
hydrogen, methyl and trifluoromethyl;
[0081] M is methoxycarbonyl or carboxy.
[0082] Another embodiment of present invention is (vi) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0083] R.sup.1 is C.sub.1-2alkoxycarbonyl;
[0084] R.sup.2 is phenyl which is once substituted by halogen;
[0085] R.sup.3 is 2-thiazolyl;
[0086] X is --N--C.sub.1-6alkyl or --N-trifluoroC.sub.1-6alkyl;
[0087] R.sup.4 is hydrogen;
[0088] R.sup.5 is hydrogen;
[0089] or R.sup.4 and R.sup.5, together with the carbon atom to
which they are attached, form a 3 to 7 membered cycloalkyl;
[0090] M is carboxy.
[0091] Further embodiment of present invention is (vii) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0092] R.sup.1 is methoxycarbonyl;
[0093] R.sup.2 is 4-fluorophenyl;
[0094] R.sup.3 is thiazol-2-yl;
[0095] X is --NCH.sub.3 or --NCH.sub.2CF.sub.3;
[0096] R.sup.4 is hydrogen;
[0097] R.sup.5 is hydrogen;
[0098] or R.sup.4 and R.sup.5, together with the carbon atom to
which they are attached, form cyclopropyl;
[0099] M is carboxy.
[0100] Another embodiment of present invention is (viii) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0101] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0102] R.sup.2 is phenyl which is once or twice substituted by
halogen;
[0103] R.sup.3 is 2-thiazolyl; or 2-pyridinyl, which is once
substituted by halogen; or 2-imidazolyl, which is once substituted
by C.sub.1-6alkyl;
[0104] X is --NR.sup.7;
[0105] one of R.sup.4 and R.sup.5 is hydrogen, and the other of
R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to which
R.sup.4 or R.sup.5 and R.sup.7 are attached form a morpholinyl;
[0106] M is C.sub.1-6alkoxycarbonyl, carboxy or
hydroxy-C.sub.yH.sub.2y--;
[0107] y is 1-6.
[0108] Further embodiment of present invention is (ix) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0109] R.sup.1 is methoxycarbonyl, ethoxycarbonyl or cyano;
[0110] R.sup.2 is 4-fluorophenyl or 3,4-difluorophenyl;
[0111] R.sup.3 is thiazol-2-yl, 5-fluoro-pyridin-2-yl or
1-methyl-imidiazolid-2-yl;
[0112] one of R.sup.4 and R.sup.5 along with R.sup.7 and the atoms
to which R.sup.4 or R.sup.5 and R.sup.7 are attached form:
##STR00014##
[0113] M is methoxycarbonyl, carboxy or hydroxymethyl-.
[0114] Another embodiment of present invention is (x) a compound of
formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0115] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0116] R.sup.2 is phenyl which is once or twice substituted by
halogen;
[0117] R.sup.3 is 2-thiazolyl, which is unsubstituted or once
substituted by C.sub.1-6alkyl or halogen; or 2-thienyl or
2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl,
which is once substituted by C.sub.1-6alkyl; or 3-isoxazolyl, which
is unsubstituted or once substituted by C.sub.1-6alkyl;
[0118] X is --NR.sup.7;
[0119] one of R.sup.4 and R.sup.5 is hydrogen or C.sub.1-6alkyl,
and the other of R.sup.4 and R.sup.5 along with R.sup.7 and the
atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached form a
pyrrolidinyl or piperidinyl, which is substituted by fluoro;
[0120] M is C.sub.1-6alkoxycarbonyl, carboxy,
diC.sub.1-6alkylaminoC.sub.2-6alkoxycarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, diC.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxy-C.sub.yH.sub.2y--,
##STR00015##
[0121] y is 1-6.
[0122] Further embodiment of present invention is (xi) a compound
of formula I or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0123] R.sup.1 is methoxycarbonyl, ethoxycarbonyl or cyano;
[0124] R.sup.2 is 4-fluorophenyl or 3,4-difluorophenyl;
[0125] R.sup.3 is
##STR00016##
[0126] X is --NR.sup.7;
[0127] one of R.sup.4 and R.sup.5 is hydrogen or methyl, and the
other of R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to
which R.sup.4 or R.sup.5 and R.sup.7 are attached form
##STR00017##
[0128] M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,
aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,
methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,
hydroxymethyl, hydroxypropyl, --C(Me).sub.2OH,
##STR00018##
[0129] Another embodiment of present invention is (xii) a compound
of formula I' or a pharmaceutically acceptable salt or tautomerism
isomers thereof,
##STR00019##
wherein
[0130] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0131] R.sup.2 is phenyl, which is substituted by halogen;
[0132] R.sup.3 is 2-thiazolyl which is unsubstituted or substituted
by C.sub.1-6alkyl or 2-pyridinyl, which is substituted by
halogen;
[0133] X is oxygen or --NR.sup.7;
[0134] R.sup.4 and R.sup.5 are independently selected from
hydrogen, C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl; or
[0135] R.sup.4 and R.sup.5, together with the carbon atom to which
they are attached, form a 3 to 7 membered cycloalkyl; or
[0136] when X is --NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen
or C.sub.1-6alkyl, and the other of R.sup.4 and R.sup.5 along with
R.sup.7 and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are
attached form a morpholinyl; or pyrrolidinyl substituted by
fluoro;
[0137] R.sup.6 is hydrogen or C.sub.1-6alkyl;
[0138] R.sup.7 is C.sub.1-6alkyl.
[0139] Further embodiment of present invention is (xiii) a compound
of formula I' or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0140] R.sup.1 is methoxycarbonyl or cyano;
[0141] R.sup.2 is phenyl substituted once or twice by fluoro;
[0142] R.sup.3 is thiazol-2-yl, 5-methyl-thiazol-2-yl or
5-fluoro-pyridin-2-yl; or;
[0143] X is oxygen or --NR.sup.7;
[0144] R.sup.4 and R.sup.5 are independently selected from
hydrogen, methyl and trifluoromethyl; or
[0145] R.sup.4 and R.sup.5 together with the carbon atom to which
they are attached form cyclopropyl; or
[0146] when X is --NR.sup.7, one of R.sup.4 and R.sup.5 is hydrogen
or methyl and the other of R.sup.4 and R.sup.5 along with R.sup.7
and the atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached
form
##STR00020##
[0147] R.sup.6 is hydrogen or methyl;
[0148] R.sup.7 is methyl.
[0149] Still further embodiment of present invention is (xiv) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0150] R.sup.1 is C.sub.1-2alkoxycarbonyl;
[0151] R.sup.2 is phenyl which is substituted by halogen;
[0152] R.sup.3 is 2-thiazolyl;
[0153] X is oxygen;
[0154] R.sup.4 and R.sup.5 are independently selected from
hydrogen, C.sub.1-6alkyl and trifluoroC.sub.1-6alkyl;
[0155] R.sup.6 is hydrogen or C.sub.1-6alkyl.
[0156] More further embodiment of present invention is (xv) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0157] R.sup.1 is methyoxycarbonyl;
[0158] R.sup.2 is 4-fluorophenyl;
[0159] R.sup.3 is thiazolidin-2-yl;
[0160] X is oxygen;
[0161] R.sup.4 and R.sup.5 are independently selected from
hydrogen, methyl and trifluoromethyl;
[0162] R.sup.6 is hydrogen or methyl.
[0163] Another further embodiment of present invention is (xvi) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0164] R.sup.1 is C.sub.1-2alkoxycarbonyl;
[0165] R.sup.2 is phenyl which is substituted by halogen;
[0166] R.sup.3 is 2-thiazolyl;
[0167] X is NC.sub.1-6alkyl;
[0168] R.sup.4 and R.sup.5, together with the carbon atom to which
they are attached, form a 3 to 7 membered cycloalkyl;
[0169] R.sup.6 is hydrogen.
[0170] Further embodiment of present invention is (xvii) a compound
of formula I' or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0171] R.sup.1 is methoxycarbonyl;
[0172] R.sup.2 is 4-fluorophenyl;
[0173] R.sup.3 is thiazolidin-2-yl;
[0174] X is --NCH.sub.3;
[0175] R.sup.4 and R.sup.5, together with the carbon atom to which
they are attached, form cyclopropyl;
[0176] R.sup.6 is hydrogen.
[0177] More further embodiment of present invention is (xviii) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0178] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0179] R.sup.2 is phenyl which is substituted by halogen;
[0180] R.sup.3 is 2-thiazolyl; or 2-pyridinyl, which is substituted
by halogen;
[0181] X is --NR.sup.7;
[0182] one of R.sup.4 and R.sup.5 is hydrogen or C.sub.1-6alkyl,
and the other of R.sup.4 and R.sup.5 along with R.sup.7 and the
atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached form
##STR00021##
[0183] R.sup.6 is hydrogen or C.sub.1-6alkyl.
[0184] Further embodiment of present invention is (xix) a compound
of formula I' or a pharmaceutically acceptable salt or tautomerism
isomers thereof, wherein
[0185] R.sup.1 is methoxycarbonyl or cyano;
[0186] R.sup.2 is 4-fluorophenyl or 3,4-difluorophenyl;
[0187] R.sup.3 is thiazolidin-2-yl or 5-fluoro-pyridin-2-yl., one
of R.sup.4 and R.sup.5 is hydrogen or methyl, and the other of
R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to which
R.sup.4 or R.sup.5 and R.sup.7 are attached form
##STR00022##
[0188] R.sup.6 is hydrogen or methyl.
[0189] Still further embodiment of present invention is (xx) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0190] R.sup.1 is C.sub.1-2alkoxycarbonyl or cyano;
[0191] R.sup.2 is phenyl which is substituted by halogen;
[0192] R.sup.3 is 2-thiazolyl which is unsubstituted or substituted
by C.sub.1-6alkyl or 2-pyridinyl, which is substituted by
halogen;
[0193] X is --NR.sup.7;
[0194] one of R.sup.4 and R.sup.5 is hydrogen or C.sub.1-6alkyl,
and the other of R.sup.4 and R.sup.5 along with R.sup.7 and the
atoms to which R.sup.4 or R.sup.5 and R.sup.7 are attached form
pyrrolidinyl substituted by fluoro;
[0195] R.sup.6 is hydrogen or C.sub.1-6alkyl.
[0196] Another further embodiment of present invention is (xxi) a
compound of formula I' or a pharmaceutically acceptable salt or
tautomerism isomers thereof, wherein
[0197] R.sup.1 is methoxycarbonyl or cyano;
[0198] R.sup.2 is 4-fluorophenyl or 3,4-difluorophenyl;
[0199] R.sup.3 is thiazol-2-yl, 5-methyl-thiazol-2-yl or
5-fluoro-pyridin-2-yl; or;
[0200] X is --NR.sup.7;
[0201] one of R.sup.4 and R.sup.5 is hydrogen or methyl, and the
other of R.sup.4 and R.sup.5 along with R.sup.7 and the atoms to
which R.sup.4 or R.sup.5 and R.sup.7 are attached form
##STR00023##
[0202] R.sup.6 is hydrogen or methyl.
[0203] Particular compounds of formula I, including their activity
data, NMR data and MS data are summarized in the following Table 1
and 2.
TABLE-US-00001 TABLE 1 Structure, name and activity data of
particular compounds HepDe19 Example EC50 CC50 No. Structure Name
(.mu.M) (.mu.M) 1 ##STR00024## 4-(4-Fluoro-phenyl)-6-
(1-methoxycarbonyl-1- methyl-ethoxymethyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 26.29 >100 2 ##STR00025## 6-(1-Carboxy-2,2,2-
trifluoro-ethoxymethyl)- 4-(4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 24.43 >100 3 ##STR00026## 6-{[(1-Carboxy-
cyclopropyl)-methyl- amino]-methyl}-4-(4- fluoro-phenyl)-4-methyl-
2-thiazol-2-yl-1,4- dihydro-pyrimidine-5- carboxylic acid methyl
ester 21.31 >100 4 ##STR00027## 4-[6-(4-Fluoro-phenyl)-
5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-
3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid
1.46 >100 5 ##STR00028## 4-[6-(4-Fluoro-phenyl)-
5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-
3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (S)-3-carboxylic
acid methyl ester 0.7 >100 6 ##STR00029##
4-[6-(4-Fluoro-phenyl)- 5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-
3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (S)-3-carboxylic
acid 1.2 >100 7 ##STR00030## (S)-4-[6-(4-Fluoro- phenyl)-5-
methoxycarbonyl-6- methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-
ylmethyl]-morpholine- (S)-3-carboxylic acid 0.77 >100 8
##STR00031## (S)-4-[6-(4-Fluoro- phenyl)-5- methoxycarbonyl-6-
methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-
ylmethyl]-morpholine- (R)-3-carboxylic acid 3.01 >100 9
##STR00032## 4-[6-(4-Fluoro-phenyl)- 2-(5-fluoro-pyridin-2-yl)-
5-methoxycarbonyl-6- methyl-3,6-dihydro- pyrimidin-4-ylmethyl]-
morpholine-(R)-3- carboxylic acid 4.18 >100 10 ##STR00033##
4-[6-(4-Fluoro-phenyl)- 2-(5-fluoro-pyridin-2-yl)-
5-methoxycarbonyl-6- methyl-3,6-dihydro- pyrimidin-4-ylmethyl]-
morpholine-(S)-3- carboxylic acid 7.04 >100 11 ##STR00034##
6-(2-(S)-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 0.46 95.5 12 ##STR00035##
6-(2-(R)-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 6.59 82 13 ##STR00036##
(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
0.15 >100 14 ##STR00037## (S)-6-((S)-2-Carboxy-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(3,4- difluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.2 >100 15 ##STR00038## 4-[(S)-6-(3,4-Difluoro-
phenyl)-5- methoxycarbonyl-6- methyl-2-thiazol-2-yl-
3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid
methyl ester 0.56 >100 16 ##STR00039## 4-[6-(3,4-Difluoro-
phenyl)-5- methoxycarbonyl-6- methyl-2-thiazol-2-yl-
3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid
0.25 >100 17 ##STR00040## 6-(4,4-Difluoro-2- methoxycarbonyl-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-2-(5-
fluoro-pyridin-2-yl)-4- methyl-1,4-dihydro- pyrimidine-5-carboxylic
acid methyl ester 0.59 90 18 ##STR00041## 6-(2-Carboxy-4,4-
difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro- phenyl)-2-(5-fluoro-
pyridin-2-yl)-4-methyl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.57 25 19 ##STR00042## 6-(2-Carboxy-4,4-
difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2-(5- methyl-thiazol-2-yl)-1,4-
dihydro-pyrimidine-5- carboxylic acid methyl ester 16.7 >100 20
##STR00043## (S)-6-((S)-2-Carboxy- 4,4-difluoro-2-methyl-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 2.8 >100 21 ##STR00044## (S)-1-[(S)-5-Cyano-6-(4-
fluoro-phenyl)-6-methyl- 2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-
ylmethyl]-4,4-difluoro- pyrrolidine-2-carboxylic acid 21 >100 22
##STR00045## (S)-4-[5-Cyano-6-(3,4- difluoro-phenyl)-6-
methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-
ylmethyl]-morpholine-3- carboxylic acid 20.4 >100 23
##STR00046## (S)-1-[(S)-5-Cyano-6- (3,4-difluoro-phenyl)-6-
methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-
ylmethyl]-4,4-difluoro- pyrrolidine-2-carboxylic acid 7 >100 24
##STR00047## (S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(3,4- difluoro-phenyl)-4- methyl-2-thiazol-2-yl-
1,4-dihydro-pyrimidine- 5-carboxylic acid ethyl ester 0.8 100 25
##STR00048## (S)-6-(2-Carboxy-5,5- difluoro-piperidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
1.09 100 26 ##STR00049## (S)-6-(2-Carboxy-4,4-
difluoro-piperidin-1- ylmethyl)4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
1.97 100 27 ##STR00050## (S)-6-((S)-2-Carboxy-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2-(1- methyl-1H-imidazol-2- yl)-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 2.72 55.8 28 ##STR00051##
(R)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(3,4-
difluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-
5-carboxylic acid ethyl ester 7.48 100 29 ##STR00052##
(S)-4-[6-(3,4-Difluoro- phenyl)-5- ethoxycarbonyl-6-
methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-
ylmethyl]-morpholine-3- carboxylic acid 3.98 100 30 ##STR00053##
(S)-4-[(S)-6-(4-Fluoro- phenyl)-5- methoxycarbonyl-6-
methyl-2-(1-methyl-1H- imidazol-2-yl)-3,6- dihydro-pyrimidin-4-
ylmethyl]-morpholine-3- carboxylic acid 6.77 100 31 ##STR00054##
(R)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-(4-
methyl-thiazol-2-yl)-1,4- dihydro-pyrimidine-5- carboxylic acid
methyl ester 1.67 100 32 ##STR00055## (S)-6-((S)-2-Carboxy-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2-(4- methyl-thiazol-2-yl)-1,4-
dihydro-pyrimidine-5- carboxylic acid methyl ester 0.13 75 33
##STR00056## (S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-2-(5-chloro- thiazol-2-yl)-4-(4-fluoro-
phenyl)-4-methyl-1,4- dihydro-pyrimidine-5- carboxylic acid methyl
ester 2.07 80 34 ##STR00057## (S)-6-((2S,4R)-2- Carboxy-4-fluoro-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 2.84 100 35 ##STR00058## 6-((S)-2-Carboxy-4,4-
difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-2-isoxazol-3-yl- 4-methyl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 15 100 36 ##STR00059##
(R)-6-((S)-2-Carboxy- 4,4-difluoro-2-methyl-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 7.49 100 37 ##STR00060## (S)-6-((S)-2-Carboxy-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2-(5- methyl-thiazol-2-yl)-1,4-
dihydro-pyrimidine-5- carboxylic acid methyl ester 0.47 85 38
##STR00061## (S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-2-(5-fluoro-
thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 2.03 39 ##STR00062## (S)-6-((2S,4S)-2-
Carboxy-4-fluoro- pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 10.5 100 40 ##STR00063## 6-((S)-2-Carboxy-4,4-
difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2-(5- methyl-isoxazol-3-yl)-
1,4-dihydro-pyrimidine- 5-carboxylic acid methyl ester 5.39 100 41
##STR00064## (S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-2-(3-fluoro-
thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.285 100 42 ##STR00065## (R)-6-((S)-2-Carboxy-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-2-(3-fluoro- thiophen-2-yl)-4-methyl-
1,4-dihydro-pyrimidine- 5-carboxylic acid methyl ester 6.81 100 43
##STR00066## (S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-2-(4-fluoro-
thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.131 100 44 ##STR00067## (S)-6-{[Carboxymethyl-
(2,2,2-trifluoro-ethyl)- amino]-methyl}-4-(4-
fluoro-phenyl)-4-methyl- 2-thiazol-2-yl-1,4- dihydro-pyrimidine-5-
carboxylic acid methyl ester 21.5 100 45 ##STR00068##
(S)-6-((S)-4,4-Difluoro- 2-methoxycarbonyl-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.783 100 46 ##STR00069## (S)-6-[(S)-2-(2-
Dimethylamino- ethoxycarbonyl)-4,4- difluoro-pyrrolidin-1-
ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
2.13 100 47 ##STR00070## (S)-6-(2-Carbamoyl-4,4-
difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
0.048 100 48 ##STR00071## (S)-6-((S)-2-Carbamoyl-
4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 0.08 100 49 ##STR00072##
(S)-6-((S)-2- Dimethylcarbarnoyl-4,4- difluoro-pyrrolidin-1-
ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
0.29 100 50 ##STR00073## 6-((S)-4,4-Difluoro-2- methylcarbamoyl-
pyrrolidin-1-ylmethyl)-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.606 100 51 ##STR00074## (S)-6-((S)-4,4-Difluoro- 2-
methanesulfonylaminocarbonyl- pyrrolidin-1- ylmethyl)-4-(4-fluoro-
phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 18.16 90 52 ##STR00075##
(S)-6-[(S)-4,4-Difluoro- 2-(thiazol-2- ylcarbamoyl)-pyrrolidin-
1-ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2-
thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
5.426 4.07 53 ##STR00076## 4-(4-Fluoro-phenyl)-6-
((R)-3-hydroxymethyl- morpholin-4-ylmethyl)-
4-methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 1.75 100 54 ##STR00077## (S)-6-[(S)-4,4-Difluoro-
2-(1-hydroxy-1-methyl- ethyl)-pyrrolidin-1- ylmethyl]-4-(4-fluoro-
phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-
pyrimidine-5-carboxylic acid methyl ester 0.7 50.4 55 ##STR00078##
(S)-6-((S)-4,4-Difluoro- 2-hydroxymethyl- pyrrolidin-1-ylmethyl)-4-
(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-
5-carboxylic acid methyl ester 0.067 100 56 ##STR00079##
(S)-6-[4,4-Difluoro-2-(3- hydroxy-propyl)-
pyrrolidin-1-ylmethyl]-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 0.66 90 57 ##STR00080## (S)-6-[(S)-4,4-Difluoro-
2-(5-methyl- [1,3,4]oxadiazol-2-yl)- pyrrolidin-1-ylmethyl]-4-
(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-
5-carboxylic acid methyl ester 1.558 100 58 ##STR00081##
(S)-6-[(S)-4,4-Difluoro- 2-(1H-tetrazol-5-yl)-
pyrrolidin-1-ylmethyl]-4- (4-fluoro-phenyl)-4-
methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid
methyl ester 1.017 100 59 ##STR00082## (S)-6-[(S)-4,4-Difluoro-
2-(3-methyl- [1,2,4]oxadiazol-5-yl)- pyrrolidin-1-ylmethyl]-4-
(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-
5-carboxylic acid methyl ester 1.238 65.3
TABLE-US-00002 TABLE 2 NMR and MS data of particular compounds
Example No. 1H NMR data MW 1 1H NMR (MeOD-d.sub.4, 400 MHz), 7.95
(d, 1H, J = 3.2 Hz), MS: calc'd 462 (MH+), 7.75 (d, 1H, J = 3.2
Hz), 7.49-7.45 (m, 2H), exp 462 (MH+). 7.04 (t, 2H, J = 8.8 Hz),
4.71-4.62 (m, 2H), 3.80 (s, 3H), 3.43 (s, 3H), 1.92 (s, 3H), 1.57
(s, 6H). 2 1H NMR (MeOD-d.sub.4, 400 MHz), 7.94 (d, 1H, J = 2.8
Hz), MS: calc'd 488 (MH+), 7.93 (d, 1H, J = 2.8 Hz), 7.53-7.49 (m,
2H), exp 488 (MH+). 7.07-7.03 (m, 2H), 4.85-4.78 (m, 2H), 4.40-4.37
(m, 1H), 3.44 (s, 3H), 1.94 (s, 3H). 3 1H NMR (MeOD-d.sub.4, 400
MHz), 8.12 (d, 1H, J = 3.2 Hz), MS: calc'd 459 (MH+), 8.06 (d, 1H,
J = 3.2 Hz), 7.63-7.60 (m, 2H), exp 459 (MH+). 7.15 (t, 2H, J = 8.8
Hz), 4.30 (s, 2H), 3.51 (s, 3H), 2.79 (s, 3H), 2.10 (s, 3H),
1.52-1.51 (m, 2H), 1.38-1.37 (m, 2H). 4 1H NMR (CD3OD, 500 MHz)
.delta. 8.10 (d, 1H), 8.03 (d, LC-MS: calc'd 1H), 7.64-7.61 (m,
2H), 7.15-7.12 (m, 2H), 475 (MH+), exp 475 (MH+). 4.32-4.31 (m,
2H), 4.18-4.14 (m, 2H), 3.99-3.72 (m, 3H), 3.51-3.49 (m, 4H), 3.02
(m, 1H), 2.11 (d, 3H). 5 1H NMR (MeOD-d4, 400 MHz), 7.95 (d, 1H, J
= 3.2 Hz), MS: calc'd (MH+) 489 7.74 (d, 1H, J = 3.2 Hz), 7.48-7.45
(m, 2H), exp (MH+) 489. 7.03 (t, 2H, J = 8.8 Hz), 4.05-3.87 (m,
4H), 3.78-3.71 (m, 5H), 3.49-3.45 (m, 1H), 3.42 (s, 3H), 3.14-3.07
(m, 1H), 2.52-2.42 (m, 1H), 1.99 (s, 3H). 6 1H NMR (MeOD-d4, 400
MHz), 7.95 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 475 7.74 (d, 1H, J
= 3.2 Hz), 7.48-7.45 (m, 2H), exp (MH+) 475. 7.03 (t, 2H, J = 8.8
Hz), 4.35-4.21 (m, 2H), 4.17-4.05 (m, 2H), 3.96-3.84 (m, 2H),
3.75-3.70 (m, 1H), 3.58-3.47 (m, 4H), 2.97-2.89 (m, 1H), 1.99 (s,
3H). 7 1H NMR (MeOD-d4, 400 MHz), 8.07 (d, 1H, J = 3.2 Hz), MS:
calc'd (MH+) 475 7.97 (d, 1H, J = 3.2 Hz), 7.62-7.59 (m, 2H), exp
(MH+) 475. 7.13 (t, 2H, J = 8.8 Hz), 4.31 (s, 2H), 4.17-4.05 (m,
2H), 3.96-3.84 (m, 3H), 3.62-3.55 (m, 1H), 3.51 (s, 3H), 3.03-2.99
(m, 1H), 2.09 (s, 3H). 8 1H NMR (MeOD-d4, 400 MHz), 8.07 (d, 1H, J
= 3.2 Hz), MS: calc'd (MH+) 475 7.97 (d, 1H, J = 3.2 Hz), 7.62-7.59
(m, 2H), exp (MH+) 475. 7.13 (t, 2H, J = 8.8 Hz), 4.28 (dd, 2H, J1
= 33.4 Hz, J2 = 16.4 Hz), 4.17-4.05 (m, 2H), 3.96-3.84 (m, 3H),
3.62-3.50 (m, 4H), 3.03-2.99 (m, 1H), 2.09 (s, 3H). 9 1H NMR
(MeOD-d4, 400 MHz), 8.60 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 487
8.53-8.50 (m, 1H), 7.80-7.78 (m, 1H), exp (MH+) 487. 7.59-7.56 (m,
2H), 7.11-7.07 (m, 2H), 4.11-4.01 (m, 3H), 3.99-3.97 (m, 1H),
3.88-3.84 (m, 1H), 3.82-3.80 (m, 1H), 3.59-3.56 (m, 1H), 3.49 (s,
3H), 3.44-3.38 (m, 1H), 2.89-2.80 (m, 1H), 2.05 (s, 3H). 10 1H NMR
(MeOD-d4, 400 MHz), 8.60 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 487
8.55-8.53 (m, 1H), 7.83-7.79 (m, 1H), exp (MH+) 487. 7.60-7.57 (m,
2H), 7.13-7.08 (m, 2H), 4.17-4.08 (m, 3H), 4.01-3.97 (m, 1H),
3.91-3.84 (m, 1H), 3.82-3.80 (m, 1H), 3.60-3.58 (m, 1H), 3.50 (s,
3H), 3.44-3.38 (m, 1H), 2.89-2.80 (m, 1H), 2.06 (s, 3H). 11 1H NMR
(CD3OD, 500 MHz) .delta. 8.15-8.15 (m, 2H), LC-MS: calc'd 7.67-7.62
(m, 2H), 7.19-7.14 (m, 2H), 4.16-3.90 (m, 495 (MH+), exp 495 (MH+).
3H), 3.65-3.61 (m, 1H), 3.51 (d, 3H), 3.25-3.20 (m, 1H), 2.86-2.82
(m, 1H), 2.63-2.61 (m, 1H), 2.15 (d, 3H). 12 1H NMR (CD3OD, 500
MHz) .delta. 7.96 (s, 1H), 7.77 (s, LC-MS: calc'd 1H), 7.52 (d,
2H), 7.06 (d, 2H), 4.00-3.95 (m, 3H), 495 (MH+), exp 495 (MH+).
3.63-3.61 (m, 1H), 3.46 (s, 3H), 3.20-3.18 (m, 1H), 2.79 (m, 1H),
2.67 (m, 1H), 1.95 (s, 3H). 13 1H NMR (MeOD-d4, 400 MHz), 8.21 (s,
2H), MS: calc'd (MH+) 495 7.67-7.65 (m, 2H), 7.21-7.17 (m, 2H,),
4.16 (d, 1H, J = 15.6 Hz), exp (MH+) 495. 4.02 (t, 1H, J = 8.0 Hz),
3.93 (d, 1H, J = 15.6 Hz), 3.72-3.61 (m, 1H), 3.53 (s, 3H),
3.29-3.19 (m, 1H), 2.91-2.78 (m, 1H), 2.59-2.55 (m, 1H), 2.17 (s,
3H). 14 1H NMR (MeOD-d4, 400 MHz), 8.11 (d, 1H, J = 3.2 Hz), MS:
calc'd (MH+) 513.1, 8.04 (d, 1H, J = 3.2 Hz), 7.55-7.49 (m, 1H),
exp (MH+) 513.1 7.40-7.38 (m, 1H), 7.34-7.29 (m, 1H,), 4.15 (d, 1H,
J = 15.6 Hz), 4.02-3.98 (m, 2H), 3.74-3.61 (m, 1H), 3.53 (s, 3H),
3.30-3.23 (m, 1H), 2.91-2.78 (m, 1H), 2.65-2.49 (m, 1H), 2.08 (s,
3H). 15 1H NMR (MeOD-d4, 400 MHz), 8.17 (d, 1H, J = 3.2 Hz), MS:
calc'd (MH+) 507, 8.10 (d, 1H, J = 3.2 Hz), 7.62-7.53 (m, 1H), exp
(MH+) 507. 7.45-7.39 (m, 1H), 7.37-7.25 (m, 1H,), 4.25-4.18 (m,
2H), 4.10-4.06 (m, 2H), 3.96-3.94 (m, 1H), 3.89-3.86 (m, 2H), 3.84
(s, 3H), 3.55 (s, 3H), 3.50-3.40 (m, 1H), 2.90-2.87 (m, 1H), 2.08
(s, 3H). 16 1H NMR (MeOD-d4, 400 MHz), 8.06 (d, 1H, J = 3.2 Hz),
MS: calc'd (MH+) 493 7.95 (d, 1H, J = 3.2 Hz), 7.53-7.51 (m, 1H),
exp (MH+) 493. 7.40-7.37 (m, 1H), 7.31-7.25 (m, 1H,), 4.39-4.28 (m,
2H), 4.15-4.12 (m, 2H), 3.58-3.50 (m, 4H), 3.05-3.01 (m, 1H), 2.05
(s, 3H). 17 1H NMR (MeOD-d4, 400 MHz), 8.80 (d, 1H, J = 2.8 Hz),
MS: calc'd (MH+) 521 8.43-8.40 (m, 1H), 8.01-7.98 (m, 1H), exp
(MH+) 521 7.70-7.66 (m, 2H), 7.24-7.18 (m, 2H), 4.16-3.94 (m, 3H),
3.84-3.83 (m, 3H), 3.61-3.55 (m, 4H), 3.22-3.18 (m, 1H), 2.91-2.78
(m, 1H), 3.61-3.48 (m, 1H), 2.24-2.21 (m, 3H). 18 1H NMR (MeOD-d4,
400 MHz), 8.77 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 507 8.46-8.42
(m, 1H), 8.00-7.95 (m, 1H), exp (MH+) 507. 7.70-7.66 (m, 2H),
7.23-7.19 (m, 2H), 4.16 (d, 1H, J = 16 Hz), 3.98 (t, 1H, J = 8.8
Hz), 3.88 (d, 1H, J = 16 Hz), 3.60-3.56 (m, 4H), 3.28-3.15 (m, 1H),
2.93-1.79 (m, 1H), 2.58-44 (m, 1H), 2.21 (s, 3H). 19 .sup.1H NMR
(400 MHz, MeOH-d4) 7.87 (s, 1 H), MS: calc'd (MH+) 509 7.47-7.51
(m, 2 H), 7.01-7.06 (m, 2 H), 3.92-4.30 (m, 2 exp (MH+) 509. H),
3.49 (s, 3 H), 3.40 (m, 2H), 2.35-2.90 (m, 3 H), 2.36 (s, 3 H),
1.85 (s, 3 H). 20 .sup.1H NMR (400 MHz, MeOH-d4) 8.02-8.18 (m, 2
H), MS: calc'd (MH+) 509 7.54-7.65 (m, 2 H), 7.08-7.20 (m, 2 H),
exp (MH+) 509. 3.88-4.14 (m, 2 H), 3.49 (s, 3 H), 2.75-2.90 (m, 2
H), 2.41-2.57 (m, 2 H), 2.09 (s, 3 H), 1.56 (s, 3 H). 21 1H NMR
(MeOD-d4, 400 MHz), 7.98 (d, 1H, J = 3.2 Hz), MS: calc'd (M+ + H)
462, 7.81 (d, 1H, J = 3.2 Hz), 7.57-7.53 (m, 2H), exp (M+ + H) 462.
7.14 (t, 2H, J = 8.8 Hz), 3.92-3.74 (m, 3H), 3.49-3.41 (m, 1H),
3.18-3.08 (m, 1H), 2.81-2.69 (m, 1H), 2.55-2.49 (m, 1H), 1.89 (s,
3H). 22 1H NMR (MeOD-d4, 400 MHz), 8.03 (d, 1H, J = 3.2 Hz), MS:
calc'd (MH+) 460 7.88 (d, 1H, J = 3.2 Hz), 7.45-7.42 (m, 1H), exp
(MH+) 460. 7.36-7.30 (m, 2H), 4.16-4.01 (m, 4H), 3.96-3.82 (m, 3H),
3.43-3.37 (m, 1H), 2.93-2.86 (m, 1H), 1.92 (s, 3H). 23 1H NMR
(MeOD-d4, 400 MHz), 7.98 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 480
7.81 (d, 1H, J = 3.2 Hz), 7.44-7.39 (m, 1H), exp (MH+) 480.
7.35-7.27 (m, 2H), 3.92-3.74 (m, 3H), 3.49-3.41 (m, 1H), 3.18-3.08
(m, 1H), 2.81-2.69 (m, 1H), 2.52-2.46 (m, 1H), 1.86 (s, 3H). 24
.sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.95 (d, J = 3.01 Hz, MS:
calc'd (MH+) 527 1 H), 7.73 (d, J = 3.26 Hz, 1 H), 7.37 (ddd, J =
12.17, exp (MH+) 527. 7.78, 1.88 Hz, 1 H), 7.28 (br. s., 1 H),
7.17-7.26 (m, 1 H), 3.85-4.06 (m, 4 H) 3.69 (t, J = 8.16 Hz, 1 H)
3.48-3.61 (m, 1 H) 2.99-3.18 (m, 1 H) 2.61-2.78 (m, 1 H) 2.39-2.58
(m, 1 H) 1.89 (s, 3 H)1.04 (t, J = 7.03 Hz, 3 H). 25 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 8.25 (s, 2 H), MS: calc'd (MH+) 509
7.58-7.75 (m, 2 H), 7.19 (t, J = 8.66 Hz, 2 H), exp (MH+) 509.
3.93-4.19 (m, 2 H), 3.75 (d, J = 1.25 Hz, 1 H), 3.53 (s, 3 H),
3.35-3.46 (m, 1 H), 2.88-3.10 (m, 1 H), 1.85-2.41 (m, 7 H). 26
.sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.97 (d, J = 3.01 Hz, MS:
calc'd (MH+) 509 1 H), 7.72 (d, J = 3.01 Hz, 1 H), 7.49 (dd, J =
8.66, exp (MH+) 509. 5.40 Hz, 2 H), 7.04 (t, J = 8.78 Hz, 2 H),
3.72-3.87 (m, 2 H), 3.44 (s, 3 H), 3.25-3.31 (m, 1 H), 3.14 (d, J =
12.05 Hz, 1 H), 2.47-2.60 (m, 1 H), 1.97-2.41 (m, 4 H), 1.89 (s, 3
H). 27 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.53 (dd, J = 8.66, MS:
calc'd (MH+) 492 5.40 Hz, 2 H), 7.19 (s, 1 H), 6.98-7.11 (m, 3 H),
exp (MH+) 492. 3.77-3.96 (m, 5 H), 3.51-3.65 (m, 2 H), 3.46 (s, 3
H), 3.01 (td, J = 15.12, 11.42 Hz, 1 H), 2.64 (qd, J = 12.84, 8.16
Hz, 1 H), 2.32-2.50 (m, 1 H), 1.84-2.00 (m, 3 H). 28 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 7.95 (d, J = 3.01 Hz, MS: calc'd (MH+) 527
1 H), 7.72 (d, J = 3.26 Hz, 1 H), 7.36 (ddd, J = 12.30, exp (MH+)
527. 7.78, 2.26 Hz, 1 H), 7.27 (br. s., 1 H), 7.21 (dd, J = 10.29,
8.28 Hz, 1 H), 3.80-4.02 (m, 4 H), 3.44-3.58 (m, 2 H), 2.87 (td, J
= 15.56, 11.04 Hz, 1 H), 2.54-2.73 (m, 1 H), 2.35-2.52 (m, 1 H),
1.89 (s, 3 H), 1.03 (t, J = 7.03 Hz, 3 H). 29 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 8.10 (d, J = 2.76 Hz, MS: calc'd (MH+) 507
1 H), 7.99-8.06 (m, 1 H), 7.52-7.63 (m, 1 H), exp (MH+) 507. 7.44
(d, J = 7.03 Hz, 1 H), 7.22-7.38 (m, 1 H), 5.36 (t, J = 4.64 Hz, 1
H), 4.30-4.54 (m, 2 H), 4.09-4.22 (m, 3 H), 3.86-4.06 (m, 4 H),
3.55-3.73 (m, 1 H), 1.98-2.15 (m, 3 H), 0.92 (t, J = 6.78 Hz, 3 H).
30 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.52 (dd, J = 8.66, MS:
calc'd (MH+) 472 5.40 Hz, 2 H), 7.21 (s, 1 H), 6.98-7.11 (m, 3 H),
exp (MH+) 472. 3.72-4.06 (m, 10 H) 3.48 (s, 3 H), 3.12-3.23 (m, 1
H), 2.61 (ddd, J = 11.54, 8.16, 3.14 Hz, 1 H), 1.93 (s, 3 H). 31
.sup.1H NMR (CDCl.sub.3, 400 MHz), 7.47-7.59 (m, 2 H), MS: calc'd
(MH+) 509 7.18 (s, 1 H), 7.01-7.12 (m, 2 H), 4.12 (d, J = 14.56 Hz,
exp (MH+) 509. 1 H), 3.98 (dd, J = 9.79, 6.02 Hz, 1 H), 3.61 (d, J
= 14.31 Hz, 1 H), 3.53 (d, J = 10.54 Hz, 1 H), 3.47 (s, 3 H), 3.12
(br. s., 1 H), 2.71-2.90 (m, 1 H), 2.50-2.67 (m, 1 H), 2.46 (s, 3
H), 1.98-2.07 (m, 3 H). 32 .sup.1H NMR (CDCl.sub.3, 400 MHz),
7.49-7.61 (m, 2 H), MS: calc'd (MH+) 509 7.17 (s, 1 H), 7.05-7.13
(m, 2 H), 4.14 (d, J = 14.31 Hz, exp (MH+) 509. 1 H), 3.92 (dd, J =
9.66, 6.15 Hz, 1 H), 3.49-3.58 (m, 2 H), 3.47 (s, 3 H), 3.18-3.33
(m, 1 H), 2.81 (dd, J = 14.68, 9.66 Hz, 1 H), 2.57 (dd, J = 12.30,
6.02 Hz, 1 H), 2.46 (s, 3 H), 2.01 (s, 3 H). 33 .sup.1H NMR
(CDCl.sub.3, 400 MHz), 7.71 (s, 1 H), MS: calc'd (MH+) 529
7.41-7.58 (m, 2 H), 7.00-7.17 (m, 2 H), 4.12-4.21 (m, 1 H), exp
(MH+) 529. 3.93-4.03 (m, 1 H), 3.70-3.78 (m, 1 H), 3.54 (s, 4 H),
3.15-3.30 (m, 1 H), 2.75-2.90 (m, 1 H), 2.52-2.69 (m, 1 H), 2.15
(s, 3 H). 34 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.93-8.01 (m, 1
H), MS: calc'd (MH+) 477 7.79-7.89 (m, 1 H), 7.55-7.67 (m, 2 H),
exp (MH+) 477. 7.06-7.17 (m, 2 H), 5.45-5.58 (m, 1 H), 5.31-5.45
(m, 1 H), 3.81-4.12 (m, 2 H), 3.48 (s, 3 H), 2.70-2.94 (m, 2 H),
2.31-2.55 (m, 2 H), 1.96-2.10 (m, 3 H). 35 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 8.80-8.87 (m, 1 H), MS: calc'd (MH+) 479
7.48-7.59 (m, 2 H), 7.10 (s, 3 H), 3.77-4.10 (m, 3 exp (MH+) 479.
H), 3.48-3.62 (m, 1 H), 3.46 (d, J = 4.27 Hz, 3 H), 3.00-3.23 (m, 1
H), 2.70-2.87 (m, 1 H), 2.42-2.64 (m, 1 H), 1.98 (d, J = 3.51 Hz, 3
H). 36 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.14-8.17 (m, 1 H), MS:
calc'd (MH+) 509 8.10-8.13 (m, 1 H), 7.58-7.65 (m, 2 H), exp (MH+)
509. 7.11-7.19 (m, 2 H), 3.99-4.06 (m, 2 H), 3.52 (s, 4 H),
3.35-3.38 (m, 1 H), 2.75-2.89 (m, 1 H), 2.41-2.56 (m, 1 H), 2.12
(s, 3 H), 1.56 (s, 3 H). 37 .sup.1H NMR (MeOD-d.sub.4, 400 MHz),
7.62 (s, 1H), 7.50 (dd, MS: calc'd (MH+) 509 J = 5.40, 8.66 Hz,
2H), 7.05 (t, J = 8.78 Hz, 2H), exp (MH+) 509. 3.90 (d, J = 5.77
Hz, 2H), 3.65 (t, J = 8.28 Hz, 1H), 3.39-3.58 (m, 7H), 3.05 (d, J =
11.54 Hz, 1H), 2.68 (dd, J = 7.91, 13.18 Hz, 1H), 2.48-2.58 (m,
4H). 38 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.62 (t, J = 3.9 Hz, 1
MS: calc'd (MH+) 512 H), 7.46 (dd, J = 8.7, 5.4 Hz, 2 H), 7.02 (t,
J = 8.8 Hz, exp (MH+)512. 2 H), 6.59 (dd, J = 4.3, 1.8 Hz, 1 H),
3.86 (d, J = 14.3 Hz, 2 H), 3.75 (t, J = 6.5 Hz, 1 H), 3.41-3.62
(m, 6 H), 3.06 (q, J = 7.3 Hz, 2 H), 2.61 (dd, J = 16.1, 7.5 Hz, 1
H), 2.26-2.45 (m, 1 H). 39 .sup.1H NMR (MeOD-d.sub.4, 400 MHz),
7.96 (d, J = 3.0 Hz, 1 MS: calc'd (MH+) 477 H), 7.85 (d, J = 3.3
Hz, 1 H), 7.65 (dd, J = 8.8, 5.3 Hz, exp (MH+)477. 2 H), 7.13 (t, J
= 8.8 Hz, 2 H), 5.29-5.52 (m, 1 H), 4.62 (d, J = 14.1 Hz, 1 H),
4.39 (d, J = 9.5 Hz, 1 H), 4.08-4.27 (m, 2 H), 3.44-3.69 (m, 5 H),
2.54-2.97 (m, 3 H). 40 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.51
(dd, J = 8.2, 5.4 Hz, MS: calc'd (MH+) 493
2 H), 7.06 (q, J = 8.8 Hz, 2 H), 6.61 (d, J = 4.0 Hz, exp (MH+)493.
1 H), 3.72-3.96 (m, 2 H), 3.40-3.63 (m, 6 H), 2.82-3.12 (m, 2 H),
2.57-2.76 (m, 1 H), 2.35-2.52 ppm (m, 5 H). 41 .sup.1H NMR
(CDCl.sub.3, 400 MHz), 7.53 (m, 2H), 7.43 (m, MS: calc'd (MH+) 512
1H), 7.08 (m, 2H), 6.85 (d, 1H, J = 5.6 Hz), 4.08 (d, exp (MH+)
512. 1H, J = 14.2 Hz), 3.86 (1H, m), 3.57 (d, 1H, J = 14.2 Hz),
3.50 (1H, m), 3.45 (3H, s), 3.20 (1H, m), 2.77 (1H, m), 2.54 (1H,
m), 1.97 (3H, s). 42 .sup.1H NMR (CDCl.sub.3, 400 MHz), 7.52 (m,
2H), MS: calc'd (MH+) 512 7.42 (m, 1H), 7.06 (m, 2H), 6.84 (d, 1H,
J = 5.6 Hz), exp (MH+) 512. 4.05 (d, 1H, J = 14.2 Hz), 3.91 (m,
1H), 3.64 (d, 1H, J = 14.2 Hz), 3.47 (m, 1H), 3.45 (3H, s), 3.10
(m, 1H), 2.78 (m, 1H), 2.55 (m, 1H), 1.98 (s, 3H). 43 .sup.1H NMR
(CDCl.sub.3, 400 MHz), 7.70 (s, 1H), 7.45 (m, MS: calc'd (MH+) 512
2H), 7.00 (m, 3H), 4.07 (d, 1H, J = 15.0 Hz), 3.72 (m, exp (MH+)
512. 1H), 3.55 (s, 3H), 3.54-3.34 (m, 2H), 3.07 (m, 1H), 2.68 (m,
1H), 2.32 (m, 1H), 2.01 (s, 3H). 44 .sup.1H NMR (MeOD-d.sub.4, 400
MHz), .quadrature.7.95 (d, J = 3.26 Hz, MS: calc'd (MH+) 501 1 H),
7.75 (d, J = 3.26 Hz, 1 H), 7.44-7.54 (m, 2 H), exp (MH+) 501. 7.05
(t, J = 8.78 Hz, 2 H), 3.90-4.09 (m, 2H), 3.63 (s, 2 H), 3.45 (s, 3
H), 1.91 (s, 3 H). 45 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.23 (d,
J = 0.75 Hz, MS: calc'd (MH+) 509 2 H), 7.61-7.70 (m, 2 H), 7.19
(t, J = 8.66 Hz, 2 H), exp (MH+) 509. 4.06-4.16 (m, 1 H), 4.02 (t,
J = 8.03 Hz, 1H), 3.92 (d, J = 15.81 Hz, 1 H), 3.82 (s, 3 H), 3.59
(d, J = 10.79 Hz, 1 H), 3.53 (s, 3 H), 3.12-3.28 (m, 1 H),
2.72-2.89 (m, 1 H), 2.43-2.61 (m, 1 H), 2.16 (s, 3 H). 46 .sup.1H
NMR (MeOD-d.sub.4, 400 MHz), 7.94 (d, J = 3.01 Hz, MS: calc'd (MH+)
566 1 H), 7.74 (d, J = 3.01 Hz, 1 H), 7.49 (br. s., 2 H), exp (MH+)
566. 7.05 (t, J = 8.78 Hz, 2 H), 4.33 (t, J = 5.65 Hz, 2 H), 3.94
(s, 3 H), 3.42-3.56 (m, 5 H), 2.66-2.82 (m, 4 H), 2.33 (s, 6 H),
1.90 (s, 3 H). 47 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.95 (br.
s., 1 H) MS: calc'd (MH+) 494 7.69-7.84 (m, 1 H) 7.61 (dd, J =
8.28, 5.52 Hz, 1 H) exp (MH+) 494. 7.48 (dd, J = 8.03, 5.52 Hz, 1
H) 6.99-7.17 (m, 2 H) 3.39-3.88 (m, 6 H) 2.91-3.30 (m, 2 H)
2.62-2.86 (m, 1 H) 2.22-2.53 (m, 1 H) 1.81-2.02 (m, 3 H). 48
.sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.13-8.00 (m, 1 H) MS: calc'd
(MH+) 494 7.98-7.82 (m, 1 H) 7.59 (br. s., 2 H) 7.13 (s, 2 H) exp
(MH+) 494.1. 3.96-3.82 (m, 1 H) 3.80-3.64 (m, 2 H) 3.62-3.44 (m, 4
H) 3.24-3.07 (m, 1 H) 2.84-2.66 (m, 1 H) 2.49-2.26 (m, 1 H) 2.02
(s, 3 H). 49 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.10-7.98 (m, 1
H) MS: calc'd (MH+) 522 7.94-7.76 (m, 1 H) 7.62-7.43 (m, 2 H) 7.10
(s, 2 H) exp (MH+) 522.0. 4.27 (s, 1 H) 3.95 (s, 1 H) 3.76-3.53 (m,
2 H) 3.47 (s, 3 H) 3.09 (s, 4 H) 3.00 (s, 3 H) 2.91-2.75 (m, 1 H)
2.43-2.21 (m, 1 H) 1.97 (s, 3 H). 50 .sup.1H NMR (MeOD-d.sub.4, 400
MHz), 8.05-7.89 (m, 1 H) MS: calc'd (MH+) 508 7.87-7.69 (m, 1 H)
7.66-7.33 (m, 2 H) 7.07 (br. s., 2 exp (MH+) 508.2. H) 3.92-3.59
(m, 3 H) 3.57-3.39 (m, 4 H) 3.27-2.95 (m, 1 H) 2.90-2.58 (m, 4 H)
2.39-2.23 (m, 1 H) 2.02-1.77 (m, 3 H). 51 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 8.14-8.03 (m, 1 H) MS: calc'd (MH+) 572
8.00-7.91 (m, 1 H) 7.65-7.51 (m, 2 H) 7.11 (s, 2 H) exp (MH+)
572.2. 4.03-3.81 (m, 3 H) 3.63 (d, J = 11.04 Hz, 1 H) 3.50 (s, 3 H)
3.28-3.10 (m, 1 H) 291-2.73 (m, 1 H) 2.68 (s, 3 H) 2.49 (qd, J =
14.01, 7.15 Hz, 1 H) 2.06 (s, 3 H). 52 .sup.1H NMR (MeOD-d.sub.4,
400 MHz), 8.00-7.84 (m, 1 H) MS: calc'd (MH+) 577 7.82-7.62 (m, 1
H) 7.60-7.29 (m, 3 H) 7.13 (br. s., 1 exp (MH+) 577.3. H) 7.03 (br.
s., 2 H) 4.10-3.76 (m, 3 H) 3.72-3.55 (m, 1 H) 3.45 (s, 3 H)
3.25-3.08 (m, 1 H) 2.95-2.73 (m, 1 H) 2.63-2.35 (m, 1 H) 1.97-1.64
(m, 3 H). 53 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 7.86-8.06 (m, 2
H) MS: calc'd (MH+) 461 7.63 (dd, J = 8.53, 5.27 Hz, 2 H) 7.13 (t,
J = 8.16 Hz, 2 exp (MH+) 461. H) 4.41-4.73 (m, 2 H) 4.02-4.24 (m, 2
H) 3.87-3.98 (m, 3 H) 3.72-3.65 (m, 2 H) 3.35-3.55 (m, 5 H) 2.09
(d, J = 4.52 Hz, 3 H). 54 .sup.1H NMR (CDCl.sub.3, 400 MHz),
7.81-7.91 (m, 1 H), MS: calc'd (MH+) 509 7.38-7.66 (m, 3 H), 7.03
(br. s., 2 H), 4.10-4.28 (m, exp (MH+) 509. 1 H), 3.88-4.09 (m, 1
H), 3.45-3.59 (m, 3 H), 3.29-3.45 (m, 1 H), 3.23 (t, J = 8.41 Hz, 1
H), 2.87-3.09 (m, 1 H), 2.41 (dd, J = 14.31, 7.28 Hz, 1 H), 2.19
(s, 1 H), 1.86-2.00 (m, 3 H), 1.18-1.33 (m, 6 H). 55 .sup.1H NMR
(CDCl.sub.3, 400 MHz), 7.86 (d, 1H, J = 3.1 Hz), MS: calc'd (MH+)
481 7.52 (m, 3H), 7.02 (m, 2H), 4.04 (m, 1H), 3.79 (m, exp (MH+)
481. 2H), 3.52 (s, 3H), 3.52 (m, 2H), 3.16 (m, 1H), 3.00 (m, 1H),
2.40 (m, 2H), 1.98 (s, 3H). 56 .sup.1H NMR (MeOD-d.sub.4, 400 MHz),
7.95 (d, J = 4.0 Hz, MS: calc'd (MH+) 509 1H), 7.75 (d, J = 4.0 Hz,
1H), 7.51-7.47 (m, 2H), exp (MH+) 509. 7.05 (t, J = 8.0 Hz, 2H),
3.96 (d, J = 16 Hz, 1H), 3.74 (d, J = 16 Hz, 1H), 3.58 (t, J = 6.0
Hz, 2H), 3.50-3.40 (m, 1H), 3.48 (s, 3H), 2.98-2.85 (m, 2H),
2.57-2.45 (m, 1H), 2.13-2.05 (m, 1H), 1.92-1.85 (m, 1H), 1.90 (s,
3H), 1.63-1.49 (m, 3H). 57 .sup.1H NMR (MeOD-d.sub.4, 400 MHz),
7.97 (br. s., 1 H) MS: calc'd (MH+) 533 7.83-7.68 (m, 1 H) 7.44
(br. s., 2 H) 7.03 (br. s., 2 H) exp (MH+) 533.2. 4.55-4.37 (m, 1
H) 3.97 (d, J = 3.26 Hz, 2 H) 3.67-3.53 (m, 1 H) 3.45 (s, 3 H)
3.27-3.13 (m, 1 H) 2.96-2.66 (m, 2 H) 2.36 (s, 3 H) 1.84 (s, 3 H).
58 .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.02-7.92 (m, 1 H) MS:
calc'd (MH+) 519 7.77 (d, J = 3.01 Hz, 1 H) 7.48 (dd, J = 8.53,
5.27 Hz, exp (MH+) 519.1. 2 H) 7.05 (t, J = 8.66 Hz, 2 H) 4.50 (t,
J = 8.28 Hz, 1 H) 3.72-3.57 (m, 2 H) 3.41 (s, 3 H) 3.24-3.08 (m, 2
H) 2.80 (td, J = 15.75, 7.15 Hz, 2 H) 1.85 (s, 3 H). 59 .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 7.95 (d, J = 3.01 Hz, 1 MS: calc'd (MH+)
533 H) 7.74 (d, J = 3.26 Hz, 1 H) 7.47 (dd, J = 8.66, 5.40 Hz, exp
(MH+) 533.2. 2 H) 7.04 (t, J = 8.78 Hz, 2 H) 4.53 (t, J = 7.91 Hz,
1 H) 3.95 (d, J = 8.53 Hz, 2 H) 3.60 (d, J = 10.79 Hz, 1 H)
3.50-3.39 (m, 3 H) 3.26 (br. s., 1 H) 2.99-2.85 (m, 1 H) 2.78-2.64
(m, 1 H) 2.35 (s, 3 H) 1.90-1.81 (m, 3 H).
[0204] More particular compounds of formula I include the
following: [0205]
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3-
,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
[0206]
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihy-
dro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid; [0207]
(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6--
dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid;
[0208]
(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6--
dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid;
[0209]
4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-meth-
yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic
acid; [0210]
4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-
-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic
acid; [0211]
6-(2-(S)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester; [0212]
6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester; [0213]
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0214]
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0215]
4-[6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6--
dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid; [0216]
6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0217]
6-(2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-
-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0218]
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0219]
6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phe-
nyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0220]
(S)-1-[(S)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-di-
hydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic
acid; [0221]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-di-
fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid ethyl ester; [0222]
(S)-6-(2-Carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester; [0223]
(S)-6-(2-Carboxy-4,4-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester; [0224]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carbox-
ylic acid methyl ester; [0225]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0226]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thia-
zol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0227]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0228]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester; [0229]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester; [0230]
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester; [0231]
(S)-6-((S)-4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-flu-
oro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0232]
(S)-6-(2-Carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl-
)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester; [0233]
(S)-6-((S)-2-Dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-f-
luoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0234]
(S)-6-[(S)-4,4-Difluoro-2-(thiazol-2-ylcarbamoyl)-pyrrolidin-1-ylmethyl]--
4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carbo-
xylic acid methyl ester; [0235]
(S)-6-[(S)-4,4-Difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethy-
l]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-ca-
rboxylic acid methyl ester; [0236]
(S)-6-((S)-4,4-Difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluor-
o-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; [0237]
(S)-6-[(S)-4,4-Difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester; [0238]
(S)-6-[(S)-4,4-Difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4--
fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester; and [0239]
(S)-6-[(S)-4,4-Difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester.
[0240] It is very important for a drug to have a moderate or low
clearance, as this often lead to a good oral bioavailability and
high exposure in target organ. Reducing the clearance of a compound
or drug could then potentially reduce drastically the daily dose
required for efficacy and therefore give a much better safety
profile as well. From the examples below, it has been found a
marked increase of metabolic stability and liver exposure of
4-methyldihydropyrimidines of current invention.
[0241] 4-Hydrogen-dihydropyrimidines such as Bay 41-4109 can be
oxidized to pyrimidine product XLVI when treated with human, rat or
mouse liver microsomes. In this experiment, pooled liver microsomes
(20 mg/ml) from human, male Wister rat and male CD-1 mouse were
obtained from BD Bioscience (Franklin Lakes, N.J. USA). Incubation
reaction mixtures contained a final concentration of 0.1M sodium
phosphate buffer (pH 7.4), 0.5 mg/ml microsomal protein, 5 .mu.M of
the tested compounds and 1 mM NADPH in a total volume of 400 .mu.l.
The incubations were done for 60 minutes and 300 .mu.l of the
mixtures was transferred to 150 .mu.l of ice cold methanol to
terminate reactions. After vortexes for 3 minutes and centrifuged
at 4000 rpm at 4.degree. C. for 10 minutes, the clear supernatant
was used directly for analysis. The samples were analyzed by
Applied Biosystems API 3200 Q TRAP LC/MS/MS system using
electrospray ionization mode.
[0242] Pyrimidine product XLVI was the major metabolite in the in
vitro clearance tests (FIG. 1), and it was inactive to HBV DNA
reduction in HepDE19 cell based assays with EC.sub.50 value above
100 .mu.M. On the other hand, the 4-methyl-dihydropyrimidines
series in this invention do not have the aromatization issues of
the core structure.
[0243] HBV viruses infect hepatocyte cells and replicate in the
liver. To have effective viral suppression, it is important for an
anti-HBV drug to have sufficient exposure in the target organ. The
following findings highlight increased metabolic stability and high
liver exposure of 4-methyldihydropyrimidine analogs in this
invention.
[0244] In this experiment, fresh mouse liver sample was homogenized
by adding saline (1 g liver tissue: 5 mL saline) immediately after
collection. After centrifuging for 10 minutes at 14000 rpm, the
pooled supernatant was used to prepare liver homogenate solutions.
The effective compounds concentrations in liver homogenate were
100, 300, and 1000 ng/mL. Then, they were incubated at rt. After
incubation time of 0, 15 and 30 minutes, 180 .mu.l aliquots of MeOH
was added into 20 .mu.l of homogenate, respectively. All these
samples were vortex mixed for 5 minutes at 1500 rpm and centrifuged
for 10 minutes at 14000 rpm. The supernatants were transferred into
a 96-well plate for LC-MS/MS analysis. The results were summarized
and showed in Table 3.
TABLE-US-00003 TABLE 3 The percentage of Bay 41-4109 and Example 13
remaining in mouse liver homogenate. Concentration Peak Incubation
Time Percentage Compound (ng/mL) Area* (mm) to 0 min Bay41-4109 100
9263 15 1.84% 504715 0 100% 300 N.D. 30 0% 1363649 0 100% 1000 7868
30 0.16% 93431 15 1.90% 4930207 0 100% Example 100 58644 15 119% 13
49480 0 100% 300 120162 30 108% 111014 0 100% 1000 368388 30 86.0%
375366 15 87.6% 428458 0 100% *the data directly calculated by
LC/MS/MS, the relative standard variation is at 20%. **: not
detected
[0245] By comparing the peak area of individual samples at 15 and
30 min to the one at 0 min from same concentration level, the
stability of Bay41-4109 and Example 13 in CD-1 mouse liver
homogenate was evaluated.
[0246] It can be obviously concluded that Bay41-4109 is not stable
in liver homogenate treated with saline. About 2% of compound was
detected after 15 minutes room temperature incubation, at three
different concentration levels. In samples incubated for 30
minutes, only 0.16% can be found (at 1000 ng/mL. Not detected in
100 ng/mL and 300 ng/mL samples due to instrument sensitivity).
[0247] It can be concluded that Example 13 is stable in in liver
homogenate treated with saline.
[0248] The in vivo DMPK of selected compounds were evaluated in
male ICR mice following intravenous (or i.v.) or oral (or p.o.)
administration. In single dose pharmacokinetics (SDPK) studies,
compounds were dissolved in 6% Solutol solution (Solutol:Ethanol,
1:1, v/v), and 94% 0.9% saline for i.v. dose. For p.o.
administration, compounds were mixed with 0.89% microcrystalline
cellulose and 0.11% carboxymethyl cellulose sodium water solution,
or 1% RC591 as suspensions. The single dose exposure levels of Bay
41-4109, Example 6, Example 11, Example 13 and Example 19 in mouse
plasma and/or liver are shown as FIG. 2-6.
Synthesis
[0249] The compounds of the present invention can be prepared by
any conventional means. Suitable processes for synthesizing these
compounds as well as their starting materials are provided in the
schemes below and in the examples. All substituents, in particular,
R.sup.1 to R.sup.5, M and X are as defined above unless otherwise
indicated. Furthermore, and unless explicitly otherwise stated, all
reactions, reaction conditions, abbreviations and symbols have the
meanings well known to a person of ordinary skill in organic
chemistry.
[0250] General synthetic scheme for
4-methyl-5-ester-6-methyl-dihydropyrimidine based analogues
Intermediate-1 (Scheme 1)
[0251] One category of the compounds described herein relates to
4-methyl-5-ester-6-methyl-dihydropyrimidine based analogues with
the formula Intermediate-1 wherein R.sup.8 is C.sub.1-6alkyl.
##STR00083##
[0252] Compound of interest Intermediate-1 can be prepared
according to the general synthesis method shown in Scheme 1.
##STR00084##
[0253] Amidine III can be prepared from commercial available
nitrile II, ammonium chloride and trimethyl aluminum. The reaction
is typically performed by adding trimethyl aluminum to the mixture
of ammonium chloride in toluene at 0.degree. C. After 30 minutes,
nitrile II is added into the flask and the reaction mixture is
stirred at 80.degree. C. overnight.
[0254] The indium triflate catalyzed condensation reaction of
commercial available ester IV and ethynyl-benzene V gives
.alpha.,.beta.-unsaturated ketone VI. The reaction is typically
performed in o-xylene at 120.degree. C. for 2 h.
[0255] As an alternative method to synthesize tetra-substituted
.alpha.,.beta.-unsaturated ketone VI, especially when R.sup.8 is
tert-butyl group. Ketone VIII can be prepared by condensation of
ester IV with substituted benzaldehyde VII. The reaction is
typically performed in ethanol with catalytic quantity of
piperidine and acetic acid at rt overnight.
[0256] Ketone IX can be prepared by 1,4-Michael addition of methyl
group to the .alpha.,.beta.-unsaturated ketone VIII. The reaction
is typically performed by adding methyl lithium solution to cuprous
iodide in THF solution at 0.degree. C. and stirred for 1 hour at
0.degree. C., then the solution of VIII in THF is added into the
mixture at -78.degree. C. and stirred for 1 hour at -78.degree.
C.
[0257] .alpha.,.beta.Unsaturated ketone VI can be prepared by
oxidative elimination of ketone IX. The reaction is typically
performed by adding sodium hydride into the solution of ketone IX
in THF, then phenylselenyl chloride is added and stirred at rt for
1 hour. After the mixture is treated with pentene, ether and
saturated sodium bicarbonate, the organic layer is treated with
H.sub.2O.sub.2 solution (30%) and stirred at rt for 1 hour.
[0258] Analogs with general structure Intermediate-1 can be
prepared by the condensation reaction of .alpha.,.beta.unsaturated
ketone VI with amidine III. The reaction is typically carried out
by adding a solution of VI in NMP dropwisely into a mixture of
amidine III and NaHCO.sub.3 in NMP at 120.degree. C., after
addition the mixture is stirred at 120.degree. C. for half an hour
before workup.
[0259] General synthetic scheme for
4-methyl-5-cyano-6-nitrogen-substituted-2,4-dihydro-pyrimidine
based analogues Intermediate-3 (Scheme-2)
##STR00085##
[0260] Compounds of interest Intermediate-3 can be prepared
according to the general synthesis method shown in Scheme 2.
##STR00086##
[0261] Compound XI can be obtained by the deprotection of
Intermediate-2. The reaction is typically performed in DCM with TFA
at rt for 2 hours.
[0262] Compound XII can be obtained by coupling reaction from XI
with ammonia. The reaction is typically performed in DCM with HATU
and ammonia of dioxane solution at rt for 1 hour.
[0263] Cyano compound Intermediate-3 can be obtained by dehydrate
reaction from compound XII. The reaction is typically performed in
1,2-dichloroethane with thionyl chloride or trifluoroacetic
anhydride under refluxing for 1 hour.
[0264] General synthetic scheme for 4-methyl-5-ester or
cyano-6-aminoalkyl-dihydropyrimidine based analogues Ia (Scheme
3)
##STR00087##
[0265] Compounds of interest Ia can be prepared according to the
general synthesis method shown in Scheme 3.
##STR00088##
[0266] The Boc-protected compound XIII can be obtained by treatment
of ester Intermediated or cyano Intermediate-3 with
di-tert-butyldicarbonate and DMAP as base in an inert organic
solvent such as DCM, typically at rt for 24 hours.
[0267] The compound XIV can be obtained by the bromination of
compound XIII. The reaction is typically performed in
tetrachloromethane with NBS and AIBN as catalyst at 80.degree. C.
for 2 hours.
[0268] The amino substituted intermediate XVI can be obtained
through substitution reaction of compound XIV with XV. The reaction
can be carried out with a suitable organic base such as
N,N-diisopropylethylamine, inorganic base such as NaH,
Na.sub.2CO.sub.3, or t-BuOK in an inert organic solvent such as
DCM, THF or DMF at rt or 50.degree. C. for 1-10 hours.
[0269] Compound Ia can be obtained from the deprotection of XVI
treated with TFA in DCM or HCl in MeOH as deprotective agent at
rt.
[0270] General synthetic scheme for 4-methyl-5-ester or
cyano-6-alkoxymethyl-dihydropyrimidine based analogue Ib (Scheme
4)
##STR00089##
[0271] Compound of interest Ib can be prepared according to the
general synthesis method shown in Scheme 4.
##STR00090##
[0272] Compound XVIII can be obtained by substitution reaction of
compound XIV with alcohol XVII. The reaction is typically performed
by adding NaH to the solution of alcohol XVII in anhydrous THF at
it, then bromide XIV is added into the flask and the mixture is
stirred at rt for 3 hours.
[0273] Compound Ib can be obtained by treating XVIII with TFA in
DCM or HCl in MeOH at rt.
[0274] This invention also relates to a process for the preparation
of a compound of formula I comprising the reaction of
(a) a Compound of Formula (A)
##STR00091##
[0275] in the presence of an acid; wherein R.sup.1 to R.sup.5, M
and X are defined above unless otherwise indicated. In step (a),
the acid can be for example TFA or HCl.
Pharmaceutical Compositions and Administration
[0276] The invention also relates to a compound of formula I for
use as therapeutically active substance.
[0277] A compound of formula (I) when manufactured according to the
above process is also an object of the invention.
[0278] Another embodiment provides pharmaceutical compositions or
medicaments containing the compounds of the invention and a
therapeutically inert carrier, diluent or excipient, as well as
methods of using the compounds of the invention to prepare such
compositions and medicaments. In one example, compounds of formula
I may be formulated by mixing at ambient temperature at the
appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
In one example, a compound of formula I is formulated in an acetate
buffer, at pH 5. In another embodiment, the compounds of formula I
are sterile. The compound may be stored, for example, as a solid or
amorphous composition, as a lyophilized formulation or as an
aqueous solution.
[0279] Compositions are formulated, dosed, and administered in a
fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular human being treated, the clinical condition
of the individual patient, the cause of the disorder, the site of
delivery of the agent, the method of administration, the scheduling
of administration, and other factors known to medical
practitioners. The "effective amount" of the compound to be
administered will be governed by such considerations, and is the
minimum amount necessary to the suppression of serum HBV DNA
levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or
normalization of alanine aminotransferase levels and improvement in
liver histology. For example, such amount may be below the amount
that is toxic to normal cells, or the human as a whole.
[0280] In one example, the pharmaceutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1
to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day. In
another embodiment, oral unit dosage forms, such as tablets and
capsules, contain from about 0.1 to about 1000 mg of the compound
of the invention.
[0281] The compounds of the invention may be administered by any
suitable means, including oral, topical (including buccal and
sublingual), rectal, vaginal, transdermal, parenteral,
subcutaneous, intraperitoneal, intrapulmonary, intradermal,
intrathecal and epidural and intranasal, and, if desired for local
treatment, intralesional administration. Parenteral infusions
include intramuscular, intravenous, intraarterial, intraperitoneal,
or subcutaneous administration.
[0282] The compounds of the present invention may be administered
in any convenient administrative form, e.g., tablets, powders,
capsules, solutions, dispersions, suspensions, syrups, sprays,
suppositories, gels, emulsions, patches, etc. Such compositions may
contain components conventional in pharmaceutical preparations,
e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents,
and further active agents.
[0283] A typical formulation is prepared by mixing a compound of
the present invention and a carrier or excipient. Suitable carriers
and excipients are well known to those skilled in the art and are
described in detail in, e.g., Ansel, Howard C., et al., Ansel's
Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,
Raymond C. Handbook of Pharmaceutical Excipients. Chicago,
Pharmaceutical Press, 2005. The formulations may also include one
or more buffers, stabilizing agents, surfactants, wetting agents,
lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents, diluents
and other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0284] An example of a suitable oral dosage form is a tablet
containing about 0.1 mg to 1000 mg of the compound of the invention
compounded with about 90 mg to 30 mg anhydrous lactose, about 5 mg
to 40 mg sodium croscarmellose, about 5 mg to 30 mg
polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium
stearate. The powdered ingredients are first mixed together and
then mixed with a solution of the PVP. The resulting composition
can be dried, granulated, mixed with the magnesium stearate and
compressed to tablet form using conventional equipment. An example
of an aerosol formulation can be prepared by dissolving the
compound, for example 5 mg to 400 mg, of the invention in a
suitable buffer solution, e.g. a phosphate buffer, adding a
tonicifier, e.g. a salt such sodium chloride, if desired. The
solution may be filtered, e.g., using a 0.2 micron filter, to
remove impurities and contaminants.
[0285] An embodiment, therefore, includes a pharmaceutical
composition comprising a compound of Formula I, or a stereoisomer
or pharmaceutically acceptable salt thereof. In a further
embodiment includes a pharmaceutical composition comprising a
compound of Formula I, or a stereoisomer or pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable carrier or excipient.
Indications and Methods of Treatment
[0286] The compounds of the invention can inhibit HBV's de novo DNA
synthesis and reduce HBV DNA levels. Accordingly, the compounds of
the invention are useful for the treatment or prophylaxis of HBV
infection.
[0287] The invention relates to the use of a compound of formula I
for the treatment or prophylaxis of HBV infection.
[0288] The use of a compound of formula I for the preparation of
medicaments useful in the treatment or prophylaxis diseases that
are related to HBV infection is an object of the invention.
[0289] The invention relates in particular to the use of a compound
of formula I for the preparation of a medicament for the treatment
or prophylaxis of HBV infection.
[0290] Another embodiment includes a method of treating or
prophylaxising HBV infection in a human in need of such treatment,
wherein the method comprises administering to said human a
therapeutically effective amount of a compound of Formula I, a
stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt
thereof.
Combination Therapy
[0291] The compounds of the invention can be used together with
interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil,
Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment
or prophylaxis of HBV.
EXAMPLES
[0292] The invention will be more fully understood by reference to
the following examples. They should not, however, be construed as
limiting the scope of the invention.
Abbreviations used herein are as follows: [0293] AIBN:
azobisisobutyronitrile [0294] Boc: tert-butoxycarbonyl [0295]
t-BuOK: potassium tert-butoxide [0296] calc'd: calculated [0297]
CC.sub.50: cytotoxic concentration 50% [0298] CCl.sub.4:
tetrachloromethane [0299] CDCl.sub.3: deuterated chloroform [0300]
CCK-8: cell counting kit-8 [0301] CDI: N,N'-Carbonyldiimidazole
[0302] CMV: cytomegalovirus [0303] d: day [0304] DIPEA:
N,N-diisopropylethylamine [0305] DCM: dichloromethylene [0306]
DMAP: N,N'-dimethylaminopyridine [0307] DMF: dimethylformamide
[0308] DMSO: dimethylsulfoxide [0309] DNA: deoxyribonucleic acid
[0310] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0311]
EDTA: ethylenediaminetetraacetic acid [0312] exp: expected [0313]
EtOAc: ethyl acetate [0314] FBS: fetal bovine serum [0315] g: gram
[0316] EC.sub.50: concentration required for 50% induction of
acetylated tubulin [0317] FES: fetal bovine serum [0318] h: hour or
hours [0319] HAP: heteroaryldihydropyrimidine [0320] HATU:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0321] HBeAb: hepatitis B e antibody [0322]
HBeAg: hepatitis B e antigen [0323] HBsAg: hepatitis B surface
antigen [0324] HCl: hydrogen chloride [0325] HPLC: high performance
liquid chromatography [0326] Hz: Hertz [0327] In(OTf).sub.3: indium
(III) trifluoromethanesulfonate [0328] IPA: isopropanol [0329] KOH:
potassium [0330] LC/MS: liquid chromatography mass spectrometer
[0331] LiOH: lithium hydroxide [0332] LDA: lithium diisopropylamide
[0333] MeOD-d4 or CD3OD:deuterated methanol [0334] MeOH: methanol
[0335] mg: milligram [0336] MHz: megahertz [0337] min: minute or
minutes [0338] mL: milliliter [0339] mM: milliliter [0340] NMP:
1-methyl-piperidin-2-one [0341] mmol: millimole [0342] NaCl: sodium
chloride [0343] NaOH: sodium hydroxide [0344] NBS:
N-bromosuccinimide [0345] NEt.sub.3: triethylamine [0346] NMR:
nuclear magnetic resonance [0347] PBS: Phosphate buffered saline
[0348] prep-HPLC: preparative high performance liquid
chromatography [0349] RP-HPLC: reverse phase high performance
liquid chromatography [0350] rt: room temperature [0351] SDPK:
single dose pharmacokinetics [0352] SFC: supercritical fluid
chromatography [0353] SSC: saline-sodium citrate buffer [0354] TEA:
triethylamine [0355] TFA: trifluoroacetic acid [0356] TFAA:
trifluoroacetic acid anhydride [0357] THF: tetrahydrofuran [0358]
.mu.l: microliter [0359] .mu.M: micromole
General Experimental Conditions
[0360] Intermediates and final compounds were purified by flash
chromatography using one of the following instruments: i) Biotage
SP1 system and the Quad 12/25 Cartridge module. ii) ISCO
combi-flash chromatography instrument. Silica gel brand and pore
size: i) KP-SIL 60 .ANG., particle size: 40-60 .mu.M; ii) CAS
registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron
silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore:
200-300 or 300-400.
[0361] Intermediates and final compounds were purified by
preparative HPLC on reversed phase column using XBridge.TM.
Prep-C.sub.18 (5 .mu.m, OBD.TM. 30.times.100 mm) column or
SunFire.TM. Prep-C.sub.18 (5 .mu.M, OBD.TM. 30.times.100 mm)
column. Waters AutoP purification System (Column: XBridge.TM.
Prep-C.sub.18, 30.times.100 mm, Sample Manager 2767, Pump 2525,
Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile
and 0.1% ammonium hydroxide in water). For SFC chiral separation,
intermediates were separated by chiral column (Daicel chiralpak IC,
5 .mu.m, 30.times.250 mm) column using Mettler Toledo SFC-Multigram
III system, solvent system: 95% CO.sub.2 and 5% IPA (0.5% TEA in
IPA), back pressure 100 bar, detection UV@ 254 nm.
[0362] LC/MS spectra of compounds were obtained using a LC/MS
(Waters.TM. Alliance 2795-Micromass ZQ). LC/MS conditions were as
follows (running time 6 min):
[0363] Acidic condition: A: 0.1% formic acid in H.sub.2O; B: 0.1%
formic acid in acetonitrile;
[0364] Basic condition: A: 0.01% NH.sub.3.H.sub.2O in H.sub.2O; B:
acetonitrile;
[0365] Neutral condition: A: H.sub.2O; B: acetonitrile.
[0366] Mass spectra (MS): generally only ions which indicate the
parent mass are reported, and unless otherwise stated the mass ion
quoted is the positive mass ion (M+H).sup.+.
[0367] LC-MS/MS instrument on liver homogenate stability test: An
Agilent 1290 series LC system composited of a binary pump, a
degasser, a CTCPAL autosampler and a thermostatted column was
applied. The Chromatographic separation was achieved on a
Chromolith Performance RP-18 endcapped (3.times.100 mm) at room
temperature.
[0368] Mass spectrometric detection was performed on an Agilent
6530 Q-TOF instrument in full scan mode with an AJS ESI interface
in positive ionization mode. Data processing was performed with
Agilent MassHunter Workstation Data Acquisition B.04.00 and Agilent
MassHunter Workstation Qualitative Analysis B.04.00.
[0369] The microwave assisted reactions were carried out in a
Biotage Initiator Sixty microwave synthesizer.
[0370] NMR Spectra were obtained using Bruker Avance 400 MHz.
[0371] All reactions involving air-sensitive reagents were
performed under an argon atmosphere. Reagents were used as received
from commercial suppliers without further purification unless
otherwise noted.
[0372] The following examples were prepared by the general methods
outlined in the schemes above. They are intended to illustrate the
meaning of the present invention but should by no means represent a
limitation within the meaning of the present invention.
PREPARATIVE EXAMPLES
Example 1
4-(4-Fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl-2-
-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester
[0373] The title compound was prepared according to the general
synthesis methods shown in Scheme 1 and Scheme 4. A detailed
synthesis route is provided as shown in Scheme 5.
##STR00092## ##STR00093##
[0374] To a stirred suspension of NH.sub.4Cl in toluene (400 mL)
was added Al(CH.sub.3).sub.3 solution (1.0 M, 56 mL) at 0.degree.
C. over 30 minutes. After the mixture solution was stirred at rt
for 30 minutes, the solution of thiazole-2-carbonitrile (5.24 g,
47.6 mmol) in toluene (10 mL) was added into the flask. The
reaction mixture was stirred at 80.degree. C. for 16 hours before
cooling to rt and then the mixture was poured into a slurry of
silica gel in DCM. After stirring for 20 minutes, the slurry was
filtered and washed with MeOH three times and concentrated in vacuo
to afford crude product of thiazole-2-carboxamidine XIX that was
used in next step reaction without further purification. MS: calc'd
(MH.sup.+) 128.2, exp (MH.sup.+) 128.1.
[0375] A mixture of 3-oxo-butyric acid methyl ester (5.0 g, 43.1
mmol), 1-ethynyl-4-fluoro-benzene (5.0 g, 41.7 mmol) and
In(OTf).sub.3 (400 mg, 0.71 mmol) in o-xylene (20 ml) was heated to
120.degree. C. for 1 to 2 h. After solvent removal, the residue was
purified by column chromatography (EtOAc/petroleum ether: 1/10) to
afford XX as light yellowish oil (4.0 g, yield: 40.8%).
[0376] To a mixture of thiazole-2-carboxamidine XIX (1.7 g, 10.5
mmol) and NaHCO.sub.3 (2.5 g, 29.8 mmol) in NMP (10 mL) which was
preheated to 120.degree. C. was added dropwisely
(E)-2-acetyl-3-(4-fluoro-phenyl)-but-2-enoic acid methyl ester XX
(2.4 g, 10.2 mmol) in NMP (10 mL) in about 1 h. The mixture was
stirred at 120.degree. C. for 0.5 h before reaction workup with
EtOAc (200 mL) and water. The organic layer was dried and
concentrated, and the residue was purified by column chromatography
(EtOAc/petroleum ether 1/4 to 1/2) to afford
4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimi-
dine-5-carboxylic acid methyl ester XXI as yellow viscous oil (1.7
g, yield: 48.3%). MS: calc'd (MH.sup.+) 346, exp (MH.sup.+) 346.
.sup.1H NMR (MeOD-d.sub.4, 400 MHz) 7.93 (d, 1H, J=3.2 Hz), 7.72
(d, 1H, J=3.2 Hz), 7.51-7.47 (m, 2H), 7.04 (t, 2H, J=8.8 Hz), 3.45
(s, 3H), 2.28 (s, 3H), 1.90 (s, 3H).
[0377] To a solution of XXI (1.0 g, 2.9 mmol) in DCM (20 mL) was
added DMAP (0.15 g, 1.2 mmol) and Boc.sub.2O (0.94 g, 4.3 mmol),
and the mixture was stirred overnight. The mixture was washed with
water (15 mL) and brine (15 mL). The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated, and the
residue was purified by column chromatography (EtOAc/petroleum
ether from 1/4 to 1/3) to afford
4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-4H-pyrimidine-1,5-dicarbo-
xylic acid 1-tert-butyl ester 5-methyl ester XXII as yellow solid
(0.91 g, yield: 70.5%).
[0378] A solution of XXII (0.90 g, 2.02 mmol) and NBS (0.54 g, 3.03
mmol) in CCl.sub.4 (30 mL) was heated to 50.degree. C., then AIBN
(30 mg) was added to initiate the reaction. The mixture was stirred
for 2 h. The mixture was purified by column chromatography
(EtOAc/petroleum ether from 1/4 to 1/3) to afford
6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine-1-
,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester XXIII as
yellow solid (1.03 g, yield: 97.3%).
[0379] Sodium hydride (12 mg, 0.5 mmol) was added to a solution of
2-hydroxy-2-methyl-propionic acid methyl ester (59 mg, 0.5 mmol) in
THF at rt. Then the mixture was stirred at rt for 30 min. Compound
XXIII (105 mg, 0.2 mmol) was added and stirred at rt overnight.
Then the mixture was partitioned between water and EtOAc. The
organic phase was dried, concentrated and used in the next step
without further purification.
[0380] The crude product XXIV from above step was dissolved in DCM
and then TFA was added. The mixture was stirred at rt for 2 hours.
The solvent was removed and the residue was purified by prep-HPLC
to afford Example 1 as yellow solid (40 mg, yield: 43% for 2
steps). MS: calc'd 462 (MH.sup.+), exp 462 (MH.sup.+). .sup.1H NMR
(MeOD-d.sub.4, 400 MHz), 7.95 (d, 1H, J=3.2 Hz), 7.75 (d, 1H, J=3.2
Hz), 7.49-7.45 (m, 2H), 7.04 (t, 2H, J=8.8 Hz), 4.71-4.62 (m, 2H),
3.80 (s, 3H), 3.43 (s, 3H), 1.92 (s, 3H), 1.57 (s, 6H).
Example 2
6-(1-Carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2--
thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester
[0381] The title compound was prepared in analogy to Example 1 in
Scheme 5 by using 3,3,3-trifluoro-2-hydroxy-propionic acid methyl
ester instead of 2-hydroxy-2-methyl-propionic acid methyl ester,
the so-obtained methyl ester was hydrolyzed by LiOH as indicated in
Scheme 3. MS: calc'd 488 (MH.sup.+), exp 488 (MH.sup.+). .sup.1H
NMR (MeOD-d.sub.4, 400 MHz), 7.94 (d, 1H, J=2.8 Hz), 7.93 (d, 1H,
J=2.8 Hz), 7.53-7.49 (m, 2H), 7.07-7.03 (m, 2H), 4.85-4.78 (m, 2H),
4.40-4.37 (m, 1H), 3.44 (s, 3H), 1.94 (s, 3H).
Example 3
6-{[(1-Carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-me-
thyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester
[0382] The title compound was prepared according to the synthesis
method shown in Scheme 1 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 6.
##STR00094##
[0383] To a solution of
6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine-1-
,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester XXIII (1.00
g, 1.90 mmol) and potassium carbonate in DMF was added
1-methylamino-cyclopropanecarboxylic acid methyl ester (258 mg,
2.00 mmol), the mixture was stirred at 40.degree. C. for 3 hours
and LC-MS indicated that the reaction was finished. The mixture was
partitioned between water and ethyl acetate. The organic phase was
dried and concentrated to afford the crude product used in the next
step without further purification.
[0384] The crude product XXV from above step was dissolved in DCM
and then TFA was added. The mixture was stirred at rt for 2 hours.
LC-MS indicated that the reaction was finished. The solvent was
removed and the residue was used in the next step without further
purification.
[0385] The crude product XXVI from above step was dissolved in MeOH
(5 mL) and LiOH in water (2 mL) was added to the mixture. The
mixture was stirred at rt for 2 h and LC-MS indicated that the
reaction was finished. The solvent was removed and the mixture was
adjusted to pH (3.about.5) with diluted hydrochloric acid. The
mixture was purified by prep-HPLC to afford Example 3 as yellow
solid (0.63 g, yield for 3 steps: 73%). MS: calc'd 459 (MH.sup.+),
exp 459 (MH.sup.+). .sup.1H NMR (MeOD-d.sub.4, 400 MHz), 8.12 (d,
1H, J=3.2 Hz), 8.06 (d, 1H, J=3.2 Hz), 7.63-7.60 (m, 2H), 7.15 (t,
2H, J=8.8 Hz), 4.30 (s, 2H), 3.51 (s, 3H), 2.79 (s, 3H), 2.10 (s,
3H), 1.52-1.51 (m, 2H), 1.38-1.37 (m, 2H).
Example 4
4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihyd-
ro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
[0386] The title compound was prepared in analogy to Example 3 in
Scheme 6 by using morpholine-3-carboxylic acid methyl ester instead
of 1-methylamino-cyclopropanecarboxylic acid methyl ester. LC-MS:
calc'd 475 (MH.sup.+), exp 475 (MH.sup.+). .sup.1H NMR
(MeOD-d.sub.4, 400 MHz) .delta. 8.10 (d, 1H), 8.03 (d, 1H),
7.64-7.61 (m, 2H), 7.15-7.12 (m, 2H), 4.32-4.31 (m, 2H), 4.18-4.14
(m, 2H), 3.99-3.72 (m, 3H), 3.51-3.49 (m, 4H), 3.02 (m, 1H), 2.11
(d, 3H).
Example 5
4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihyd-
ro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid methyl
ester
[0387] The title compound was prepared in analogy to Example 3 in
Scheme 6 by using morpholine-(S)-3-carboxylic acid methyl ester
instead of 1-methylamino-cyclopropanecarboxylic acid methyl
ester.
Example 6
4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihyd-
ro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid
[0388] The title compound was prepared by from the hydrolysis of
Example 5 with LiOH in MeOH as shown in Scheme 6.
Example 7
(S)-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-d-
ihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic acid
[0389] The title compound was prepared according to the synthesis
method shown in Scheme 1 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 7.
##STR00095##
[0390] The chiral intermediate compound XXVII was separated from
XXI by SFC and the absolute stereochemistry was determined by X-ray
diffraction study (please see FIG. 7). The title compound was
prepared in analogy to Example 3 in Scheme 6 by using
morpholine-(S)-3-carboxylic acid methyl ester XXVIII instead of
1-methylamino-cyclopropanecarboxylic acid methyl ester in the
replacement reaction.
Example 8
(S)-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-d-
ihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid
[0391] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using morpholine-(R)-3-carboxylic acid methyl ester
instead of 1-methylamino-cyclopropanecarboxylic acid methyl
ester.
Example 9
4-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methy-
l-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic
acid
[0392] The title compound was prepared according to the methods
shown in Scheme 8.
##STR00096##
[0393] 5-Fluoro-pyridine-2-carbonitrile was used in the synthesis
of Compound XXIX in the same methods as shown in Scheme 5.
Following similar procedures to Scheme 5 and Scheme 6, XXIX was
converted to Example 9 by using morpholine-(R)-3-carboxylic acid
methyl ester XXX in the replacement reaction.
Example 10
4-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methy-
l-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic
acid
[0394] The title compound was prepared in analogy to Example 9 in
Scheme 8 by using morpholine-(S)-3-carboxylic acid methyl ester
instead of morpholine-(R)-3-carboxylic acid methyl ester in the
replacement reaction.
Example 11
6-(2-(S)-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0395] The title compound was prepared in analogy to Example 3 in
Scheme 6 by using 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid
methyl ester instead of 1-methylamino-cyclopropanecarboxylic acid
methyl ester.
Example 12
6-(2-(R)-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0396] The title compound was prepared in analogy to Example 3 in
Scheme 6 by using 4,4-difluoro-pyrrolidine-(R)-2-carboxylic acid
methyl ester instead of 1-methylamino-cyclopropanecarboxylic acid
methyl ester.
Example 13
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-pheny-
l)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0397] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid
methyl ester instead of using morpholine-(S)-3-carboxylic acid
methyl ester XXVIII in the replacement reaction.
Example 14
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-p-
henyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0398] The title compound was prepared according to the synthesis
method shown in Scheme 1 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 9.
##STR00097## ##STR00098##
[0399] A mixture of 3,4-difluoro-benzaldehyde (8.96 g, 63.1 mmol),
3-oxo-butyric acid methyl ester (7.32 g, 63.1 mmol), piperidine
(0.27 g, 3.16 mmol) and acetic acid (0.19 g, 3.16 mmol) in
anhydrous ethanol (200 mL) was stirred for 12 hours at room
temperature. After removal of the solvent, the residue was purified
by flash column chromatography (EtOAc:hexane=1:10) to afford the
product of
2-[1-(3,4-difluoro-phenyl)-meth-(Z)-ylidene]-3-oxo-butyric acid
methyl ester XXXI as yellow solid (13.6 g). Yield: 90%. MS: calc'd
(M.sup.++H) 241.0, exp (M.sup.++H) 241.1.
[0400] A solution of methylithium (1.6 M in ether, 48.7 mL, 78
mmol) was added to a suspension of copper(I) iodide (14.9 g, 78
mmol) in 200 mL of anhydrous THF under argon at 0.degree. C. and
the mixture was stirred for 1 hour at 0.degree. C. A solution of
XXXI (8.0 g, 31.2 mmol) in 50 mL of anhydrous THF was added
dropwisely into the mixture at -78.degree. C. After stirring at
-78.degree. C. for 1 hour, the reaction mixture was quenched with
saturated ammonium chloride solution, extracted with EtOAc, washed
with brine and dried over anhydrous sodium sulfate. After removal
of organic solvent, the residue was purified by flash column
chromatography (EtOAc:hexane=1:10) to afford 6.39 g of XXXII as
oil. Yield: 80%. MS: calc'd (M.sup.++H) 257.1.
[0401] NaH (60%, 1.10 g, 27.5 mmol) was added into a solution of
XXXII (5.0 g, 18.3 mmol) in anhydrous THF (100 mL) under argon. A
solution of phenylselenyl chloride (5.3 g, 27.5 mmol) in THF (20
mL) was added into the flask at rt through syringe and the mixture
was stirred at rt for 1 h. 60 mL of pentene/ether mixture (v/v=1/1)
and 30 mL of saturated NaHCO.sub.3 solution were added into the
reaction mixture. The organic layer was separated and washed with
brine, and treated with H.sub.2O.sub.2 solution (30%, 4 mL) in DCM
(50 mL) The mixture was stirred at rt (for 0.5.about.2 hours) and
diluted with DCM (100 mL). The organic phase was separated, washed
with saturated sodium bicarbonate, sodium sulfite, water and brine
in sequential and dried over anhydrous sodium sulfate. After
removal of organic solvent, the residue was purified by flash
column chromatography (EtOAc:hexane=1:10) to afford 3.97 g of
XXXIII as yellow oil. MS: calc'd (M.sup.++H) 255.1, exp (M.sup.++H)
255.1
[0402] A mixture of XXXIII (2.54 g, 10 mmol),
thiazole-2-carboxamidine hydrochloride XIX (1.6 g, 10 mmol) and
sodium bicarbonate (1.68 g, 20 mmol) in NMP (15 mL) was stirred for
3 hours at 120.degree. C. After cooling, the mixture was separated
between water and ethyl acetate. The organic phase was dried and
concentrated. The residue was purified to afford the product of
4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester XXXIV as yellow solid (2.00 g).
Yield: 55%. MS: calc'd (M.sup.++H) 363.1, exp (M.sup.++H)
363.1.
[0403] The chiral intermediate XXXV was separated from XXXIV by SFC
and the absolute configuration was assigned through comparing its
retention time on SFC with that of the stereochemistry known
compound XXVII.
[0404] The title compound Example 14 was prepared in analogy to
Example 7 in Scheme 7 from Compound XXXV.
Example 15
4-[(S)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3-
,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
methyl ester
[0405] The title compound was prepared by the methods shown in
Scheme 10 by using XXXIV in the bromination and following
replacement reactions, which were carried out in the same
procedures as Scheme 5 and Scheme 6.
##STR00099##
Example 16
4-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-d-
ihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
[0406] The title compound was obtained by hydrolysis of Example 15
with LiOH in MeOH.
Example 17
6-(4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-pheny-
l)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0407] The title compound was prepared in analogy to Example 9 in
Scheme 8 by using 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid
methyl ester instead of morpholine-(R)-3-carboxylic acid methyl
ester XXXVIII in the replacement reaction.
Example 18
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-pheny-
l)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0408] The title compound was prepared in the methods as shown in
Scheme 11.
##STR00100##
[0409] Compound XXXVI was obtained by SFC chiral separation of
intermediate XXIX and the absolute configuration was assigned
through comparing its retention time on SFC with that of the
stereochemistry known compound XXVII. Example 9 was prepared from
XXXVI by following the procedures in Scheme 5 and Scheme 6, except
that 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl ester
XXXVII was used in the replacement reaction.
Example 19
6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0410] The title compound was prepared in the methods as shown in
Scheme 12 by using 5-methyl-thiazole-2-carbonitrile in the
preparation of ammidine. Compound XXXVIII was obtained by following
the procedures in Scheme 5. And
4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl ester XXXVII
was used in the preparation of Example 19, in methods similar to
Scheme 5 and Scheme 6.
##STR00101##
Example 20
6-(2-Carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0411] The title compound was prepared in analogy to Example 3 in
Scheme 6 by using 4,4-difluoro-2-methyl-pyrrolidine-2-carboxylic
acid methyl ester instead of morpholine-3-carboxylic acid methyl
ester.
Example 21
(S)-1-[(S)-5-Cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-
-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic
acid
[0412] The title compound was prepared according to the synthesis
method shown in Scheme 2 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 13.
##STR00102## ##STR00103##
[0413] Compound
4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5--
carboxylic acid tert-butyl ester XXXIX was prepared in analogy to
XXXIV in Scheme 9 by using 3-oxo-butyric acid tert-butyl ester and
4-fluoro-benzaldehyde instead of 3-oxo-butyric acid methyl ester
and 3,4-difluoro-benzaldehyde in the condensation reaction.
[0414] To a solution of
4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5--
carboxylic acid tert-butyl ester XXXIX (1.0 g, 2.58 mmol) in DCM
(15 mL) was added TFA (2 mL), and the mixture was stirred for 3 hr.
After that, the solvent and excess TFA was removed in vacuum. The
residue XL was dissolved in DCM (15 mL), to which was added HATU
(1.21 g, 3.70 mmol) and NH.sub.3 in dioxane (10 mL, 0.5 M), and the
mixture was stirred overnight. The mixture was diluted with DCM (50
mL), and washed with aqueous NaHCO.sub.3 and brine. The organic
layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to give 0.89 g of
4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5--
carboxylic acid amide as light yellow solid which was directly for
next use without purification.
[0415] The above crude intermediate (0.89 g) was dissolved in THF
(10 mL), TFAA (3 mL) was added and the mixture was stirred for 3
hr. After removal of THF and excess TFAA, the residue was dissolved
in MeOH (20 mL). To the solution, K.sub.2CO.sub.3 (2.0 g, 14.5
mmol) was added, and the mixture was stirred at rt for 3 hr. Then
the mixture was filtered, the solid was washed with EtOAc (10
mL.times.2). The combined filtrate was concentrated, the residue
was purified by column chromatography (EtOAc/petroleum ether 1/3 to
1/2) to afford XLI as yellow solid (700 mg, totally yield:
87.0%).
[0416] The chiral intermediate XLII was separated from XLI by
SFC.
[0417] The title compound Example 21 was prepared from XLII in
analogy to Example 3 in Scheme 6.
Example 22
(S)-4-[5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-
-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
[0418] The title compound was prepared according to the synthesis
method shown in Scheme 2 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 14.
##STR00104##
[0419] Compound
4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid tert-butyl ester XLIII was prepared in analogy
to XXXIV in Scheme 9 by using 3-oxo-butyric acid tert-butyl ester
and 3,4-difluorobenzaldehyde as starting material.
[0420] Compound
4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carbonitrile XLIV was prepared from tert-butyl ester XLIII in
the same method as XLI in Scheme 13.
[0421] The title compound Example 22 was prepared in the same
method as shown in Scheme 5 and Scheme 6 by using
morpholine-(S)-3-carboxylic acid methyl ester XXVIII in the
replacement reaction.
Example 23
(S)-1-[(S)-5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dih-
ydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic
acid
[0422] The title compound was prepared according to the synthesis
method shown in Scheme 2 and Scheme 3. A detailed synthesis route
is provided as shown in Scheme 15.
##STR00105##
[0423] Compound XLV was chiral separated from racemate XLIV by SFC
and the absolute configuration was assigned through comparing its
retention time on SFC with that of the stereochemistry known
compound XXVII. The title compound was prepared in the same method
as shown in Scheme 5 and Scheme 6 by using XXXVII in the
replacement reaction.
Example 24
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid ethyl ester
[0424] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 4-ethynyl-1,2-difluoro-benzene instead of
(S)-morpholine-3-carboxylic acid methyl ester.
Example 25
Preparation of
(S)-6-(2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-
-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0425] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 5,5-difluoro-piperidine-2-carboxylic acid instead
of (S)-morpholine-3-carboxylic acid methyl ester.
Example 26
Preparation of (S)-6-(2-carboxy-4,4-difluoro-piperidin-1-ylmethyl)
4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carb-
oxylic acid methyl ester
[0426] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 4,4-difluoro-piperidine-2-carboxylic acid instead
of (S)-morpholine-3-carboxylic acid methyl ester.
Example 27
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carbox-
ylic acid methyl ester
[0427] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 1-methyl-1H-imidazole-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 28
Preparation of
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid ethyl ester
[0428] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 4-ethynyl-1,2-difluoro-benzene instead of
1-ethynyl-4-fluoro-benzene.
Example 29
Preparation of
(S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-2-thiazol-2-yl-3-
,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
[0429] The title compound was prepared in analogy to Example 28 by
using (S)-morpholine-3-carboxylic acid instead of
(S)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 30
Preparation of
(S)-4-[(S)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-(1-methyl-1H--
imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic
acid
[0430] The title compound was prepared in analogy to Example 27 by
using (S)-morpholine-3-carboxylic acid instead of
(S)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 31
Preparation of
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0431] The title compound was prepared in analogy to Example 13 by
using 4-methyl-thiazole-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 32
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0432] The title compound was prepared in analogy to Example 13 by
using 4-methyl-thiazole-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 33
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thia-
zol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0433] The title compound was prepared in analogy to Example 13 by
using 5-chloro-thiazole-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 34
Preparation of
(S)-6-((2S,4R)-2-Carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0434] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (2S,4R)-4-fluoro-pyrrolidine-2-carboxylic acid
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 35
Preparation of
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
2-isoxazol-3-yl-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0435] The title compound was prepared in analogy to Example 11 by
using isoxazole-3-carbonitrile instead of
thiazole-2-carbonitrile.
Example 36
Preparation of
(R)-6-((S)-2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fl-
uoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0436] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using
(S)-4,4-difluoro-2-methyl-pyrrolidine-2-carboxylic acid instead of
(S)-morpholine-3-carboxylic acid methyl ester.
Example 37
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0437] The title compound was prepared in analogy to Example 13 by
using 5-methyl-thiazole-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 38
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester
[0438] The title compound was prepared in analogy to Example 13 by
using 5-fluoro-thiophene-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 39
Preparation of
(S)-6-((2S,4S)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0439] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (2S,4S)-4-fluoro-pyrrolidine-2-carboxylic acid
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 40
Preparation of
6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)--
4-methyl-2-(5-methyl-isoxazol-3-yl)-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0440] The title compound was prepared in analogy to Example 11 by
using 5-methyl-isoxazole-3-carbonitrile instead of
thiazole-2-carbonitrile.
Example 41
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester
[0441] The title compound was prepared in analogy to Example 13 by
using 3-fluoro-thiophene-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 42
Preparation of
(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester
[0442] The title compound was prepared in analogy to Example 13 by
using 3-fluoro-thiophene-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 43
Preparation of
(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phen-
yl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxyli-
c acid methyl ester
[0443] The title compound was prepared in analogy to Example 13 by
using 4-fluoro-thiophene-2-carbonitrile instead of
thiazole-2-carbonitrile.
Example 44
Preparation of
(S)-6-{[carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-(4-fluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0444] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (2,2,2-trifluoro-ethylamino)-acetic acid instead
of (S)-morpholine-3-carboxylic acid methyl ester.
Example 45
Preparation of
(S)-6-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-flu-
oro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0445] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
methyl ester instead of (S)-morpholine-3-carboxylic acid methyl
ester.
Example 46
Preparation of
(S)-6-[(S)-2-(2-dimethylamino-ethoxycarbonyl)-4,4-difluoro-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester
[0446] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
2-dimethylamino-ethyl ester instead of (S)-morpholine-3-carboxylic
acid methyl ester.
Example 47
Preparation of
(S)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl-
)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester
[0447] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 4,4-difluoro-pyrrolidine-2-carboxylic acid amide
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 48
Preparation of
(S)-6-((S)-2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-ph-
enyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0448] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
amide instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 49
Preparation of
(S)-6-((S)-2-dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-f-
luoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0449] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
dimethylamide instead of (S)-morpholine-3-carboxylic acid methyl
ester.
Example 50
Preparation of
6-((S)-4,4-difluoro-2-methylcarbamoyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro--
phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0450] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
methylamide instead of (S)-morpholine-3-carboxylic acid methyl
ester.
Example 51
Preparation of
(S)-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl-pyrrolidin-1-ylmet-
hyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5--
carboxylic acid methyl ester
[0451] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using
N--((S)-4,4-difluoro-pyrrolidine-2-carbonyl)-methanesulfonamide
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 52
Preparation of
(S)-6-[(S)-4,4-difluoro-2-(thiazol-2-ylcarbamoye-pyrrolidin-1-ylmethyl]-4-
-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carbox-
ylic acid methyl ester
[0452] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid
thiazol-2-ylamide instead of (S)-morpholine-3-carboxylic acid
methyl ester.
Example 53
Preparation of
4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4-ylmethyl)-4-methyl-
-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl
ester
[0453] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using (R)-1-morpholin-3-yl-methanol instead of
(S)-morpholine-3-carboxylic acid methyl ester.
Example 54
Preparation of
(S)-6-[(S)-4,4-difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethy-
l]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-ca-
rboxylic acid methyl ester
[0454] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 2-((S)-4,4-difluoro-pyrrolidin-2-yl)-propan-2-ol
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 55
Preparation of
(S)-6-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluor-
o-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0455] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using ((S)-4,4-difluoro-pyrrolidin-2-yl)-methanol
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 56
Preparation of
(S)-6-[4,4-difluoro-2-(3-hydroxy-propyl)-pyrrolidin-1-ylmethyl]-4-(4-fluo-
ro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0456] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using ((S)-4,4-difluoro-pyrrolidin-2-yl)-propan-1-ol
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 57
Preparation of
(S)-6-[(S)-4,4-difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester
[0457] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using
2-((S)-4,4-difluoro-pyrrolidin-2-yl)-5-methyl-[1,3,4]oxadiazole
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 58
Preparation of
(S)-6-[(S)-4,4-difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4--
fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic
acid methyl ester
[0458] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using 5-((S)-4,4-difluoro-pyrrolidin-2-yl)-1H-tetrazole
instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 59
Preparation of
(S)-6-[(S)-4,4-difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-y-
lmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin-
e-5-carboxylic acid methyl ester
[0459] The title compound was prepared in analogy to Example 7 in
Scheme 7 by using
5-((S)-4,4-difluoro-pyrrolidin-2-yl)-3-methyl-[1,2,4]oxadiazole
instead of (S)-morpholine-3-carboxylic acid methyl ester.
BIOLOGICAL EXAMPLES
Example 60
HBV Inhibition Assays (Biochemical Assay)
[0460] Cells and culture conditions: HepDE19 (Haitao Guo et al,
Journal of Virology, 81, November 2007, 12472-12484; Richeng Mao et
al, Journal of Virology, 85, January 2011, 1048-1057) cells were
derived from HepG2 (ATCC, American Type Culture Collection) cells
through transfection with pTet-off plasmid (Clontech) that
expresses the Tet-responsive transcriptional activator and
pTREHBVDE plasmid in which HBV pgRNA expression is controlled by a
CMV early promoter with a tetracycline-responsive element. The
transfected cells were selected with G418 (also known as Genticin,
purchased from Invitrogen). In tetracycline-free medium, cells
support high levels of HBV DNA replication and HBV virus secretion.
These cells were maintained in Dulbecco's modified Eagle's medium
(DMEM)-F12 medium (Invitrogen) supplemented with 10% fetal bovine
serum, 100 U/ml penicillin, and 100 .mu.g/ml streptomycin, 0.5
mg/ml of G418 and 1 .mu.g/ml tetracycline.
[0461] Anti-HBV activity and cytotoxicity: HepDE19 cells were
seeded into 96-well plates (3.times.10.sup.4 cells/well) with
tetracycline-free medium and incubated overnight at 37.degree. C.
The test or control compounds were serially half-log diluted with
medium and added into the plates (the final concentration of DMSO
kept at 0.5% in each well). Five days after compound treatment,
cells were washed with PBS and lysed with 50 mM Tris-1 mM EDTA-0.2%
CA-630 (pH 8.0) at 37.degree. C. for 20 min. After centrifugation
to remove nuclei and other debris, the supernatant was transferred
into a new plate and incubated with 2M NaOH/20.times.SSC (3M NaCl,
0.3M Sodium citrate, pH7.0) at rt for 30 min. Then the samples were
transferred to nylon membrane and neutralized withlM Tris
(pH7.4)/2M NaCl. The presence of HBV DNA was detected by dot-blot
with DIG-labeled HBV specific DNA probe and quantified by dot
density. The compound concentrations that inhibited HBV DNA by 50%
(EC.sub.50) were determined (See Table 1).
[0462] To determine if the anti-HBV effect of compound is due to
cytotoxicity, HepDE19 cells (5.times.10.sup.3 cells/well) were
seeded into 96-well plates and compounds were treated as described
above. Five days after treatment, cell viability was measured by
addition of 20 .mu.l of CCK-8 reagent. Four hours after incubation
at 37.degree. C., the absorbance at wavelengths of 450 nm and 630
nm (OD.sub.450 and OD.sub.630) was recorded by a plate reader. The
50% cytotoxic concentration (CC.sub.50) of each compounds were
determined accordingly.
[0463] The compounds of the present invention were tested for their
capacity to inhibit a HBV activity and activation as described
herein. The Examples were tested in the above assay and found to
have EC.sub.50 of about 0.01 .mu.M to about 50 .mu.M. Particular
compounds of formula I were found to have EC.sub.50 of about 0.1
.mu.M to about 30 .mu.M.
[0464] Results of HepDe19 EC.sub.50 (.mu.M) and CC.sub.50 (.mu.M)
are given in Table 1.
Example A
[0465] A compound of formula I can be used in a manner known per se
as the active ingredient for the production of tablets of the
following composition:
[0466] Per Tablet
TABLE-US-00004 Active ingredient 200 mg Microcrystalline cellulose
155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20
mg 425 mg
Example B
[0467] A compound of formula I can be used in a manner known per se
as the active ingredient for the production of capsules of the
following composition:
[0468] Per Capsule
TABLE-US-00005 Active ingredient 100.0 mg Corn starch 20.0 mg
Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg
* * * * *