U.S. patent application number 10/182221 was filed with the patent office on 2006-08-17 for 3-aminoquinazolin-2,4-dione antibacterial agents.
Invention is credited to Paul Bird, Edmund Lee Ellsworth, Dai Quoc Nguyen, Joseph Peter Sanchez, Howard Daniel Hollis Showalter, Rajeshwar Singh, Michael Andrew Stier, Tuan Phong Tran, Brian Morgan Watson, Judy Yip.
Application Number | 20060183762 10/182221 |
Document ID | / |
Family ID | 26874138 |
Filed Date | 2006-08-17 |
United States Patent
Application |
20060183762 |
Kind Code |
A1 |
Bird; Paul ; et al. |
August 17, 2006 |
3-AMINOQUINAZOLIN-2,4-DIONE ANTIBACTERIAL AGENTS
Abstract
Antibacterial 3-aminoquinazolin-2,4-diones have formula (I)
wherein: R.sub.1 and R.sub.3 include alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heterocyclic, and heteroaryl; R.sub.5, R.sub.6,
and R.sub.8 include H, alkyl, alkoxy, halo, NO.sub.2, CN, NH.sub.2,
alkyl and dialkylamino; R.sub.7 includes hydrogen, alkyl,
cycloalkyl, heterocyclic, fused heterocyclic, aryl and fused aryl;
J and K are C or N; and pharmaceutically acceptable salts thereof.
##STR1##
Inventors: |
Bird; Paul; (Alberta,
CA) ; Ellsworth; Edmund Lee; (Brighton, MI) ;
Nguyen; Dai Quoc; (Alberta, CA) ; Sanchez; Joseph
Peter; (Novi, MI) ; Showalter; Howard Daniel
Hollis; (Ann Arbor, MI) ; Singh; Rajeshwar;
(Edmonton, CA) ; Stier; Michael Andrew;
(Ypsilanti, MI) ; Tran; Tuan Phong; (Canton,
MI) ; Watson; Brian Morgan; (Carmel, IN) ;
Yip; Judy; (Alberta, CA) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
26874138 |
Appl. No.: |
10/182221 |
Filed: |
December 12, 2000 |
PCT Filed: |
December 12, 2000 |
PCT NO: |
PCT/US00/33656 |
371 Date: |
December 9, 2002 |
Current U.S.
Class: |
514/266.2 ;
514/266.3; 544/284; 544/285 |
Current CPC
Class: |
A61P 31/14 20180101;
C07D 487/04 20130101; A61P 31/04 20180101; C07D 401/04 20130101;
C07D 403/14 20130101; C07D 239/96 20130101; C07D 403/04 20130101;
C07D 487/10 20130101; C07D 471/04 20130101 |
Class at
Publication: |
514/266.2 ;
514/266.3; 544/284; 544/285 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 403/02 20060101 C07D403/02; C07D 239/96 20060101
C07D239/96 |
Claims
1. A compound of Formula I ##STR290## or a pharmaceutically
acceptable salt thereof wherein: R.sub.1 and R.sub.3 independently
are H, C.sub.1-C.sub.12 alkyl and substituted alkyl,
C.sub.2-C.sub.12 alkenyl and substituted alkenyl, C.sub.2-C.sub.12
alkynyl and substituted alkynyl, C.sub.3-C.sub.12 cycloalkyl and
substituted cycloalkyl, aryl and substituted aryl, heterocyclic and
substituted heterocyclic, or heteroaryl and substituted heteroaryl;
R.sub.5, R.sub.6, and R.sub.8 independently are H,
(O).sub.nC.sub.1-C.sub.12 alkyl and substituted alkyl,
(O).sub.nC.sub.2-C.sub.12 alkenyl and substituted alkenyl,
(O).sub.nC.sub.2-C.sub.12 alkynyl and substituted alkynyl, wherein
n is 0 or 1, halo, NO.sub.2, CN, NR'R''; R' and R'' independently
are H, C.sub.1-C.sub.12 alkyl and substituted alkyl,
C.sub.2-C.sub.12 alkenyl and substituted alkenyl, C.sub.2-C.sub.12
alkynyl and substituted alkynyl, CO--C.sub.1-C.sub.12 alkyl and
substituted alkyl, or R' and R'' taken together with the nitrogen
to which they are attached form a 3- to 7-membered ring containing
from 1 to 3 heteroatoms selected from N, O, and S, said ring being
unsubstituted or substituted with up to 4 substituent groups;
R.sub.1 and R.sub.8 can be taken together with the atoms to which
they are attached to form a cyclic ring having from 1 to 3
heteroatoms selected from N, O, and S, and optionally substituted
by R' and R''; R.sub.7 is C.sub.2-C.sub.12 alkenyl and substituted
alkenyl, C.sub.2-C.sub.12 alkynyl and substituted alkynyl,
NO.sub.2, CN, NR'R'', COOR', aryl, fused aryl, heterocyclic, fused
heterocyclic, bicyclic heterocyclic, or spiro heterocyclic, wherein
all ring groups can be substituted; and J and K are C.
2. A compound of Formula II ##STR291## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 and R.sub.3 independently
are H, C.sub.1-C.sub.12 alkyl and substituted alkyl,
C.sub.2-C.sub.12 alkenyl and substituted alkenyl, C.sub.2-C.sub.12
alkynyl and substituted alkynyl, C.sub.3-C.sub.12 cycloalkyl and
substituted cycloalkyl, aryl and substituted aryl, heterocyclic and
substituted heterocyclic, or heteroaryl and substituted heteroaryl;
R.sub.6 and R.sub.8 independently are H, (O).sub.nC.sub.1-C.sub.12
alkyl and substituted alkyl, (O).sub.nC.sub.2-C.sub.12 alkenyl and
substituted alkenyl (O).sub.nC.sub.2-C.sub.12 alkynyl and
substituted alkynyl, wherein n is 0 or 1, halo, NO.sub.2, CN,
NR'R''; R.sub.7 is C.sub.2-C.sub.12 alkenyl and substituted
alkenyl, C.sub.2-C.sub.12 alkynyl and substituted alkynyl,
NO.sub.2, CN, NR'R'', COOR', aryl, fused aryl, heterocyclic, fused
heterocyclic, bicyclic heterocyclic, or spiro heterocyclic, wherein
all ring groups can be substituted.
3. (canceled)
4. (canceled)
5. A compound of Formula V ##STR292## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 and R.sub.3 independently
are H, C.sub.1-C.sub.12 alkyl and substituted alkyl,
C.sub.2-C.sub.12 alkenyl and substituted alkenyl, C.sub.2-C.sub.12
alkynyl and substituted alkynyl, C.sub.3-C.sub.12 cycloalkyl and
substituted cycloalkyl, aryl and substituted aryl, heterocyclic and
substituted heterocyclic, or heteroaryl and substituted heteroaryl;
R.sub.6 and R.sub.8 independently are H, (O).sub.nC.sub.1-C.sub.12
alkyl and substituted alkyl, (O).sub.nC.sub.2-C.sub.12 alkenyl and
substituted alkenyl, (O).sub.nC.sub.2-C.sub.12 alkynyl and
substituted alkynyl, wherein n is 0 or 1, halo, NO.sub.2, CN,
NR'R''; R' and R'' independently are H, C.sub.1-C.sub.12 alkyl and
substituted alkyl, C.sub.2-C.sub.12 alkenyl and substituted
alkenyl, C.sub.2-C.sub.12 alkynyl and substituted alkynyl,
CO--C.sub.1-C.sub.12 alkyl and substituted alkyl, or R' and R''
taken together with the nitrogen to which they are attached form a
3- to 7-membered ring containing from 1 to 3 heteroatoms selected
from N, O, and S; said ring being unsubstituted or substituted with
up to 4 substituent groups.
6. (canceled)
7. (canceled)
8. A compound of claim 1 wherein R.sub.7 is selected from:
##STR293## ##STR294## ##STR295## ##STR296## ##STR297## ##STR298##
##STR299##
9. A compound of claim 8 wherein R.sub.7 is pyrrolidinyl,
substituted pyrrolidinyl, piperazinyl, substituted piperazinyl,
piperidinyl or substituted piperidinyl.
10. A compound selected from:
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro--
1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinazoline-2-
,4-dione;
3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1--
cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-
-fluoro-1H-quinazolin-2,4-dione;
3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroanilino)-6-
-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluoro-1H-q-
uinazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-qui-
nazoline-2,4-dione;
7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-difluoro-1H--
quinazoline-2,4-dione;
3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluor-
o-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione;
3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-
-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinaz-
oline-2,4-dione;
3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-
e-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1H-quina-
zoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H-quina-
zoline-2,4-dione;
3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-qu-
inazoline-2,4-dione;
3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quinazoline--
2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-1H-qui-
nazoline-2,4-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluoro-1H-qu-
inazoline-2,4-dione;
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropylmet-
hyl-8-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazoline-2,-
4-dione;
3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrol-
idin-1-yl]-1H-quinazoline-2,4-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazol-
ine-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-qui-
nazoline-2,4-dione;
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl--
1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-1H-qu-
inazoline-2,4-dione;
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-
-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-1H-qui-
nazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3-
,4-tetrahydroquinazoline-8-carbonitrile;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl-pyrroli-
din-1-yl)-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihydro-1-ox-
a-3a,5-diazaphenalene-4,6-dione;
5-Amino-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-
-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione;
2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihydro-5H-p-
yrido[3,2,1-ij]quinazoline-1,3-dione;
2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-methyl-6,7-
-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione;
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2-
,3-d]pyrimidine-2,4-dione;
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
1H-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-yl)-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-yl)-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[-
2,3-d]pyrimidine-2,4-dione;
trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclop-
ropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylamino-ethyl)pyrrolid-
in-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-met-
hyl-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylaminoethyl)-
pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione;
1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)piperidine-3-carboxylic acid amide;
3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-
-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoro-ethylamino-
)methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydropyrrolo[3,4-c-
]pyrrol-2-yl)-1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-1-
H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-benzylpyrroIidin-1-yl)-8-chloro-1-cyclopropyl--
6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropy-
l-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyamino-pyrrolidin-1-yl-
) -1H-quinazoline-2,4-dione;
3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyc-
lopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)-1-methylaminoethyl)p-
yrrolidin-1-yl]-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8chloro-1-cyclopropyl-6-
-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-c-
yclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydr-
oquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;
3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione;
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylamino-methyl)pyrro-
lidin-1-yl]-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropyl-1H-qu-
inazoline-2,4-dione;
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydr-
oquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-1H-qui-
nazoline-2,4-dione;
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-5-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclop-
ropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-metho-
xy-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl--
1H-quinazoline-2,4-dione;
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
yl-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-
-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1-
H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-met-
hyl-1H-quinazolin-2,4-dione;
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-met-
hoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
oxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3(-((S)-3-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-ethy-
l-6-fluoro-1H-quinazoline-2,4-dione;
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidine-3-carboxylic acid trifluoroacetate;
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)pyrrolidine-3-carboxylic acid trifluoroacetate;
3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-flu-
oro-8-methoxy-1H-quinazoline-2,4 -dione;
3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]pyridin-
-6-yl)-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-cyclop-
ropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluo-
ro-1H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
yl-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinazoline-2-
,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-qu-
inazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin--
1-yl]-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin--
1-yl]-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)-
pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1--
yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1-
H-quinazoline-2,4-dione;
cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-flu-
oro-8-methoxy-1H-quinazoline-2,4-dione;
trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(1-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-met-
hoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8--
methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8--
methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8--
methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(isopropylaminomethyl)pyrrolidin-1-yl-
]-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyrrolo[3,-
4-b]pyridin-6-yl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-amino-4-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-qui-
nazoline-2,4-dione;
3-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-qui-
nazoline-2,4-dione;
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(R)-3-((S)-1-methylaminoethyl-
)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
3-Amino-7-(3-aminoazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quin-
azoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl)-1--
cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyI)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l)-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo--
1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl }urea;
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo--
1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino
1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7--
yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3-
,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-di-
oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
((S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,-
3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)-4fluoropyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-
-tetrahydroquinolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclop-
ropyl-8-methoxy-1-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-6fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cycloprop-
yl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-
-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopro-
pyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-y-
l]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-y-
l]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl-
]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-
-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-
-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-d-
ioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea-
;
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,-
2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-d-
ioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea-
;
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,-
2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,-
4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,-
4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-meth-
yl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl)
-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-pyrrolidin-1-yl]-1-cyclopropyl-8-me-
thyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cycl-
opropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-meth-
yl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[4,3d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclo-
propyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-me-
thyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopr-
opyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopr-
opyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[4,3d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[4,3-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[4,3-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[4,3-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-meth-
yl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cycl-
opropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cycl-
opropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-flu-
oro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-met-
hyl-1H-pyrido[3,2]-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopro-
pyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cycl-
opropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cycl-
opropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-meth-
yl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclo-
propyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclo-
propyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-me-
thyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopr-
opyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopr-
opyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydropyrido[3,2d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylur-
ea;
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;
3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinaz-
oline-2,4-dione;
3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinaz-
oline-2,4-dione;
3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quina-
zoline-2,4-dione;
3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-
-dione;
3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-1H-quinazo-
line-2,4-dione;
3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,-
4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H--
quinazoline-2,4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-1H-quinazoli-
ne-2,4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinazoli-
ne-2,4-dione;
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quinazol-
ine-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-6-fluoro--
1H-quinazoline-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro--
1H-quinazoline-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fluoro-
-1H-quinazoline-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-1H-quinaz-
oline-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinaz-
oline-2,4-dione;
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quina-
zoline-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-1H-quinazol-
ine-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-1H-quinazol-
ine-2,4-dione;
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-1H-quinazo-
line-2,4-dione;
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopro-
pyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopro-
pyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopr-
opyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopro-
pyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopro-
pyl-1H-quinazoline-2,4-dione
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopr-
opyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cycl-
opropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclo-
propyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclo-
propyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cycl-
opropyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chlor-
o-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methy-
l-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-metho-
xy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chlor-
o-1-cyclopropyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methy-
l-1-cyclopropyl-1H-quinazoline-2,4-dione;
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-metho-
xy-1-cyclopropyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5,8-di-
methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-5,8-dimethyl-1H-
-quinazoline-2,4-dione;
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
oxy-5-methyl-1H-quinazoline-2,4-dione;
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-8-methoxy-5-met-
hyl-1H-quinazoline-2,4-dione;
3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5--
methyl-1H-quinazoline-2,4-dione; and
3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-5-methyl-1H-
-quinazoline-2,4-dione.
11. A pharmaceutical composition comprising a compound of claim 1
admixed with a carrier, diluent, or excipient.
12. A pharmaceutical composition comprising a compound of claim 2
admixed with a carrier, diluent, or excipient.
13. (canceled)
14. (canceled)
15. A pharmaceutical composition comprising a compound of claim 5
admixed with a carrier, diluent, or excipient
16. (canceled)
17. (canceled)
18. A pharmaceutical composition comprising a compound of claim 10
admixed with a carrier, diluent, or excipient.
19. A method of treating a bacterial infection in a mammal
comprising administering to the mammal an antibacterial effective
amount of a compound of claim 1, wherein the bacterial infection is
caused by E. faecalis, S. aureus, S. pyogenes or E. coli.
20. A method of treating a bacterial infection in a mammal
comprising administering to the mammal an antibacterial effective
amount of a compound of claim 2, wherein the bacterial infection is
caused by E. faecalis, S. aureus, S. pyogenes or E. coli.
21. (canceled)
22. (canceled)
23. A method of treating a bacterial infection in a mammal
comprising administering to the mammal an antibacterial effective
amount of a compound of claim 5, wherein the bacterial infection is
caused by E. faecalis, S. aureus, S. pyogenes or E. coli.
24. (canceled)
25. (canceled)
26. A method of treating a bacterial infection in a mammal
comprising administering to the mammal an antibacterial effective
amount of a compound of claim 10, wherein the bacterial infection
is caused by E. faecalis, S. aureus. S. pyogenes or E. coli.
27. (canceled)
28. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention relates to 3-aminoquinazolin-2,4-diones that
have potent in vitro and in vivo antibacterial activity. In
addition, this invention relates to a method of inhibiting both
wild-type and quinolone resistant mutants of DNA gyrase. This
invention further relates to a method of treating patients having
antibiotic resistance and in need of treatment for bacterial
infections.
BACKGROUND OF THE INVENTION
[0002] Antibiotic resistance is a worldwide problem with
catastrophic potential. The American Society of Microbiology Task
Force recently issued a report defining the resistance problem and
calling for new antibacterial agents with novel structures or
mechanisms to offer alternatives to existing therapeutic choices
(Southern Med. J., 1995;88:797).
[0003] The quinolones are a class of antibacterials that are widely
used throughout the world. The quinolones are potent inhibitors of
gram positive and gram negative bacteria, and may be administered
orally or intravenously. The quinolones are routinely used even
though they have side effects (J. Antimicrob. Chemother.,
1994;33:685), and significant resistance has been frequently noted
(Gootz, Medicinal Research, 1996; Rev. 16:433). One of the most
widely used quinolones is ciprofloxacin, which has the following
chemical structure: ##STR2##
[0004] The quinolones have a distinct structure activity
relationship (SAR) which is defined by several thousands of analogs
prepared over the last 30 years (S. Mitsuhashi, ed. Progress in
Drug Research, 1992;38:11-147). In the quinolone SAR (referring to
the formula below representing substituted quinolones), it is
well-established that the N.sub.1 group, in combination with the
C.sub.3-carboxyl and the C.sub.4-carbonyl, are essential for
activity, and that any substituents at C.sub.2 detract from
activity (J. Antimicrob. Chemother, 1994;33:685 and Gootz, supra.,
1996). It is also well-established that R.sub.6 is ideally
fluorine, and that R.sub.7 is a nitrogen containing heterocycle.
R.sub.1 is ideally a small alkyl, a cycloalkyl, or a phenyl group.
##STR3##
[0005] The quinolones inhibit bacterial growth by inhibition of DNA
gyrase and topoisomerase IV (Gootz, supra., 1996). The gyrase
interaction appears to rely on the
N.sub.1/C.sub.4-carbonyl/C.sub.3-carboxyl relationship.
[0006] Attempts to design novel quinolone mimics have focused on
the N.sub.1/C.sub.4-carbonyl/C.sub.3-carboxyl relationship. Certain
tricyclic isothiazole analogs were designed to keep an all-planar
relationship, and to have the NH of the isothiazole ring be as
acidic as the quinolone C.sub.3-carboxyl group (Chu, Drugs Exptl.
Clin. Res., 1990;16:215). ##STR4## While maintaining excellent
antibacterial activity, these compounds also show antitumor and
mammalian topoisomerase activity (Drugs of the Future,
1992;17:1101). These activities are undesired in an antibacterial
agent.
[0007] Several publications (U.S. Pat. No. 5,283,248; J. Med.
Chem., 1992;35:1358; Antimicrob. Agents Chemother., 1995;39:163)
disclose tricyclic compounds (such as the structure below) having
antibacterial activity and DNA gyrase inhibiting activity. ##STR5##
For such compounds, the relationship of the N.sub.1 to the
C4-carbonyl is skewed. Compounds of this type are ineffective
against bacteria that are quinolone resistant.
[0008] Other tricyclic analogs of the following structure are
disclosed as quinolone mimics (JP 4,091,090 March 1992;
Interscience Conference on Antimicrobial Agents and Chemotherapy
1991, Abstract 1494). ##STR6## While the ideal quinolone
N.sub.1-C.sub.4-carbonyl relationship is maintained, the C.sub.2
region, where substitution is undesirable, is part of a
fused-ringed system. These compounds are not active against
quinolone resistant bacteria.
[0009] WO 96/04288 describes a series of benzoheterocycles of the
formulas ##STR7## where X, Y, and Z are hydrogen bond acceptor and
donator groups. Among the compounds depicted are
N-hydroxy-quinazoline-2,4-diones, where R.sub.1-R.sub.4 can
represent hydroxy, amino, nitro, a variety of alkyls, esters, and
amides. In all cases, the substituent on N.sub.1 is hydrogen. None
of the substituents R.sub.1-R.sub.4 are nitrogen containing
heterocycles. No antibacterial activity is disclosed for these
compounds.
[0010] U.S. Pat. No. 5,155,110 describes
N.sub.1-aryl-N-hydroxy-quinazoline-2,4-diones of the formula
##STR8## where R may be halo, cyano, hydroxy, alkoxy, and
substituted amino. Amino heterocycles are not included in R, and no
antibacterial activity is reported for such compounds.
[0011] Compounds taught in International Publication No. WO
95/19346 as AMPA, NMDA, and kinase receptor antagonists have the
formula ##STR9## where R substituents are defined as alkyl or
phenyl, and R.sub.1 and R.sub.2 are defined as H, alkyl, alkoxy,
alkenyl, halogen, NO.sub.2, (un)substituted NH.sub.2, CN, etc.
Again, no antibacterial activity is disclosed for these
compounds.
[0012] Kornet and coworkers (Kornet M. J. et al., J. Heterocyl.
Chem., 1984;21:1533-1535) disclosed anticonvulsant compounds having
the formula ##STR10## where R is defined as H, Me, or Cl; R.sub.1
and R.sub.2 as H or Me; and R.sub.3 as Me or t-butyl.
Alternatively, R.sub.2 and R.sub.3, together with the nitrogen atom
to which they are attached, can form a heterocyclic ring such as
piperidinyl, morpholinyl, etc. These compounds are not reported to
have antibacterial activity.
[0013] A number of publications teach compounds having diuretic and
sedative activities and with the generic structure as follows (ES
80/489675, JP 80/33323, BE 80/199792, FR 78/33438, JP 70/97932;
Baronnet R., Callendret R., Blanchard L., Foussard-Blanpin O.,
Bretaudeau J., Eur. J. Med.-Chim. Ther., 1983;18:241-247).
##STR11## These are compounds in which NR.sub.1R.sub.2 can form a
heterocycle, or R.sub.1 and R.sub.2 independently can represent H
or a small alkyl. R.sub.3 and R.sub.4 can represent H, halogen,
sulphonamide, alkyl, or alkoxy. No antibacterial activity is
reported for these compounds.
[0014] International Publication No. WO 99/21840 describes
3-hydroxy-quinazoline-2,4-diones as antibacterial agents. ##STR12##
Compounds of this type are quinolone mimics where the 3-position
exocyclic carboxylic acid of the quinolones is replaced by an oxo
at the 2-position and a hydroxy at the N-3-position. Compounds of
this type are designed to keep an all-planar relationship and to
have the N--OH remain acidic, as in the quinolone CO.sub.2H (Chu,
Drugs Exptl. Clin. Res., 1990;16:215). These compounds inhibit DNA
gyrase and topoisomerase IV, and demonstrate antibacterial activity
in vitro. However, such compounds are not effective against
quinolone resistant bacteria.
[0015] The need continues to find new antibacterial agents that
have the potency of the quinolones, but which are active against
quinolone resistant bacterial strains. The present invention
provides such compounds, which are characterized as
3-aminoquinazolin-2,4-diones. An object of this invention is to
provide these new compounds, and a method for treating bacterial
infections in mammals by administering these compounds.
SUMMARY OF THE INVENTION
[0016] The present invention provides 3-aminoquinazolin-2,4-diones
having antibacterial activity. The compounds inhibit DNA gyrase,
but are not cross-resistant with quinolone mutants that are no
longer sensitive to agents such as ciprofloxacin.
[0017] The invention provides compounds of Formula I ##STR13## or a
pharmaceutically acceptable salt thereof wherein: [0018] R.sub.1
and R.sub.3 independently are H, [0019] C.sub.1-C.sub.12 alkyl and
substituted alkyl, [0020] C.sub.2-C.sub.12 alkenyl and substituted
alkenyl, [0021] C.sub.2-C.sub.12 alkynyl and substituted alkynyl,
[0022] C.sub.3-C.sub.12 cycloalkyl and substituted cycloalkyl,
[0023] aryl and substituted aryl, [0024] heterocyclic and
substituted heterocyclic, [0025] or heteroaryl and substituted
heteroaryl; [0026] R.sub.5, R.sub.6, and R.sub.8 independently are
H, [0027] (O).sub.nC.sub.1-C.sub.12 alkyl and substituted alkyl;
[0028] (O).sub.nC.sub.2-C.sub.12 alkenyl and substituted alkenyl;
[0029] (O).sub.nC.sub.2-C.sub.12 alkynyl and substituted alkynyl;
[0030] halo, [0031] NO.sub.2, [0032] CN, [0033] NR'R'' wherein n is
0 or 1; [0034] R' and R'' independently are H, [0035]
C.sub.1-C.sub.12 alkyl and substituted alkyl, [0036]
C.sub.2-C.sub.12 alkenyl and substituted alkenyl, [0037]
C.sub.2-C.sub.12 alkynyl and substituted alkynyl, [0038]
CO--C.sub.1-C.sub.12 alkyl and substituted alkyl, [0039] or R' and
R'' taken together with the nitrogen to which they are attached
form a 3- to 7-membered ring containing from 1 to 3 heteroatoms
selected from N, O, and S, said ring being unsubstituted or
substituted with up to 4 substituent groups; [0040] R.sub.1 and
R.sub.8 can be taken together with the atoms to which they are
attached to form a cyclic ring having from 1 to 3 heteroatoms
selected from N, O, and S, and optionally substituted by R' and
R''; [0041] R.sub.7 is hydrogen, [0042] C.sub.1-C.sub.12 alkyl and
substituted alkyl, [0043] C.sub.2-C.sub.12 alkenyl and substituted
alkenyl, [0044] C.sub.2-C.sub.12 alkynyl and substituted alkynyl,
[0045] halo, [0046] NO.sub.2, [0047] CN, [0048] NR'R'', [0049]
COOR', [0050] aryl, [0051] fused aryl, [0052] heterocyclic, [0053]
fused heterocyclic, [0054] bicyclic heterocyclic, or [0055] Spiro
heterocyclic wherein all ring groups can be substituted; [0056] J
and K independently are C or N, provided that when J or K is N,
R.sub.6 or R.sub.8 is absent at that position.
[0057] R.sub.7 is referred to herein as the "side chain" of the
3-aminoquinazolin-2,4-dione nucleus. The R.sub.7 side chain can be
any group known in the quinolone art as a suitable substituent at
the 7-position of the quinolone ring.
[0058] Preferred compounds of this invention have Formula II
##STR14## wherein R.sub.1, R.sub.3, R.sub.6, R.sub.7, and R.sub.8
are as defined above.
[0059] Further preferred compounds have Formula III ##STR15##
wherein R.sub.3, R.sub.6, R.sub.7, and R' are as defined above.
[0060] Another preferred group of compounds have Formula IV
##STR16## wherein R.sub.1, R.sub.3, R.sub.6, and R.sub.7 are as
defined above.
[0061] The most preferred compounds of this invention have Formula
V ##STR17## wherein R.sub.1, R.sub.3, R.sub.6, R.sub.8, R', and R''
are as defined above. An especially preferred embodiment are
compounds of Formula V wherein R' and R'' are taken together with
the nitrogen to which they are attached to complete a ring which is
optionally substituted with groups such as alkyl and substituted
alkyl, and amino, alkylamino, dialkylamino, and aryl amino.
[0062] A further preferred group of compounds have Formula VI
##STR18## wherein R.sub.1, R.sub.3, R.sub.6, R', and R'' are as
defined above.
[0063] Still another preferred group of invention compounds are
those of Formula VII ##STR19## wherein R.sub.1, R.sub.3, R.sub.7,
and R.sub.8 are as defined above.
[0064] Especially preferred compounds provided by the invention
are:
[0065]
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6--
fluoro-1H-quinazoline-2,4-dione;
[0066]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinaz-
oline-2,4-dione;
[0067]
3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyc-
lopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0068]
3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-g-chloro-1-cyclop-
ropyl-6-fluoro-1H-quinazolin-2,4-dione;
[0069]
3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopro-
pyl-6-fluoro-1H-quinazoline-2,4-dione;
[0070]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroani-
lino)-6-fluoro-1H-quinazoline-2,4-dione;
[0071]
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difl-
uoro-1H-quinazoline-2,4-dione;
[0072]
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difl-
uoro-1H-quinazoline-2,4-dione;
[0073]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluo-
ro-1H-quinazoline-2,4-dione;
[0074]
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-
-1H-quinazoline-2,4-dione;
[0075]
7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-diflu-
oro-1H-quinazoline-2,4-dione;
[0076]
3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl--
6-fluoro-1H-quinazoline-2,4-dione;
[0077]
3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
[0078]
3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclop-
ropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0079]
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0080]
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
[0081]
3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-qui-
nazoline-2,4-dione;
[0082]
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1-
H-quinazoline-2,4-dione;
[0083]
3-Amino-7-(3-aminopyrrolin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H--
quinazoline-2,4-dione;
[0084]
3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methox-
y-1H-quinazoline-2,4-dione;
[0085]
3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fl-
uoro-1H-quinazoline-2,4-dione;
[0086]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quina-
zoline-2,4-dione;
[0087]
3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-
-1H-quinazoline-2,4-dione;
[0088]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluor-
o-1H-quinazoline-2,4-dione;
[0089]
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopr-
opylmethyl-8-fluoro-1H-quinazoline-2,4-dione;
[0090]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazo-
line-2,4-dione;
[0091]
3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrolid-
in-1-yl]-1H-quinazoline-2,4-dione;
[0092]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-q-
uinazoline-2,4-dione;
[0093]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-
-1H-quinazoline-2,4-dione;
[0094]
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8--
methyl-1H-quinazoline-2,4-dione;
[0095]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methox-
y-1H-quinazoline-2,4-dione;
[0096]
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8--
methoxy-1H-quinazoline-2,4-dione;
[0097]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-
-1H-quinazoline-2,4-dione;
[0098]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-diox-
o-1,2,3,4-tetrahydroquinazoline-8-carbonitrile;
[0099]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl--
pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;
[0100]
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0101]
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0102]
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0103]
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0104]
5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihyd-
ro-1-oxa-3a,5-diazaphenalene-4,6-dione;
[0105] 5-Amino
-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-dihydr-
o-1-oxa-3a,5-diazaphenalene-4,6-dione;
[0106]
2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihyd-
ro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione,;
[0107]
2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-met-
hyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione;
[0108]
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-p-
yrido[2,3-d]pyrimidine-2,4-dione;
[0109]
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fl-
uoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione,;
[0110]
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione,;
[0111]
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-
-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0112]
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-
-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0113]
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0114]
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H--
pyrido[2,3-d]pyrimidine-2,4-dione;
[0115]
trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-
-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0116]
3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylamino-ethyl)p-
yrrolidin-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0117]
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;
[0118]
3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
[0119]
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylamin-
oethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
[0120]
3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2.4]hept-5-yl]-1-cyclopropy-
l-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0121]
1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetra-
hydroquinazolin-7-yl)piperidine-3-carboxylic acid amide;
[0122]
3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-
-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0123]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoro-eth-
ylamino)methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dione;
[0124]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydro-pyrro-
lo[3,4-c]pyrrol-2-yl)-1H-quinazoline-2,4-dione;
[0125]
3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-f-
luoro-1H-quinazoline-2,4-dione;
[0126]
3-Amino-7-(3-aminomethyl-3-benzylpyrrolidin-1-yl)-8-chloro-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione;
[0127]
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyc-
lopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0128]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyimino-pyrrolid-
in-1-yl)-1H-quinazoline-2,4-dione;
[0129]
3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chlor-
o-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0130]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)-1-methylamino-
ethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
[0131]
3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione;
[0132]
3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chl-
oro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0133]
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;
[0134]
3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
[0135]
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylamino-methy-
l)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
[0136]
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropy-
l-1H-quinazoline-2,4-dione;
[0137]
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;
[0138]
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0139]
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0140]
3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0141]
3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0142]
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-
-1H-quinazoline-2,4-dione;
[0143]
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-5-methyl-1H-quinazoline-2,4-dione;
[0144]
3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0145]
3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopro-
pyl-6-fluoro-1H-quinazoline-2,4-dione;
[0146]
3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-
-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0147]
3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro--
8-methoxy-1H-quinazoline-2,4-dione;
[0148]
3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8--
methyl-1H-quinazoline-2,4-dione;
[0149]
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0150]
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopr-
opyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0151]
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methyl-1H-quinazoline-2,4-dione;
[0152]
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0153]
3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0154]
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-
-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0155]
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0156]
3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0157]
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethyl-1H-quinazoline-2,4-dione;
[0158]
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione;
[0159]
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione;
[0160]
3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione;
[0161]
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0162]
3-Amino-7-[(R)-3(-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-
-8-ethyl-6-fluoro-1H-quinazoline-2,4-dione;
[0163]
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)pyrrolidine-3-carboxylic acid
trifluoroacetate;
[0164]
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydroquinazolin-7-yl)pyrrolidine-3-carboxylic acid
trifluoroacetate;
[0165]
3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropy-
l-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0166]
3-Amino-7-(i-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropy-
l-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0167]
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0168]
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0169]
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]-
pyridin-6-yl)-1H-quinazoline-2,4-dione;
[0170]
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-
-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0171]
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopro-
pyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0172]
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopro-
pyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0173]
3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0174]
3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethoxy-1H-quinazoline-2,4-dione;
[0175]
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethoxy-1H-quinazoline-2,4-dione;
[0176]
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0177]
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-
-6-fluoro-1H-quinazoline-2,4-dione;
[0178]
3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methyl-1H-quinazoline-2,4-dione;
[0179]
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinaz-
oline-2,4-dione;
[0180]
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-quina-
zoline-2,4-dione;
[0181]
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrr-
olidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;
[0182]
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrr-
olidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;
[0183]
3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylamin-
oethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
[0184]
(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrol-
idin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0185]
3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-
-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0186]
3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclop-
ropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0187]
3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethoxy-1H-quinazoline-2,4-dione;
[0188]
3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-me-
thoxy-1H-quinazoline-2,4-dione;
[0189]
cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropy-
l-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0190]
trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopro-
pyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0191]
3-Amino-7-(1-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione;
[0192]
3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fl-
uoro-8-methoxy-1H-quinazoline-2,4-dione;
[0193]
3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fl-
uoro-8-methyl-1H-quinazoline-2,4-dione;
[0194]
3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0195]
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fl-
uoro-8-methyl-1H-quinazoline-2,4-dione;
[0196]
3-Amino-7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0197]
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(isopropylaminomethyl)pyrrolid-
in-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;
[0198]
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyr-
rolo[3,4-b]pyridin-6-yl-1H-quinazoline-2,4-dione;
[0199]
3-Amino-7-(3-amino-4-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0200]
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0201]
3-Amino-7-(4-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-
-1H-quinazoline-2,4-dione;
[0202]
3-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-
-1H-quinazoline-2,4-dione;
[0203]
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(R)-3-((S)-1-methylami-
noethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;
[0204]
3-Amino-7-(3-aminoazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione;
[0205]
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0206]
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0207]
3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0208]
3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0209]
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0210]
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0211]
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0212]
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0213]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0214]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0215]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0216]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0217]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0218]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0219]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0220]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0221]
3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0222]
3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0223]
3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0224]
3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0225]
3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0226]
3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0227]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0228]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0229]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0230]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0231]
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0232]
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0233]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0234]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0235]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0236]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0237]
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0238]
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0239]
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0240]
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0241]
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0242]
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0243]
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0244]
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0245]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0246]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0247]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0248]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0249]
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0250]
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0251]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0252]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0253]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0254]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0255]
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0256]
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0257]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0258]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0259]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0260]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0261]
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0262]
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0263]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0264]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0265]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;
[0266]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;
[0267]
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-
-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0268]
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,-
2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0269]
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-
-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0270]
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,-
2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0271]
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-
-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethy-
l}urea;
[0272]
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-diox-
o-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
[0273]
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-
-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethy-
l}urea;
[0274]
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-diox-
o-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
[0275]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo--
1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
[0276]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
[0277]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo--
1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
[0278]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
[0279]
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0280]
3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0281]
3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0282]
3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-
-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0283]
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0284]
3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0285]
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0286]
3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-
-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0287]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0288]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0289]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0290]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0291]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0292]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0293]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0294]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0295]
3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0296]
3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0297]
3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0298]
3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0299]
3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0300]
3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0301]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0302]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0303]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0304]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0305]
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0306]
3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cy-
clopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0307]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0308]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0309]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0310]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0311]
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0312]
3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0313]
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0314]
3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0315]
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0316]
3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0317]
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0318]
3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyc-
lopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0319]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0320]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0321]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0322]
3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0323]
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0324]
3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0325]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0326]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0327]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0328]
3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidi-
n-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0329]
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0330]
3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0331]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0332]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0333]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0334]
3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0335]
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0336]
3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-c-
yclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0337]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0338]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrroli-
din-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0339]
3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrroli-
din-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;
[0340]
-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolid-
in-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;
[0341]
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,-
4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0342]
{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1-
,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0343]
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,-
4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0344]
{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1-
,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;
[0345]
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methox-
y-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]eth-
yl}urea;
[0346]
{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dio-
xo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
[0347]
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methox-
y-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]eth-
yl}urea;
[0348]
{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dio-
xo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;
[0349]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-
-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
[0350]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;
[0351]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-
-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea-
;
[0352]
{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;
[0353]
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-
-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0354]
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0355]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0356]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0357]
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0358]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-pyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0359]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0360]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0361]
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0362]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-
-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0363]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0364]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0365]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]--
1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0366]
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0367]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0368]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;
[0369]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
[0370]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[4,3-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;
[0371]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[4,3-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;
[0372]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[4,3-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea-
;
[0373]
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0374]
3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-
-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0375]
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0376]
3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0377]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-6,-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0378]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0379]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0380]
3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0381]
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0382]
3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0383]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0384]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropy-
l-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0385]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0386]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0387]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0388]
3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-c-
yclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0389]
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-
-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0390]
3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl)-
-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0391]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-
-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0392]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-
-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0393]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0394]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0395]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0396]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cy-
clopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0397]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]--
1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0398]
3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]--
1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0399]
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cycloprop-
yl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0400]
3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cycloprop-
yl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0401]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0402]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0403]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0404]
3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1--
cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;
[0405]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1-
,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
[0406]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;
[0407]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1-
,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethy-
lurea;
[0408]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;
[0409]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1-
,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethy-
lurea;
[0410]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;
[0411]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1-
,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]-
ethylurea;
[0412]
{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea-
;
[0413]
3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
[0414]
3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-6-fluoro-1H-
-quinazoline-2,4-dione;
[0415]
3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione;
[0416]
3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-1H-quinazol-
ine-2,4-dione;
[0417]
3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-1H-quinazol-
ine-2,4-dione;
[0418]
3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-1H-quinazo-
line-2,4-dione;
[0419]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-6-flu-
oro-1H-quinazoline-2,4-dione;
[0420]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-6-flu-
oro-1H-quinazoline-2,4-dione;
[0421]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fl-
uoro-1H-quinazoline-2,4-dione;
[0422]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-1H-qu-
inazoline-2,4-dione;
[0423]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-1H-qu-
inazoline-2,4-dione;
[0424]
3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-q-
uinazoline-2,4-dione;
[0425]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-6--
fluoro-1H-quinazoline-2,4-dione;
[0426]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-6--
fluoro-1H-quinazoline-2,4-dione;
[0427]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-6-
-fluoro-1H-quinazoline-2,4-dione;
[0428]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-1H-
-quinazoline-2,4-dione;
[0429]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-1H-
-quinazoline-2,4-dione;
[0430]
3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-1-
H-quinazoline-2,4-dione;
[0431]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-6-fl-
uoro-1H-quinazoline-2,4-dione;
[0432]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-6-fl-
uoro-1H-quinazoline-2,4-dione;
[0433]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione;
[0434]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-1H-q-
uinazoline-2,4-dione;
[0435]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-1H-q-
uinazoline-2,4-dione;
[0436]
3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-1H--
quinazoline-2,4-dione;
[0437]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-c-
yclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0438]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-c-
yclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0439]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1--
cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0440]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-c-
yclopropyl-1H-quinazoline-2,4-dione;
[0441]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-c-
yclopropyl-1H-quinazoline-2,4-dione
[0442]
3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1--
cyclopropyl-1H-quinazoline-2,4-dione;
[0443]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro--
1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0444]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl--
1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0445]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-
-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0446]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro--
1-cyclopropyl-1H-quinazoline-2,4-dione;
[0447]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl--
1-cyclopropyl-1H-quinazoline-2,4-dione;
[0448]
3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-
-1-cyclopropyl-1H-quinazoline-2,4-dione;
[0449]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0450]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0451]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;
[0452]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;
[0453]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;
[0454]
3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)--
8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;
[0455]
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-5,8-dimethyl-1H-quinazoline-2,4-dione;
[0456]
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-5,8-dime-
thyl-1H-quinazoline-2,4-dione;
[0457]
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-5-methyl-1H-quinazoline-2,4-dione;
[0458]
3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-8-methox-
y-5-methyl-1H-quinazoline-2,4-dione;
[0459]
3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-5-methyl-1H-quinazoline-2,4-dione; and
[0460]
3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-5-me-
thyl-1H-quinazoline-2,4-dione.
[0461] A further embodiment of the invention is a pharmaceutical
composition comprising a compound of Formula I together with an
excipient, carrier, or diluent. Preferred compositions will have a
compound of Formulas II, III, IV, V, VI, or VII mixed with an
excipient, carrier, or diluent.
[0462] Still another embodiment of the invention is a method of
treating bacterial infections in mammals comprising administering
an antibacterial effective amount of a compound of Formula I.
Preferred methods comprise administering a compound of Formulas II,
III, IV, V, VI, or VII.
[0463] Another embodiment is a method of preventing or eliminating
bacterial growth on surfaces comprising applying to the surface an
antibacterially effective amount of a compound of Formulas
I-VII.
DETAILED DESCRIPTION
[0464] All references cited herein, including patents, are
incorporated herein by reference.
[0465] The terms used in this specification and the appended claims
have the following meanings. The term "halo" means chloro, bromo,
fluoro, and iodo.
[0466] The term "alkyl" means a straight or branched hydrocarbon
radical having from 1 to 12 carbon atoms and includes, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
2-isopropylheptyl, 3-n-butyloctyl, n-nonyl, n-decyl, undecyl, and
dodecyl.
[0467] Preferred alkyl groups are C.sub.1-C.sub.6 alkyl such as
methyl, isopropyl, neopentyl, and 1-methylpentyl.
[0468] The term "C.sub.2-C.sub.12 alkenyl" means a straight or
branched hydrocarbon radical having from 1 to 3 double bonds.
Examples include ethenyl, 2-propen-1-yl, 1,3-butadien-1-yl,
3-hexen-1-yl, 5-octen-2-yl, 2-isopropyl-3,5-octadien-1-yl,
cis-3-hexen-1-yl, and trans-2-hepten-1-yl. Preferred alkenyl groups
include C.sub.2-C.sub.6 alkenyls such as ethenyl, 2-propen-1-yl,
2-buten-1-yl, and 3-penten-1-yl.
[0469] The term "C.sub.2-C.sub.12 alkynyl" means a straight or
branched hydrocarbon radical having from 1 to 3 triple-bonds.
Examples include ethynyl, propynyl, 3-butyn-1-yl, 4-hexyn-1-yl,
5-octyn-3-yl, 4,6-octadiyn-1-yl, 4-decyn-1-yl, and
1,1-dimethyl-5-decyn-1-yl. Preferred alkynyl groups are
C.sub.2-C.sub.6 alkynyls such as ethynyl, propynyl, 3-butyn-1-yl,
and 5-hexyn-1-yl.
[0470] The alkyl, alkenyl, and alkynyl groups can be substituted
with 1 to 3 groups selected from halo, hydroxy, cyano,
C.sub.1-C.sub.6 alkoxy, nitro, amino, C.sub.1-C.sub.6 alkylamino,
di-C.sub.1-C.sub.6 alkylamino, carboxy, C.sub.1-C.sub.6
alkoxycarbonyl, aminocarbonyl, halo-dihalo and trihalomethyl,
thiol, alkylsulfanyl, alkylsulfinyl, and aminosulfonyl. Examples of
substituted alkyl groups include fluoromethyl, tribromomethyl,
hydroxymethyl, 3-methoxypropyl, 3-carboxypentyl,
3,5-dibromo-6-aminocarbonyldecyl, and 4-ethylsulfinyloctyl.
Examples of substituted alkenyl groups include 2-bromoethenyl,
1-amino-2-propen-1-yl, 3-hydroxypent-2-en-1-yl,
4-methoxycarbonyl-hex-2-en-1-yl, and
2-nitro-3-bromo-4-iodo-oct-5-en-1-yl. Typical substituted alkynyl
groups include 2-hydroxyethynyl, 3-dimethylamino-hex-5-yn-1-yl, and
2-cyano-hept-3-yn-1-yl.
[0471] The term "cycloalkyl" means a hydrocarbon ring which
contains from 3 to 12 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norpinanyl, and
adamantyl. Where possible, the cycloalkyl group may contain double
bonds, for example, 3-cyclohexen-1-yl. The cycloalkyl ring may be
unsubstituted or substituted by 1 to 3 substituents selected from
alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino,
alkyl and dialkylamino, formyl, carboxyl, CN, --NH--CO--R' ,
--CO--NHR'--, --CO.sub.2R', --COR', aryl, or heteroaryl, wherein
alkyl, aryl, and heteroaryl are as defined herein. Examples of
substituted cycloalkyl groups include fluorocyclopropyl,
2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl,
and 3-phenylcyclopentyl.
[0472] The term "heterocyclic" means a cyclic or fused bicyclic or
polycyclic ring system having from 3 to 12 ring atoms, with from 1
to 5 being heteroatoms selected from N, O, and S. The heterocyclic
groups can be substituted with 1 to 3 of the substituents listed
above for the cycloalkyl groups. Examples of heterocyclic groups
include cyclic ethers (oxiranes) such as ethyleneoxide,
tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein
the substituents are those described above for the alkyl and
cycloalkyl groups. Typical substituted cyclic ethers include
propyleneoxide, phenyloxirane(styrene oxide),
cis-2-butene-oxide(2,3-dimethyloxirane), 3-chlorotetrahydrofuran,
2,6-dimethyl-1,4-dioxane, and the like. Heterocycles containing
nitrogen are groups such as pyrrolidine, piperidine, piperazine,
tetrahydrotriazine, tetrahydropyrazole, and substituted groups such
as 3-aminopyrrolidine, 4-methylpiperazin-1-yl, and the like.
Typical sulfur containing heterocycles include tetrahydrothiophene,
dihydro-1,3-dithiol-2-yl, and hexahydrothiepin-4-yl. Other commonly
employed heterocycles include dihydro-oxathiol-4-yl,
tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl,
tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl,
morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,
octahydrobenzofuranyl, octahydrobenzimidazolyl, and
octahydrobenzothiazolyl. For heterocycles containing sulfur, the
oxidized sulfur heterocycles containing SO or SO.sub.2 groups are
also included. Examples include the sulfoxide and sulfone forms of
tetrahydrothiophene.
[0473] The term "aryl" means a cyclic or polycyclic aromatic ring
having from 5 to 12 carbon atoms, and being unsubstituted or
substituted with up to 3 of the substituent groups recited above
for alkyl, alkenyl, and alkynyl. Examples of aryl groups include
phenyl, 2,6-dichlorophenyl, 3-methoxyphenyl, naphthyl,
4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl,
benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and
4'-bromobiphenyl.
[0474] The term "heteroaryl" means an aromatic cyclic or polycyclic
ring system having from 1 to 4 heteroatoms selected from N, O, and
S. Typical heteroaryl groups include 2- or 3-thienyl, 2- or
3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or
5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or
4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or
5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-,
5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl,
2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or
7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-,
6-, or 7-benzothiazolyl. The heteroaryl groups may be unsubstituted
or substituted by 1 to 3 substituents selected from those described
above for alkyl, alkenyl, and alkynyl, for example, cyanothienyl
and formylpyrrolyl.
[0475] Preferred aromatic fused heterocyclic rings of from 8 to 10
atoms include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or
8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-,
4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl,
2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or
7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
[0476] Preferred compounds of the invention have Formula I wherein
R.sub.7 is a heterocyclic or heteroaryl group such as those
described above. Such heterocyclic and heteroaryl groups will be
referred to herein generically as "{circle around (N)}".
[0477] Further examples of typical heterocycles, fused
heterocycles, and heteroaryl groups that are preferred as R.sub.7
substituents are listed below in Table A. TABLE-US-00001 TABLE A
##STR20## ##STR21## ##STR22## ##STR23## ##STR24## ##STR25##
##STR26## ##STR27## ##STR28## ##STR29## ##STR30## ##STR31##
##STR32## ##STR33## ##STR34## ##STR35## ##STR36## ##STR37##
##STR38## ##STR39## ##STR40## ##STR41## ##STR42## ##STR43##
##STR44## ##STR45## ##STR46## ##STR47## ##STR48## ##STR49##
##STR50## ##STR51## ##STR52## ##STR53## ##STR54## ##STR55##
##STR56## ##STR57## ##STR58## ##STR59## ##STR60## ##STR61##
##STR62## ##STR63## ##STR64## and ##STR65## ##STR66## ##STR67##
##STR68## ##STR69## ##STR70## ##STR71## ##STR72## ##STR73##
##STR74## ##STR75## ##STR76## ##STR77## ##STR78## ##STR79##
##STR80## ##STR81## ##STR82## ##STR83## ##STR84## ##STR85##
##STR86## ##STR87## ##STR88## ##STR89## ##STR90## ##STR91##
##STR92## ##STR93## ##STR94## ##STR95## ##STR96## ##STR97##
##STR98## ##STR99## ##STR100## ##STR101## ##STR102## ##STR103##
##STR104## ##STR105## ##STR106## ##STR107## ##STR108## ##STR109##
##STR110## ##STR111## ##STR112## ##STR113## ##STR114## ##STR115##
##STR116## and ##STR117##
[0478] The foregoing groups are especially preferred as R.sub.7
side chains on the quinazoline ring system. The heterocycles and
heteroaryl groups such as those depicted above are known in the
quinolone art and are prepared by literature methods such as J.
Med. Chem., 1992;35:1764; J. Med. Chem., 1996;39:3070;
Synlett.,1996:1097; and J. Med. Chem., 1986;29:445. Any of the
primary or secondary amines shown as substituents on the heteroaryl
or heterocyclic groups may be substituted by alkyl, such as methyl,
ethyl, isopropyl, and the like.
[0479] Some of the compounds of Formula I are capable of forming
pharmaceutically acceptable acid addition and/or base salts. All of
these forms are within the scope of the present invention and are
prepared by art recognized methods. For example, an acid addition
salt is prepared by contacting the free base form of the invention
compound with a sufficient amount of the desired acid to produce
the salt in the conventional manner. Pharmaceutically acceptable
acid addition salts of the compounds of Formula I include salts
derived from inorganic acids such as hydrochloric, nitric,
phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric,
phosphorous, and the like, as well as the salts derived from
organic acids, such as aliphatic mono- and dicarboxylic acids,
phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. Such salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, acetate, trifluoroacetate, propionate, caprylate,
isobutyrate, oxalate, malonate, succinate suberate, sebacate,
fumarate, maleate, mandelate, benzoate, chlorobenzoate,
methylbenzoate, dinitrobenzoate, phthalate, benzensulfonate,
toluenesulfonate, phenylacetate, citrate, lactate, tartrate,
methanesulfonate, and the like. Also contemplated are salts of
amino acids such as arginate and the like, as well as gluconate and
galacturonate. All such salts are readily prepared, for example as
described by Berge S. M. et al., "Pharmaceutical Salts," Journal of
Pharmaceutical Science, 1977;66:1-19.
[0480] Pharmaceutically acceptable base addition salts are formed
with metals or amines, such as alkali and alkaline earth metals or
organic amines, when compounds of Formula I have an acidic group
such as carboxy. The base addition salts of acidic invention
compounds are prepared by contacting the free acid form with a
sufficient amount of the desired base to produce the salt in the
conventional manner. Typical bases include sodium hydroxide,
calcium oxide, diethylamine, and pyridine. Examples of metals used
as cations are sodium, potassium, magnesium, calcium, and the like.
Examples of suitable amines are N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, dicyclohexylamine,
ethylenediamine, N-methylglucamine, and procaine (see, for example,
Berge S. M., supra., 1977).
[0481] Certain of the compounds of the present invention can exist
in unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms, including hydrated forms,
are equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention.
[0482] Certain of the compounds of the present invention possess
one or more chiral centers. Each center may exist in the R or S
configuration. The present invention includes all diastereomeric,
enantiomeric, and epimeric forms, as well as the appropriate
mixtures thereof. Additionally, the compounds of the present
invention may exist as geometric isomers. The present invention
includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z)
isomers, as well as the mixtures thereof.
[0483] Structures of representative compounds of the invention are
shown below in Table 1. TABLE-US-00002 TABLE 1 ##STR118## 1
##STR119## 2 ##STR120## 3 ##STR121## 4 ##STR122## 5 ##STR123## 6
##STR124## 9 ##STR125## 11 ##STR126## 18 ##STR127## 21 ##STR128##
25 ##STR129## 33 ##STR130## 42 ##STR131## 46 ##STR132## ##STR133##
##STR134## ##STR135##
[0484] The compounds of Formula I can be prepared utilizing
standard synthetic methodology well-known to those skilled in the
art of organic chemistry. Many of the compounds have reactive
functional groups that generally need to be derivatized with a
protecting group in order to avoid unwanted side reactions. For
example, functional groups such as alcohols, acid groups, and
amines generally are protected while a reaction is carried out at a
different site in the molecule, and then the protecting group is
subsequently removed following the desired chemical transformation.
The use of such protecting groups is standard in organic chemistry
synthesis, as described, for example, in T. W. Green and P. G.
Wuts, Protective Groups in Organic Synthesis, 2.sup.nd edition, New
York City: John Wiley & Sons, 1991. Thus, for example,
protecting groups such as the following may be utilized to protect
suitable amino, hydroxyl, and other groups of related reactivity:
carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl;
alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl
(BOC), .beta.,.beta.,.beta.-trichloroethoxycarbonyl (TCEC),
.beta.-iodoethoxycarbonyl; aryloxycarbonyl groups, such as
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl;
trialkyl silyl groups, such as trimethylsilyl and
t-butyldimethylsilyl (TBDMS); and groups such as trityl,
tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,
diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be
utilized. The protecting group may be removed, after completion of
the synthetic reaction of interest, by procedures known to those
skilled in the art. For example, a BOC group may be removed by
acidolysis, a trityl group by acidolysis or hydrogenolysis, TBDMS
by treatment with fluoride ions, and TCEC by treatment with
zinc.
[0485] Illustrations of typical preparations of compounds of the
present invention having Formula I are shown in Schemes 1-22.
Typical heterocyclic and aromatic side chains defined by R.sub.7 in
Formula I are prepared as described in Schemes A1-A8. All of the
3-aminoquinazoline-2,4-diones of the invention may be prepared from
appropriately substituted benzoic acid starting materials.
Protecting groups (referred to in the schemes as "Pro") may be used
when appropriate throughout many of the schemes. Although
specifically noted in certain schemes, the appropriate use and
choice of protecting groups is well-known by those skilled in the
art, and is not limited to the specific illustrations shown below.
It should also be understood that such protecting groups not only
serve to protect chemically reactive sites, but also to enhance
solubility or otherwise change physical properties of the
underlying invention compound. A number of general reactions such
as oxidations and reductions are not shown in detail in the
schemes, but can be carried out by standard methods well-known to
those skilled in the art. In general, the starting materials used
in the following schemes are obtained from commercial sources, or
are readily prepared by standard methods. All cited published
articles, patents, books, and the like are incorporated herein by
reference.
[0486] As shown in Scheme 1, a difluoro substituted benzoic acid is
reacted with oxalyl chloride or an equivalent acylating reagent
(such as an acid anhydride), and the acid halide or anhydride is
reacted with an alcohol (ZOH) to afford the respective ester (Z is
C.sub.1-C.sub.6 alkyl such as methyl, ethyl, isopropyl, etc.). The
ester is reacted with an amine, for example, a heterocyclic amine,
to produce the desired 4-heterocyclic phenyl derivative.
Alternatively, carbocycles and aryls may also be introduced at this
4-position using palladium catalyzed couplings of tin or boronate
carbocycles and aryls, with starting materials containing a Br, I,
or triflate at the 4-position as described by Suzuki A., Pure Appl.
Chem., 1994;66(2):213-222 and Stille J. K., Angew. Chem.
1986;98(6):504-519.
[0487] Reaction of the 2-fluoro benzoic acid analog with a primary
amine R.sub.1NH.sub.2 affords the corresponding 2-amino benzoic
acid ester. The ester group is readily hydrolyzed by reaction with
an acid such as hydrochloric acid or a base such as sodium
hydroxide to give the corresponding polysubstituted 2-amino benzoic
acid. The acid is then coupled to an appropriately protected
hydrazine to provide the corresponding amide, which in turn is
cyclized to generate the quinazoline-2,4-dione by treatment with,
for example, phosgene. At this point, the protecting group may be
removed to give the free amine A of Formula I, which can represent
a final product of the invention, and which can be further
derivatized, if desired, for instance by alkylation with
R.sub.3Cl.
[0488] Alternatively, the quinazoline-2,4-dione may also be
metallated at low temperatures with bases such as, for example,
NaH, KH, and lithium diisopropylamine, and then alkylated or
acylated to provide the corresponding N-protected-mono-substituted
(R.sub.3) amine. The protecting group (Pro) of the
N-protected-mono-substituted amine is removed by conventional
methods such as hydrogenation, treatment with acid or base, or
metal catalysis to afford invention compound C.
[0489] If R.sub.5 is a leaving group such as F, it is activated
towards displacement with a nucleophile HY-Pro' where Y is N or O
and Pro' is a protecting group such as trimethylsilyl. Other
R.sub.5 groups such as chlorine, bromine, or sulfonyl are also good
leaving groups. The displacement generally is carried out in a
solvent such as ethanol, DMSO, DMF, THF, and at a temperature of
about 0.degree. C. to 120.degree. C.
[0490] The protecting groups (Pro) may be selectively removed by
hydrogenation, acid or base treatment, metal catalysis, or such
other standard methods. When Pro is benzyl, the benzyl may be
removed with Pd/C and hydrogen. A t-butyl carbamate group may be
removed by alcoholic HCl, TFA, or TFA in dichloromethane, ethyl
acetate or diethyl ether. Allylic carbamates may be removed by
PhSiH.sub.3 and Pd catalyst. Solvents such as alcohol, THF,
alcohol/THF, alcohol/THF/DMF, diethyl ether, etc. are generally
employed in such protecting group cleavage reactions.
##STR136##
[0491] In Scheme 2, an ortho-aminobenzoic acid is utilized as the
starting material, and is alkylated on the amino group. For
example, when R.sub.1 is cyclopropyl, the alkylation is carried out
according to the method of Gillaspy (Tetrahedon Letters, 1995:7399)
to provide the cyclopropyl amine. When R.sub.1 is phenyl or
substituted phenyl, the respective amine is prepared from the
ortho-fluorobenzoic acid using a base, such as, lithium
diisopropylamide or Li-hexamethyl disilazide, and the appropriate
aryl amine (R.sub.1NH.sub.2). When R.sub.1 is any alkyl group, such
as t-butyl or isopropyl, the R.sub.1 can be introduced by reacting
the amine and ortho halo benzoic acid with a Cu catalyst such as
copper, bronze, or cupric acetate in the presence of a base such as
potassium acetate, triethylamine, or pyridine.
[0492] The resulting R.sub.1-substituted amino benzoic acid is then
coupled to an appropriately protected hydrazine to provide the
corresponding benzamide using methods described in the literature.
The corresponding amide can be further reacted, if R.sub.7 is a
leaving group such as fluoro, with various heterocyclic amines
(e.g., piperidine or pyrrolidine) to form the desired
4-heterocyclic benzamide derivative. Alternatively, carbocycles and
aryls (e.g., cyclobutyl or phenyl) may also be introduced at this
4-position using palladium catalyzed couplings of tin or boronate
carbocycles and aryls, if the starting material contains a Br, I,
or triflate at the 4-position.
[0493] The 4-substituted benzamide derivative is then cyclized to
generate the quinazoline-2,4-dione by reaction with
carbonyldiimidazole (CDI), phosgene, triphosgene or the like in
ethereal solvents such as diethyl ether, chlorinated hydrocarbons
such as dichloromethane, or aromatic hydrocarbons such as toluene,
in the presence of a base such as triethylamine or NaHCO.sub.3.
[0494] Alternatively, the corresponding amide is first cyclized and
then the R.sub.7 halo group is displaced by reaction with a
carbocyclic amine {circle around (N)}H to afford the same product.
Deprotection by conventional methods provides the invention
compound A. ##STR137##
[0495] Scheme 3 illustrates alkylation at the 1-position of a
3-aminoquinazolin-2,4-dione to provide invention compounds wherein
R.sub.1 is alkyl. A 2-aminobenzoic acid is reacted with an
N,N-diprotected hydrazine such as dibenzyl hydrazine
(H.sub.2N--NBn.sub.2) to provide the corresponding N-protected
amide. This intermediate can then be reacted with phosgene or
phosgene/base in an ethereal solvent, or with a phosgene equivalent
such as triphosgene in a chlorinated hydrocarbon such as
dichloromethane, to give the quinazoline-2,4-dione. The alkylation
of the quinazoline-2,4-dione to provide a
1-alkylated-quinazoline-2,4-dione is accomplished by reaction with
an alkyl halide as described by Bouzard, supra., 1990. Typically,
such reactions are carried out in THF, ether, DMSO, an alkanol, or
DMF, and in the presence of a base. Typical alkyl halides (R.sub.1X
where X is halo) include ethyl iodide, ethyl bromide, cyclopropyl
iodide, n-decyl bromide, and the like. Typical bases include sodium
hydride, potassium carbonate, and the like. Conversion of the
1-alkylated-quinazoline-2,4-dione to other invention compounds (and
removal of protecting groups such as benzyl Bn) can be carried out
according to Scheme 1, for example, to give the corresponding
1-alkyl (R.sub.1=alkyl) 3-amino (NH.sub.2)compounds such as A.
##STR138##
[0496] Displacement of leaving groups located at the 7-position of
the quinazolin (e.g., R.sub.7=halo) as shown in Schemes 1 and 2
is-not limited to nitrogen heterocycles. Other nucleophiles (Nu)
such as CH.sub.3O--, N.sub.3--, R'R''NH, R'--NH.sub.2, and R' S--
(where R' and R'' are defined above) also displace a leaving group
such as F, Cl, or NO.sub.2 at the 7-position as shown in Scheme 4.
When the leaving group is a triflate or higher halide, organo tin
reagents or organoboronates may be used with palladium catalysts to
deliver a carbon nucleophile. The methodology shown in Scheme 4
follows that of Stille et al., Angew. Chem. Int. Ed. Eng.,
1986;25:508 and is exemplified by Mitchell (Synthesis, 1992:803).
##STR139##
[0497] All of the chemistry depicted and described in Schemes 1 to
4 is applicable to make compounds of Formula I wherein J and K both
are carbon, or where one or both of J and K are N. When either J or
K is nitrogen, the displacement reactions described above is even
more facile than when J and K are carbon.
[0498] Compounds of the invention where J and/or K of Formula I are
nitrogen may be prepared by the Schemes 1, 2, 3, and 4, or by
routes which take advantage of the activation of leaving groups
ortho and para to the J and/or K nitrogen atom. Such routes will
systematically introduce R.sub.7 and R.sub.1 groups as desired.
This methodology also applies to cases in Formula I where
K--R.sub.8 is C--H or C--F and J-R.sub.6 is C--F. Such systematic
substitutions are illustrated in Scheme 5. For example, a pyridine
amide has leaving groups such as halo on both sides of the
nitrogen. Such groups are generally chlorine, but fluorine,
alkylthiol, and sulfoxides such as methyl sulfoxides are also good
leaving groups for such compounds. These leaving groups may be
sequentially displaced based on reactivity. In Scheme 5, where J=N
or J-R.sub.6.dbd.CF, the 4-chloro (para to the aminocarbonyl group)
is displaced preferentially (relative to the 2-chloro group) using
a nucleophilic amine such as diethylamine, pyrrolidine,
methylpiperazine, and the like to give the corresponding amino
substituted analog. This analog is then reacted with
R.sub.1NH.sub.2 to displace the second leaving group (e.g., the
2-chloro group). The resulting 2,6-disubstituted-pyridylamide is
then reacted with CDI, 5 phosgene, or other phosgene equivalents to
form the cyclized quinazoline product. Amination at the 3-position
NH is achieved by reaction with any number of aminating reagents
such as ammonia and N-alkylamines, for example, as described by
Kloetzer (Sci. Pharm., 1984;52:46-50) to give the corresponding
invention compound. ##STR140##
[0499] Tricyclic compounds (i.e., where R.sub.1 and R.sub.8 in
Formula I are taken together with the atoms to which they are
attached to form a ring) can be prepared according to Schemes 6 and
7. Schemes 6 and 7 differ in the introduction of the R.sub.1
substitutions in Structures B and C wherein R.sub.1.dbd.R.sub.1'
and R.sub.1 is as defined above for Formula I and R.sub.1' is
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and the
like. In Scheme 6, the ortho-fluoro nitro compound (other leaving
groups such as chlorine, bromine, and sulfonyl may also be employed
in place of fluoro) is displaced by the .alpha.-nucleophile
substituted ester (where Q is a nucleophile Nu such as methyl or
methoxy). The nitro group is then reduced using, for example, Raney
Ni, H.sub.2 over Pd/C, or an active metal in acid such as iron or
tin in HCl or acetic acid. The newly formed amine readily cyclizes
with the ester (other acid analogs may be employed such as
thioesters, amides, and the like). The cyclized product is then
reduced with hydride reducing agents such as LiAlH.sub.4 and the
like to produce the dihydroquinoline derivative, which in turn is
reacted with chloral hydrate and then an acid to form the dione
ring. The dione ring is subsequently opened using, for example,
sodium hydroxide and hydrogen peroxide to give the benzoic acid.
The 3-aminoquinazolinedione ring is then prepared using the
chemistry described in Schemes 2, 3, or 5 to give the invention
compound B, where R.sub.3' is alkyl, alkenyl, cycloalkyl, aryl, and
heteroaryl. ##STR141##
[0500] In a similar series of reactions depicted in Scheme 7, the
ortho-fluoro nitro compound is reacted with an .alpha.-nucleophile
substituted ketone, and the resulting product is likewise reduced.
In this sequence, the resulting aniline forms a cyclic imine, which
is further reduced with H.sub.2 on Pd/C or by chemical hydride
reducing agents such as sodium borohydride or sodium
cyanoborohydride to give the dihydroquinoline. Such reductive
aminations are well-known in the art and are typically performed in
THF, alcohol, water alcohol mixtures, or in water DMF mixtures. The
remaining steps to produce C follow those of Scheme 6. When the C-7
substituent is a leaving group (e.g., R.sub.7=halo), compounds B
and C may be further reacted with nucleophiles (such as pyrrolidine
or piperidine) to give compounds of Formula I as in the previous
schemes. ##STR142##
[0501] In Scheme 8, the target tricylic compounds as C are prepared
in a slightly different manner. In this case, the nucleophile Q
(such as hydroxymethyl) is attached to the phenyl ring of the
starting aniline, and a leaving group L (such as halo) is attached
alpha to the ketone reactant. The nucleophile may be activated with
bases such as sodium hydride or potassium hydride, triethylamine or
1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), or sodium, potassium, or
cesium carbonate to displace the leaving group L. In this sequence,
the resulting aniline forms a cyclic imine, which is further
reduced with H.sub.2 on Pd/C or by chemical hydride reducing agents
such as sodium borohydride or sodium cyanoborohydride to give a
dihydroquinoline. Such reductive aminations are well-known in the
art and are typically performed in THF, alcohol, water alcohol
mixtures, or in water DMF mixtures. The dihydroquinoline
intermediate is reacted with chloral hydrate, and then an acid to
form the dione ring. The dione ring is subsequently opened by
reaction with a base, for example sodium hydroxide and hydrogen
peroxide, to give the benzoic acid. The 3-aminoquinazolindione ring
is then prepared by first forming an ester on the benzoic acid as
in Scheme 2, followed by reaction of the benzoic acid ester with
chlorosulfonylisocyanate or the like at temperatures of 0.degree.
C. and below, followed by treatment with a base such as
triethylamine or diisopropylethylamine. Amination can then be
carried out in the same manner as described in Scheme 5 to provide
compounds of structure C. When R.sub.7 is a leaving group such as
Cl or F, the invention compounds of structures B (in Scheme 6) and
D (in Scheme 8) can be prepared by coupling to the R.sub.7 side
chain, e.g., various heterocyclic amines ##STR143## to produce the
desired derivatives. Alternatively, carbocycles and aryls may also
be introduced as R.sub.7 side chains using palladium catalyzed
couplings with tin or bornate carbocycles and aryls, for example
when R.sub.7 is a Br, I, or triflate. ##STR144##
[0502] It should be noted from Schemes 6, 7, and 8 that R.sub.1'
and R.sub.3' will form chiral centers, giving R and S enantiomers
and diastereomers. Such enantiomers or 5 diastereomers may be
separated, if desired, at any stage by chiral HPLC, or by other
conventional resolution techniques. Resolution of the precursor
benzoic acid may also be accomplished by fractional crystallization
using mandelic acid, tartaric acid, or other chiral, optically pure
acid bearing resolving agents. Chiral amides may also be prepared
from the benzoic acids using chiral amines such as
camphorsulfonamide, benzylamine, or the like. The isomers can then
be separated and the chiral amide hydrolyzed as desired.
[0503] Scheme 9 illustrates synthesis of compounds of Formula I
wherein one or both of R.sub.6 and R.sub.8 are halo via
halogenation. The halogenation is carried out on a 2-aminobenzoic
acid where one or both of R.sub.6 and R.sub.8 is hydrogen. If both
R.sub.6 and R.sub.8 in the benzoic acid are H, then halogenation
can be accomplished at both positions selectively or
simultaneously. Thus, for example, chlorination at R.sub.6 or
R.sub.8 is achieved by reaction of the benzoic acid with
N-chlorosuccinamide, t-butylhypochlorite, chlorine gas, and the
like. Similarly, bromination at R.sub.6 and R.sub.8 can also be
accomplished by reaction of the benzoic acid with Br.sub.2,
N-bromosuccinimide, and the like. Such halogenations are well-known
in the art. Halogenation provides the respective mono- or dihalo
compound. The halogenated benzoic acid can be further reacted as
shown in Schemes 1 and 2 to provide the quinazoline-2,4-diones of
Formula I. ##STR145##
[0504] In Scheme 10, compounds where R.sub.8 is H are halogenated
as described in Scheme 9 to provide the corresponding
3-halo-2-aminobenzoic acid (Y=halo). This intermediate can then be
diazotized by reaction of the 2-amino group with sodium nitrite or
t-butyl nitrite, which is then converted to a 2-halobenzoic acid in
the presence of an appropriate sodium, potassium, or copper salt
such as sodium iodide, potassium chloride, and the like. The
resulting 2,3-dihalobenzoic acid (where X and Y both are halo) is
then converted to the 3-halo-2-aminobenzoic acid by reaction with
an amine R.sub.1NH.sub.2 in the presence of a copper catalyst. The
3-halo-2-aminobenzoic acid is converted to an amide and cyclized to
the corresponding 8-halo-3-amino-quinazolin-2,4-dione, as
illustrated in Scheme 2. ##STR146##
[0505] Compounds of Formula I wherein R.sub.6 and/or R.sub.8 is
halo such as chloro or bromo are readily dehalogenated by reaction
with metal catalysts under hydrogen pressure (Scheme 11). Suitable
catalysts include the many variations of Pd on 10 carbon, Raney
nickel, or other reagents that are well-known to effect such
dehalogenation. ##STR147##
[0506] Compounds of Formula I wherein R.sub.6 and/or R.sub.8 are
hydrogen can be halogenated to give the mono- or dihalo compound
(e.g., R.sub.6 or R.sub.8.dbd.Cl or Br). The invention compounds
are preferably prepared by first halogenating a benzoic acid
derivative, and then cyclizing the halogenated benzoate (Scheme
12). If both R.sub.6 and R.sub.8 are H, then halogenation can be
accomplished at both positions selectively or simultaneously.
Halogenations can be carried out as described above for Scheme 10.
The resulting compound is then converted to the
2-substituted-aminobenzoic acid as depicted in Scheme 1, which is
subsequently cyclized and aminated. ##STR148##
[0507] Invention compounds of Formula I can also be prepared as
shown in Scheme 13. Substituted benzoic acids can be converted into
esters (where Z is an ester forming group such as alkyl or benzyl)
by a number of methods known by those skilled in the art. The ester
is reacted with an isocyanate such as trimethylsilylisocyanate,
chlorosulfanyl isocyanate, and chlorocarbonyl isocyanate, followed
by treatment with a base such as triethylamine, sodium t-butoxide
or the like, to provide a quinazoline-2,4-dione. The
quinazoline-2,4-dione can be aminated by reaction with an aminating
agent such as ammonia as described in Scheme 5 to generate the
corresponding 3-aminoquinazoline-2,4-dione. This compound may be
further reacted, when R.sub.7 is a leaving group such as fluoro,
with various heterocyclic amines. Again, carbocycles and aryls may
also be introduced at R.sub.7 if R.sub.7 is a Br, I, or triflate,
using palladium catalyzed couplings of tin or boronate carbocycles
and aryls. Removal of any protecting groups (Pro) by normal means
provides invention compounds such as A, as described above in
Scheme 1. ##STR149##
[0508] Invention compounds of Formula I having a cyano substituent
can be prepared as shown in Scheme 14. For example, a benzoic acid
wherein R.sub.8 is hydrogen can be metallated with a strong base
such as lithium hexamethyldisilazane or lithium diisopropylamine.
The resulting metallated intermediate can then be quenched with
dimethylformamide or an equivalent to provide an aldehyde. The
aldehyde can be converted to an oxime by reaction with an alkoxy
amine (other electrophiles such as alkyl halides, activated amides,
esters and halide sources such as 1,2-dichloro-tetrafluoroethane
may also be employed to provide other benzoic acid derivatives that
can be used as defined in Schemes 1, 2, 13, and 15). The oxime is
converted into a cyano group under the cyclization conditions
required to form the quinazolinedione ring system (e.g., reaction
with phosgene) as described in Schemes 1, 12, and 13. Deprotection
provides invention compounds where R.sub.8 is --CN. ##STR150##
[0509] Another alternative for preparing invention compounds is
illustrated in Scheme 15. Appropriately substituted benzoic acids
can be converted into benzamides by any number of methods as
described above. A benzamide can then be treated with oxalyl
chloride in a chlorinated solvent such as dichloroethane or an
equivalent to provide an isocyanate. The isocyanate is reacted with
a substituted primary amine to give a benzoyl substituted urea.
This intermediate can be cyclized to form a quinazolinedione ring
system by reaction with sodium hydride, potassium
hexamethyldisilazane or other non-nucleophilic bases, generally in
a solvent such as tetrahydrofuran (THF)/dimethylformamide, THF with
18-crown-6, THF/dioxane, THF/glyme, THF/diglyme,
dimethoxyethane/toluene or an equivalent. The quinazolinedione can
then be aminated by reaction with any number of aminating reagents
as described by Kloetzer (Sci. Pharm., 1984;52:46-50). The
resulting 3-anminoquinazolinedione ring system can then be readily
coupled with an appropriately substituted heterocyclic amine (such
as those noted above in Table A) by reaction in the presence of a
base such as triethyl amine, diisopropylethyl amine, tetramethyl
guanidine, and the like in solvents such as dimethyl sulfoxide,
dimethylformamide, dimethylacetamide, sulfolane or the equivalent.
Any protecting group associated with the heterocyclic amine side
chain is then removed by methods known to those skilled in the art
to provide invention compounds having Structure A. ##STR151##
[0510] Tricyclic compounds (i.e., where R.sub.1 and R.sub.8,
together with the atoms to which they are attached, form a
carbocyclic ring in invention compounds of Formula I) can be
prepared according to Scheme 16 where a palladium mediated carbon
monoxide insertion on a quinoline (X.dbd.Br, I, or triflate) under
well-precedented conditions gives rise to an ester. The quinoline
ring can then be hydrogenated to provide a tetrahydroquinoline by
standard hydrogenation conditions. The remainder of Scheme 16
follows that of Scheme 8 to provide invention compounds such as G,
substituted with a displaceable substituent at R.sub.7 (e.g.,
halo). These compounds may be further reacted with nucleophiles
such as amines from Table A to give compounds of Formula I.
##STR152##
[0511] Compounds of Formula I where K is N may be prepared by the
routes shown in Schemes 1, 2, 3, 4, and 6, or by routes such as the
one illustrated in Scheme 17, which follows closely the chemistry
shown in Scheme 15. The leaving groups (e.g. halo) ortho and para
to the carboxyl group of the pyridyl starting material are highly
activated. The two leaving groups ortho to the pyridine nitrogen
are generally chlorine, but fluorine, alkylthiol, and sulfoxides
such as methylsulfoxide are also good leaving groups for such
compounds. The urea intermediate readily cyclizes to the
7-halo-quinazolinedione. Amination at the 3-position gives an
invention compound that is an important intermediate due to the
good leaving group at the 7-position (R.sub.7=halo), which is
readily displaced by reaction with an amine ##STR153##
##STR154##
[0512] Scheme 18 illustrates the synthesis of benzoic acid starting
materials that have a bromo for R.sub.7. A difluoro substituted
benzoic acid is converted to an ester by first reaction with oxalyl
chloride or an equivalent reagent (including acid anhydride), and
the acid halide or anhydride is reacted with an alkanol to afford
the respective ester (Z=methyl, ethyl, isopropyl, etc.). The ester
is then reacted with 4-methoxybenzylamine or an equivalent to
produce the desired 4-substituted benzoic acid derivative. This
intermediate is reacted with triethylsilane and trifluoroacetic
acid in a chlorinated solvent such as dichloromethane or an
equivalent to provide an aniline derivative. Alternatively, one
skilled in the art might also employ transition metal catalysis.
The resulting aniline is then subjected to diazotization and
converted to a bromide by treatment with cuprous bromide. The ester
is then hydrolyzed by well-known methods to the desired benzoic
acid, which can be used as a starting material as illustrated in
Scheme 20 below. ##STR155##
[0513] In Scheme 19, 4-bromo-2-fluorobenzoic acid derivatives can
be selectively chlorinated by treatment with chlorine gas in
chlorosulfonic acid at a temperature of 40.degree. C.-100.degree.
C. ##STR156##
[0514] Scheme 20 illustrates use of 4-bromobenzoic acids as
starting materials to make invention compounds wherein R.sub.7 is
aryl. The 4-bromobenzoic acids are converted into benzamides by any
number of methods known in the art. A benzamide is reacted with
oxalyl chloride in a chlorinated solvent such as dichloroethane or
an equivalent to provide an isocyanate. The isocyanate is reacted
with a substituted primary amine to give a benzoyl substituted
urea. This intermediate can be cyclized to form a quinazolinedione
ring system by reaction with sodium hydride, potassium
hexamethyldisilazane or other non-nucleophilic bases in
tetrahydrofuran/dimethylformamide, tetrahydrofuran with 18-crown-6,
toluene/dioxane, tetrahydrofuran/glyme, tetrahydrofuran/diglyme,
glyme/toluene or an equivalent. The quinazolinedione can then be
aminated with a number of aminating reagents as described in Scheme
15. The resulting 3-aminoquinazolinedione ring system can then be
readily coupled with a stannane or boronic acid derivative of a
substituted aryl such as phenyl or substituted aromatic heterocycle
(Ar).
[0515] Alternatively, the 3-position amine can be protected with a
protecting group such as a tert-butyl carbamate or
trifluoroacetamide. Protecting groups of these types are well known
in the art. The 3-derivatized aminoquinazolinedione ring system can
then be coupled via palladium catalysis with an aromatic (Ar)
stannane or boronic acid.
[0516] Each of the outlined routes, upon deprotection by standard
procedures, provides invention compounds of Formula I where R.sub.7
is aryl such as phenyl or substituted phenyl, or heteroaryl such as
pyridyl or substituted pyridyl. ##STR157##
[0517] Compounds of Formula I wherein R.sub.7 is a heteroaryl group
(such as those in Table A) are alternatively prepared as
illustrated in Scheme 21, where R.sub.7 is a substituted thiazole.
A 3-protected 3-amino-7-bromoquinazolinedione from Scheme 20 is
reacted with 1-tributyl-ethoxyvinyltin in the presence of a
palladium catalyst. The resulting 7-substituted adduct is reacted
with a brominating reagent such as n-bromosuccinimide and the like
in tetrahydrofuran/H.sub.2O to provide an .alpha.-bromoketone at
the quinazolinedione 7-position. Reaction of this intermediate with
a thioamide (or thiourea) in a polar solvent such as dimethyl
formamide, dimethylacetamide, or ethanol, and at an elevated
temperature of about 80.degree. C. to 120.degree. C., effects
cyclization to form a thiazolyl group. Deprotection by known
methods can then be applied to provide invention compounds of
Formula I wherein R.sub.7 is the heteroaryl, optionally substituted
with T, which is H, alkyl, substituted alkyl, NH.sub.2, NH-allyl
and N-dialkyl. ##STR158##
[0518] Alternatively, 7-aromatic or heterocyclic aromatic compounds
of Formula I are prepared as shown in Scheme 22. A
4-bromo-2-fluorobenzoic acid (Schemes 18 or 19) is first esterified
(Z is alkyl or benzyl), and the ester is reacted with a substituted
primary amine (R.sub.1NH.sub.2) in dimethylsulfoxide (DMSO) at
elevated temperature of about 100.degree. C. to provide an
anthranilic ester. The resulting aniline is then reacted with an
appropriately protected hydrazine to provide the corresponding
amide, for example as described in Scheme 1. The resulting amido
aniline is then cyclized by reaction with phosgene, CDI, or the
like to generate the quinazoline-2,4-dione. The cyclization
typically is carried out in a solvent, such as ethereal solvents,
chlorinated hydrocarbons such as chloroform, or aromatic
hydrocarbons such as toluene, and in the presence of a base such as
triethylamine or NaHCO.sub.3. The quinazolin-2,4-dione ring system
is then further modified as described in Scheme 20 to provide the
desired 7-aryl (Ar) compound of Formula I. ##STR159##
[0519] As noted above, R.sub.7 in Formula I is referred to as the
"side chain" of the 3-aminoquinazolin-2,4-dione nucleus. The
R.sub.7 side chains are any of those typically found on the
quinolone antibiotics. Most of the R.sub.7 side chain reactants
that are required to make the Formula I compounds are readily
available from commercial sources. Typical R.sub.7 side chains are
shown in Table A above.
[0520] The synthesis of the R.sub.7 side chains can be accomplished
by standard synthetic methods, for example as shown in the
following schemes or as found in the literature. Those of ordinary
skill in the art will be able to make any of the starting materials
required to prepare the invention compounds, although most are
available from commercial sources. The following schemes are
provided to illustrate the synthesis of typical R.sub.7 side chain
reactants.
[0521] Scheme A1 illustrates the synthesis of typical pyrrolidines,
which are preferred side chains (R.sub.7) for invention compounds
of Formula I. In Scheme A1, appropriately activated enones can
undergo [3+2]cycloadditions under the conditions described by Tsuge
et al. (Recent advances in azomethine ylid chemistry. In: Advances
in Heterocyclic Chemistry [Katritsky A., ed.] San Diego: Academic
Press, 231-349). These reactions are carried out in a chlorinated
hydrocarbon solvent such as dichloromethane, chloroform, or
dichloroethane and the like, and in the presence of a catalytic
acid such as trifluoacetic acid, to provide substituted
pyrrolidines (wherein S.sub.1, S.sub.2, S.sub.3, and S.sub.4
independently are alkyl, substituted alkyl, aryl, amino, alkyl and
dialkylamino). These intermediates can then be treated with
hydroxylamine or any O-alkylated or arylated hydroxylamine under a
variety of conditions known to those skilled in the art to provide
oximated substituted pyrrolidines. The oximes are reduced to amines
with lithium aluminum hydride, diisobutylaluminum hydride, borane,
or by selective catalytic hydrogenation. The resulting primary
amines can then be protected using a number of methods as described
in "Protecting Groups in Organic Synthesis" by Theodora Green
(supra). The benzylic pyrrolidine can then be deprotected by
hydrogenation, and the resulting pyrrolidine used in the
preparation of 7-cyclic amino substituted 3-aminoquinazolinediones
of Formula I as shown in the schemes above. ##STR160##
[0522] In Scheme A2, enoates (or vinylogous nitrites) may also be
used in [3+2]cycloadditions to provide 3- and 4-substituted
pyrrolidines. The ester (or nitrile) functionality can then be
treated directly with alkyl lithium reagents at low temperature
(0.degree. C.) in ether to provide SI substituted ketones, or the
ester (Z is alkyl or benzyl) can be hydrolyzed under conditions
usually employed by those skilled in the art to provide carboxylic
acids. This intermediate can then be transformed into an acid
chloride with oxalyl chloride and catalytic dimethyl formamide in
solvents such as dichloromethane or chloroform or into an activated
amide (Singh J., Satyamurthi N., Aidhen I., Singh J., Prakt. Chem.
[Weinheim, Ger.], 2000;342(4):340-347). An acid chloride can be
converted into a ketone using organocopper reagents (Lipshutz B.
H., Sengupta S., Org. React. [N.Y.], 1992;41 :135-631), and Weinreb
amides can be converted into ketones according to the methods
described by Weinreb (Tetrahedron Lett., 1981;22(39):3815-3818)
using organo Grignard reagents. The resulting ketones can then be
converted into pyrrolidines (optionally substituted with S.sub.2,
S.sub.3, and S.sub.4) as described in Scheme A1. As noted above,
pyrrolidines and substituted pyrrolidines are preferred R.sub.7
groups in Formula I. ##STR161##
[0523] In Scheme A3, 3-carboxylic acid N-benzyl substituted
pyrrolidines (Scheme A2) can be converted into amides by a number
of methods well-known to those who practice the art of organic
synthesis. The amides can then be treated with lithium aluminum
hydride in an ethereal solvent such as diethyl ether or
tetrahydrofuran or the like to provide amines that can be protected
as described in Scheme A1. Hydrogenation with palladium catalysis
provides an appropriately substituted pyrrolidine (S.sub.2,
S.sub.3, S.sub.4 are independently alkyl, lower alkyl, aryl, etc.).
##STR162##
[0524] In Scheme A4, a 3-carboxypyrrolidinone (Culbertson T. P.,
Domagala J. M., Nichols J. B., Priebe S., Skeean R. W., J. Med.
Chem., 1987;30(10):1711-1715) can be converted into an acid
chloride or Weinreb amide in the same fashion as that defined in
Scheme A3. The acid chlorides are reacted with an organocopper
reagent or an organo Grignard reagent (for a Weinreb amide) to
provide a ketone that can be manipulated as described in Scheme A1
to provide an appropriately substituted pyrrolidine with a variety
of substitutions at S.sub.1 (alkyl, lower alkyl, substituted alkyl,
aryl). The use of S-methylbenzyl (or R-methylbenzyl) as a
protecting group for the pyrrolidine nitrogen allows for the
separation of enantiomers and diastereomers at any step in the
reaction sequence. ##STR163##
[0525] In Scheme A5, carboxybenzyl protected 3-pyrrolidinone is
reacted with a Wittig salt in the presence of sodium hydride or an
equivalent in dimethylsulfoxide or any polar aprotic solvent to
give an olefin. The resulting olefin is oxidized with
3-chloroperoxybenzoic acid in dichloromethane or other suitable
chlorinated hydrocarbon to provide an epoxide. The epoxide is
reacted with ammonium hydroxide in methanol, ethanol,
dimethylformamide, dimethylacetamide or the like to generate an
aminoalcohol. Methylation of the tertiary hydroxyl group can then
be carried out by formation of a Schiff-base, followed by alkoxide
formation with sodium hydride and treatment with iodomethane.
Hydrolysis of the Schiff-base under standard conditions liberates
the amine. Reaction of the amine with di-tert-butyldicarbonate in
methanol, followed by hydrogenation via palladium catalysis
provides R.sub.7 side chains (S.sub.1 is alkyl, lower alkyl, and
aryl) that can be used in the synthesis of compounds of Formula I.
##STR164##
[0526] In Scheme A6, the aminoalcohol intermediate described in
Scheme A5 is reacted with di-tert-butyldicarbonate in methanol to
produce the N-protected intermediate. Other amine protection
strategies familiar to those skilled in the art can also be
utilized. Hydrogenation under palladium catalysis provides
substituted pyrrolidine R.sub.7 side chains that are used in the
synthesis of compounds of Formula I. ##STR165##
[0527] In Scheme A7, an epoxide intermediate (Scheme A5) is
selectively opened with hydrofluoric acid in pyridine, and the
resulting secondary alcohol is reacted with
methanesulfonylchloride, or an equivalent sulfonating reagent, in
dichloromethane or another chlorinated hydrocarbon and
triethylamine. Other appropriate bases include
diisopropylethylamine, pyridine, collidine, n-methylmorpholine, and
the like. The mesylate is then displaced by reaction with sodium
azide, and the azide is reduced with Raney nickel under hydrogen
pressure in methanol. Such transformations are well-precedented in
the art. The resulting amine is then treated with
di-tert-butyldicarbonate in methanol as shown in Schemes A4-A6, and
the product is hydrogenated to provide the R.sub.7 side chain as
shown above. ##STR166##
[0528] The synthesis of 3-substituted piperidines is demonstrated
in Scheme A8. Esterification and alkylation of 3-piperidine
carboxylic acid is simultaneously accomplished by treatment with a
benzylbromide in a polar solvent such as dimethylformamide or
dimethylsulfoxide and a base such as potassium carbonate
(K.sub.2CO.sub.3) or an equivalent. The ester is then hydrolyzed,
and the resulting carboxylic acid is converted to a methyl ketone
by treatment with methyllithium at low temperature (0.degree. C.).
This intermediate is then converted to an oxime by a number of
methods known by those skilled in the art. The oxime is reduced
with lithium aluminum hydride in tetrahydrofuran to provide an
amine. The amine is reacted with di-tert-butyldicarbonate in
dichloromethane and triethylamine as a base. As shown in Schemes
A4-A6, the product is then hydrogenated to provide the R.sub.7 side
chain. ##STR167##
[0529] It should be recognized from Schemes A1-A8 that
substitutions on ring systems such as a pyrrolidine, piperazine, or
piperidine ring will form chiral centers giving R and S enantiomers
and diastereomers. Such enantiomers or diastereomers may be
separated, if desired, by chiral HPLC at any stage. Resolution of
any of the intermediates may be performed with techniques of
fractional crystallization using mandelic acid, tartaric acid, or
other chiral, optically, pure acid resolving agents. Chiral
benzylic amines can be used in the preparation of starting
materials for the above schemes, and chiral amides may also be
prepared using chiral acids, such as mandelic acid and the like.
The isomers can then be separated and the chiral amine can be
hydrogenated, or the chiral amide can be hydrolyzed.
[0530] The synthesis of invention compounds of Formula I is further
illustrated by the following detailed examples. The examples are
not to be construed as limiting the invention in scope or spirit to
the specific procedures described. The starting materials and
various intermediates utilized in the following examples may be
obtained from commercial sources, or are readily prepared from
commercially available organic compounds, using well-known
synthetic methods.
EXAMPLE 1
Synthesis of Benzoates
(a) 2,3,4,5-Tetrafluorobenzoic acid ethyl ester
[0531] ##STR168##
[0532] A solution of 2,3,4,5-tetrafluorobenzoic acid (4.68 g, 24.1
mmol) in dichloromethane (50 mL) at 0.degree. C. is treated with
oxalyl chloride (11.5. mL, 132 mmol) followed by
N,N-dimethylformamide (4 drops). The mixture is stirred at
0.degree. C. for 5 minutes and then at room temperature for 1.5
hours. The mixture is concentrated to dryness and subsequently
co-evaporated from benzene. The resulting acid chloride is diluted
with dichloromethane (50 mL), cooled to 0.degree. C., and anhydrous
ethanol (15.0 mL, 256 mmol) is added dropwise. The resulting
solution is stirred at room temperature for 4.5 hours, then poured
into saturated NaHCO.sub.3 and extracted with chloroform. The
combined organic extracts are washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to afford
the title compound (5.37 g). .sup.1H NMR (CDCl.sub.3): .delta.
7.67-7.55 (m, 1H), 4.42 (q, 2H), 1.41 (t, 3H).
(b) 2,3,4,6-Tetrafluorobenzoic acid ethyl ester
[0533] ##STR169##
[0534] 2,3,4,6-Tetrafluorobenzoic acid (4.8 g, 24.7 mmol) in
dichloromethane (80 mL) is cooled to 0.degree. C. under a nitrogen
atmosphere and treated with oxalyl chloride (11.2 mL, 128 mmol)
followed by anhydrous N,N-dimethylformamide (2 drops). The mixture
is warmed to room temperature and stirred for 2 hours. The solution
is co-evaporated with benzene to yield an oil that is taken up in
dichloromethane (80 mL), cooled to 0.degree. C. under an inert
atmosphere, and treated with anhydrous ethanol (15 mL, 258 mmol).
After 5 hours at room temperature, the solution is poured into
saturated NaHCO.sub.3 and extracted with chloroform. The organic
phase is washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated under vacuum to provide the title compound (3.3
g). This material is used without further purification. .sup.1H NMR
(CDCl.sub.3): .delta. 6.93-6.75 (m, 1H), 4.42 (q, 2H), 1.39 (t,
3H).
(c) 3-Chloro-2,4,5-trifluorobenzoic acid ethyl ester
[0535] ##STR170##
[0536] To a solution of 3-chloro-2,4,5-trifluorobenzoic acid
(Example 20, 4.90 g, 23.3 mmol) in dichloromethane (50 mL) is added
oxalyl chloride (5.1 mL, 58.2 mmol) and N,N-dimethylformamide (1
drop). After 45 minutes, the reaction mixture is concentrated under
vacuum. The resulting residue is dissolved in dichloromethane (50
mL) and treated with ethanol (10 mL, 172 mmol). After 30 minutes,
the reaction mixture is diluted with dichloromethane and washed
with saturated NaHCO.sub.3, water, and brine. The organic layer is
dried over MgSO.sub.4, filtered, and the filtrate is concentrated
to afford the title compound (5.59 g). .sup.1H NMR (CDCl.sub.3):
.delta. 7.76-7.68 (m, 1 H), 4.40 (q, 2 H), 1.39 (t, 3 H).
(d) 2,3,4,5,6-Pentafluorobenzoic acid benzyl ester
[0537] ##STR171##
[0538] A solution of 2,3,4,5,6-pentafluorobenzoic acid (15.25 g,
71.9 mmol), 4-dimethylaminopyridine (4.4 g, 36.0 mmol) and benzyl
alcohol (7.4 mL, 71.5 mmol) in dichloromethane (150 mL) is cooled
to 0.degree. C. under an inert atmosphere.
1-[3-(Dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride
(16.7 g, 87.1 mmol) is added and the mixture stirred at 0.degree.
C. for 2 hours. The mixture is warmed to ambient temperature,
stirred for 24 hours, and then poured into brine. The mixture is
extracted with chloroform and the organic phase washed with
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum to yield the title compound as a white solid (16.7 g).
This material is used without further purification. .sup.1H NMR
(CDCl.sub.3): .delta. 7.49-7.27 (m, 5 H), 5.40 (s, 2 H).
(e) 2,4,5-Trifluorobenzoic acid ethyl ester
[0539] ##STR172##
[0540] To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6
mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5
mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes,
the reaction mixture is concentrated under vacuum. The resulting
residue is dissolved in dichloromethane (100 mL), and to this
solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the
reaction mixture is diluted with dichloromethane and washed with
saturated NaHCO.sub.3, water, and brine. The organic layer is dried
over MgSO.sub.4, filtered, and the filtrate is concentrated to
afford the title compound as an oil (12.23 g). .sup.1H
NMR(CDCl.sub.3): .delta. 7.85-7.73 (m, 1 H), 7.06-6.94 (m, 1 H),
4.38 (q, 2 H), 1.38 (t, 3 H).
(f) 2,4,5-Trifluoro-3-methoxybenzoic acid ethyl ester
[0541] ##STR173##
[0542] A solution of 2,4,5-trifluoro-3-methoxybenzoic acid (2.513
g, 12.19 mmol) in dichloromethane (50 mL) at 0.degree. C. is
treated with oxalyl chloride (5.4 mL, 61.9 mmol) followed by
N,N-dimethylformamide (4 drops). The mixture is stirred at
0.degree. C. for 5 minutes and then at room temperature for 2.5
hours. The mixture is concentrated to near dryness and then
co-evaporated from benzene. The resulting acid chloride is diluted
with dichloromethane (50 mL), cooled to 0.degree. C., and then
anhydrous ethanol (7.30 mL, 124 mmol) is added dropwise. The
resulting solution is stirred at room temperature for 4.5 hours,
poured into saturated NaHCO.sub.3 solution, and extracted with
dichloromethane. The combined organic extracts are washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under vacuum to afford the title compound as a light yellow liquid
(2.82 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.47 (ddd, 1 H), 4.39
(q, 2 H), 4.05 (s, 3 H), 1.40 (t, 3 H).
(g) 2,3,4-Trifluorobenzoic acid ethyl ester
[0543] ##STR174##
[0544] To a solution of 2,3,4-trifluorobenzoic acid (10.85 g, 61.6
mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5
mL, 154 mmol) and N,N-dimethylformamide (3 drops). After 45
minutes, the reaction mixture is concentrated under vacuum. The
resulting residue is dissolved in dichloromethane (100 mL) and to
this solution is added ethanol (18 mL, 310 mmol). After 30 minutes,
the reaction mixture is diluted with dichloromethane and washed
with saturated NaHCO.sub.3, water, and brine. The organic layer is
dried over MgSO.sub.4, filtered, and the filtrate is concentrated
to afford the title compound as an oil (12.23 g). .sup.1H NMR
(CDCl.sub.3): .delta. 7.93-7.67 (m, 1 H), 7.09-6.96 (m, 1 H), 4.39
(q, 2H), 1.40(t,3 H).
(h) 2,3,4-Trifluoro-5-methoxybenzoic acid ethyl ester
[0545] ##STR175##
[0546] A solution of 2,3,4-trifluoro-5-methoxybenzoic acid (Hayashi
et al., Bull. Chem. Soc. Jap., 1972;45(9):2909-2914, 3.443 g, 16.7
mmol) in dichloromethane (100 mL) at 0.degree. C. is treated with
oxalyl chloride (7 mL, 80 mmol) followed by N,N-dimethylformamide
(4 drops). The mixture is stirred at room temperature for 3.5
hours, concentrated to near dryness, and co-evaporated with
benzene. The acid chloride is then diluted with dichloromethane,
cooled to 0.degree. C., and treated with absolute ethanol (10 mL,
170 mmol). The resulting solution is stirred at room temperature
for 20 hours, poured into saturated NaHCO.sub.3 solution, and
extracted with dichloromethane. The organic extracts are washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under vacuum to afford the title compound (3.785 g). .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta. 7.36-7.29 (m, 1H), 4.42 (q, 2H),
3.93 (s, 3H), 1.44 (t, 3H).
(i) 2,4,5-Trifluoro-3-methylbenzoic acid ethyl ester
[0547] ##STR176##
[0548] A solution of 3-methyl-2,4,5-trifluorobenzoic acid (Shimizu
T., Asai T., Kumai S., Jpn. Kokai Tokkyo Koho (1997) Japanese Appl.
JP 95-219069, 4.3 g, 22.6 mmol) in dichloromethane (100 mL) at
0.degree. C. is treated with oxalyl chloride (4.2 g, 33 mmol)
followed by N,N-dimethylformamide (2 drops). The mixture is stirred
at room temperature for 3 hours, concentrated and dried in vacuo.
The acid chloride is diluted with dichloromethane, cooled to
0.degree. C., and treated with absolute ethanol (10 mL, 170 mmol).
The resulting solution is stirred at room temperature for 20 hours,
poured into saturated NaHCO.sub.3 solution and extracted with
dichloromethane. The organic extracts are washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to
afford the title compound (3.8 g). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.67-7.26 (m, 1H), 4.44 (q, 2H), 2.27 (dd,
3H), 1.42 (t, 3H).
(j) 3-(Benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid ethyl
ester
[0549] ##STR177##
[0550] 2,4,5-Trifluoro-3-formylbenzoic acid (Horiuchi N., Yonezawa
T., Chiba K., Yoshida H., PCT Int. Appl.[1999] WO 97-JP2918), (5.70
g, 27.9 mmol), triethylamine (11 mL, 78.9 mmol),
O-benzylhydroxylamine hydrochloride (4.47 g, 28.0 mmol) and
anhydrous tetrahydrofuran (150 mL) are stirred at room temperature
for 50 hours. The mixture is poured into brine and the pH adjusted
to 5.5-6.0 using 1.0 M hydrochloric acid. The mixture is extracted
with ethyl acetate. The organic phase is dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to provide
3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (8.63 g),
which is used without further purification. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 9.82-9.18 (bs, 1H), 8.24 (s, 1H), 7.94-7.68
(m, 1H), 7.55-7.23 (m, 5H), 5.23 (d, 2H). MS (EI, M-1) m/z 308.
[0551] 3-(Benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (0.117
g, 0.378 mmol), 4-dimethylaminopyridine (0.023 g, 0.189 mmol),
anhydrous ethanol (0.030 mL, 0.517 mmol) are mixed in
dichloromethane (6 mL), cooled to 0.degree. C., and treated with
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.082
g, 0.427 mmol). After 2 hours at 0.degree. C. and room temperature
for 21 hours, the solvents are evaporated. The residue is dissolved
in chloroform, washed with saturated NaHCO.sub.3 and brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
Purification by chromatography (1:8 ethyl acetate/hexanes) provided
the title compound (0.068 g). .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta. 8.27 (s, 1H), 7.87-7.66 (m, 1H), 7.49-7.28 (m, 5H), 5.27
(s, 2H), 4.48-4.29 (q, 2H), 1.46-1.31 (t, 3H).
EXAMPLE 2
Synthesis of 4-Heterocyclic Benzoates
General Procedure
[0552] A mixture of 4-fluoro substituted benzoic acid ester (1
eq.), substituted pyrrolidine (1.3-2.5 eq.), and triethylamine
(2-10 eq.) in N,N-dimethylacetamide or acetonitrile is heated to
50.degree. C.-100.degree. C. for 15 to 60 hours. The solution is
then concentrated to near dryness, poured into saturated
NaHCO.sub.3 solution, and extracted with ethyl acetate. The
combined organic extracts are washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
resulting residue is purified by column chromatography (ethyl
acetate/hexanes) to afford 4-pyrrolidinyl substituted benzoic acid
esters.
(a)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2,3,5-trifluorobenzo-
ic acid ethyl ester
[0553] ##STR178##
[0554] A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester
(Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3 -ylcarbamic acid
tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J.
M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J.
Med. Chem., 1992;35(10):1764-1773), and triethylamine (18.0 mL, 129
mmol) in acetonitrile (50 mL) is heated at 50.degree. C. under a
nitrogen atmosphere for 4.5 hours. The yellow solution is
concentrated in vacuo and poured into a saturated NaHCO.sub.3
solution. The mixture is then extracted with chloroform, and the
combined organic extracts are washed with brine, dried with
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
resulting residue is then purified by flash column chromatography
(1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g).
.sup.1H NMR (CDCl.sub.3): .delta. 7.35 (ddd, 1H), 4.70-4.65 (bs,
1H), 4.42-4.20 (m, 3H), 3.90-3.62 (m, 3H), 3.58-3.42 (m, 1H),
2.28-2.03 (m, 1H), 1.99-1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t,
3H).
(b) 4-[(S
)-3-tert-Butoxycarbozylaminopyrrolidin-1-yl]-2,3,6-trifluorobenz-
oic acid ethyl ester
[0555] ##STR179##
[0556] A solution of 2,3,4,6-tetrafluorobenzoic acid ethyl ester
(Example 1b, 5.1 g, 22.9 mmol), triethylamine (22 mL, 157 mmol),
and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (5.2 g, 27.9
mmol) in acetonitrile (60 mL) is stirred at room temperature for 64
hours. The mixture is concentrated in vacuo and the residue
dissolved in chloroform, washed with NaHCO.sub.3 and then brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum to afford a solid. The solid is purified by column
chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford
the title compound (6.21 g). .sup.1H NMR (CDCl.sub.3): .delta. 6.07
(ddd, 1H), 4.78-4.63 (bd, 1H), 4.49-4.22 (m, 3H), 3.80-3.68 (m,
1H), 3.66-3.28 (m, 3H), 2.33-2.13 (m, 1H), 2.04-1.83 (m, 1H), 1.45
(s, 91), 1.36 (t, 3H).
(c)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2,5-difluor-
obenzoic acid ethyl ester
[0557] ##STR180##
[0558] To a solution of 3-chloro-2,4,5-trifluorobenzoic acid ethyl
ester (Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is
added triethylamine (6.43 mL, 46.1 mmol) and
(S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.72 g, 25.4
mmol). After 48 hours, the mixture is diluted with ethyl acetate
and washed with saturated NaHCO.sub.3, water, and brine. The
organic layer is dried over MgSO.sub.4, filtered, and the filtrate
is concentrated to afford the title compound (9.34 g). MS CI: m/z
405 (MH.sup.+).
(d)
4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluor-
obenzoic acid benzyl ester
[0559] ##STR181##
[0560] A solution of 2,3,4,5,6-pentafluorobenzoic acid benzyl ester
(Example 1d, 8.05 g, 26.6 mmol), triethylamine (26 mL, 186 mmol),
and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.6 g, 30
mmol) in acetonitrile (150 mL) is stirred at room temperature for
24 hours. The solvent is removed under vacuum and the residue
dissolved in chloroform, washed with NaHCO.sub.3 and then brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
afford a solid. The solid is then purified by column chromatography
(1:1:6 ethyl acetate/chloroform/hexanes) to yield the title
compound as a solid (7.92 g). .sup.1H NMR (CDCl.sub.3): .delta.
7.48-7.30 (m, 5H), 5.35 (s, 2H), 4.77-4.50 (m, 1H), 4.37-4.19 (m,
1H), 4.01-3.63 (m, 3H), 3.59-3.46 (m, 1H), 2.29-2.09 (m, 1H),
2.01-1.82 (m, 1H), 1.45 (s, 9H).
(e) 4-(Pyrrolidin-1-yl)-2,5-difluorobenzoic acid ethyl ester
[0561] ##STR182##
[0562] To a solution of 2,4,5-trifluorobenzoic acid ethyl ester
(Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added
triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4
mmol). After 24 hours, the reaction mixture is diluted with ethyl
acetate and washed with saturated NaHCO.sub.3, water, and brine.
The organic layer is dried over MgSO.sub.4, filtered, and the
filtrate is concentrated to afford the title compound as an oil
(5.25 g). MS CI: m/z 256 (MH.sup.+).
(f)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxy-
benzoic acid ethyl ester
[0563] ##STR183##
[0564] A solution of 2,4,5-trifluoro-3-methoxybenzoic acid ethyl
ester (Example 1f, 2.821 g, 12.05 mmol), pyrrolidin-3-ylcarbamic
acid tert-butyl ester (3.310 g, 17.77 mmol), and triethylamine
(9.13 g, 12.6 mL, 90.23 mmol) in acetonitrile (50 mL) is heated at
40.degree. C. under nitrogen for 2 days. The yellow solution is
concentrated to near dryness and poured into saturated NaHCO.sub.3
solution and extracted with dichloromethane. The combined organic
extracts are washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum. The resulting residue is
purified by flash column chromatography (1:7 ethyl acetate/hexanes)
to afford the title compound as a yellow solid (3.743 g). MS EI:
m/z 401 (MH.sup.+).
(g)
4-[3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2,5-difluoroben-
zoic acid ethyl ester
[0565] ##STR184##
[0566] To a solution of 3-chloro-2,4,5-tri-fluorobenzoic acid ethyl
ester (Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is
added triethylamine (6.43 mL, 46.1 mmol) and
pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.72 g, 25.4 mmol).
After 48 hours, the mixture is diluted with ethyl acetate and
washed with saturated NaHCO.sub.3, water, and brine. The organic
layer is dried over MgSO.sub.4, filtered, and the filtrate is
concentrated to afford the title compound (9.2 g). MS CI: m/z 405
(MH.sup.+).
(h)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic
acid ethyl ester
[0567] ##STR185##
[0568] A solution of 2,3,4-trifluorobenzoic acid ethyl ester
(Example 1g, 3.70 g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid
tert-butyl ester (4.02 g, 21.6 mmol), and triethylamine (18.0 mL,
129 mmol) in acetonitrile (50 mL) is heated at 50.degree. C. under
nitrogen atmosphere for 4.5 hours. The solution is concentrated in
vacuo and poured into a saturated NaHCO.sub.3 solution. The mixture
is then extracted with chloroform, and the combined organic
extracts are washed with brine, dried with Na.sub.2SO.sub.4,
filtered, and the mixture concentrated in vacuo. The resulting
residue is then purified by column chromatography (1:7 ethyl
acetate/hexanes) to afford the title compound (4.70 g). .sup.1H NMR
(CDCl.sub.3): .delta. 7.59-7.49 (m, 1H), 6.35-6.26 (m, 1H),
4.88-4.84 (bd, 1M), 4.39-4.28 (m, 3H), 3.81-3.50 (m, 3H), 3.48-3.34
(m, 1H), 2.32-2.15 (m, 1H), 2.02-1.76 (m, 1H), 1.45 (s, 9H), 1.40
(t, 3H).
(i)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluorobenzoic
acid ethyl ester
[0569] ##STR186##
[0570] To a solution of 2,4,5-trifluorobenzoic acid ethyl ester
(Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added
triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid
tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction
mixture is diluted with ethyl acetate and washed with saturated
NaHCO.sub.3, water, and brine. The organic layer is dried over
MgSO.sub.4, filtered, and the filtrate is concentrated to afford an
oil. The resulting residue is purified by flash chromatography (1:5
ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1)
m/z 371, mp 98-100.degree. C.
[0571] The following compounds are synthesized according to general
procedures described in Examples 2a-i above.
[0572] (k)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluoro-3-methylbenzoi-
c acid ethyl ester (MS ES, MH.sup.+) m/z 385) using
2,4,5-trifluoro-3-methylbenzoic acid ethyl ester (Example 1i),and
pyrrolidin-3-ylcarbamic acid tert-butyl ester.
[0573] (l)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2,5-difluoro-3-meth-
ylbenzoic acid ethyl ester (MS ES, MH.sup.+) m/z 399) using
2,4,5-trifluoro-3-methylbenzoic acid ethyl ester (Example 1i) and
3-(tert-butoxycarbonylaminomethyl)pyrrolidine (Rogers D. H.,
Saunders J., Williams J. P., DE 19955794).
[0574] (m)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,3-difluoro-5-methoxybenzo-
ic acid ethyl ester (MS ES, MH.sup.+) m/z 401) using
2,3,4-trifluoro-5-methoxybenzoic acid ethyl ester (Example 1h) and
pyrrolidin-3-ylcarbamic acid tert-butyl ester.
[0575] (n)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2,5-difluoro-3-meth-
oxybenzoic acid ethyl ester (MS ES, MH.sup.+) m/z 415) using
2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example 1f) and
3-(tert-butoxycarbonylaminomethyl)pyrrolidine (Rogers D. H.,
Saunders J., Williams J. P., DE 19955794).
[0576] (o)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-3-ethoxy-2,5-difluorobenzoi-
c acid ethyl ester. (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.31 (dd, 1H), 4.71 (bs, 1H), 4.34-3.4 (m, 9H), 2.23-1.81 (m, 2H),
1.45 (s, 9H), 1.37 (t, 3H), 1.33 (t, 3H); ((MS ES, MH.sup.+) m/z
415.) using 3-ethoxy-2,5-difluorobenzoic acid ethyl ester (Sanchez
J. P., Gogliotti R. D., Domagala J. M., Gracheck S. J., Huband M.
D., Sesnie J. A., Cohen M. A., Shapiro M. A., J. Med. Chem.,
1995;38(22):4478-4487) and pyrrolidin-3-ylcarbamic acid tert-butyl
ester.
[0577] (p)
3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,-
5-difluorobenzoic acid ethyl ester (MS ES, MH.sup.+) m/z 504) using
3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid ethyl ester
(Example 1j) and pyrrolidin-3-ylcarbamic acid tert-butyl ester.
[0578] (q)
3-Chloro-2,5-difluoro-4-(3-[1,2,3]-triazol-1-ylpyrrolidin-1-yl)benzoic
acid ethyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.79
(s, 1H), 7.65 (s, 1H), 7.41-7.51 (m, 1H), 5.40-5.30 (m, 1H),
4.34-4.24 (q, 2H), 4.13-3.45 (m, 4H), 2.65-2.50 (m, 1H), 2.43-2.28
(m, 1H), 1.34-1.27 (t, 3H)) using 3-chloro-2,4,5-trifluorobenzoic
acid ethyl ester (Example 1c) and
1-pyrrolidin-3-yl-1H-[1,2,3]triazole (Singh R., Singh I. P., Thomas
G., Singh M. P., Micetich R. G., Fahti-Afshar R., Doerksen T. R.,
PCT Int. Appl., 1992, WO 9210492 A1).
EXAMPLE 3
Synthesis of 2-Substituted-Amino Benzoates
General Procedure
[0579] A solution of 4-(pyrrolidin-1-yl)-2-fluorobenzoic acid ethyl
esters (Example 2) and cyclopropylamine (10-15 eq.) in dimethyl
sulfoxide and triethylamine (2-5 eq.) is heated in a sealed glass
tube for 3 days at 140.degree. C. Compressed air is blown into the
mixture to remove excess cyclopropylamine. The resulting solution
is concentrated under vacuum and purified by column chromatography
(ethyl acetate/hexanes) to afford 4-(substituted
pyrrolidin-1-yl)-2-cyclopropylamino-benzoic acid esters.
(a)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3-
,5-difluorobenzoic acid ethyl ester
[0580] ##STR187##
[0581] A solution of
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5-trifluorobenzoi-
c acid ethyl ester (Example 2a, 1.95 g, 5.01 mmol) and
cyclopropylamine (14.0 mL, 201 mmol) in dimethyl sulfoxide (5 mL)
is heated in a sealed glass tube for 44.5 hours at 100.degree. C.
Compressed air is blown into the black solution to remove excess
cyclopropylamine. The solution is concentrated under high vacuum
and purified by flash column chromatography (1:9 ethyl
acetate/hexanes) to afford the title compound (1.77 g). .sup.1H NMR
(CDCl.sub.3): .delta. 7.32 (dd, 1H), 4.81-4.67 (bs, 1H), 4.35-4.16
(m, 3H), 3.95-3.40 (m, 4H), 2.92-2.80 (m, 1H), 2.25-2.08 (m, 1H),
1.97-1.77 (m, 1H), 1.46 (s, 9H), 1.34 (t, 3H), 0.72-0.63 (m, 2H),
0.57-0.49 (m, 2H).
(b)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3-
,6-difluorobenzoic acid ethyl ester
[0582] ##STR188##
[0583] A solution of
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,6-trifluorobenzoi-
c acid ethyl ester (Example 2b, 5.4 g, 13.9 mmol), cyclopropylamine
(40 mL, 577 mmol), and dimethyl sulfoxide (28 mL) in a sealed glass
tube is heated at 100.degree. C. for 27 hours. The excess amine is
removed by blowing in compressed air before the solution is
concentrated under high vacuum. The residue is then purified by
column chromatography (1:1:8 ethyl acetate/chloroform/hexanes) to
afford the title compound (4.80 g). .sup.1H NMR (CDCl.sub.3):
.delta. 7.42 (bs, 1H), 5.69 (ddd, 1H), 4.76-4.61 (m, 1H), 4.37-4.19
(m, 3H), 3.81-3.66 (m, 1H), 3.65-3.43 (m, 2H), 3.39-3.28 (m, 1H),
2.98-2.82 (m, 1H), 2.30-2.09 (m, 1H), 1.98-1.82 (m, 1H), 1.45 (s,
9H), 1.34 (t, 3H), 0.72-0.68 (m, 2H), 0.67-0.44 (m, 2H).
(c)
4-[(s)-3-tert-Butoxycarbonylaminopyrroldin-1-yl]-3-chloro-2-cyclopropy-
lamino-5-fluorobenzoic acid ethyl ester
[0584] ##STR189##
[0585] A solution of
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluoro-
benzoic acid ethyl ester (Example 2c, 9.34 g, 23.1 mmol),
cyclopropylamine (16 mL, 228 mmol), and dimethyl sulfoxide (30 mL)
is heated in a sealed tube at 110.degree. C. for 3 days. After
cooling to room temperature, the reaction mixture is diluted with
ethyl acetate and washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried over MgSO.sub.4, filtered, and
the filtrate is concentrated to afford a brown residue. The residue
is then purified via flash column chromatography (1:1 ethyl
acetate/hexanes) to afford the title compound (4.41 g). MS CI: m/z
442 (MH.sup.+).
(d)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3-
,5,6-trifluorobenzoic acid benzyl ester
[0586] ##STR190##
[0587] A solution of
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluorobe-
nzoic acid benzyl ester (Example 2d, 2.5 g, 5.3 mmol),
cyclopropylamine (40 mL, 577 mmol), and dimethyl sulfoxide (20 mL)
in a sealed glass tube is heated at 80.degree. C. for 24 hours. The
excess amine is removed by blowing in compressed air, and the
solution is then concentrated under high vacuum. The residue is
purified by column chromatography (1:1:7 ethyl
acetate/chloroform/hexanes) to afford the title compound as a solid
(2.31 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.47-7.27 (m, 5H), 7.12
(bs, 1H), 5.30 (s, 21), 4.78-4.62 (m, 1H), 4.35-4.17 (m, 1H),
3.96-3.56 (m, 3H), 3.54-3.39 (m, 1H), 2.91-2.73 (m, 1H), 2.24-2.02
(m, 1H), 1.96-1.77 (m, 1H), 1.45 (s, 9H), 0.69-0.56 (m, 2H),
0.53-0.40 (m, 2H).
(e) 2-Cyclopropylamino-5-fluoro-4-pyrrolidin-1-ylbenzoic acid ethyl
ester
[0588] ##STR191##
[0589] 4-(Pyrrolidin-1-yl)-2,5-difluorobenzoic acid ethyl ester
(Example 2e, 5.25 g, 20.6 mmol) and cyclopropylamine (30 mL, 428
mmol) are stirred in dimethyl sulfoxide (30 mL) at 110.degree. C.
for 3 days in a sealed tube. After cooling to room temperature, the
reaction mixture is diluted with ethyl acetate and washed with
saturated NaHCO.sub.3, water, and brine. The organic layer is dried
over MgSO.sub.4, filtered, and the filtrate concentrated to afford
a brown residue. The residue is purified via flash column
chromatography (1:9 hexanes/dichloromethane) to afford the title
compound as a solid (5.39 g). MS CI: m/z 293 (MH.sup.+).
(f)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylam-
inobenzoic acid ethyl ester
[0590] ##STR192##
[0591]
4-[3-(tert-Butoxycarbonylamino)-pyrrolidin-1-yl]-2,5-difluorobenzo-
ic acid ethyl ester (Example 2j, 5.4 g, 13.9 mmol), isopropylamine
(40 mL, 469 mmol), and dimethyl sulfoxide (25 mL) are heated at
100.degree. C. for 4 days in a sealed glass tube. The excess amine
is removed by blowing in compressed air. The residue is filtered
and concentrated under vacuum to a thick oil. Purification by
column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to
provide the title compound as a solid (1.6 g). MS: m/z 410
(MH.sup.+).
(g)
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-
-chloro-5-fluorobenzoic acid ethyl ester
[0592] ##STR193##
[0593]
4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-d-
ifluorobenzoic acid ethyl ester (Example 2c, 1.95 g, 4.81 mmol),
sec-butylamine (30 mL, 296 mmol), and dimethyl sulfoxide (20 mL)
are heated in a sealed glass tube at 110.degree. C. for 24 hours.
The reaction mixture is evaporated, and purification by column
chromatography (1:8, ethyl acetate/hexanes) provides the title
compound as a yellow syrup (3.69 g). MS EI: m/z 458 (MH.sup.+).
(h)
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fl-
uoro-3-methoxybenzoic acid ethyl ester
[0594] ##STR194##
[0595] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxyben-
zoic acid ethyl ester (Example 2f, 3.087 g, 7.71 mmol) and
cyclopropylamine (12.0 mL, 172 mmol) in dimethyl sulfoxide (5 mL)
is heated in a sealed glass tube for 3 days at 110.degree. C.
Compressed air is blown into the black solution to remove excess
cyclopropylamine. The solution is concentrated under vacuum and
purified by flash column chromatography (1:5 ethyl acetate/hexanes)
to afford the title compound as a yellow solid (0.875 g). .sup.1H
NMR (CDCl.sub.3): .delta. 7.33 (d, 1H), 7.15 (bs, 1H), 4.78-4.65
(m, 1H), 4.33-4.15 (m, 3H), 3.92-3.50 (m, 3H), 3.55 (s, 3H),
3.45-3.34 (m, 1H), 3.02-2.89 (m, 1H), 2.28-2.09 (m, 1H), 1.93-1.77
(m, 1H), 1.46 (s, 9H), 1.34 (t, 3H), 0.7-0.59 (m, 2H), 0.49-0.42
(m, 2H).
(i)
4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-flu-
orobenzoic acid ethyl ester
[0596] ##STR195##
[0597] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluorobenzoic
acid ethyl ester (2j, 3.059 g, 8.26 mmol) and cyclobutylamine (15.0
mL, 175 mmol) in dimethyl sulfoxide (20 mL) is heated in a sealed
vessel for 4 days at 110.degree. C. Compressed air is blown into
the black solution to remove excess cyclobutylamine. The solution
is concentrated under vacuum and purified by flash column
chromatography (1:5 ethyl acetate/hexanes) to afford the title
compound as a yellow solid (1.715 g). 1H NMR (CDCl.sub.3): .delta.
7.67 (bs, 1H), 7.48 (d, 1H), 5.54 (d, 1H), 4.77-4.64 (bs, 1H),
4.38-4.18 (m, 3H), 3.97-3.85 (m, 1H), 3.80-3.42 (m, 3H), 3.41-3.30
(m, 1H), 2.50-2.32 (m, 2H), 2.28-2.12 (m, 1H), 2.05-1.70 (m, 5H),
1.46 (s, 9H), 1.35 (t, 3H).
(j)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-f-
luorobenzoic acid ethyl ester
[0598] ##STR196##
[0599] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic
acid ethyl ester (Example 2h, 1.85 g, 5.01 mmol) and
cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5
mL) is heated in a sealed glass tube for 48 hours at 100.degree. C.
The solution is then concentrated under high vacuum and purified by
column chromatography (1:9 ethyl acetate/hexanes) to afford the
title compound (1.57 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.59
(bs, 1H), 7.57 (dd, 1H), 6.00 (dd, 1H), 4.82-4.68 (bd, 1H),
4.39-4.18 (m, 3H), 3.80-3.49 (m, 3H), 3.41-3.30,(m, 1H), 3.00-2.88
(m, 1H), 2.31-2.11 (m, 1H), 2.00-1.85 (m, 1H), 1.45 (s, 9H), 1.37
(t, 3H), 0.73-0.50 (m, 4H).
(k)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropyl-
amino-3-fluorobenzoic acid ethyl ester
[0600] ##STR197##
[0601] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2,3-difluorobenz-
oic acid ethyl ester (Example 21, 3.75 g, 9.3 mmol) and
cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5
mL) is heated in a sealed glass tube for 48 hours at 100.degree. C.
The solution is then concentrated under high vacuum and purified by
column chromatography (1:9 ethyl acetate/hexanes) to afford the
title compound (2.0 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.64 (d,
1H), 7.56 (bs, 1H), 4.98-4.90 (bd, 1H), 4.40-4.20 (m, 3H),
3.78-3.63 (m, 4H), 2.97-2.83 (m, 1H), 2.35-2.21 (m, 1H), 1.93-1.81
(m, 1H), 1.46 (s, 9H), 1.38 (t, 3H), 0.75-0.61 (m, 21), 0.57-0.50
(m, 2H).
[0602] The following compounds are synthesized according to general
procedures Examples 3a-k described above.
[0603] (l)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-
-3-methylbenzoic acid ethyl ester ([MS ES, MH.sup.+] m/z 422) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluoro-3-methyl-benzo-
ic acid ethyl ester (Example 2k).
[0604] (m)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methylbenzoic acid ethyl ester. ([MS ES, M+1] m/z 436)
using
4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2,5-difluoro-3-met-
hylbenzoic acid ethyl ester (Example 2l).
[0605] (n)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-
-5-methoxybenzoic acid ethyl ester. ([MS ES, M+1] m/z 439) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,3-difluoro-5-methoxybenzo-
ic acid ethyl ester (Example 2m).
[0606] (o)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methoxybenzoic acid ethyl ester ([MS ES, MH.sup.+] m/z
453) using
4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2,5-difluoro-
-3-methoxybenzoic acid ethyl ester (Example 2n)
[0607] (p)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-
-5-fluorobenzoic acid ethyl ester ([MS ES, MH.sup.+] m/z 452) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-3-ethoxy-2,5-difluorobenzoi-
c acid ethyl ester (Example 2o).
[0608] (q)
3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2--
cyclopropylamino-5-fluorobenzoic acid ethyl ([MS ES, MH.sup.+] m/z
541) using
3-(benzyloxyiminomethyl)4-(3-tert-butoxycarbonylaminopyrrolidin-1-y-
l)-2,5-difluorobenzoic acid ethyl ester (Example 2p).
[0609] (r)
3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3]-triazol-1-yl-pyrrolidin-
-1-yl)benzoic acid ethyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3):
.delta. 8.00 (s, 1H), 7.73 (s, 1H), 7.52 (d, 1H), 7.19 (bs, 1H),
5.53-5.39 (m, 1H), 4.36-4.21 (q, 2H), 4.14-4.01 (m, 1H), 3.98-3.83
(m, 1H), 2.71-2.58 (m, 1H), 2.43-2.29 (m, 1H), 1.41-1.28 (t, 3H),
0.73-0.59 (m, 2H), 0.52-0.37 (m, 2H)) using
3-chloro-2,5-difluoro-4-(3-[1,2,3]-triazol-1-yl-pyrrolidin-1-yl)benzoic
acid ethyl ester (Example 2q)
EXAMPLE 4
Ester Hydrolysis
General Procedure
[0610] A solution of
4-(substituted-pyrrolidin-1-yl)-2-cyclopropylaminobenzoic acid
ester (Example 3) and aqueous. sodium hydroxide (10-20 eq., 1.0N)
in tetrahydrofuran and methanol is heated for 16 to 24 hours at
70.degree. C. The solution is cooled, diluted with water, and
partially concentrated under vacuum. The resulting solution is
acidified to pH 6 with aqueous 1.0N hydrochloric acid, then the pH
is adjusted to pH 7-8 with 5% NaHCO.sub.3 solution and extracted
with ethyl acetate. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford
4-(substituted-pyrrolidin-1-yl)-2-cyclopropylaminobenzoic acid.
(a)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3-
,5-difluorobenzoic acid
[0611] ##STR198##
[0612] A solution of
4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5-
-difluorobenzoic acid ethyl ester (Example 3a,1.40 g, 3.29 mmol)
and aqueous sodium hydroxide (1.33 N, 15.0 mL, 20.0 mmol) in
tetrahydrofuran (20 mL) and methanol (50 mL) is heated for 3 hours
at 50.degree. C. The solution is cooled, diluted with water, and
partially concentrated in vacuo. The resulting solution is
acidified to pH 6 with aqueous 1N hydrochloric acid, and then the
pH is adjusted to pH 7-8 with 5% NaHCO.sub.3 and extracted with
chloroform. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound as a pale yellow solid (1.31 g). .sup.1H NMR
(DMSO-d.sub.6): .delta. 12.65 (bs, 1H), 7.48 (bs, 1H), 7.27-7.14
(m, 2H), 4.08-3.92 (m, 1H), 3.85-3.45 (m, 3H), 3.45-3.29 (m, 1H),
2.86-2.74 (m, 1H), 2.10-1.91 (m, 1H), 1.89-1.72 (m, 1H), 1.39 (s,
9H), 0.71-0.60 (m, 2H), 0.47-0.38 (m, 2H).
(b)
4-[(5)-3-tert-Butoxycarbonylaminopyrridin-1-yl]-2-cyclopropylamino-3,6-
-difluorobenzoic acid
[0613] ##STR199##
[0614] A solution of
4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,6-
-difluorobenzoic acid ethyl ester (Example 3b, 1.45 g, 3.40 mmol)
and aqueous sodium hydroxide (1.33N, 17.0 mL, 22.6 mmol) in
tetrahydrofuran (20 mL) and methanol (50 mL) is heated for 21 hours
at 50.degree. C. The solution is cooled, diluted with water, and
then partially concentrated in vacuo. The resulting solution is
acidified to pH 6 with aqueous 1N hydrochloric acid, and then the
pH is adjusted to pH 7-8 with 5% NaHCO.sub.3 and extracted with
ethyl acetate three times. The combined organic extracts are dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to
give the title compound as a pale green solid (1.33 g). .sup.1H NMR
(DMSO-d.sub.6): .delta. 7.21 (bd, 1H), 5.83 (dd, 1H), 4.12-3.98 (m,
1H), 3.75-3.20 (m, 5H), 2.88-2.78 (m, 1H), 2.14-1.96 (m, 1H),
1.90-1.73 (m, 1H), 1.39 (s, 9H), 0.69-0.59 (m, 2H), 0.45-0.36 (m,
2H).
(c)
4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2-cycloprop-
ylamino-5-fluoro-benzoic acid
[0615] ##STR200##
[0616] To a solution of
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropy-
lamino-5-fluorobenzoic acid ethyl ester (Example 3c, 2.90 g, 6.56
mmol) in methanol (30 mL) and tetrahydrofuran (30 mL) is added a 1N
solution of sodium hydroxide (50 mL). The reaction mixture is
stirred at 80.degree. C. for 20 hours, cooled to room temperature,
and diluted with ethyl acetate. The organic layer is washed with 1N
hydrochloric acid, water, and brine. The organic layer is dried
over MgSO.sub.4, filtered, and filtrate concentrated to the title
compound as a solid (2.74 g). MS CI: m/z 414 (MH.sup.+).
(d)
4-t(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3-
,5,6-trifluorobenzoic acid
[0617] ##STR201##
[0618] A solution of benzyl
4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,-
5,6-trifluorobenzoate (Example 3d, 3.68 g, 7.31 mmol), 1.0 M NaOH
(75 mL), methanol (50 mL), and tetrahydrofuran (50 mL) is heated at
50.degree. C. for 24 hours. The mixture is partially concentrated
under vacuum and then extracted with dichloromethane. The aqueous
phase is brought to pH 7.5 using 1.0 M HCl and extracted with ethyl
acetate. The combined ethyl acetate extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to afford
4-[(S)-3-tert-butoxycarbonylamino-pyrridin-1-yl]-2-cyclopropylamino-3,5,6-
-trifluorobenzoic acid as a solid (2.9 g). This material is used
without further purification. .sup.1H NMR (DMSO-d.sub.6): .delta.
7.19 (bd, 1H), 4.12-3.95 (m, 1H), 3.83-3.52 (m, 3H), 3.48-3.33 (m,
1H), 2.83-2.69 (m, 1H), 2.10-1.94 (m, 1H), 1.89-1.72 (m, 1H), 1.49
(s, 9H), 0.70-0.56 (m, 2H), 0.44-0.33 (m, 2H).
(e) 2-Cyclopropylamino-5-fluoro-4-pyrrolidin-1-ylbenzoic acid
[0619] ##STR202##
[0620] To a solution of
4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoic acid ethyl
ester (Example 3e, 3.10 g, 10.4 mmol) in methanol (50 mL) and
tetrahydrofuran (20 mL) is added 1N solution of sodium hydroxide
(35 mL). The reaction mixture is stirred at 80.degree. C. for 20
hours, cooled to room temperature, and diluted with ethyl acetate.
The organic layer is washed with 1N hydrochloric acid, water, and
brine. The organic layer is dried over MgSO.sub.4, filtered, and
the filtrate concentrated to afford the title compound as a solid
(2.47 g). MS CI: m/z 263 (M.sup.+).
(f)
4-[3-tert-Butoxycarbonylamino)pyrrolidin-4-yl]-5-fluoro-2-isopropylami-
nobenzoic acid
[0621] ##STR203##
[0622] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylamino-
benzoic acid ethyl ester (Example 3f, 1.5 g, 3.40 mmol), aqueous 1
M sodium hydroxide (50 mL), tetrahydrofuran (40 mL), and methanol
(40 mL) are heated for 25 hours at 70.degree. C. The solution is
cooled, diluted with water, and then partially concentrated. The
resulting solution is acidified to pH 7-8 with aqueous 1.0 M
hydrochloric acid and extracted with ethyl acetate. The combined
organic extracts are dried over Na.sub.2SO.sub.4, filtered, and
concentrated under vacuum to give the title compound as a solid
(1.25 g). MS EI: m/z 380 (M.sup.+).
(g)
4-13-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chl-
oro-5-fluorobenzoic acid
[0623] ##STR204##
[0624] A solution of
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro--
5-fluorobenzoic acid ethyl ester (Example 3g, 3.57 g, 7.79 mmol),
1.0N sodium hydroxide (50 mL), and methanol (80 mL) are heated at
80.degree. C. for 16.5 hours. The mixture is partially evaporated,
diluted with water (150 mL), and the pH adjusted to 7.0-8.0 using
1.0 M hydrochloric acid. The mixture is extracted with ethyl
acetate, dried over Na.sub.2SO.sub.4, and concentrated under vacuum
to give the title compound as an off-white solid (3.26 g) which is
used without farther purification. MS EI: m/z 430 (M.sup.+).
(h)
4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fl-
uoro-3-methoxybenzoic acid
[0625] ##STR205##
[0626] A solution of
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluor-
o-3-methoxybenzoic acid ethyl ester (Example 3h, 0.173 g, 0.395
mmol) and aqueous sodium hydroxide (1.33N, 2.0 mL, 2.66 mmol) in
tetrahydrofuran (10 mL) and methanol (30 mL) is heated for 22 hours
at 70.degree. C. The solution is cooled, diluted with water, and
partially concentrated under vacuum. The resulting solution is
acidified to pH 6 with aqueous 1N hydrochloric acid, and then the
pH is adjusted to pH 7-8 with 5% NaHCO.sub.3 solution and extracted
with ethyl acetate. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the
title compound as a yellow solid (0.160 g). .sup.1H NMR
(CDCl.sub.3): .delta. 7.46 (d, 1H), 4.80-4.69 (bs, 1H), 4.33-4.18
(m, 1H), 3.90-3.45 (m, 3H), 3.62 (s, 3H), 3.43-3.32 (m, 1H),
2.91-2.80 (m, 1H), 2.28-2.10 (m, 1H), 1.96-1.78 (m, 1H), 1.46 (s,
9H), 0.63-0.52 (m, 4H).
(i)
4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-flu-
orobenzoic acid
[0627] ##STR206##
[0628] A solution of
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluoro-
benzoic acid ethyl ester (Example 3i, 1.51 g, 3.58 mmol) and
aqueous sodium hydroxide (1.33N, 20.0 mL, 26.6 mmol) in
tetrahydrofuran (15 mL) and methanol (40 mL) is refluxed for 19
hours. The solution is cooled, diluted with water, and partially
concentrated under vacuum. The resulting solution is acidified to
pH 6 with aqueous 1.0N hydrochloric acid, and then the pH is
adjusted to pH 7-8 with 5% NaHCO.sub.3 solution and extracted with
ethyl acetate. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to afford
the title compound as a yellow solid (1.353 g). MS EI: m/z 394
(MH.sup.+).
(j)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2cyclopropylamino-3-fl-
uorobenzoic acid
[0629] ##STR207##
[0630] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluo-
robenzoic acid ethyl ester (Example 3j, 1.34 g, 3.29 mmol) and
aqueous sodium hydroxide (2N, 20 mL) in tetrahydrofuran (20 mL) and
methanol (20 mL) is refluxed for 1 hour. The solution is partially
concentrated in vacuo, then acidified to pH 6 and extracted with
chloroform. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound (1.40 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.59 (dd, 1H),
6.06 (dd, 1H), 4.80-4.70 (bd, 1H), 4.38-4.22 (m, 1H), 3.79-3.50 (m,
3H), 3.47-3.35 (m, 1H), 2.98-2.87 (m, 1H), 2.30-2.14 (m, 1H),
1.97-1.84 (m, 1H), 1.46 (s, 9H), 0.69-0.54 (m, 4H).
(k)
4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropyl-
amino-3-fluorobenzoic acid
[0631] ##STR208##
[0632] A solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylami-
no-3-fluorobenzoic acid ethyl ester (Example 3k, 2.00 g, 4.50 mmol)
and aqueous sodium hydroxide (2.0N, 20 mL) in tetrahydrofuran (20
mL), and methanol (20 mL) is refluxed for 1 hour. The solution is
partially concentrated in vacuo, acidified to pH 6, and extracted
with chloroform. The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound (1.70 g). .sup.1H NMR (CDCl.sub.3): .delta. 7.71 (d, 1H),
4.91-4.82 (bd, 1H), 4.40-4.25 (m, 1H), 3.77-3.69 (m, 2H), 3.53-3.34
(m, 2H), 3.00-2.88 (m, 1H), 2.24-2.15 (m, 1H), 1.90-1.80 (m, 1H),
1.46 (s, 9H), 0.72-0.54 (m, 4H).
[0633] The following compounds are synthesized according to general
procedures of Examples 4a-k.
[0634] (l)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-
-3-methylbenzoic acid ([MS ES, MH.sup.+] m/z 394.) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-
-3-methylbenzoic acid ethyl ester (Example 3l).
[0635] (m)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methylbenzoic acid ([MS ES, M+1] m/z 408) using
4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methylbenzoic acid ethyl ester (Example 3m).
[0636] (n)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-
-5-methoxybenzoic acid (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
12.50 (bs, 1H), 7.18-7.09 (m, 1H), 7.07 (d, 1H), 4.07-3.90 (m, 1H),
3.80-3.50 (m, 2H), 3.66 (s, 3H), 3.42-3.29 (m, 2H), 2.88-2.71 (m,
1H), 2.10-1.91 (m, 1H), 1.86-1.67 (m, 1H), 1.39 (s, 9H), 0.70-0.57
(m, 2H), 0.46-0.32 (m, 2H)) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-
-5-methoxy-benzoic acid ethyl ester (Example 3n).
[0637] (o)
4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methoxybenzoic acid. ([MS ES, M+1] m/z 424) using
4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methoxybenzoic acid ethyl ester (Example 3o)
[0638] (p)
4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-
-5-fluorobenzoic acid ([MS ES, MH.sup.+] m/z 424) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-
-5-fluorobenzoic acid ethyl ester (Example 3p).
[0639] (q)
3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2--
cyclopropylamino-5-fluorobenzoic acid (MS ES: m/z 513 (MH.sup.+])
using
3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-
-cyclopropylamino-5-fluorobenzoic acid ethyl ester (Example 3q)
[0640] (r)
3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-
-1-yl)benzoic acid (1H NMR (200 MHz, CDCl.sub.3): .delta. 8.50 (bs,
1H), 8.03 (s, 1 H), 7.72 (s, 1H), 7.60 (d, 1H), 7, 5.54-5.39 (m,
1H), 4.13-3.97 (m, 1H), 3.92-3.85 (m, 1H), 3.68-3.63 (m, 1H),
3.54-3.42 (m, 1H), 3.10-3.00 (m, 1H), 2.78-2.60 (m, 1H), 2.39-2.33
(m, 1H), 0.70-0.58 (m, 2H), 0.58-0.46 (m, 2H)) using
3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-
-1-yl)benzoic acid ethyl ester (Example 3r).
EXAMPLE 5
Synthesis of N-Substituted Anthranilic Acids
(a) 2-Cyclopropylamino-4,5-difluorobenzoic acid
[0641] ##STR209##
[0642] To a solution of 4,5-difluoroanthranilic acid (1.13 g, 6.53
mmol) in anhydrous methanol (40 mL) is added molecular sieves (3
.ANG.), acetic acid (3.70 mL, 65.3 mmol) and
[(1-ethoxycyclopropyl)oxy]trimethylsilane (5.25 mL, 26.11 mmol).
After 30 minutes, sodium cyanoborohydride (2.08 g, 32.64 mmol) is
added, and the reaction mixture is heated to reflux. After 16
hours, the reaction is cooled to room temperature, filtered, washed
with methanol, and the combined filtrate concentrated under vacuum
to afford a viscous oil. The resulting oil is dissolved in ethyl
acetate and washed with 1.0 M hydrochloric acid, water, and brine.
The organic layer is dried over MgSO.sub.4, filtered, and the
filtrate is concentrated under vacuum to afford as a beige solid
(1.32 g). MS CI: m/z 212 (M.sup.+).
(b) 5-Chloro-2-cyclopropylamino-4-fluorobenzoic acid
[0643] ##STR210##
[0644] To a solution of 4,5-difluoroanthranilic acid (1.20 g, 6.37
mmol) in anhydrous methanol (50 mL) is added molecular sieves (3
.ANG.), acetic acid (3.70 mL, 65.3 mmol), and
[(1-ethoxycyclopropyl)oxy]trimethylsilane (5.12 mL, 25.5 mmol).
After 30 minutes, sodium cyanoborohydride (2.03 g, 31.9 mmol) is
added, and the reaction mixture is heated to reflux. After 16
hours, the reaction is cooled to room temperature, filtered, washed
with methanol, and the combined filtrate concentrated under vacuum
to afford a viscous oil. The resulting oil is dissolved in ethyl
acetate and washed with 1.0 M hydrochloric acid, water, and brine.
The organic layer is dried over MgSO.sub.4, filtered, and the
filtrate is concentrated under vacuum to afford as a beige solid
(1.78 g). MS CI: m/z 228 (M.sup.+).
(c) 2-(2,4-Difluoroanilino)-4,5-difluorobenzoic acid
[0645] ##STR211##
[0646] Lithium diisopropylamide is generated at -5.degree. C. by
combining diisopropylamine (7.2 mL, 51 mmol) and n-butyllithium (33
mL, 53 mmol) in anhydrous tetrahydrofuran (150 mL) under an inert
atmosphere. After 0.5 hour, the solution is cooled to -78.degree.
C. and 2,4-difluoroaniline (3.46 mL, 34 mmol) is added and stirred
for 2 hours. 2,4,5-Trifluorobenzoic acid (3.0 g, 17 mmol) is added,
and the mixture is subsequently allowed to warm to room temperature
over 18 hours. A saturated solution of hydrogen chloride/dioxane
(10 mL) is added, and after 1 hour, the mixture is concentrated to
a solid. The solid is dissolved in chloroform and washed with 1.0 M
hydrochloric acid, water, and brine. The solution is dried,
concentrated in vacuo, and purified by column chromatography (3:1
ethyl acetate/hexanes) to give
2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid as a solid (2.18
g). .sup.1H NMR (CDCl.sub.3): .delta. 8.95 (bs, 1H), 7.80-7.75 (m,
2H), 7.50-6.85 (m, 3H), 6.62-6.40 (m, 1H). MS EI: m/z 286
(M.sup.+).
(d) 3-Chloro-2-cyclopropylamino-4,5-difluorobenzoic acid
[0647] ##STR212##
[0648] In a sealed tube a mixture of
2-bromo-3-chloro-4,5-difluorobenzoic acid (Example 20, 7.96 g, 29.3
mmol), cyclopropyl amine (4.20 mL, 58.7 mmol), potassium acetate
(5.77 g, 58.6 mmol), cupric acetate monohydrate (0.50 g, 2.5 mmol),
and triethylamine (4.9 mL, 35.19 mmol) in isopropyl alcohol is
stirred at 80.degree. C. After 16 hours, the reaction mixture is
concentrated under vacuum, and the resulting residue is dissolved
in ethyl acetate. The organic layer is washed with 1.0 M
hydrochloric acid, water, and brine. The organic layer is dried
over MgSO.sub.4 and filtered. The filtrate is concentrated under
vacuum and purified via flash column chromatography (5% isopropyl
alcohol/1% formic acid/94% dichloromethane) to afford the title
compound (4.62 g). MS CI: m/z 248 (MH.sup.+).
EXAMPLE 6
Synthesis of Hydrazinecarboxylic t-Butyl Esters
(a) (2-Cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylic
acid tert-butyl ester
[0649] ##STR213##
[0650] To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid
(Example 5) (1.32 g, 6.19 mmol) and tert-butyl carbazate (1.30 g,
9.75 mmol) in dichloromethane (30 mL) is added
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.87 g, 9.75 mmol).
After 16 hours, the reaction mixture is diluted with
dichloromethane and washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried over MgSO.sub.4 and filtered. The
filtrate is concentrated under vacuum and purified via flash column
chromatography (1:2 ethyl acetate/hexanes) to afford
N.sub.2-(2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarbox-
ylic acid tert-butyl ester as a solid (1.65 g). MS EI: m/z 328
(M.sup.+).
(b)
[2-(2,4-Difluoroanilino)-4,5-difluorobenzoyl]hydrazinecarboxylic
acid tert-butyl ester
[0651] ##STR214##
[0652] To a solution of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic
acid (Example 5, 2.18 g, 7.6 mmol) and tert-butyl carbazate (1.57
g, 11.8 mmol) in dichloromethane (30 mL) is added
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.25 g, 11.77
mmol). After stirring for 16 hours at room temperature, the
reaction mixture is diluted with dichloromethane and then washed
with saturated NaHCO.sub.3, water, and brine. The organic layer is
dried over Na.sub.2SO.sub.4, concentrated under vacuum, and
purified via column chromatography (1:3 ethyl acetate/hexanes) to
afford
[2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic
acid tert-butyl ester as a solid (2.20 g). MS EI: m/z 400
(M.sup.+).
(c)
(3-Chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic
acid tert-butyl ester
[0653] ##STR215##
[0654] To a solution of
3-chloro-2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5d,
2.09 g, 8.45 mmol) in dichloromethane (30 mL) is added tert-butyl
carbazate (1.67 g, 12.7 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.43 g, 12.7 mmol).
After 16 hours, the reaction mixture is diluted with
dichloromethane and washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried over MgSO.sub.4 and filtered. The
filtrate is concentrated under vacuum and purified via flash column
chromatography (1:2 ethyl acetate/hexanes) to afford the title
compound (1.93 g). MS EI: m/z 360 (M.sup.+).
(d)
(5-Chloro-2-cyclopropylamino-4-fluorobenzoyl)-hydrazinecarboxylic
acid tert-butyl ester
[0655] ##STR216##
[0656] To a solution of 5-chloro-2-cyclopropylamino-4-fluorobenzoic
acid (Example 5, 1.48 g, 6.46 mmol) in dichloromethane (50 mL) is
added tert-butyl carbazate (1.28 g, 9.69 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.86 g, 9.69 mmol).
After 16 hours, the reaction mixture is diluted with
dichloromethane and washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried over MgSO.sub.4 and filtered. The
filtrate is concentrated under vacuum and purified via flash column
chromatography (1:2 ethyl acetate/hexanes) to afford
(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarbo-
xylic acid tert-butyl ester as a solid (1.04 g). MS CI: m/e 344
(M.sup.++1).
EXAMPLE 7
Synthesis of 4-Heterocyclic-benzoylhydrazinecarboxylic acid t-butyl
esters
General Procedure A
[0657] A solution of a substituted benzoylhydrazinecarboxylic acid
tert-butyl ester from Example 6 (where R.sub.7.dbd.F), heterocyclic
amine (2 eq.), and triethylamine (10 eq.) is stirred in dimethyl
sulfoxide or N,N-dimethylformamide (6 mL) at 120.degree. C. in a
sealed tube for 16 hours. After cooling to room temperature, the
reaction mixture is diluted with ethyl acetate and washed with
saturated NaHCO.sub.3, water, and brine. The organic layer is dried
over MgSO.sub.4, filtered, and the filtrate concentrated to afford
a brown residue. Trituration with diethyl ether or purification via
flash column chromatography (ethyl acetate/hexanes) yields the
product.
General Procedure B
[0658] To a suspension of a benzoic acid of Example 4 (3.30 mmol)
and tert-butyl carbazate (1.5 eq.) in anhydrous dichloromethane is
added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(1.5 eq.). The mixture is stirred at room temperature for 20 hours,
poured into saturated NaHCO.sub.3, and extracted with
dichloromethane. The combined organic extracts are washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. Purification by flash column chromatography (ethyl
acetate/hexanes) afford the title compounds.
[0659] The following compounds are synthesized according to General
Procedures A or B above:
[0660] (a)
N'-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS
CI: m/z 508 (MH.sup.+)) using
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) and
3-(tert-butoxycarbonylaminomethyl)pyrrolidine (General Method
A).
[0661] (b)
N'-4-[4-(tert-Butoxycarbonylpiperazin-1-yl)-2-cyclopropylamino-5-fluorobe-
nzoyl]hydrazinecarboxylic acid tert-butyl ester (MS CI: m/z 494
(MH+)) using
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) and 4-tert-butoxycarbonylpiperazine
(General Method A).
[0662] (c)
N'-{4-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-2-cycl-
opropylamino-5-fluorobenzoylthydrazinecarboxylic acid tert-butyl
ester (MS CI: m/z 522 (MH.sup.+)) using
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) and
3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidine (Sanchez J.
P., Bridges A. J., Bucsh R., Domagala J. M., Gogliotti R. D., Hagen
S. E., Heifetz C. L., Joannides E. T., Sesnie J. C., et al. J. Med.
Chem., 1992;35(2):361-367) (General Method A).
[0663] (d)
N'-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-2-cyclopro-
pylamino-5-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl ester
(MS CI: m/z 506 (MH.sup.+)) using
(.sup.2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic
acid tert-butyl ester (Example 6a) and
(3-azabicyclo[3.1.0]hex-6-yl)carbamic acid tert-butyl ester
(Brighty K. E., 1991, EP 4134551 (General Method A).
[0664] (e)
N'-{4-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-2-cyclop-
ropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl
ester (MS CI: m/z 508 (MH.sup.+)) using
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) and
(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidine (Chu D. T., Li
Q., Cooper C. S., Fung A. K. L., Lee C. M., Plattner J. J., PCT
Int. Appl., 1995:255. WO 9510519) (General Method A).
[0665] (f)
N'-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-(2,4-difluoroan-
ilino)-5-fluorobenzoyl)hydrazinecarboxylic acid tert-butyl ester
(MS CI: m/z 566 (MH.sup.+)) using
[.sup.2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic
acid tert-butyl ester (Example 6b) and (S)-pyrrolidin-3-ylcarbamic
acid tert-butyl ester (General Method A).
[0666] (g)
N'-{4-[(S)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-
-3,5-difluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester MS
CI: m/z 538 (MH.sup.+) using
4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5--
difluorobenzoic (Example 4a) (General Method B).
[0667] (h)
N'-{4-[(S)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-
-3,6-difluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester
(.sup.1H NMR (CDCl.sub.3): .delta. 8.08 (bs, 2H), 6.50 (bs, 1H),
5.70 (dd, 1H), 4.76-4.68 (m, 1H), 4.37-4.23 (m, 1H), 3.78-3.68 (m,
1H), 3.65-3.42 (m, 2H), 3.40-3.30 (m, 1H), 2.96-2.83 (m, 1H),
2.28-2.14 (m, 1H), 2.00-1.84 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H),
0.68-0.61 (m, 2H), 0.58-0.48 (m, 2H)) using
.sup.4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-
-3,6-difluorobenzoic acid (Example 4b) (General Method B).
[0668] (i)
N'-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamin-
o-3,5,6-trifluorobenzoyl}hydrazine carboxylic acid tert-butyl ester
(.sup.1H NMR (CDCl.sub.3): .delta. 8.04 (bd, 1H), 7.55 (bs, 1H),
6.52.(bs, 1H), 4.79-4.67 (m, 1H), 4.37-4.19 (m, 1H), 3.97-3.55 (m,
3H), 3.53-3.40 (m, 1H), 2.90-2.75 (m, 1H), 2.29-2.06 (m, 1H),
1.96-1.75 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 0.69-0.57 (m, 2H),
0.54-0.43 (m, 2H)) using
4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamin-
o-3,5,6-trifluorobenzoic acid (Example 4d) (General Method B).
[0669] (j)
N'-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclop-
ropylamino-5-fluorobenzoyl}hydrazinecarboxylic tert-butyl ester (MS
CI: m/z 528 (MH.sup.+)) using
4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2-cyclopropyla-
mino-5-fluorobenzoic acid (Example 4c) (General Method B).
[0670] (k)
N'-[(S)-4-(7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-2-cyclopr-
opylamino-5-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl ester
(MS CI: m/z 520 (MH.sup.+)) using
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) and
(5-azaspiro[2,4]hept-7-yl)carbamic acid tert-butyl ester (General
Method A).
[0671] (l)
N'-{4-[(R)-3-(1-tert-Butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-3-
-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/z 570 (MH.sup.+)) using
(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic
acid tert-butyl ester (Example 6c) and
[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine (Fedij
V., Lenoir E. A., III, Suto M. J., Zeller J. R., Wemple J.,
Tetrahedron: Asymmetry, 1994;5[7]:1131-1134) (General Method
A).
[0672] (m)
N'-[4-(Pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]-hydrazinecarb-
oxylic tert-butyl ester (MS CI: m/z 379 (MH.sup.+)) using
2-cyclopropylamino-5-fluoro-4-pyrrolidin-1-ylbenzoic acid (Example
4e) (General Method B).
[0673] (n)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropyla-
minobenzoyl}hydrazine carboxylic acid tert-butyl ester (MS EI: m/z
496 (MH.sup.+)) using
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminob-
enzoic acid (Example 4f) (General Method B).
[0674] (o)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-ch-
loro-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS
EI: m/z 544 (MH.sup.+)) using
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-
-5-fluorobenzoic acid (Example 4g) (General Method B).
[0675] (p)
N'-{4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-f-
luoro-3-methoxybenzoyl}hydrazinecarboxylic acid tert-butyl ester
(MS EI: m/z 524 (MH.sup.+)) using
4-[3-tert-butoxycarbonylamino)-pyrrolidin-1-yl]-2-cyclopropylamino-5-fluo-
ro-3-methoxybenzoic acid (Example 4h) (General Method B).
[0676] (q)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-f-
luorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS EI: m/z
394 (M.sup.+)) using
4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluoro-
benzoic acid (Example 4i) (General Method B).
[0677] (r)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3--
fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS EI: m/z
494 (MH.sup.+)) using
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluo-
robenzoic acid (Example 4j) (General Method B).
[0678] (s)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropy-
lamino-3-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester
(.sup.1H NMR (CDCl.sub.3): .delta. 8.77 (bs, 1H), 7.35 (d, 1H),
6.82 (bs, 1H), 6.55 (bs, 1H), 5.01-4.97 (m 1H), 4.29 (bs, 1H),
3.74-3.57 (m, 2H), 3.41-3.24 (m, 2H), 2.84-2.75 (m, 1H), 2.33-2.16
(m, 1H), 1.92-1.72 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 0.69-0.62
(m, 2H), 0.60-0.50 (m, 2H)) using
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopro-
pylamino-3-fluorobenzoic acid (Example 4k) (General Method B).
[0679] (t)
N'-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fl-
uoro-3-methylbenzoyl]hydrazinecarboxylic acid tert-butyl ester ([MS
ES, MH.sup.+] m/z 508) using
4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-
-3-methylbenzoic acid (Example 4l) (General Method B).
[0680] (u)
N'-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluoro-3-methylbenzoyl)hydrazinecarboxylic acid tert-butyl
ester ([MS ES, MH.sup.+] m/z 522) using
4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2-cyclopropylamino-
-5-fluoro-3-methylbenzoic acid (Example 4m) (General Method B).
[0681] (v)
N'-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fl-
uoro-5-methoxybenzoyl]hydrazinecarboxylic acid tert-butyl ester.
([MS ES, MH.sup.+] m/z 525) using
4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-fluor-
o-5-methoxybenzoic acid (Example 4n) (General Method B).
[0682] (w)
N'-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylic acid tert-butyl
ester ([MS ES, MH.sub.2.sup.+2] m/z 539) using
4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino--
5-fluoro-3-methoxybenzoic acid (Example 4o) (General Method B).
[0683] (x)
N'-[3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl-
)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylic acid
tert-butyl ester. ([MS ES, MH.sup.+] m/z 627) using
3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2--
cyclopropylamino-5-fluorobenzoic acid (Example 4q) (General Method
B)
[0684] (y)
N'-[3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrol-
idin-1-yl)benzoyl]hydrazinecarboxylic acid tert-butyl ester
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 9.90 (bs, 1H), 7.97 (s,
1H), 7.72 (s, 1H, 7.52 (d, 1H), 7.17 (bs, 1H), 5.51-5.41 (m, 1H),
4.59 (bs, 1H), 4.06-3.95 (m, 1H), 3.87-3.74 (m, 1H), 3.61-3.55 (m,
1H), 3.48-3.36 (m, 1H), 2.97-2.90 (m, 1H), 2.77-2.59 (m, 1H)
2.42-2.31 (m, 1H), 1.46 (s, 9H), 0.68-0.50 (m, 4H)) using
3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-ylpyrrolidin--
1-yl)benzoic acid (Example 4r) (General Method B).
[0685] (z)
N-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)-piperidin-1-yl]-2-cyclopropyl-
amino-5-fluorophenyl}methanoyl)hydrazinecarboxylic acid tert-butyl
ester (MS CI: m/e 522 (MH.sup.+)) from piperidin-3-ylmethylcarbamic
acid tert-butyl ester (Hilpert K., Ackermann J., Banner D. W., Gast
A., Gubernator K., Hadvary P., Labler L., Mueller K., Schmnid G.,
et al., J. Med. Chem., 1994;37[23]:3889-3901) and
(2-Cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) (General Method A).
[0686] (aa)
N-[1-(4-{3-[(tert-Butoxycarbonylisopropylamino)-methylpyrrolidin-1-yl}-2--
cyclopropylamino-5-fluorophenyl)methanoyl]-hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/e 550 (MH.sup.+)) using
isopropylpyrrolidin-3-ylmethylamine (Mich T. F., Culbertson T. P.,
U.S. Pat. No. 4,550,103) and
(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 6a) (General Method B).
[0687] (bb)
N'-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-5-chloro-2-c-
yclopropylaminophenyl}methanoyl)hydrazinecarboxylic acid tert-butyl
ester (MS CI: m/e 524 [M.sup.++1]) using
(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylic
acid tert-butyl ester (Example 6c) and
3-(tert-butoxycarbonylaminomethyl)pyrrolidine (General Method
A).
[0688] (cc)
N'-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-et-
hoxy-5-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl ester (MS
ES: m/z 537 (MH.sup.+)) from
(4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-etho-
xy-5-fluorobenzoic acid (Example 4p) (General Method A).
EXAMPLE 8
Synthesis of (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic
acid tert-butyl esters
General Method A
[0689] To a solution of a benzoylhydrazinecarboxylic acid
tert-butyl ester (from Example 7 (0.435 mmol) in tetrahydrofuran
(15 mL) is added potassium carbonate (0.300 g, 2.18 mol) and
triphosgene (0.167 g, 0.566 mmol). The reaction mixture is refluxed
for 90 minutes, cooled to room temperature, and diluted with ethyl
acetate. The organic layer is washed with water and brine, then
dried over MgSO.sub.4, and filtered. The filtrate is concentrated
under vacuum and purified by flash column chromatography (ethyl
acetate/hexanes) to afford the title compounds.
General Method B
[0690] A solution of
(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acid tert-butyl
ester (such as, for example, Example 14), pyrrolidine side chain (2
eq.), and triethylamine (10 eq.) are stirred in dimethyl sulfoxide
or acetonitrile (3 mL) at 80.degree. C. for 48 hours. After cooling
to room temperature, the reaction mixture is diluted with ethyl
acetate and washed with saturated NaHCO.sub.3, water, and brine.
The organic layer is dried over MgSO.sub.4, filtered, and
concentrated. The resulting residue is purified via flash column
chromatography (ethyl acetate/hexanes) to afford the title
compounds
General Method C
[0691] To a solution of a C-6- and/or
C-8-halogenated-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic
acid tert-butyl ester in ethanol and tetrahydrofuran is added
triethylamine and 20% palladium on carbon. Hydrogen is introduced
to the reaction mixture at high pressure for several days, then the
reaction mixture is filtered through Celite, washed with ethanol,
and the combined filtrate concentrated in vacuo and purified via
flash column chromatography (ethyl acetate/hexanes) to afford the
title compounds.
General Method D
[0692] A suspension of benzoylhydrazinecarboxylic acid tert-butyl
ester (from Example 7) and triethylamine (10 eq.) are stirred in
anhydrous tetrahydrofuran for 5 minutes. Phosgene (20% solution in
toluene, 2 eq.) is added in one portion to the suspension. The
reaction mixture is heated at 60.degree. C. for 4.5 hours, cooled
to room temperature, poured into saturated NaHCO.sub.3 solution,
and extracted with chloroform. The combined organic extracts are
washed with water, brine, and then dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum. The resulting residue is
purified by flash column chromatography (1:1 ethyl acetate/hexanes)
to afford the title compounds.
General Method E
[0693] An appropriately substituted pyrrolidine (1.5-2 eq.), a
3-dibenzylamino-6,7-difluoro-1-substituted-1H-quinazoline-2,4-dione
(Example 16) (1 eq.), and triethylamine (10 eq.) are combined in
acetonitrile and heated to reflux for 72 hours. The solution is
cooled, concentrated, and re-dissolved in chloroform. The organic
solution is washed with 1.0 N hydrochloric acid, saturated
NaHCO.sub.3, brine, and dried over magnesium sulfate. The solution
is concentrated to give the title compounds.
General Method F
[0694] A solution of
(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acid tert-butyl
ester (such as, for example, Example 14), pyrrolidine side chain (2
eq.), and triethylamine (10 eq.) are stirred in dimethyl sulfoxide
or acetonitrile (3 mL) at 80.degree. C. for 20 to 40 hours. After
cooling to room temperature, the reaction mixture is diluted with
ethyl acetate and washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried over MgSO.sub.4, filtered, and
concentrated. The resulting residue is redissolved in methylene
chloride and then treated with di-tert-butyl dicarbonate (2 eq).
After 1 hour, the reaction mixture is concentrated and the product
purified via flash column chromatography (ethylacetate/hexanes) to
afford the title compounds.
[0695] The following compounds are synthesized according to General
Procedures A-F of Example 8:
[0696] (a)
{7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopr-
opyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (MS CI: m/z 568 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-3-chloro-2-cycl-
opropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl
ester (Example 18a) (General Method A)
[0697] (b)
7-[4-(tert-Butoxycarbonylpiperazin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro--
2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl
ester (MS CI: m/z 554 (MH.sup.+)) from
N'-4-[4-(tert-butoxycarbonylpiperazin-1-yl)-3-chloro-2-cyclopropylamino-5-
-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl ester (Example
18b) (General Method A).
[0698] (c)
{7-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (MS CI: m/z 582 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-3-chlo-
ro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (Example 18c) (General Method A).
[0699] (d)
[7-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-8-chloro-1-cy-
clopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamic
acid tert-butyl ester (MS CI: m/z 566 (MH.sup.+)) from
N'-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo
[3.1.0]hex-3-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecar-
boxylic acid tert-butyl ester (Example 18d) (General Method A).
[0700] (e)
{7-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1--
cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester (MS CI: m/z 568 (MH.sup.+)) from N'-
{4-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-3-chloro-2--
cyclopropylamino-5-fluoro-benzoyl}hydrazinecarboxylic acid
tert-butyl ester (Example 18e) (General Method A).
[0701] (f)
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-(2,4-difl-
uoroanilino)-6-fluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester (.sup.1H NMR (CDCl.sub.3): .delta. 7.45-7.38
(m, 1H), 6.97-6.81 (m, 1H), 6.73-6.66 (m, 1H), 6.54-6.42 (m, 1H),
4.90-4.81 (bs, 1H), 4.31-4.21 (bs, 1H), 3.86-3.36 (m, 4H),
2.32-2.04 (m, 1H), 1.96-1.84 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H))
from
N'-{4-[(S)-3-(tert-butoxycarbonyl-N-amino)-pyrrolidin-1-yl]-3-chloro-2-(2-
,4-difluoroanilino)-5-fluorobenzoyl}-hydrazinecarboxylic acid
tert-butyl ester (Example 18f) (General Method A).
[0702] (g)
7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropylamino-6,-
8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic acid
tert-butyl ester (.sup.1H NMR (CDCl.sub.3): .delta. 7.54 (dd, 1H),
6.67 (bs, 1H), 4.79-4.68 (bs, 1H), 4.39-4.23 (m, 1H1), 4.10-3.65
(m, 3H), 3.58-3.45 (m, 1H), 3.37-3.25 (m, 1H), 2.30-2.11 (m, 1H),
2.03-1.86 (m, 1H), 1.50 (s, 9H), 1.47 (s, 9H), 1.20-1.12 (m, 2H),
0.83-0.74 (bs, 2H)) from
N'-{4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropyl-
amino-3,5-difluorobenzoyl}-hydrazinecarboxylic acid tert-butyl
ester (Example 5g) (General Method A).
[0703] (h)
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropylamino-5-
,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic acid
tert-butyl ester (MS CI: m/z 538 (M.sup.+)) from
N'-{4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-
-3,6-difluorobenzoyl}-hydrazinecarboxylic acid tert-butyl ester
(Example 5h) (General Method A).
[0704] (i)
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-di-
hydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}-carbamic acid
tert-butyl ester (MS CI: m/z 556 (MH.sup.+)) from
N'-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamin-
o-3,5,6-trifluorobenzoyl}hydrazine carboxylic acid tert-butyl ester
(Example 5i) (General Method A)
[0705] (j)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-
-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS CI: m/z 552 (MH.sup.+)) from
N'-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclop-
ropylamino-5-fluorobenzoyl}hydrazinecarboxylic tert-butyl ester
(Example 5j) (General Method A).
[0706] (k)
[7-(3-Hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-d-
ioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester
(MS CI: m/z 467 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
3-Hydroxymethylpyrrolidine (Roussi G., Zhang J., Tetrahedron Lett.,
1988;29(28):3481-3482) (General Method B).
[0707] (l)
{7-[3-(tert-Butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopro-
pyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS CI: m/z 580 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
3-(tert-butoxycarbonylaminoethyl)pyrrolidine (Antonsson K. T.,
Bylund R. E., Gustafsson N. D., Nilsson N. O. I. WO 9429336)
(General Method B).
[0708] (m)
[7-(7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclo-
propyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamic
acid tert-butyl ester (MS CI: m/z 580 (MH.sup.+)) from
N'-[(S)-4-(7-tert-butoxycarbonylamino-5-azaspiro
[2.4]hept-5-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarb-
oxylic acid tert-butyl ester (Example 18g) (General Method A).
[0709] (n)
{7-[(R)-3-(1-tert-Butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-8-ch-
loro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carba-
mic acid tert-butyl ester (MS CI: m/z 596 (MH.sup.+) from
N'-{4-[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-3-
-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (Example 7l) (General Method A).
[0710] (o)
{7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS CI: m/z 534 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopr-
opyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8a) (General Method C).
[0711] (p)
[7-(Pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydr-
o-2H-quinazolin-3-yl]carbamic acid tert-butyl ester (MS CI: m/z 437
(MH.sup.+)) using
N'-[4-(Pyrrolidin-1-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydra-
zinecarboxylic tert-butyl ester (Example 18h) (General Method
A).
[0712] (q)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-6-fluoro-1-isop-
ropyl-2,4-dioxo-6-fluoro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester. (MS EI: m/z 530 (M.sup.+)) using
N'-{4-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl)-3-chloro-5-fluoro-2--
isopropylaminobenzoyl}-hydrazinecarboxylic acid tert-butyl ester
(Example 18i) (General Method A).
[0713] (r)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-sec-butyl-8-chloro-6-f-
luoro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester
(MS EI: m/z 570 (MH.sup.+)) using
N'-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-ch-
loro-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester
(Example 7o) (General Method A).
[0714] (s)
(7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-
-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS EI: m/z 550 (MH.sup.+)) using
N'-{4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-f-
luoro-3-methoxybenzoyl}hydrazinecarboxylic acid tert-butyl ester
(Example 7p) (General Method D).
[0715] (t)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclobutylami-
no-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS EI: m/z 568 (MH.sup.+)) using
N'-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-f-
luorobenzoyl}-hydrazinecarboxylic acid tert-butyl ester (Example
7q) (General Method A).
[0716] (u)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-8-fluoro-2-
,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl
ester (MS EI: m/z 520 (MH.sup.+)) using
N'-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3--
fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (Example
7r) (General Method D).
[0717] (v)
{7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-6-chloro-1-cyclopropyl-8-
-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (.sup.1H NMR (CDCl.sub.3): .delta. 7.36 (d, 1H),
6.64 (bs, 1H), 4.86-4.80 (bd, 1H1), 4.31-4.25 (m, 1H), 3.81-3.66
(m, 2H), 3.51-3.31 (m, 2H), 3.02-2.97 (m, 1H), 2.32-2.22 (m, 1H),
1.95-1.85 (m, 1H), 1.63 (s, 9H), 1.46 (s, 9H), 0.77-0.73 (m, 2H),
0.63-0.57 (bs, 2H)) using
N'-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropy-
lamino-3-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester
(Example 7s) (General Method D).
[0718] (w)
[(S)-1-(1-Cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl
ester (MS CI, m/z 614 (MH.sup.+)) using
3-dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline-2,4-dione
(Example 17a) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester
(General Method E).
[0719] (x)
{1-[(R)-1-(Cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}-carbamic
acid tert-butyl ester (MS CI: m/z 656 (MH.sup.+)) using
3-dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline-2,4-dione
(Example 17a) and
(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine
(General Method E).
[0720] (y)
[(S)-1-(3-Dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquin-
azolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (mp
104-106.degree. C., MS CI: m/z 588 (MH.sup.+)) using
3-dibenzylamino-6,7-difluoro-1-ethyl-1H-quinazoline-2,4-dione
(Example 17b) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester
(General Method E).
[0721] (z)
[(R)-1-(3-Dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-1-methyl-1-pyrrolidin-3-ylethyl]carbamic acid
tert-butyl ester (MS CI: m/z 630 (MH.sup.+)) using
3-dibenzylamino-6,7-difluoro-1-ethyl-1H-quinazoline-2,4-dione
(Example 17b) and
(R)-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine (General
Method E).
[0722] (aa)
[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester ([MS ES, MH.sup.+] m/z 534) using
N'-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fl-
uoro-3-methylbenzoyl]-hydrazinecarboxylic acid tert-butyl ester
(Example 7t) (General Method D).
[0723] (bb)
{7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester (MS ES, MH.sup.+) m/z 548)) using
N'-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluoro-3-methylbenzoyl}hydrazinecarboxylic acid tert-butyl
ester (Example 7u) (General Method D.
[0724] (cc)
[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-m-
ethoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester ([MS ES, MH.sub.2.sup.+] m/z 551) using
N'-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fl-
uoro-5-methoxybenzoyl]-hydrazinecarboxylic acid tert-butyl ester
(Example 7v) (General Method D).
[0725] (dd)
{7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester ([MS ES, MH.sub.2.sup.+2] m/z 565) using
N'-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylic acid tert-butyl
ester (Example 7w) (General Method D).
[0726] (ee)
[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-f-
luoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester ([MS ES, MH.sub.2.sup.+2] m/z 565) from
N'-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-et-
hoxy-5-fluorobenzoyl]-hydrazinecarboxylic acid tert-butyl ester
(Example 7cc) (General Method A).
[0727] (ff)
[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-8-cyano-1-cyclopropyl-6-fl-
uoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester ([MS ES, MH.sup.+] m/z 545) from
N-[3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-
-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylic acid
tert-butyl ester (Example 7x) (General Method A).
[0728] (gg)
[8-Chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-(3-[1,2,3-triazol]-1-yl-pyrr-
olidin-1-yl)-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.96
(s, 1H), 7.74 (s, 1H), 7.29 (d, 1H), 6.26 (bs, 1H), 5.51-5.39 (m,
1H), 4.17-4.07 (m, 1H), 3.99-3.88 (m, 1H), 3.71-3.66 (m, 1H),
3.57-3.45 (m, 1H), 3.15-3.05 (m, 1H), 2.74-2.60 (m, 1H), 2.44-2.32
(m, 1H), 1.64 (s, 9H), 0.76-0.49 (m, 4H)) from
N'-[3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-
-yl-pyrrolidin-1-yl)benzoyl]hydrazinecarboxylic acid tert-butyl
ester (Example 7y) (General Method A).
[0729] (hh)
[7-(3-Carbamoylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo--
1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester (MS
CI: m/z 496 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
3-carbamoyl-piperidine (General Method B).
[0730] (ii)
{7-[(trans-3-(tert-Butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidin-
-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-
-3-yl}carbamic acid tert-butyl ester (MS CI: m/z 635 (M.sup.+))
from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)-carbamic acid tert-butyl ester (Example 14) and
trans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidine
(Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K.,
Tufano M., et al., J. Med. Chem. Lett., 1998;8[15]:1953-1958)
(General Method B).
[0731] (jj)
8-Chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-{3-[(2,2,2-trifluoroethylamin-
o)methyl]pyrrolidin-1-yl}-1,4-dihydro-2H-quinazolin-3-yl)carbamic
acid tert-butyl ester (MS CI: m/z 548 (M.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
{3-[(2,2,2-trifluoroethylamino)methyl]pyrrolidin-1-yl}carbamic acid
tert-butyl ester (Domagala J. M., Mich T. F., Sanchez J. P. U.S.
Pat. No. 5,097,032) (General Method B).
[0732] (kk)
[8-Chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-
-2-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (MS CI: m/z 494 (MH.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
5-methyloctahydropyrrolo[3,4-c]pyrrole (Ohnmacht C. J. Jr., Draper
C. W., Dedinas R. F., Loftus P., Wong J. J., J. Heterocycl. Chem.,
1983;20[2]:321-329) (General Method B).
[0733] (ll)
[8-Chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-2,4-diox-
o-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester (MS
CI: m/z 494 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(2,7-diaza-spiro[4.4]non-2-yl)carbamic acid tert-butyl ester
(Culbertson T. P., Sanchez J. P., Gambino L., Sesnie J. A., J. Med.
Chem., 1990;33(8):2270-2275) (General Method B).
[0734] (mm)
(7-[3-Benzyl-3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester (MS CI: m/z 658 (MH.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(3-benzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester
(Example A7o) (General Method B).
[0735] (nn)
{7-[(R)-3-((S)-1-tert-Butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester ((MS CI: m/z 582 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester
(Johnson D. R., Szoteck D. L., Domagala J. M., Stickney T. M.,
Michel A., Kampf J. W., J. Heterocycl. Chem., 1992;29[6]:1481-1488)
(General Method B).
[0736] (oo)
[8-Chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyiminopyrrolidinyl)-2,4-dioxo-
-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester (MS
CI: m/z 469 (ME+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
pyrrolidin-3-one oxime (Example A7) (General Method B).
[0737] (pp)
[7-trans-(3-tert-Butoxycarbonylamino-4-trifluoromethylpyrrolidin-1-yl)-8--
chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-ca-
rbamic acid tert-butyl ester (MS CI: m/z 622 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
trans-(4-trifluoromethylpyrrolidin-3-yl)carbamic acid tert-butyl
ester (Fukui H., Shibata T., Naito T. Nakano J., Maejima T., Senda
H., Iwatani W., et al., Bioorg. Med. Chem. Lett.,
1998;8[20]:2833-2838) (General Method B).
[0738] (qq)
(7-{(R)-3-(S)-1-(tert-Butoxycarbonylmethylamino)ethyl]pyrrolidin-1-yl}-8--
chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)car-
bamic acid tert-butyl ester (MS CI: m/z 596 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(R)-3-((S)-1-methylaminoethyl)pyrrolidine (J. Het. Chem.,
1992;29:1481) (General Method F).
[0739] (rr)
trans-[7-((3-tert-Butoxycarbonylamino-4-phenylpyrrolidin-1-yl)-8-chloro-1-
-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (MS CI: m/z 630 (MH.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
trans-4-phenylpyrrolidin-3-ylamine carbamic acid tert-butyl ester
(Bucsh R. A., Domagala J. M., Laborde E., Sesnie J. C., J. Med.
Chem., 1993;36[26]:4139-1451) (General Method B).
[0740] (ss)
trans-{7-[3-tert-Butoxycarbonylamino-4-(4-hydroxyphenyl)-pyrrolidin-1-yl]-
-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-
-carbamic acid tert-butyl ester (MS: m/z 646 (MH.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
trans-4-(4-hydroxyphenyl)-pyrrolidin-3-ylamine carbamic acid
tert-butyl ester (Bucsh R. A., Domagala J. M., Laborde E., Sesnie
J. C., J. Med. Chem., 1993;36[26]:4139-4151) (General Procedure
B).
[0741] (tt)
{7-[3-(tert-Butoxycarbonylaminomethyl)piperidin-1-yl]-8-chloro-1-cyclopro-
pyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS CI: m/z 580 (M.sup.+)) using
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(piperidin-3-ylmethyl)carbamic acid tert-butyl ester (General
Method B).
[0742] (uu)
(7-{3-[(tert-Butoxycarbonylisopropylamino)methyl]pyrrolidin-1-yl}-8-chlor-
o-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-carbami-
c acid tert-butyl ester (MS CI: m/z 608 (M.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
3-(isopropylaminomethyl)pyrrolidine (Domagala et al., J. Med.
Chem., 1994;3889-3901) (General Method F).
[0743] (vv)
{7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-6,8-dichloro-1-cyc-
lopropyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (MS CI: m/z 584 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
(pyrrolidine-3-ylmethyl)carbamic acid tert-butyl ester (General
Method B).
[0744] (ww)
[7-(3-tert-Butoxycarbonylamino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclop-
ropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3) .delta.
7.68 (d, 1H), 7.50-7.29 (m, 5H), 6.72 (s, 1H), 5.24 (s, 1H),
4.18-3.85 (m, 3H), 3.78-3.52 (m, 2H), 2.70 (s, 1H), 2.58-2.39 (m,
1H), 1.62-0.62 (m, 22H)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinaz-
olin-3-yl)carbamic acid tert-butyl ester (Example 14) and
(3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Example
A30) using General Method B.
[0745] (xx)
{7-[3-(tert-Butoxycarbonylaminomethyl)-4-methylpyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (MS ES: m/z 582 (MH.sup.+)) from
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14) and
trans-(4-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester
(Kuniyoshi M., Seigo S., Keiji H., Takayoshi I., Eur. Pat. Appl.,
1987, EP 208210) using general procedure F.
EXAMPLE 9
Deprotection of Quinazolin-2,4-diones
General Method A
[0746] Hydrogen chloride gas is bubbled into diethyl ether (or
dichloromethane or dichloroethane for 15 minutes. The resulting
solution is then cooled to 0.degree. C. and added to a solution of
a 2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl
ester (Example 6), The reaction mixture is slowly warmed to room
temperature. After 30 hours, the precipitate is filtered, washed
with ether (or dichloromethane or dichloroethane) and hexanes, and
dried under vacuum to afford the hydrochloride salt of the desired
deprotected amine as a solid.
General Method B
[0747] A compound is dissolved in trifluoroacetic acid and stirred
at 0.degree. C. for 3 to 8 hours. The acid is removed by blowing
compressed air over the solution or concentrate in vacuo. The
residue is twice co-evaporated with ethanol and dried in vacuo to
yield the trifluoroacetate salt of the title compound as a
solid.
General Method C
[0748] A
3-dibenzylamino-6-fluoro-1-substituted-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester
and 20% Pd/C (cat.) are combined in methanol and shaken under 50
psi of hydrogen for 22.5 hours. The suspension is filtered through
Celite and concentrated. The residue is purified via chromatography
(SiO.sub.2, CHCl.sub.3) to give a solid. The solid is then
dissolved in methylene chloride, cooled to 0.degree. C., and HCl
gas is passed through the solution for 10 minutes. The suspension
is stirred for 2 hours and concentrated to give the title
compound.
General Method D
[0749] Hydrogen chloride gas is bubbled through a solution of
substrate in diethyl ether, and the solution stirred for 2 hours.
The solvent is removed under reduced pressure to afford the desired
title compound as a solid.
General Method E
[0750] A solution of substrate in ethanol is treated with a
solution of ethanol saturated with gaseous hydrogen chloride. The
reaction mixture is stirred at room temperature for 18 hours, and
the solvent is removed in vacuo. The residue is dissolved in water,
filtered through a fiber glass pad to clarify, and lyophilized. The
solid residue is triturated with ether, filtered, washed with ether
and dried in vacuo.
General Method F
[0751] A solution of
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b), 1.2 eq. of heterocyclic amine side chain, and
1:3 N,N-diisopropylethylamine/acetonitrile is heated at 50.degree.
C. for 18 hours. The reaction mixture is diluted with water, cooled
to 0.degree. C., and the solid is removed by filtration, washed
with 50% aqueous acetonitrile, and dried in vacuo to give a solid
that is dissolved in ethanol and treated with a solution of ethanol
saturated with gaseous hydrogen chloride. The mixture is then
stirred at room temperature for 18 hours. The solvent is removed in
vacuo and the residue is triturated with ether. The solid is
removed by filtration, washed with ether and dried in vacuo.
[0752] The following compounds are synthesized according to General
Procedures A-F of Example 9:
[0753] (a)
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro--
1H-quinazoline-2,4-dione hydrochloride (Compound 1) (mp
153-155.degree. C., MS CI: m/z 368 (MH.sup.+)) from
7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopro-
pyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8a) using General Method A.
[0754] (b)
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinazoline-2-
,4-dione hydrochloride (Compound 2) (mp 156-159.degree. C., MS CI:
m/z 354 (MH.sup.+)) from
7-[4-(tert-butoxycarbonylpiperazin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro--
2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl
ester (Example 8b) using General Method A.
[0755] (c)
3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropy-
l-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 3) (mp
166-168.degree. C., MS CI: m/z 382 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8c) using General Method A.
[0756] (d)
3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-
-fluoro-1H-quinazolin-2,4-dione hydrochloride (Compound 4) (mp
111-114.degree. C., MS CI: m/z 366 (MH.sup.+)) from
[7-(6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-8-chloro-1-cy-
clopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (Example 8d) using General Method A.
[0757] (e)
3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione hydrochloride (Compound 5) (mp
118-120.degree. C., MS CI: m/z 368 (MH.sup.+)) from
{7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1--
cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8e) using General Method A.
[0758] (f)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroanilino)-6-
-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 6) (mp
184-186.degree. C., MS CI: m/z 427(MH.sup.+)) from
{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-(2,4-difl-
uoroanilino)-6-fluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8f) using General Method A.
[0759] (g)
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1H-
-quinazoline-2,4-dione hydrochloride (Compound 7) (mp 288.degree.
C. (dec.), MS EI: m/z 338 (M.sup.+)) from
7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropylamino-6-
,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8g) using General Method A.
[0760] (l)
3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1H-
-quinazoline-2,4-dione hydrochloride (Compound 8) (mp 338.degree.
C. (dec), MS EI: m/z 338 (M.sup.+)) from
{7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropylamino--
5,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl carbamic acid
tert-butyl ester (Example 8h) using General Method A
[0761] (i)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluoro-1H-q-
uinazoline-2,4-dione hydrochloride (Compound 9) (mp 271.degree. C.
(dec.), MS CI: m/z 356 (MH.sup.+)) from
{7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropyl-1,4-d-
ihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}-carbamic acid
tert-butyl ester (Example 8i) using General Method A.
[0762] (j)
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-qui-
nazoline-2,4-dione hydrochloride (Compound 10) (mp 134-136.degree.
C., MS CI: m/z 354 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl--
6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8a) using General Method A.
[0763] (k)
7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-difluoro-1H--
quinazoline-2,4-dione hydrochloride (Compound 11) (mp
215-218.degree. C. (dec.), MS EI: 352 (M.sup.+)) from
{5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropy-
l-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 12) using Method A.
[0764] (l)
3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluor-
o-1H-quinazoline-2,4-dione hydrochloride (Compound 12) (mp
78-80.degree. C., MS CI: m/z 369 (MH.sup.+)) from
[7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-d-
ioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester
(Example 8k) using Method A.
[0765] (m)
3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione hydrochloride (Compound 13) (mp
158-160.degree. C., MS CI: m/z 382 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopro-
pyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8l) using Method A.
[0766] (n)
3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-
-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 14) (mp
177-179.degree. C., MS CI: m/z 380 (MH.sup.+) from
[7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclo-
propyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (Example 8m) using General Method A.
[0767] (o)
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclo-
propyl-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound
15) (mp 117-120.degree. C., MS CI: m/z 396 (MH.sup.+)) from
{7-[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-8-ch-
loro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carba-
mic acid tert-butyl ester (Example 8n) using General Method A.
[0768] (p)
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinaz-
oline-2,4-dione hydrochloride (Compound 16) (mp 170-172.degree. C.,
MS CI: m/z 334 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8o) using General Method A.
[0769] (q)
3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-
e-2,4-dione hydrochloride (Compound 17) (mp 96-98.degree. C., MS
CI: m/z 339 (MH.sup.+)) from
[7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydr-
o-2H-quinazolin-3-yl]carbamic acid tert-butyl ester (Example 8p)
using General Method A.
[0770] (r)
3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1H-quina-
zoline-2,4-dione trifluoroacetate (Compound 18) (mp 151 .degree.
C., MS EI: m/z 356 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-8-chloro-6-fluoro-1-iso-
propyl-2,4-dioxo-6-fluoro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8q) using General Method B.
[0771] (s)
3-Amino-7-(3-aminopyrrolin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H-quinazo-
line-2,4-dione trifluoroacetate (Compound 19) (mp 115.degree. C.)
from
{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-sec-butyl-8-chloro-6-f-
luoro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester
(Example 8r) using General Method B.
[0772] (t)
3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-qu-
inazoline-2,4-dione hydrochloride (Compound 20) (mp 216-218.degree.
C., MS EI: m/z 350 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro--
8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8s) using Method A.
[0773] (u)
3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-1H-
-quinazoline-2,4-dione hydrochloride (Compound 21) (mp
205-208.degree. C. (dec.), MS EI: m/z 368 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclobutylami-
no-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8t) using General Method A.
[0774] (v)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quinazoline--
2,4-dione trifluoroacetate (Compound 22) (mp 210-212.degree. C., MS
EI: m/z 320 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-8-fluoro-2-
,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl
ester (Example 8u) using Method A.
[0775] (w)
3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-
1H-quinazoline-2,4-dione trifluoroacetate (Compound 23) (mp
135-137.degree. C., MS EI: m/z 354 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-6-chloro-1-cyclopropyl--
8-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8v) using General Method B.
[0776] (x)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluoro-1H-qu-
inazoline-2,4-dione hydrochloride (Compound 24) (mp >250.degree.
C., MS CI: m/z 334 (MH.sup.+)) from
[(S)-1-(1-cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 8w) using General Method C.
[0777] (y)
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropylmet-
hyl-8-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 25)
(mp >250.degree. C., MS CI: m/z 376 (MH.sup.+)) from
{1-[(R)-1-(cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl)carbamic
acid tert-butyl ester (Example 8x) using General Method C.
[0778] (z)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazoline-2,-
4-dione hydrochloride (Compound 26) (mp 248-251 .degree. C., MS CI:
m/z 308 (MH.sup.+)) from
[(S)-1-(3-dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquin-
azolin-7-yl)pyrrolidin-3-yl]-carbamic acid tert-butyl ester
(Example 8y) using General Method C.
[0779] (aa)
3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrolidin-1-yl-
]-1H-quinazoline-2,4-dione hydrochloride (Compound 27)
(mp>250.degree. C., MS CI: m/z 350 (MH.sup.+)) from
[(R)-1-(3-dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquin-
azolin-7-yl)-1-methyl-1-pyrrolidin-3-ylethyl]carbamic acid
tert-butyl ester (Example 8z) using Method C.
[0780] (bb)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazol-
ine-2,4-dione hydrochloride (Compound 28) (mp >250.degree. C.,
MS CI: m/z 320 (MH.sup.+)) from
3-amino-{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-1H-quinazoline-2,4-dione (Example 25) using General
Method A.
[0781] (cc)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-qui-
nazoline-2,4-dione trifluoroacetate (Compound 29) (mp
110-112.degree. C., MS ES, MH.sup.+) m/z 334) from
[7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-m-
ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (Example 8aa) using General Method B.
[0782] (dd)
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl--
1H-quinazoline-2,4-dione trifluoroacetate (Compound 30) (mp
82-84.degree. C., MS ES, m/z 348 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-f-
luoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8bb) using General Method B.
[0783] (ee)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-1H-qu-
inazoline-2,4-dione hydrochloride (Compound 31) (mp 208-210.degree.
C., MS ES, m/z 350(MH.sup.+)) from
[7-(3-tert-butoxycarbonylamimopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-m-
ethoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (Example 8cc) using General Method A.
[0784] (ff)
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-
-1H-quinazoline-2,4-dione hydrochloride (Compound 32) (mp
180-182.degree. C., MS ES, m/z 364 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fl-
uoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester (Example 8dd) using General Method A.
[0785] (gg)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-1H-qui-
nazoline-2,4-dione hydrochloride (Compound 33) (mp 220.degree. C.,
MS ES, m/z 364 (MH.sup.+)) from
[7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-f-
luoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (Example 8ee) using General Method A.
[0786] (hh)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3-
,4-tetrahydroquinazoline-8-carbonitrile hydrochloride (Compound 34)
(mp 277.degree. C., MS ES, m/z 345 (MH.sup.+)) from
[7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-8-cyano-1-cyclopropyl-6-fl-
uoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (Example 8ff) using General Method A.
[0787] (ii)
3-Aminio-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl-pyrrol-
idin-1-yl)-1H-quinazoline-2,4-dione trifluoroacetate (Compound 35)
(mp 145-147.degree. C., MS ES, m/z 406 (MH.sup.+)) from
[8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-(3-[1
,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1,4-dihydro-2H-quinazolin-3-yl]carbam-
ic acid tert-butyl ester (Example 8gg) using General Method B.
[0788] (jj)
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 36),
(mp 215-217.degree. C.) from
{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic acid
tert-butyl ester (Example 28a) using General Method E.
[0789] (kk)
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 37)
(mp 221-223.degree. C.) from
{(S)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic acid
tert-butyl ester (Example 28b) using General Method A.
[0790] (ll)
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1 H-quinazoline-2,4-dione hydrochloride (Compound 38)
(mp 197-199.degree. C.) from
{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28c) using General Method E.
[0791] (mm)
3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl- 1H-quinazoline-2,4-dione hydrochloride (Compound 39)
(mp 192-194.degree. C.) from
{(S)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-ethyl}carbamic acid
tert-butyl ester (Example 28d) using General Method E.
[0792] (nn)
5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihydro-1-ox-
a-3a,5-diazaphenalene-4,6-dione hydrochloride (Compound 40) (mp
202-204.degree. C.) from
[(S)-1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3-
a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 28e) using General Method E.
[0793] (oo)
5-Amino-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-
-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione hydrochloride
(Compound 41) (mp 192-194.degree. C.) from
{(S)-1-[(R)-1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H--
1-oxa-3a,5-diazaphenalen-9-yl)-pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28f) using General Method E.
[0794] (pp)
2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihydro-5H-p-
yrido[3,2,1-ij]quinazoline-1,3-dione, hydrochloride (Compound 42)
(mp 202-204.degree. C.) from
[(S)-1-(2-amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyri-
do[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamic acid
tert-butyl ester (Example 28g) using General Method E.
[0795] (qq)
2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-methyl-6,7-
-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione hydrochloride
(Compound 43) (mp 197-199.degree. C.) from
{(R)-3-[(S)-1-(2-amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,-
5H-pyrido[3,2,1-ij]quinazolin-8-yl)-pyrrolidin-3-yl}ethyl]carbamic
acid tert-butyl ester (Example 28h) using General Method E.
[0796] (rr)
3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2-
,3-d]pyrimidine-2,4-dione hydrochloride (Compound 44) (mp
213-215.degree. C.) from
[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro--
pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]carbamic acid
tert-butyl ester (Example 28i) using General Method E.
[0797] (ss)
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione, hydrochloride (Compound 45) (mp
268-270.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and 3-azabicyclo[3.1.0]hex-6-ylcarbamic acid
tert-butyl ester using General Method F.
[0798] (tt)
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
1H-pyrido[2,3-d]pyrimidine-2,4-dione, hydrochloride (Compound 46)
(mp 187-189.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and
[1-methyl-(3-methylpyrrolidin-3-yl)]methylcarbamic acid tert-butyl
ester (J. Med. Chem., 1992;361-367) using General Method F.
[0799] (uu)
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-yl)-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride (Compound 47) (mp
200-203.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and
(3aS,7aR)-octahydropyrrolo[3,4-c]pyridine-5-carboxylic acid
tert-butyl ester (Example A27) using General Method F.
[0800] (vv)
3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-yl)-1H-
-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride (Compound 48) (mp
200-202.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and octahydropyrrolo[3,4-b]pyridine-5-carboxylic
acid tert-butyl ester using General Method F.
[0801] (ww)
3-Amino-7-[(R1)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-
-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride
(Compound 49) (mp >260.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and (R)-3-(1-amino-1-methylethyl)-pyrrolidine
using General Method F.
[0802] (xx)
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[-
2,3-d]pyrimidine-2,4-dione, dihydrochloride(Compound 50) (mp
152-154.degree. C.) from 3-amino-7-chloro-1-cyclopropyl-6-fluoro-1
H-pyrido [2,3-d]pyrimidine-2,4-dione (Example 24b) and
(3-aminomethylpiperidin-1-yl)carbamic acid tert-butyl ester
(Hilpert K. et al., J. Med. Chem., 1994;37[23]:3889-3901) using
General Method F.
[0803] (yy)
trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclop-
ropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride
(Compound 51) (mp 214-216.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and 3-aminomethyl-4-trifluoromethylpyrrolidine
(Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K.,
Tufano M., et al., Bioorg. Med. Chem. Lett., 1998;8:1953-1958)
using General Method F.
[0804] (zz)
3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylaminoethyl)pyrrolidi-
n-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride
(Compound 52) (mp 137-139.degree. C.) from
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b) and (R)-3-((R)-1-methylaminoethyl)pyrrolidine
using General Method F.
[0805] (aaa)
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o- I H-pyrido[2,3-d]pyrimidine-2,4-dione hydrochloride (Compound
53) (mp >260.degree. C.) from
{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydr-
opyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]-ethyl}carbamic acid
tert-butyl ester (Example 28j) using General Method E.
[0806] (bbb)
3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-met-
hyl-1H-quinazoline-2,4-dione hydrochloride (Compound 54) (MS CI:
m/z 376 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)pyrrolidin-3-ylpropyl}carbamic acid tert-butyl
ester (Example 28ooo) using General Method E.
[0807] (ccc)
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylaminoethyl)-
pyrrolidin-1-yl]-1H-quinazoline-2,4-dione hydrochloride (Compound
55) (mp 153-5.degree. C.) from
{(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-ethyl}methylcarbamic
acid tert-butyl ester (Example 28ppp) using General Method E.
[0808] (ddd)
3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 56)
(mp 178-80.degree. C., MS CI: m/z 388 (MH.sup.+)) from
{1-[5-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-5-aza-spiro[2.4]hept-7-yl]-ethyl}carbamic acid
tert-butyl ester (Example 28qqq) using General Method E.
[0809] (eee)
1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)piperidine-3-carboxylic acid amide (Compound 58) (mp
141-144.degree. C., MS CI: m/z 396 (MH.sup.+)) from
[7-(3-carbamoylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo--
1,4-dihydro-2H-quinazolin-3-yl]-carbamic acid tert-butyl ester
using General Method A (Example 8hh).
[0810] (fff)
3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-
-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione hydrochloride
(Compound 59) (mp 171-173.degree. C., MS CI: m/z 436.(MH.sup.+))
from
{7-[trans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidin--
1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl}carbamic acid tert-butyl ester (Example 8ii) using General
Method E.
[0811] (ggg)
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoroethylamino)-
methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dione hydrochloride
(Compound 60) (mp 163-164.degree. C., MS CI: m/z 450 (MH.sup.+))
from
8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-{3-[(2,2,2-trifluoroethylamin-
o)methyl]-pyrrolidin-1-yl}-1,4-dihydro-2H-quinazolin-3-yl)carbamic
acid tert-butyl ester (Example 8jj) using General Method E.
[0812] (hhh)
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydropyrrolo[3,4-c-
]pyrrol-2-yl)-1H-quinazoline-2,4-dione hydrochloride (Compound 61)
(mp 133-1355.degree. C., MS CI: m/z 394 (MH.sup.+)) from
[8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-
-2-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid
tert-butyl ester (Example 8kk) using General Method E.
[0813] (iii)
3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-1-
H-quinazoline-2,4-dione (Compound 62) (mp 147-149.degree. C., MS
CI: m/z 394 (MH.sup.+)) from
[8-chloro-1-cyclopropyl-7-(2,7-diazaspiro
[4.4]non-2-yl)-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (Example 8ll) using General Method E.
[0814] (jjj)
3-Amino-7-(3-aminomethyl-3-benzylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl--
6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 63) (mp
148-150.degree. C., MS CI: m/z 458 (MH.sup.+)) from
(7-[3-benzyl-3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro--
1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8mm) using General Method E.
[0815] (kkk)
3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropy-
l-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 64) (mp
164-166.degree. C., MS CI: m/z 382 (MH.sup.+)) from
{7-[R)-3-((S)-1-tert-butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-
-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester (Example 8nn) using General Method E.
[0816] (lll)
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyiminopyrrolidin-1-yl)-
-1H-quinazoline-2,4-dione (Compound 65) (mp 147-9.degree. C., MS
CI: m/z 368 (MH.sup.+)) from)
[8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyiminopyrrolidin-yl)-2,4-diox-
o-1,4-dihydro-2H-quinazolin-3-yl]carbamic acid tert-butyl ester
(Example 8oo) using General Method E.
[0817] (mmm)
3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyc-
lopropyl-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound
66) (mp 181-183.degree. C., MS CI: m/z 422 (MH.sup.+)) from
[7-(trans-3-tert-butoxycarbonylamino-4-trifluoromethylpyrrolidin-1-yl)-8--
chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]car-
bamic acid tert-butyl ester (Example 8pp) using General Method
E.
[0818] (nnn) 3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)
1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione
hydrochloride (Compound 67) (mp 122-124.degree. C., MS CI: m/z 396
(MH.sup.+)) from
(7-{(R)-3-(S)-1-(tert-butoxycarbonylmethylamino)ethyl]pyrrolidin-1-yl}-8--
chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)car-
bamic acid tert-butyl ester (Example 8qq) using General Method
E.
[0819] (ooo)
3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl--
6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 68) (mp
174-175.degree. C., MS CI: m/z 430 (MH.sup.+)) from
[7-(trans-3-tert-butoxycarbonylamino-4-phenylpyrrolidin-1-yl)-8-chloro-1--
cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (Example 8rr) using General Method E.
[0820] (ppp)
3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-c-
yclopropyl-6-fluoro-1H-quinazoline-2,4-dione hydrochloride.
(Compound 69) (mp>200.degree. C., MS CI: m/z 446 (MH.sup.+))
using
7-[trans-3-tert-butoxycarbonylamino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-
-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}ca-
rbamic acid tert-butyl ester (Example 8ss) and General Method
E.
[0821] (qqq)
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydr-
oquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide
hydrochloride (Compound 70) (mp 109-112.degree. C., MS CI: m/e 446
(M.sup.+)) from
{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)-pyrrol-
idin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 36) using General Method E.
[0822] (rrr)
3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1-
H-quinazoline-2,4-dione hydrochloride (Compound 71) (mp
131-133.degree. C., MS CI: m/z 382 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]-8-chloro-1-cyclopro-
pyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 8tt) using General Method E.
[0823] (sss)
3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylaminomethyl)pyrrol-
idin-1-yl]-1H-quinazoline-2,4-dione hydrochloride (Compound 72) (mp
125-127.degree. C., MS CI: m/z 410 (MH.sup.+)) from
(7-{3-[(tert-butoxycarbonylisopropylamino)methyl]pyrrolidin-1-yl}-8-chlor-
o-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic
acid tert-butyl ester (Example 8uu) using General Method E.
[0824] (ttt)
3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropyl-1H-qu-
inazoline-2,4-dione hydrochloride (Compound 73) (mp 147-149.degree.
C., MS CI: m/z 384 (MH.sup.+)) from
{7-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-6,8-dichloro-1-cy-
clopropyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester using General Method E.
[0825] (uuu)
N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydr-
oquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide (Compound
74) (mp 109-112.degree. C., MS CI: m/z 446 (MH.sup.+)) from
{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrroli-
din-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (Example 36) using General Method E.
[0826] (vvv)
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 75) (mp
194-196.degree. C., .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.
8.25 (bs, 3H), 7.47 (d, 1H), 4.68 (bs, 3H), 3.59-3.23 (m, 7H), 2.49
(s, 3H), 2.02-1.92 (m, 1H), 1.80-1.60 (m, 1H), 1.30 (d, 3H),
1.12-1.08 (m, 2H), 0.62-0.50 (m, 2H); MS ES: m/z 362 (MH.sup.+))
from
{1-[1-[(R)-3-(S)-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3-
,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28k) using General Method A.
[0827] (www)
3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound
76) (mp 200-202.degree. C., MS ES: m/z 376 (MH.sup.+)) from
{1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}carbamic acid
tert-butyl ester (Example 281) using Method A.
[0828] (xxx)
3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 77)
(mp 190-192.degree. C., .sup.1H NMR (200 MHz, DMSO-d.sub.6):
.delta. 8.07 (bs, 3H), 7.49 (d, 1H), 3.89-3.10 (m, 12H), 2.42 (s,
3H), 2.39-2.08 (m, 2H), 1.29 (d, 3H), 1.07-1.03 (m, 2H), 0.62-0.52
(m, 2H); MS ES: m/z 392 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-3-methoxypyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28m) using General Method A.
[0829] (yyy)
3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 78)
(mp 190-192.degree. C., MS ES: m/z 396 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-3-fluoropyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28o) using General Method A.
[0830] (zzz)
3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-1H-qui-
nazoline-2,4-dione hydrochloride (Compound 79) (mp 238-240.degree.
C., MS ES: m/z 334 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester
(Example 28p) using General Method A.
[0831] (aaaa)
3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-5-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 80) (mp
245-247.degree. C., MS ES: m/z 362 (MH.sup.+)) from
{1-(S)-[1-(R)-(3-amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28q) using General Method A.
[0832] (bbbb)
3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound
81) (mp 172-177.degree. C., MS ES: m/z 392 (H+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-methoxymethylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28r) using General Method A.
[0833] (cccc)
3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-1H-quinazoline-2,4-dione hydrochloride (Compound 82) (mp
160-163.degree. C., MS ES: m/z 380 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-fluoromethylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28s) using General Method A.
[0834] (dddd)
3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclop-
ropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride
(Compound 83) (mp 205-207.degree. C., MS ES: m/z 432 (MH.sup.+))
from
[trans-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydroquinazolin-7-yl)-4-trifluoromethylpyrrolidin-3-ylmethyl]carbamic
acid tert-butyl ester (Example 28t) using General Method A.
[0835] (eeee)
3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-metho-
xy-1H-quinazoline-2,4-dione hydrochloride (Compound 84) (mp
198.degree. C., MS ES: m/z 392 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)piperidin-3-yl]ethyl}carbamic acid tert-butyl
ester (Example 28u) using General Method A.
[0836] (ffff)
3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl--
1H-quinazoline-2,4-dione hydrochloride (Compound 85) (mp
200.degree. C., .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 8.25
(bs, 3H), 7.52 (d, 1H), 6.36 (bs, 3H), 3.54-2.80 (m, 6H), 2.48 (s,
3H), 2.02-1.15 (m, 8H), 1.02-0.50 (m, 4H); MS ES: m/z
376(MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)piperidin-3-yl]ethyl}carbamic acid tert-butyl
ester Example 28v) using General Method A.
[0837] (gggg)
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound
86) (mp 230.degree. C., MS ES: m/z 406 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28w) using General Method A.
[0838] (hhhh)
3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride. (Compound
87) (mp 246.degree. C., MS ES: m/z 390 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28x) using General Method A.
[0839] (iiii)
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
yl-1H-quinazoline-2,4-dione hydrochloride (Compound 88) (mp
236.degree. C., MS ES: m/z 410 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-phenylpyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 28z) using General Method A.
[0840] (jjjj)
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 89)
(mp 240.degree. C., MS ES: m/z 376 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28y) using General Method A.
[0841] (kkkk)
3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 90) (mp
227-231.degree. C., MS ES: m/z 424 (H+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)3-phenylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28aa) using General Method A.
[0842] (llll)
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-
-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 91) (mp
167.degree. C., MS ES: m/z 374 (MH.sup.+)) from
[5-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamic acid
tert-butyl ester (Example 28bb) using General Method A.
[0843] (mmmm)
3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 92) (mp
178.degree. C., MS ES: m/z 390 (MH.sup.+)) from
[5-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamic acid
tert-butyl ester (Example 28cc) using General Method A.
[0844] (nnnn)
3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 93) (mp
202.degree. C., MS ES: m/z 380 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-3-hydroxypyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28dd) using General Method A.
[0845] (oooo)
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1-
H-quinazoline-2,4-dione hydrochloride (Compound 95) (mp
219-221.degree. C., MS ES: m/z 362 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)piperidin-3-ylmethyl]carbamic acid tert-butyl ester
(Example 28ee) using General Method A.
[0846] (pppp)
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-met-
hyl-1H-quinazoline-2,4-dione hydrochloride (Compound 96)
(mp>250.degree. C., MS ES: m/z 364 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 28ff) using General Method A.
[0847] (qqqq)
3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-met-
hoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 97)
(mp>250.degree. C., MS ES: m/z 380 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 28gg) using General Method A.
[0848] (rrrr)
3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
oxy-1H-quinazoline-2,4-dione hydrochloride (Compound 98)
(mp>250.degree. C., MS ES: m/z 368 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-4-fluoropyrrolidin-3-yl]carbamic acid tert-butyl
ester (Example 28hh) using General Method A.
[0849] (ssss)
3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 99) (mp
210.degree. C., MS ES: m/z 362 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-methylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28ii) using General Method A.
[0850] (tttt)
3-Amino-7-[(R)-3(-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-ethy-
l-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound 100)
(mp 155-157.degree. C., MS ES: m/z 376 (MH.sup.+)) from
{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-8-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28jj) using General Method A.
[0851] (uuuu)
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidine-3-carboxylic acid trifluoroacetate
(Compound 101) (mp 252.degree. C. (decomp), MS ES: m/z 379
(MH.sup.+)) from
1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidine-3-carboxylic acid tert-butyl ester
(Example 28kk) using General Method B.
[0852] (vvvv)
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)pyrrolidine-3-carboxylic acid trifluoroacetate
(Compound 102) (mp 226.degree. C. (decomp), MS ES: m/z 363
(MH.sup.+)) from
1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)pyrrolidine-3-carboxylic acid tert-butyl ester
(Example 28ll) using General Method A.
[0853] (wwww)
3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-flu-
oro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 103)
(mp 183-185.degree. C., MS ES: m/z 376 MH.sup.+)) from
[3-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamic acid
tert-butyl ester (Example 28mm) using General Method A.
[0854] (xxxx)
3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-flu-
oro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 104)
(mp 189-194.degree. C., MS ES: m/z 360 (MH.sup.+)) from
[3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamic acid
tert-butyl ester (Example 28nn) using General Method A.
[0855] (yyyy)
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 105)
(mp 175-179.degree. C., MS ES: m/z 378 (MH.sup.+)) from
{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28oo) using General Method A.
[0856] (zzzz)
3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluor-
o-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 106)
(mp 172-176.degree. C., MS (ES: m/z 362 (MH.sup.+)) from
{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28pp) using General Method A.
[0857] (aaaaa)
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]pyridin-
-6-yl)-1H-quinazoline-2,4-dione hydrochloride (Compound 107) (mp
220.degree. C., MS ES: m/z 374 (MH.sup.+)) from
6-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)octahydropyrrolo[3,4-b]pyridine-1-carboxylic acid
tert-butyl ester (Example 28qq) using General Method A.
[0858] (bbbbb)
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-cyclop-
ropyl-6-fluoro-1H-quinazoline-2,4-dione hydrochloride (Compound
108) (mp 215-217.degree. C., MS ES: m/z 382 (MH.sup.+)) from
{7-[trans-3-(tert-butoxycarbonyl-aminomethyl)-4-methylpyrrolidin-1-yl]-8--
chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}car-
bamic acid tert-butyl ester (Compound 109) (Example 8xx) using
General Method A.
[0859] (ccccc)
3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound
110) (mp 189.degree. C., MS ES: m/z 378 (MH.sup.+)) from
[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28rr) using General Method A.
[0860] (ddddd)
3-Amino-7-(trans-3-aminomethyl-74-methylpyrrolidin-1-yl)-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound
111) (mp 220.degree. C., MS ES: m/z 362 (MH.sup.+)) from
[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28ss) using General Method A.
[0861] (eeeee)
3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro--
8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 112) (mp
209.degree. C., MS ES: m/z 364 (MH.sup.+)) from
[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]carbamic acid
tert-butyl ester (Example 28tt) using General Method A.
[0862] (fffff)
3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione hydrochloride (Compound 113) (mp
195.degree. C., MS ES: m/z 380 (MH.sup.+)) from
[4-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)morpholin-2-ylmethyl]carbamic acid tert-butyl ester
(Example 28uu) using General Method A.
[0863] (ggggg)
3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione hydrochloride (Compound 114) (mp
201.degree. C., MS ES: m/z 378 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)piperidin-3-ylmethyl]-carbamic acid tert-butyl
ester (Example 28vv) using General Method A.
[0864] (hhhhh)
3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluo-
ro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 115)
(mp 204.5.degree. C., MS ES: m/z 392 (MH.sup.+)) from
{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28ww) using General Method A.
[0865] (iiiii)
3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluo-
ro-1H-quinazoline-2,4-dione hydrochloride (Compound 116) (mp
198-200.degree. C., MS ES: m/z 430 (MH.sup.+)) from
[7-(3-tert-butoxycarbonylamino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclop-
ropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamic
acid tert-butyl ester (Example 6ww) using General Method A.
[0866] (jjjjj)
3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-meth-
yl-1H-quinazoline-2,4-dione hydrochloride (Compound 117) (mp
237-240.degree. C., MS ES: m/z 348 (MH.sup.+)) from
[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoli-
n-7-yl)-3-methylpyrrolidin-3-yl]]carbamic acid tert-butyl ester
(Example 28xx) using General Method A.
[0867] (kkkkk)
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinazoline-2-
,4-dione hydrochloride (Compound 118) (mp 178-180.degree. C., MS
ES: m/z 319 (MH.sup.+)) from
3-amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1-yl-1H-quinazoline--
2,4-dione (Example 28yy) using General Method A.
[0868] (lllll)
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-quinazoline--
2,4-dione hydrochloride (Compound 119) (mp 92-94.degree. C., MS ES:
m/z 335 (MH.sup.+)) from
3-amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1-yl-1H-quinazoline-
-2,4-dione (Example 28zz) using General Method A.
[0869] (mmmmm)
33-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin--
1-yl]-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound
120) (mp 116-120.degree. C., MS ES: m/z 377 (MH.sup.+)) from
3-amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)
pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione (Example 28aaa)
using General Method E.
[0870] (nnnnn)
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin-1-
-yl]-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound
121) (mp 134.degree. C. (decomp), MS ES: m/z 393 (MH.sup.+)) from
3-amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)
pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione (Example 28bbb)
using General Method E.
[0871] (ooooo)
3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)-
pyrrolidin-1-yl]-1H-quinazoline-2,4-dione hydrochloride (Compound
122) (mp 182-185.degree. C., MS ES: m/z 376 (MH.sup.+)) from
{(S)-1-[(R)-3-amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methy-
laminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione (Example
28ccc) using General Method E.
[0872] (ppppp) (S)-1-[(R)-1-(3-Amino-1-
cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1-yl)-6-fluoro-8-methoxy-1-
H-quinazoline-2,4-dione hydrochloride (Compound 123) (mp
185-190.degree. C., MS ES: m/z 406 (MH+)) from
(S)-1-[(R)-1-(3-amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1--
yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione (Example 28ddd)
using General Method E.
[0873] (qqqqq)
3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound
124) (mp 210-215.degree. C., MS ES: m/z 390 (MH.sup.+)) from
3-amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione (Example 28eee) using
General Method E.
[0874] (rrrrr)
3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound
125) (mp>190.degree. C., MS ES: m/z 390 (MH.sup.+)) from
3-amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione (Example 28fff) using
General Method E.
[0875] (sssss)
3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione hydrochloride (Compound 126) (mp
201.degree. C., MS ES: m/z 378 (MH.sup.+)) from
3-amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione (Example 28hhh) using General Method
E.
[0876] (ttttt)
3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1-
H-quinazoline-2,4-dione hydrochloride (Compound 127) (MS ES: m/z
350 (MH.sup.+)) from
3-amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1-
H-quinazoline-2,4-dione (Example 28ggg) using General Method E.
[0877] (uuuuu)
cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-flu-
oro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 128)
(mp 169-179.degree. C., MS ES: m/z 382 (MH.sup.+)) from
cis-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28iii) using General Method A.
[0878] (vvvvv)
trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound
129) (mp 144-147.degree. C., MS ES: m/z 382 (MH.sup.+)) from
trans-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Example 28jjj) using General Method A.
[0879] (wwwww)
3-Amino-7-(1-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-met-
hoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 130)
(mp>250.degree. C., MS APCI: m/z 376 (MH.sup.+)) from
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)- (1-amino-5-azaspiro[2.4]hept-5-yl)]carbamic acid
tert-butyl ester (Example 28kkk) using General Method A.
[0880] (xxxxx)
3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-
-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 131)
(mp>250.degree. C., MS APCI: m/z 418 (MH.sup.+)) from
1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-aminomethyloctahydroisoindol-2-yl]carbamic acid
tert-butyl ester (Example 28lll) using General Method A
[0881] (yyyyy)
3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-
-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 132)
(mp>250.degree. C., MS APCI: m/z 402 (MH.sup.+)) from
1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)-3-aminomethyloctahydroisoindol-2-yl]carbamic acid
tert-butyl ester (Example 28mmm) using General Method A
[0882] (zzzzz)
3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 133)
(mp 228-230.degree. C., MS APCI: m/z 378 (MH.sup.+)) from
{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (Example 28nnn) using General Method E
[0883] (aaaaaa)
3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8--
methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 134) (mp
180-182.degree. C., MS ES: m/z 346(MH.sup.+)) from
[3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid
tert-butyl ester (Example 28n) using General Method A.
EXAMPLE 10
Synthesis of
[7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cycl-
opropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester
[0884] ##STR217##
[0885] A solution of
{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-di-
hydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester from Example 8 (0.51 g, 0.914 mmol), triethylamine
(1.3 mL, 9.3 mmol), and benzylamine (0.50 mL, 4.6 mmol) in dimethyl
sulfoxide (7.5 mL) is heated at 100.degree. C. for 16 hours in a
sealed glass tube. The mixture is concentrated under high vacuum
and the residue purified by column chromatography (1:2 ethyl
acetate/hexanes) to afford
{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cycl-
opropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester as a solid (0.51 g). .sup.1NMR (CDCl.sub.3):
.delta. 8.50 (bs, 1H), 7.37-7.18 (m, 5H), 6.56 (bs, 1H), 4.76-4.62
(bd, 1H), 4.59-4.48 (m, 2H), 4.34-4.18 (m, 1H), 3.93-3.49 (m, 3H),
3.48-3.20 (m, 2H), 2.24-2.04 (m, 1H), 1.96-1.74 (m, 1H), 1.49 (s,
9H), 1.46 (s, 9H), 1.13-1.00 (m, 21), 0.75-0.61 (m, 2H).
EXAMPLE 11
Synthesis of
{7-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1--
cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-methylcarba-
mic acid tert-butyl ester
[0886] ##STR218##
[0887] To a solution of
{7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)-pyrrolidin-1-yl]-8-chloro-1-
-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester from Example 8 (0.238 g, 0.421 mmol) in
N,N-dimethylformamide (5 mL) at -78.degree. C. under nitrogen
atmosphere is added sodium hydride (60% dispersion in mineral oil,
0.025 g, 0.631 mmol). After 30 minutes, iodomethane (0.052 mL,
0.842 mmol) is added, and the reaction mixture is warmed to room
temperature. After 1 hour, the reaction mixture is diluted with
ethyl acetate and washed with saturated ammonium chloride solution,
water, and brine. The organic layer is dried over MgSO.sub.4,
filtered, and the filtrate concentrated. The resulting residue is
purified by flash column chromatography (1:1 ethyl acetate/hexanes)
to afford the title compound (0.118 g). .sup.1H NMR (CDCl.sub.3):
.delta. 7.63 (dd, 1H), 4.78 (bs, 1H), 3.87-3.45 (m, 6 H), 2.62-2.44
(m, 6 H), 2.31-2.12 (m, 2 H), 1.49-1.47 (m, 18 H), 1.23-1.07 (m, 2
H), 0.75-0.53 (m, 2H). MS CI: m/z 582 (MH.sup.+).
EXAMPLE 12
Synthesis of
(5-Amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropy-
l-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic
acid tert-butyl ester
[0888] ##STR219##
[0889]
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-
-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carba-
mic acid tert-butyl ester from Example 10 (0.435 g, 0.676 mmol) in
tetrahydrofuran (20 mL) is hydrogenated at room temperature and
atmospheric pressure over 20% palladium hydroxide on carbon (0.114
g) for 27 hours. The mixture is filtered through Celite, the solid
is washed with chloroform, and the combined filtrates concentrated
under vacuum. Purification by column chromatography (2:3 ethyl
acetate/hexanes) gives
{5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropy-
l-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic
acid tert-butyl ester as a solid (0.284 g). .sup.1H NMR
(CDCl.sub.3): .delta. 6.61 (bs, 1H), 5.94 (bs, 2H), 4.82-4.69 (bd,
1H), 4.40-4.21 (m, 1H), 4.00-3.59 (m, 3H), 3.55-3.41 (m, 1H),
3.35-3.21 (m, 1H), 2.32-2.08 (m, 1H), 2.01-1.80 (m, 1H), 1.50 (s,
9H), 1.46 (s, 9H), 1.17-1.01 (m, 2H), 0.77-0.63 (m, 2H).
EXAMPLE 13
Synthesis of
8-Chloro-1-cyclopropyl-6-fluoro-3-methylamino-7-[(S)-3-methylaminopyrroli-
din-1-yl]-1H-quinazoline-2,4-dione
[0890] ##STR220##
[0891] Hydrogen chloride gas is bubbled into diethyl ether (30 mL)
for 15 minutes. The resulting solution is then cooled to 0.degree.
C. and added to
{7-[(S)-3-(tert-butoxycarbonylmethylamino)pyrrolidin-1-yl]-8-chloro-1--
cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}methyl-carba-
mic acid tert-butyl ester from Example 11 (0.118 g, 0.202 mmol).
The reaction mixture is slowly warmed to room temperature. After 30
hours, the precipitate is filtered, washed with ether and hexanes,
and dried under vacuum to afford the hydrochloride salt of the
title compound as a solid (0.0632 g, mp 77-79.degree. C.). MS CI:
m/z 382 (MH.sup.+).
EXAMPLE 14
Synthesis of
(8-Chloro-4-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester
[0892] ##STR221##
[0893] To a solution of
(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic
acid tert-butyl ester (Example 6c) (1.93 g, 5.34 mmol) in
tetrahydrofuran (50 mL) is added potassium carbonate (3.69 g, 26.7
mol) and triphosgene (2.06 g, 6.95 mmol). The reaction mixture is
refluxed for 90 minutes, cooled to room temperature, and diluted
with ethyl acetate. The organic layer is washed with water and
brine, then dried over MgSO.sub.4 and filtered. The filtrate is
concentrated under vacuum and purified via flash column
chromatography (1:2 ethyl acetate/hexanes) to afford the title
compound (1.27 g). MS EI: m/z 386 (M.sup.+).
EXAMPLE 15
Synthesis of 2-Amino-4,5-difluorobenzoic acid,
2,2-dibenzylhydrazide
[0894] ##STR222##
[0895] 4,5-Difluoroanthranilic acid (4.73 g, 27.3 mmol) and
N,N-dibenzylhydrazine (8.69 g, 42 mmol) are combined in 200 mL of
methylene chloride. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDAC) (7.85 g, 41 mmol) is then added to this
solution, and the mixture is stirred for 18 hours at 25.degree. C.,
The solution is washed with saturated NaHCO.sub.3, brine, and dried
over magnesium sulfate. The solution is concentrated to give 15.8 g
of a dark oil and purified via chromatography (SiO.sub.2,
CHCl.sub.3) to give 3.4 g of the title compound as a solid. MS CI:
m/z 368 (MH.sup.+).
EXAMPLE 16
Synthesis of
3-Dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione
[0896] ##STR223##
[0897] 2-Amino-4,5-difluorobenzoic acid, 2,2-dibenzylhydrazide
(Example 15) (0.81 g, 2.2 mmol) and triphosgene (0.33 g, 1.1 mmol)
are combined in 100 mL of methylene chloride and stirred at
25.degree. C. for 20 hours. The solution is poured into 200 mL of
saturated NaHCO.sub.3, the layers are separated, and the aqueous
layer is washed three times with ethyl acetate. The combined
organic layers are dried over magnesium sulfate and then
concentrated to give 0.86 g of the title compound as a solid. MS
CI: m/z 394 (MH.sup.+).
EXAMPLE 17
Synthesis of
3-Dibenzylamino-6,7-difluoro-1-substituted-1H-quinazoline-2,4-dione
(a)
3-Dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline-2,4-di-
one
[0898] ##STR224##
[0899] A solution of
3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16)
(0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a
suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of
N,N-dimethylformamide and stirred for 30 minutes.
Bromomethylcyclopropane (0.16 mL, 1.6 mmol) is added, and the
mixture is stirred at 25.degree. C. for 18 hours. The reaction is
quenched with 1 mL of water and concentrated in vacuo. The residue
is dissolved in chloroform, washed with water, brine, and dried
over magnesium sulfate. The solution is concentrated and purified
via chromatography (SiO.sub.2, CHCl.sub.3) to give 0.33 g of the
title compound as a solid. MS CI: m/z 448 (MH.sup.+).
(b)
3-Dibenzylamino-6,7-difluoro-1-ethyl-4H-quinazoline-2,4-dione
[0900] ##STR225##
[0901] A solution of
3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16)
(0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a
suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of
N,N-dimethylformamide and stirred for 30 minutes. Ethyl iodide
(0.13 mL, 1.6 mmol) is added, and the mixture is stirred at
25.degree. C. for 18 hours. The reaction is quenched with 1 mL of
water and concentrated in vacuo. The residue is dissolved in
chloroform, washed with water, brine, and dried over magnesium
sulfate. The solution is concentrated and purified via
chromatography (SiO.sub.2, CHCl.sub.3) to give 0.34 g of the title
compound as a solid, mp 133-135.degree. C., MS CI, m/z 422
(MH.sup.+).
EXAMPLE 18
Chlorination
General Chlorination Method
[0902] To a solution of a benzoylhydrazinecarboxylic acid
tert-butyl ester (Example 7) in acetic acid (5 mL) is added
N-chlorosuccinimide (1.2 eq.). After 1 hour, the reaction mixture
is diluted with ethyl acetate and washed with saturated
NaHCO.sub.3, water, and brine. The organic layer is dried over
MgSO.sub.4 and filtered. The filtrate is concentrated under vacuum
and purified via flash column chromatography (ethyl
acetate/hexanes) to afford the corresponding
chlorobenzoylhydrazinecarboxylic acid tert-butyl ester.
[0903] The following compounds are synthesized according to the
General Chlorination Method above:
[0904] (a)
N'-{4-[3-(tert-Butoxyearbonylaminomethyl)pyrrolidin-1-yl]-3-chloro-2-cycl-
opropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl
ester (MS CI: m/z 542 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylam-
ino-5-fluorobenzoyl}-hydrazinecarboxylic acid tert-butyl ester
(Example 7a).
[0905] (b)
N'-4-[4-(tert-Butoxycarbonylpiperazin-1-yl)-3-chloro-2-cyclopropylamino-5-
-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl ester (MS CI:
m/z 528 (MH.sup.+)) from
N'-4-[4-(tert-butoxycarbonylpiperazin-1-yl)-2-cyclopropylamino-5-fluorobe-
nzoyl]hydrazinecarboxylic acid tert-butyl ester (Example 7b).
[0906] (c)
N'-{4-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-3-chlo-
ro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/z 556 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-2-cycl-
opropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl
ester (Example 7c).
[0907] (d)
N'-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-3-chloro-2-
-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/z 540 (MH.sup.+)) from
N'-[4-(6-tert-butoxycarbonylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-2-cyclopr-
opylamino-5-fluorobenzoyl]-hydrazinecarboxylic acid tert-butyl
ester (Example 7d).
[0908] (e)
N'-{4-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-3-chloro-
-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/z 542 (MH.sup.+)) from
N'-{4-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-2-cyclop-
ropylamino-5-fluorobenzoyl}-hydrazinecarboxylic acid tert-butyl
ester (Example 7e).
[0909] (f)
N'-{4-[(S)-3-(tert-Butoxycarbonyl-N-amino)pyrrolidin-1-yl]-3-chloro-2-(2,-
4-difluoroanilino)-5-fluorobenzoyl}hydrazinecarboxylic acid
tert-butyl ester (CDCl.sub.3): .delta. 9.70 (bs, 1H), 7.76 (d, 1H),
6.93-6.82 (m, 1H), 6.70-6.62 (m, 2H), 6.48-6.34 (m, 2H), 4.91-4.87
(bs, 1H), 4.29-4.20 (m, 1H), 3.78-3.60 (m, 2H), 3.50-3.28 (m, 2H),
2.33-2.20 (m, 1H), 1.94-1.66 (m, 1H), 1.44 (s, 9H), 1.42 (s, 9H),
(MS CI: m/z 601 (MH.sup.+)) from
N'-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(2,4-difluoroan-
ilino)-5-fluorobenzoyl}-hydrazinecarboxylic acid tert-butyl ester
(Example 7f).
[0910] (g)
N'-[4-((S)-7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-3-chloro--
2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylic acid
tert-butyl ester (MS CI: 554 (MH.sup.+)) from
N'-[(S)-4-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-2-cyclop-
ropylamino-5-fluorobenzoyl]hydrazinecarboxylic acid tert-butyl
ester (Example 7k).
[0911] (h)
N'-[4-(Pyrrolidin-1-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydra-
zinecarboxylic tert-butyl ester (MS CI: m/z 413 (MH.sup.+)) from
N'-[4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarbo-
xylic tert-butyl ester (Example 7m).
[0912] (i)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl)-3-chloro-5-fluoro-2-i-
sopropylaminobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS:
m/z 530 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropyla-
minobenzoyl}hydrazine carboxylic acid tert-butyl ester (Example
7n).
[0913] (j)
N'-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-3-c-
hloro-5-fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS
EI: m/e 542 (MH.sup.+)) from
N'-{4-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-2-cyclobutylamino-5--
fluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (Example
7q).
[0914] (k)
N'-(1-{4-[3-(tert-Butoxycarbonylamino-methyl)piperidin-1-yl]-3-chloro-2-c-
yclopropylamino-5-fluorophenyl}methanoyl)hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/e 556 (MH.sup.+)) from
N'-(1-{4-[3-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]-2-cyclopropyl-
amino-5-fluoro-phenylmethanoyl)hydrazinecarboxylic acid tert-butyl
ester (Example 7z).
[0915] (l)
N'-[1-(4-{3-[(tert-Butoxycarbonylisopropylamino)methyl]-pyrrolidin-1-yl}--
3-chloro-2-cyclopropylamino-5-fluorophenyl)methanoyl]-hydrazine-carboxylic
acid tert-butyl ester (MS CI: m/e 584 (MH.sup.+)) from
N'-[1-(4-{3-[(tert-butoxycarbonylisopropylamino)methyl]pyrrolidin-1-yl}-2-
-cyclopropylamino-5-fluorophenyl)methanoyl]hydrazinecarboxylic acid
tert-butyl ester (Example 7aa).
[0916] (m)
N'-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-3,5-dichloro-
-2-cyclopropylaminophenyl}methanoyl)hydrazinecarboxylic acid
tert-butyl ester (MS CI: m/e 558 (MH.sup.+)) from
N'-(1-{4-[3-(tert-butoxyearbonylamino-methyl)pyrrolidin-1-yl]-5-chloro-2--
cyclopropylaminophenyl}methanoyl)-hydrazinecarboxylic acid
tert-butyl ester (Example 7bb).
EXAMPLE 19
Chlorination of Substituted Benzoic Acids
(a) Synthesis of 3-Chloro-4,5-difluoroanthranilic acid
[0917] ##STR226##
[0918] To a solution of 4,5-difluoroanthranilic acid (2.45 g, 14.2
mmol) in dichloromethane (25 mL) is added acetic acid (10 mL) and
hypochlorous acid tert-butyl ester (1.75 mL, 15.6 mmol). After 2
hours, the reaction mixture is diluted with ethyl acetate and
washed with water and brine. The organic layer is dried over
MgSO.sub.4, filtered, and concentrated. The resulting residue is
purified via flash column chromatography (5% isopropyl alcohol/1%
formic acid/94% dichloromethane) to afford
3-chloro-4,5-difluoroanthranilic acid as an oil (2.97 g). MS CI:
m/z 206 (M.sup.+).
(b) 5-Chloro-4-fluoroanthranilic acid
[0919] ##STR227##
[0920] To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69
mmol) in methylene chloride (50 mL) and acetic acid (10 mL) is
added tert-butyl hypochlorite (0.71 mL, 6.25 mmol) solution in
dichloromethane (1 mL) dropwise over 1 minute. After 90 minutes,
the reaction mixture is washed with water and brine. The organic
layer is dried over MgSO.sub.4, filtered, and the filtrate
concentrated to afford 5-chloro-4-fluoroanthranilic acid (1.20 g).
MS CI: m/e 188 (M.sup.+).
EXAMPLE 20
Synthesis of 2-Bromo-3-chloro-4,5-difluorobenzoic acid
[0921] ##STR228##
[0922] A solution of cuprous bromide (10.96 g, 49.2 mmol)) in
acetonitrile (100 mL) is cooled to 0.degree. C. and then tert-butyl
nitrite (7.31 mL, 61.5 mmol) and 3-chloro-4,5-difluoroanthranilic
acid (Example 19) (8.51 g, 41.0 mmol) are added. The mixture is
slowly warmed to room temperature, and after 20 hours, the solvent
is removed under vacuum. The resulting residue is dissolved in
ethyl acetate and washed with 1.0 M hydrochloric acid, water, and
brine. The organic layer is dried over MgSO.sub.4 and filtered. The
filtrate is concentrated under vacuum and purified via flash column
chromatography (5% isopropyl alcohol/1% formic acid/94%
dichloromethane) to afford 2-bromo-3-chloro-4,5-difluorobenzoic
acid as a solid (7.96 g). MS CI: m/z 271 (MH.sup.+).
EXAMPLE 21
Synthesis of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic
acid ethyl ester
[0923] ##STR229##
[0924] To a solution of
4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic
acid ethyl ester (Example 2h) (3.50 g, 9.50 mmol) in
dichloromethane (80 mL) is added acetic acid (8 mL) and tert-butyl
hypochlorite (1.75 mL, 15.6 mmol). After 20 minutes, the reaction
mixture is diluted with ethyl acetate and washed with water and
brine. The organic layer is dried over sodium sulfate, filtered,
and the filtrate concentrated. The resulting residue is purified by
column chromatography (1:4 ethyl acetate/hexanes) to afford the
title compound (3.75 g) as an oil. .sup.1H NMR (CDCl.sub.3):
.delta. 7.69 (dd, 1H), 4.85-4.76 (bd, 1H), 4.50-4.20 (m, 3H),
3.90-3.74 (m, 2H), 3.62-3.36 (m, 2H), 2.40-2.20 (m, 1H), 1.91-1.84
(m, 1H), 1.45 (s, 9H), 1.40 (s, 9H).
EXAMPLE 22
Synthesis of 2-cyclopropylamino-4,5-difluorobenzoic acid methyl
ester
[0925] ##STR230##
[0926] To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid
(Example 5a) (6.0 g, 28.1 mmol), dichloromethane (100 mL), and
methanol (20 mL) is added (trimethylsilyl)diazomethane (2.9 M
solution in hexane) dropwise until the evolution of gas stops. The
solution is stirred at room temperature for 0.5 hour and 88% formic
acid is added dropwise until the evolution of gas again stops.
Water is added, and the solution is extracted with dichloromethane,
dried over MgSO.sub.4, filtered, and the solvent removed under
reduced pressure. The residue is purified by silica gel column
chromatography using hexane/EtOAc (9:1) as the eluent to afford a
5.4 g of the title compound as a clear oil. MS CI: m/z 228
(MH.sup.+).
EXAMPLE 23
(a) Synthesis of
1-Cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione
[0927] ##STR231##
[0928] To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid
ethyl ester (Example 22) (5.0 g, 22.0 mmol ) in dry dichloromethane
(120 mL) under a N.sub.2 atmosphere is added chlorosulfanyl
isocyanate (3.11 g, 22 mmol). The solution is reacted at room
temperature for 4 hours, and the solvent is removed under reduced
pressure. The residue is cooled to -20.degree. C., and a cold brine
solution (100 mL) buffered with NaHCO.sub.3 is added. The solution
is warmed to room temperature for 1 hour. The volume is reduced by
half with a stream of air, and the solid is collected by
filtration. The dry solid is added to a solution of triethylamine
(5 mL) in THF (250 mL),and refluxed overnight. The reaction is
cooled, the solvent removed under reduced pressure, dissolved in
water (100 mL), and acidified to pH 1-2 with 1.0 M hydrochloric
acid. The resulting precipitate is collected via filtration to
afford 2.0 g of the title compound. MS CI: m/z 239 (MH.sup.+).
(b)
1-Cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
[0929] ##STR232##
[0930] A solution of
1-cyclopropyl-3-(3-methoxy-2,4,5-trifluorobenzoyl)urea (Example
27b, 0.94 g, 3.26 mmol) in tetrahydrofuran (20 mL) and
N,N-dimethylformamide (5 mL) is treated with sodium hydride (0.275
g, 6.8 mmol, 60% in mineral oil dispersion) and heated at reflux
for 16 hours. The mixture is cooled, treated with saturated
NH.sub.4Cl and extracted with dichloromethane. The organic layer is
then washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash column chromatography
(1:3 ethyl acetate/hexanes) afforded the title compound. MS (EI,
M+1) m/z 269.
(c) Synthesis of
8,9-Difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione
[0931] ##STR233##
[0932] A solution of 1.5 g (6.2 mmol) of
7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic
acid methyl ester (Example 32a) in 25 mL of dichloromethane is
cooled to -20.degree. C. and treated dropwise with 0.92 g (6.5
mmol) of chlorosulfonyl isocyanate. The reaction is stirred at room
temperature for 18 hours and the solvent removed in vacuo. The
residue is treated with a saturated sodium bicarbonate solution and
extracted with dichloromethane. The organic layer is dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The residue is
dissolved in 50 mL of tetrahydrofuran, and the resulting solution
is treated with 5.0 g (5.0 mmol) of triethylamine. After heating at
reflux for 4 hours, the solvent is removed in vacuo, and the
residue is triturated with 5 mL of dichloromethane/ethyl acetate
(80:20). The insoluble material is removed by filtration, washed
with the above solvent mixture (2 mL) to give 0.25 g of the title
compound, mp 259-261.degree. C. The filtrate is chromatographed
over flash grade silica gel (230-400 mesh) eluting with
dichloromethane/ethyl acetate (80:20) to give 0.38 g of starting
material. Continued elution afforded an additional 0.2 g of the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): 11.78 (s, 1H),
7.50 (m, 1H), 4.68 (m, 1H), 4.52 (d, 1H), 4.17 (d, 1H), 1.23 (d,
3H).
(d) Synthesis of
8,9-Difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dion-
e
[0933] ##STR234##
[0934] A solution of 1.07 g (4.4 mmol) of
5,6-difluoro-2-methyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic
acid methyl ester (Example 32) in 25 mL of dichloromethane is
cooled to -20.degree. C. and treated dropwise with 0.85 g (6.0
mmol) of chlorosulfonyl isocyanate. The reaction is stirred at
-20.degree. C. for 1 hour, treated with 1.0 g (12 mmol) of solid
sodium acetate, and the solvent is removed in vacuo. The residue is
cooled in an ice bath and triturated with a saturated solution of
sodium acetate in brine. The precipitate is removed by filtration,
washed with the sodium acetate solution and dried in vacuo. The
dried precipitate is washed with ether to remove starting material
and dried in vacuo. The dried solid is suspended in 40 mL of dry
tetrahydrofuran, cooled to 5.degree. C. and treated portionwise
with 1.2 g (12 mmol) of sodium tert-butoxide. After the addition is
complete, the reaction mixture is stirred at 5.degree. C. for 30
minutes, the bath is removed, and the reaction is stirred to room
temperature over 1 hour. The solvent is removed in vacuo; the
residue is dissolved in water, cooled to 5.degree. C. and acidified
with formic acid. The resulting precipitate is removed by
filtration, washed with water and dried in vacuo affording 0.8 g of
the title compound, mp 212-214.degree. C.
(e)
1-Cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-
-dione
[0935] ##STR235##
[0936] A solution of 4.1 g (15.2 mmol) of ethyl
2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34)
in 125 mL of dichloromethane is cooled to -20.degree. C. and
treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl
isocyanate. The reaction is stirred at -20.degree. C. for 3 hours
and allowed to come to room temperature overnight. The mixture is
recooled to -20.degree. C. and treated with 6.8 g (80 mmol) of
solid sodium acetate. After stirring for 1 hour without cooling,
the solvent is removed in vacuo without heating. The residue is
triturated with a saturated solution of sodium acetate in brine and
extracted with ethyl acetate (3.times.75 mL). The combined organic
layers are dried (MgSO.sub.4), filtered and evaporated in vacuo.
The residue is suspended in 100 mL of tetrahydrofuran and treated
with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at
room temperature for 36 hours. The solvent is removed in vacuo, the
residue triturated with 100 mL of 0.1 M formic acid and extracted
with ethyl acetate (3.times.100 mL). The combined organic layers
are washed with water, dried (MgSO.sub.4), filtered and evaporated
in vacuo to give a residue which is chromatographed over flash
grade silica gel (230-400 mesh) eluting with dichloromethane to
give 0.75 g of the title compound, mp 220-222.degree. C.
General Procedure A
[0937] Sodium hydride (3 eq., 60% mineral oil dispersion) is added
portionwise to a solution of 1-cyclopropyl-3-benzoylurea (Example
27) in 20:1 tetrahydrofuran/N,N-dimethylformamide at -25.degree. C.
The mixture is stirred at room temperature for 30 minutes, then
refluxed overnight. It is poured into ice water, and the solution
is acidified with 10% hydrochloric acid and extracted with ethyl
acetate. The extract is washed with brine, dried, and concentrated.
The residue is purified by silica gel column chromatography (ethyl
acetate/hexanes) to afford 8-substituted
1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-diones.
[0938] The following compounds are synthesized according to General
Procedure A of Example 23:
[0939] (e)
1-Cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.61 (bs, 1H), 7.83
(dd, 1H), 3.37-3.35 (m, 1H), 2.60 (dd, 3H), 1.31-1.12 (m, 2H),
0.71-0.63 (m, 2H) from
1-cyclopropyl-3-(2,4,5-trifluoro-3-methylbenzoyl)urea (Example
27c).
[0940] (f)
1-Cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.37 (bs, 1H), 7.96
(dd, 1H), 2.81-2.74 (m, 1H), 2.61 (d, 3H), 1.26-1.14 (m, 2H),
0.81-0.73 (m, 2H)) from
1-cyclopropyl-3-(3,4,6-trifluoro-2-methylbenzoyl)urea (Example
27d).
[0941] (g)
1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 9.41 (bs, 1H),
7.86-7.77 (m, 1H), 3.40-3.20 (m, 3H), 1.30-1.10 (m, 5H), 0.75-0.67
(m, 2H)) from 1-cyclopropyl-3-(3-ethyl-2,4,5-trifluorobenzoylurea
(Example 27e).
[0942] (i)
7-Chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione
(mp 214-216.degree. C.) from
1-cyclopropyl-3-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)urea
(Example 27a).
EXAMPLE 24
(a) Synthesis of
3-Amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione
[0943] ##STR236##
[0944] To a solution of
1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23a,
2.0 g, 8.92 mmol) in dioxane (7.5 mL) and dimethylformamide (7.5
mL) is added NaH (60% dispersion in oil, 428 mg, 10.7 mmol). The
solution is heated to 60.degree. C. for 10 minutes and cooled to
room temperature. To the cooled solution is added
O-(2,4-dinitrophenyl)hydroxylamine (1.77 g, 8.92 mmol), and the
solution is heated to 80.degree. C. for 30 minutes. The resulting
red solution is cooled to room temperature, poured over crushed
ice, and extracted with EtOAc. The combined organic layers are
dried over MgSO.sub.4, filtered, and the solvent removed under
reduced pressure. The resulting solid is triturated with Et.sub.2O
and air dried to afford 1.44 g of the title compound. MS CI: m/z
254 (MH.sup.+).
(b)
3-Amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-
-dione
[0945] ##STR237##
[0946] A solution of 3.83 g (15 mmol) of
7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione
(Example 23i) in 50 mL of dimethylformamide-dioxane (1:1) is cooled
to 0.degree. C. and treated portionwise with 0.8 g (20 mmol) of 60%
sodium hydride/mineral oil. The reaction is stirred to room
temperature for 30 minutes, re-cooled to 0.degree. C. and 3.2 g (16
mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After
stirring at room temperature overnight, the dioxane is removed in
vacuo and the residue is diluted to 300 mL with ice and water and
stirred at 5.degree. C. for 1 hour. The precipitate is removed by
filtration, washed with water, ether and dried in vacuo to give
2.65 g of the title compound, mp 192-194.degree. C. A second crop,
(0.6 g) could be isolated by evaporating the filtrate and
triturating the residue with petroleum ether.
(c)
3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-
-d]pyrimidine-7-thiosulfonic acid
[0947] ##STR238##
[0948] A solution of 0.47 g (1.57 mmol) of
1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidi-
ne-7-thiosulfonic acid (Example 35) in 20 mL of
dimethylformamide/dioxane (1:1) is treated portionwise with 0.08 g
(2.0 mmol) of 60% sodium hydride/mineral oil. The reaction is
stirred at room temperature for 1 hour and 0.32 g (1.6 mmol) of
2,4-dinitrophenylhydroxylamine is added all at once. After stirring
at room temperature overnight, the dioxane is removed in vacuo and
the residue is diluted to 100 mL with ice and water and stirred at
5.degree. C. for 1 hour. The aqueous solution is extracted with
ethyl acetate (3.times.50 mL) with the combined organic layers
being washed with water, dried (MgSO.sub.4), filtered and
evaporated in vacuo to give 0.4 g of the title compound, mp
167-169.degree. C.
General Procedure A (Example 24)
[0949] To a solution of a
1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23) in
1:1 dry tetrahydrofuran or dioxane and dry N,N-dimethylformamide is
added portionwise sodium hydride (1.1 eq., 60% mineral oil
dispersion) at room temperature. After stirring at 50.degree. C.
for 20 to 30 minutes, the resulting solution is cooled to room
temperature and 2,4-dinitrophenylhydroxylamine (4 eq.) is added.
The mixture is heated at 60.degree. C. to 80.degree. C. for 30
minutes, cooled, and the dioxane removed reduced pressure. The
residue is poured into ice water and extracted with ethyl acetate.
The organic layers are combined, washed with brine, dried with
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue is
purified by flash column chromatography (ethyl acetate/hexanes) to
afford a
3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione.
[0950] The compounds are synthesized according to General Procedure
A of Example 24:
[0951] (d)
3-Amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(MS El: m/z 284 (MH.sup.+)) from
1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 23b).
[0952] (e)
3-Amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.86 (dd, 1H), 5.20
(bs, 2H), 3.48-3.38 (m, 1H), 2.61 (dd, 3H), 1.29-1.17 (m, 2H),
0.73-0.62 (m, 2H)) from
1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 23e).
[0953] (f)
3-Amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.45 (dd, 1H), 5.28
(bs, 2H), 2.94-2.83 (m, 1H), 2.77 (d, 3H), 1.41-1.31 (m, 2H),
0.98-0.93 (m, 2H)) from
1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(Example 23f).
[0954] (g)
3-Amino-1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.84-7.75 (t, 1H), 5.37
(bs, 2H), 3.50-3.40 (m, 1H), 3.37-3.21 (m, 2H), 1.29-1.15 (m, 5H),
0.75-0.66 (m, 2H)) from
1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione
(Example 23 g).
[0955] (h)
5-Amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diaza-phenalene-4,6--
dione (mp 171-173.degree. C.) from
8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diaza-phenalene-4,6-dione
(Example 23c).
[0956] (i)
2-Amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline--
1,3-dione, mp 140-142.degree. C., .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.90 (m, 1H), 5.30 (bs, 2H), 5.07 (m, 1H), 3.08 (m,
1H), 2.85 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.31 (d, 3H)) from
8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dion-
e (Example 23d).
EXAMPLE 25
Synthesis of
{3-Amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropy-
l-6-fluoro-1H-quinazoline-2,4-dione
[0957] ##STR239##
[0958] To a solution of
3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione
(Example 24a) (50.0 mg, 0.20 mmol) and triethylamine (74 mg, 0.74
mmol) in acetonitrile (3 mL) is added (S)-pyrrolidin-3-yl carbamic
acid tert-butyl ester (74 mg, 0.40 mmol). The solution is refluxed
for 18 hours, the solvent is removed under reduced pressure, and
the residue triturated with water. The solid is collected by
filtration and air dried to afford 74 mg of the title compound. MS
CI: m/z 420 (MH.sup.+).
EXAMPLE 26
Synthesis of Benzamides
General Procedure A
[0959] A solution of an appropriately substituted benzoic acid,
oxalyl chloride (1.5 eq.), and dichloromethane is treated with
N,N-dimethylformamide (2 drops), the solution is stirred at room
temperature for 2 hours. The mixture is concentrated under reduced
pressure, and the residue is dissolved in dry THF and slowly added
to a solution of ammonia in diethyl ether at -70.degree. C. The
mixture is then allowed to warm to ambient temperature and stirred
for 30 minutes. The mixture is then filtered and the resulting
solid dissolved in ethyl acetate, washed with water, and dried over
Na.sub.2SO.sub.4. The solvent is then concentrated in vacuo to
provide the desired amide.
[0960] The following compounds are synthesized according to the
General Procedure A method above:
[0961] (a) 3,4,6-Trifluoro-2-methylbenzamide. (.sup.1H NMR (200
MHz, CDCl.sub.3): .delta. 6.89-6.77 (m, 1H), 6.41 (bs, 1H), 5.95
(bs, 1H), 2.39 (d, 3H)) from 3,4,6-trifluorobenzoic acid (Hagen S.
et al., Heterocycl. Chem., 1990;27[6]:1609-1616).
[0962] (b) 3-Ethyl-2,4,5-trifluorobenzamide, (.sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.78-7.60 (m, 1H), 6.61 (bs, 2H), 2.67 (q,
2H), 1.15 (t, 3H)) from 3-ethyl-2,4,5-trifluorobenzoic acid
(Takemura, PCT Int. Appl., 1996, WO 9623782).
EXAMPLE 27
Synthesis of 1-cyclopropyl-3-benzoyl substituted ureas
[0963] (a)
1-Cyclopropyl-3-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)urea
##STR240##
[0964] A solution of 5.8 g (27.8 mmol) of
2,6-dichloro-5-fluoronicotinamide (Chem. Pharm. Bull.,
1987;35:2280) in 60 mL of dichloromethane is treated dropwise with
5.1 g (40 mmol) of oxalyl chloride, and the reaction mixture is
heated at reflux for 18 hours. The solvent is removed in vacuo, and
the residue is dissolved in 50 mL of dichloromethane, which is also
removed in vacuo. The residue is dissolved in 50 mL of
dichloromethane, cooled to -20.degree. C. and treated dropwise with
2.28 g (40 mmol) of cyclopropylamine. The reaction mixture is
stirred at -20.degree. to -10.degree. C. for 1/2 hour, then allowed
to come to room temperature over 2 hours. The solvent is removed in
vacuo and the residue is triturated with 25 mL of dichloromethane,
which is also removed in vacuo to give 8.0 g of the title compound,
mp 171-173.degree. C.
General Procedure A
[0965] To a solution of substituted benzamide (Example 26) in
1,2-dichloroethane is added oxalyl chloride (1.5 eq.) and the
mixture refluxed for 16 hours. The solvent is then removed under
reduced pressure to obtain a crude isocyanate. The isocyanate is
then taken up into dioxane, cooled to 0.degree. C. and treated with
cyclopropylamine (1.5 eq.) in dioxane. The mixture is then warmed
to ambient temperature and stirred for 3 hours. The mixture is then
concentrated under reduced pressure, dissolved in ethyl acetate,
washed with water, dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure. The resulting residue is then purified by flash
column chromatography (ethyl acetate/hexanes) to afford the
1-cyclopropyl-3-benzoyl urea.
[0966] The following compounds are synthesized according to the
General Procedure A method above:
[0967] (b) 1-Cyclopropyl-3-(2,4,5-trifluoro-3-methoxy-benzoyl)urea
(MS ES (MH.sup.+): m/z 289) from 2,4,5-trifluoro-3-methoxybenzamide
(Masuzawa K., Suzue S., Hirai K., Ishizaki T., Eur. Pat. Appl.,
1987, EP 230295).
[0968] (c) 1-Cyclopropyl-3-(2,4,5-trifluoro-3-methylbenzoyl)urea
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.69 (d, 1H), 8.48 (bs,
1H), 7.75-7.62 (m, 1H), 2.83-2.71 (m, 1H), 2.30 (dd, 3H), 0.87-0.78
(m, 2H), 0.67-0.59 (m, 2H)) from 2,4,5-trifluoro-3-methylbenzamide
(Masuzawa K., Suzue S., Hirai K., Ishizaki T., Eur. Pat. Appl.,
1987, EP 237955).
[0969] (d) 1-Cyclopropyl-3-(3,4,6-trifluoro-2-methylbenzoyl)urea
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.99 (bs, 1H), 8.37
(bs, 1H), 6.93-6.80 (m, 1H), 2.74-2.65 (m, 1H), 2.35 (d, 3H),
0.84-0.71 (m, 2H), 0.66-0.58 (m, 2H)) from
3,4,6-trifluoro-2-methylbenzamide (Example 26a).
[0970] (e) 1-Cyclopropyl-3-(3-ethyl-2,4,5-trifluorobenzoyl)urea
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.76-8.69 (bd, 1H),
8.50 (bs, 1H), 7.76-7.63 (m, 1H), 2.84-2.72 (m, 3H), 1.27-1.20 (m,
3H), 0.91-0.81 (m, 2H), 0.71-0.61 (m, 2H)) from
3-ethyl-2,4,5-trifluorobenzamide (Example 26b).
EXAMPLE 28
(a) Synthesis of
{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl{-carbamic acid
tert-butyl ester
[0971] ##STR241##
[0972] A solution of 0.57 g (2.0 mmol) of
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d), 0.64 g (3.0 mmol) of
((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J.
Het. Chem., 1992;29:1481), 0.81 g (8.0 mmol) of triethylamine and
10 mL of dimethyl sulfoxide is heated at 110.degree. C. for 4
hours. The reaction mixture is cooled to room temperature, poured
into 150 mL of ice and water, and extracted with ethyl acetate
(2.times.125 mL). The combined organic layers are washed with
water, dried (MgSO.sub.4), filtered and evaporated in vacuo to give
1.1 g of crude product. Chromatography on flash grade silica gel
(230-400 mesh) eluting with dichloromethane/ethanol (9:1) provided
0.92 g of the title compound, mp 96-98.degree. C.
(b) Synthesis of
{(S)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl-pyrrolidin-3-yl]ethyl)-carbamic acid
tert-butyl ester
[0973] ##STR242##
[0974] A solution of 0.57 g (2.0 mmol) of
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d), 0.64 g (3.0 mmol) of
((S)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J.
Het. Chem., 1992;29:1481), 0.81 g (8.0 mmol) of triethylamine, and
10 mL of dimethyl sulfoxide is heated at 110.degree. C. for 4
hours. The reaction mixture is cooled to room temperature, poured
into 150 mL of ice and water and extracted with ethyl acetate
(2.times.125 mL). The combined organic layers are washed with
water, dried (MgSO.sub.4), filtered and evaporated in vacuo to give
1.08 g of crude product. Chromatography on flash grade silica gel
(230-400 mesh) eluting with dichloromethane/ethanol (9:1) provided
0.9 g of the title compound, mp 87-89.degree. C.
(c) Synthesis of
{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-carbamic acid
tert-butyl ester
[0975] ##STR243##
[0976] A solution of 0.5 g (1.9 mmol) of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e), 0.64 g (3.0 mmol) of
((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester,
0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide
is heated at 110.degree. C. for 24 hours. After thin layer
chromatography showed incomplete reaction, an additional 0.43 g
(2.0 mmol) of pyrrolidine derivative and 0.81 g (8.0 mmol) of
triethylamine are added and the reaction is heated at 120.degree.
C. for 18 hours. The reaction mixture is cooled to room
temperature, poured into 200 mL of ice and water and extracted with
ethyl acetate (2.times.125 mL). The combined organic layers are
washed with water, dried (MgSO.sub.4), filtered and evaporated in
vacuo to give 1.1 g of crude product. Chromatography on flash grade
silica gel (230-400 mesh) eluting with ethyl acetate provided 0.4 g
of the title compound, mp 86-88.degree. C.
(d) Synthesis of
{(S)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic acid
tert-butyl ester
[0977] ##STR244##
[0978] A solution of 0.5 g (1.9 mmol) of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e), 0.64 g (3.0 mmol) of
((S)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester,
0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide
is heated at 110.degree. C. for 24 hours. After thin layer
chromatography showed incomplete reaction, an additional 0.43 g
(2.0 mmol) of pyrrolidine derivative and 0.81 g (8.0 mmol) of
triethylamine are added and the reaction is heated at 120.degree.
C. for 18 hours. The reaction mixture is cooled to room
temperature, poured into 200 mL of ice and water and extracted with
ethyl acetate (2.times.125 mL). The combined organic layers are
washed with water, dried (MgSO.sub.4), filtered and evaporated in
vacuo to give 1.3 g of crude product. Chromatography on flash grade
silica gel (230-400 mesh) eluting with 400 mL of
dichloromethane/ethyl acetate (8:2), 600 mL of (6:4) and 1 L of
(4:6) provided 0.46 g of the title compound, mp 84-86.degree.
C.
(e) Synthesis of
[(S)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3-
a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamic acid tert-butyl
ester
[0979] ##STR245##
[0980] A solution of 0.2 g (0.75 mmol) of
5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-d-
ione (Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic
acid tert-butyl ester (J. Med. Chem., 1992;35:1764), 0.5 g (0.5
mmol) of triethylamine and 20 mL of acetonitrile is heated at
reflux for 18 hours. The solvent is removed in vacuo and the
residue is partitioned between dichloromethane-water. The organic
layer is washed with water, dried (MgSO.sub.4) and concentrated in
vacuo. The residue is chromatographed over flash grade silica gel
(230-400 mesh) eluting with dichloromethane/ethanol (95:5) to give
0.34 g of the title compound, mp 114-116.degree. C.
(f)
{(S)-1-[(R)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro--
4H-1-oxa-3a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]ethyl}carbamic
acid tert-butyl ester
[0981] ##STR246##
[0982] A solution of 0.11 g (0.41 mmol) of
5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-d-
ione (Example 24h), 0.26 g (1.3 mmol) of
((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J.
Het. Chem., 1992;29:1481), 0.25 g (2.5 mmol) of triethylamine and
10 mL of acetonitrile is heated at reflux for 18 hours. The solvent
is removed in vacuo and the residue is partitioned between ethyl
acetate/water. The organic layer is washed with water, dried
(MgSO.sub.4) and concentrated in vacuo. The residue is
chromatographed over flash grade silica gel (230-400 mesh) eluting
with dichloromethane/ethanol (95:5) to give 0.14 g of the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.43 (d, 1H), 5.24
(bs, 2H), 4.82 (m, 1H), 4.56 (m, 1H), 4.33 (d, 1H), 3.99 (m, 1H),
3.86 (m, 1H), 3.73 (m, 1H), 3.59 (m, 2H), 2.18 (m, 1H), 3.01 (m,
1H), 1.67 (m, 1H), 1.44 (s, 9H), 1.40 (m, 3H), 1.25 (m, 1H), 1.20
(d, 3H).
(g)
[(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-p-
yrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamic acid
tert-butyl ester
[0983] ##STR247##
[0984] A solution of 0.12 g (0.45 mmol) of
5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline--
1,3-dione (Example 24i), 0.34 g (1.8 mmol) of
(S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem.,
1992;35:1764), 0.2 g (2.0 mmol) of triethylamine and 7 mL of
dimethyl sulfoxide is heated at 110.degree. C. for 18 hours. The
reaction is cooled to room temperature, diluted with 80 mL of ice
and water and stirred at 5.degree. C. for 1 hour. The resulting
precipitate is removed by filtration, washed with water and dried
in vacuo. The solid is chromatographed over flash grade silica gel
(230-400 mesh) eluting with dichloromethane/ethanol (9:1) to give
0.14 g of the title compound, mp 98-100.degree. C.
(h)
{(R)-3-[(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro--
1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-y}ethylcarbamic
acid tert-butyl ester
[0985] ##STR248##
[0986] A solution of 0.12 g (0.45 mmol) of
5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline--
1,3-dione (Example 24i), 0.39 g (1.8 mmol) of
((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J.
Het. Chem., 1992;29:1481), in 5 mL of dimethyl sulfoxide is heated
at 110.degree. C. for 18 hours. The reaction is cooled to room
temperature, diluted with 80 mL of ice and water and stirred at
5.degree. C. for 1 hour. The resulting precipitate is removed by
filtration, washed with water and dried in vacuo. The solid is
chromatographed over flash grade silica gel (230-400 mesh) eluting
with dichloromethane/ethanol (9:1) to give 0.13 g of the title
compound, mp 93-95.degree. C.
(i)
[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[-
2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl
ester
[0987] ##STR249##
[0988] A solution of 0.11 g (0.4 mmol) of
3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 24b), 0.105 g (0.56 mmol) of
(S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem.,
1992;35:1764), 1.2 mL of N,N-diisopropylethylamine and 3 mL of
acetonitrile is heated at 50.degree. C. for 18 hours. The reaction
mixture is diluted with 9 mL of water, cooled to 0.degree. C. and
the solid is removed by filtration, washed with 50% aqueous
acetonitrile and dried in vacuo to give 0.14 g of the title
compound, mp 108-110.degree. C.
(j)
{(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrah-
ydropyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic
acid tert-butyl ester
[0989] ##STR250##
[0990] A solution of 0.12 g (0.38 mmol) of
3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]-
pyrimidine-7-thiosulfonic acid (Compound 24c) in 10 mL of
acetonitrile is treated with 0.24 g (1.14 mmol) of
((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J.
Het. Chem., 1992;29:1481), 0.25 g (2.5 mmol) of triethylamine and
stirred at room temperature for 18 hours then 50.degree. C. for 1
hour. The solvent is removed in vacuo and the residue is
partitioned between ethyl acetate (50 mL) and water (25 mL). The
organic layer is washed with water, dried (MgSO.sub.4), filtered
and evaporated in vacuo to give 0.28 g. Chromatography on flash
grade silica gel (230-400 mesh) column (2.times.12 cm) eluting with
dichloromethane/ethanol (95:5) provided 0.1 g of the title
compound, mp 175-177.degree. C.
General Procedure A
[0991] A solution of Example 24, 1-2.5 eq of heterocyclic amine
side chain, and 3-3.5 eq. 1,8-diazabicyclo-5,4,0-undecen-7-ene
(DBU) or triethylamine are stirred in dimethyl sulfoxide (1 mL) at
130.degree. C. for 3 to 48 hours. After cooling to room
temperature, the reaction mixture is diluted with ethyl acetate and
washed with saturated NaHCO.sub.3, water, and brine. The organic
layer is dried over MgSO.sub.4, filtered, and the filtrate
concentrated. The resulting residue is purified via flash column
chromatography (isopropanol/dichloromethane) to afford the
product.
General Procedure B
[0992] A solution of Example 24 and heterocyclic diamine side chain
(1.5-3.0 eq.) is stirred in dimethyl sulfoxide at 130.degree. C.
for 3 hours. After cooling to room temperature the reaction mixture
is diluted with ethyl acetate and washed with saturated
NaHCO.sub.3, water, and brine. The organic layer is; dried over
MgSO.sub.4, filtered, and the filtrate concentrated. The resulting
residue is redissolved in dichloromethane and while stirring,
di-tert-butyl dicarbonate (0.41 g, 1.87 mmol) is added. After 1
hour, the reaction mixture is concentrated and the product is
purified via flash column chromatography (1:1 EtOAc/hexanes) to
afford the product.
General Procedure C
[0993] A solution of Example 24, heterocyclic diamine side chain
(1.5-3.0 eq.) and tetramethyl guanidine (1-5.0 eq.) is stirred in
dimethyl sulfoxide at (80.degree. C.-130.degree. C.) for 36 to 24
hours. After cooling to room temperature the reaction mixture is
diluted with water and saturated NH.sub.4Cl. The solid is washed
with water and dried to give the crude solid. The product is
purified via flash column chromatography (SiO.sub.2) using
(CHCl.sub.3/MeOH or ethyl acetate/hexanes) to afford the
product.
[0994] The following compounds are synthesized according to the
General Procedures A, B, and C of Example 28:
[0995] (k)
{1-[(R)-1-((S)-3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 462 (MH+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (R)-((S)-1-pyrrolidin-3-yl)ethylcarbamic acid
tert-butyl ester (Kimura Y., Atarashi S., Takahashi M., Hayakkawa
I., Chem. Pharm. Bull., 1994;42:1442) using General Method A.
[0996] (l)
{1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}carbamic acid
tert-butyl ester (MS ES: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and [(S)-(pyrrolidin-3-yl)-1-methylethyl]carbamic
acid tert-butyl ester using General Method A.
[0997] (m)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-3-methoxypyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 492 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and [1-(3-methoxypyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (Example A5b) using General Method A.
[0998] (n)
[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid
tert-butyl ester (MS ES: m/z 446 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 3-azabicyclo[3.1.0]hex-6-ylcarbamic acid
tert-butyl ester (Brighty K. E., 1991, EP 413455) using General
Method A.
[0999] (o)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-3-fluoropyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 496 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (4-fluoro-pyrrolidin-3-yl)ethylcarbamic acid
tert-butyl ester (Example A5c) using General Method A.
[1000] (p)
[1-(3-Amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (MS
ES: m/z 434 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(Example 24f) and (pyrrolidin-3-yl)carbamic acid tert-butyl ester
using General Method A.
[1001] (q)
{1-(R)-[1-(S)-(3-Amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4--
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES:m/z 462 (MH+)) from
3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(Example 24f) and ((R)-((S)-1-pyrrolidin-3-yl-ethyl)amine using
General Method A.
[1002] (r)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-methoxymethylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 493 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (3-methoxymethylpyrrolidin-3-ylmethyl)carbamic
acid tert-butyl ester (Example A5d) using General Method A.
[1003] (s)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-fluoromethylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.60
(d, 1H), 5.18 (bs, 1H), 4.97 (bs, 2H), 4.61-4.10 (m, 4H), 3.72-3.19
(m, 5H), 2.46 (s, 3H), 2.00-1.71 (m, 2H), 1.45 (s, 9H), 1.21-1.10
(m, 2H), 0.68-0.56 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 1-(3-fluoromethylpyrrolidin-3-ylmethyl]carbamic
acid tert-butyl ester (Li Q., Wang W., Berst K. B., Claiborne A.,
Hasvold L., Raye K., Tufano M., et al., Bioorg. Med. Chem. Lett.,
1998;8:1953-1958) using General Method A.
[1004] (t)
[trans-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydroquinazolin-7-yl)-4-trifluoromethylpyrrolidin-3-ylmethyl]carbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.56 (d, 1H), 5.17 (s, 2H), 4.75 (bs, 1H), 3.97-3.68 (m, 3H), 3.57
(s, 3H), 3.51-3.13 (m, 4H), 2.98-2.60 (m, 2H), 1.45 (s, 9H),
1.20-1.08 (m, 2H), 0.71-0.55 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and
[trans-(4-trifluoromethylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (Li Q., Wang W., Berst K. B., Claiborne A.,
Hasvold L., Raye K., Tufano M., et al., Bioorg. Med. Chem. Lett.,
1998;8:1953-1958) using General Method A.
[1005] (u)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)piperidin-3-yl]ethyl}carbamic acid tert-butyl
ester (MS (ES, M+1) m/z 492 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (1-piperidin-3-ylethyl)carbamic acid tert-butyl
ester (Example A5e) using General Method A.
[1006] (v)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)piperidin-3-yl]ethyl}carbamic acid tert-butyl
ester (MS ES: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 1-(piperidin-3-yl)ethylcarbamic acid tert-butyl
ester (Example A5e) using General Method A.
[1007] (w)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 506 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and [1-(4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic
acid tert-butyl ester (Example A5f) using General Method A.
[1008] (x)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 490 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and [1-(4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic
acid tert-butyl ester (Example A5f) using General Method A.
[1009] (y)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and [1-(4-methylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (Example A5g) using General Method A.
[1010] (z)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-phenylpyrrolidin-3-yl]carbamic acid tert-butyl
ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.61 (d, 1H),
7.50-7.12 (m, 5H), 5.19 (bs, 2H), 4.07-3.70 (m, 3H), 3.62-3.34 (m,
2H), 2.68-2.52 (m, 1H), 2.45 (s, 3H), 1.68 (m, 2H), 1.50-0.95 (m,
11H), 0.62 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl
ester (Example A30) (using General Method A).
[1011] (aa)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-phenylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.68
(d, 1H), 7.50-7.29 (m, 5H), 6.72 (s, 1H), 5.24 (s, 2H), 4.18-3.85
(m, 3H), 3.78-3.52 (m, 2H), 2.70 (s, 1H), 2.58-2.39 (m, 4H),
1.62-0.62 (m, 15H) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (3-phenylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester.(Example A5p) using General Method A.
[1012] (bb)
[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 474 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid
tert-butyl ester (Example A5h) using General Method A.
[1013] (cc)
[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 490 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and 5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid
tert-butyl ester (Example A5h) using General Method A.
[1014] (dd)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-3-hydroxypyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 480 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (3-hydroxypyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (Example A5i) using General Method A.
[1015] (ee)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)piperidin-3-ylmethyl]carbamic acid tert-butyl ester
(REF) (MS ES: m/z 462 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (piperidin-3-ylmethyl]carbamic acid tert-butyl
ester (Hilpert K., Ackermann J., Banner D. W., Gast A., Gubernator
K., Hadvary P., Labler L., et al., J. Med. Chem.,
1994;37[23]:3889-3901) using General Method A.
[1016] (ff)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamic acid tert-butyl
ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.60-7.54 (d,
1H), 5.16 (s, 2H), 4.82 (s, 1H), 4.20-3.85 (m, 5H), 3.42 (s, 3H),
3.23 (t, 2H), 2.41 (s, 3H), 1.47 (s, 9H), 1.18-1.10 (m, 2H), 0.61
(s, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 4-(methoxypyrrolidin-3-yl)carbamic acid
tert-butyl ester (Li Q., Cooper C. S., Anthony K. L., Lee C. M.,
Plattner J. J., Ma Z., Wang W., 1996, WO 9639407) using Method
A.
[1017] (gg)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamic acid tert-butyl
ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.21 (d, 1H),
5.23-5.14 (m, 3H), 4.33-3.22 (m, 13H), 1.40 (s, 9H), 1.18 (m, 2H),
0.60 (s, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and 4-(methoxypyrrolidin-3-yl)carbamic acid
tert-butyl ester (Li Q., Cooper C. S., Anthony K. L., Lee C. M.,
Plattner J. J., Ma Z., Wang W., 1996, WO 9639407) using Method
A.
[1018] (hh)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-4-fluoropyrrolidin-3-yl]carbamic acid tert-butyl
ester (.sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 7.40-7.34 (d,
1H), 5.30-4.80 (m, 3H) 4.50-3.10 (m, 10H), 1.47 (s, 9H), 1.30-0.50
(m, 4H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dion-
e (Example 24d) and 4-(fluoropyrrolidin-3-yl)carbamic acid
tert-butyl ester (Li Q., Wang W., Berst K. B., Claiborne A.,
Hasvold L., Raye K., Tufano M., et al., Bioorg. & Med. Chem.
Lett., 1998;8:1953-1958) using General Method A.
[1019] (ii)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-methylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 462 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (3-methylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (J. Med. Chem, 1992:361-367) using General Method
A.
[1020] (jj)
{(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-8-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-t-
etrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-8-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione
(Example 24g) and ((R)-[(S)-1-pyrrolidin-3-yl-ethyl)ethyl]carbamic
acid tert-butyl ester using General Method A.
[1021] (kk)
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)pyrrolidine-3-carboxylic acid tert-butyl ester
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.51 (d, 1H), 5.15 (s,
2H), 3.88-3.58 (m, 4H), 3.50 (s, 3H), 3.42-3.30 (m, 1H), 3.14-3.02
(m, 1H), 2.25-2.17 (m, 2H), 1.48 (s, 9H), 1.14-1.05 (m, 2H),
0.68-0.61 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and pyrrolidine-3-carboxylic acid tert-butyl ester
(Hayakawa I., Tanaka Y., EP 101829) using General Method A.
[1022] (ll)
1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)pyrrolidine-3-carboxylic acid tert-butyl ester
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.61 (d, 1H), 5.16 (s,
2H), 3.70-3.40 (m, 5H), 3.17-3.03 (m, 1H), 2.43 (s, 3H), 2.29-2.19
(m, 2H), 1.47 (s, 9H), 1.22-1.12 (m, 2H), 0.67-0.57 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and pyrrolidine-3-carboxylic acid tert-butyl ester
(Hayakawa I., Tanaka Y., EP 101829) using General Method A.
[1023] (mm)
[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.53
(d, 1H), 5.31 (bs, 2H), 4.73 (bs, 1H), 3.82-3.01 (m, 11H), 1.45 (s,
9H), 1.42-1.34 (m, 1H), 1.14-1.10 (m, 3H), 0.71-0.63 (m, 2H)), from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (3-azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acid
tert-butyl ester (Example A5j) using General Method A.
[1024] (nn)
[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamic acid
tert-butyl ester (MS ES: m/z 460) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (3-azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acid
tert-butyl ester (Example A5j) using General Method A.
[1025] (oo)
{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 478 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (R)-1-((S)-pyrrolidine-3-yl)ethyl)carbamic acid
tert-butyl ester (Schroeder M. C., Kiely J. S., Johnson D. R.,
Szotek D. L., Domagala J. M., Stickney T. M., Kampf J. W., J.
Heterocyclic Chem., 1992;29:1481) using General Method A.
[1026] (pp)
{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.51-7.44 (d, 1H), 5.17 (bs, 2H), 4.62 (bs, 0.5H), 4.58 (bs, 0.5H),
3.79-3.74 (m, 3H), 3.61-3.53 (m, 2H), 3.49 (s, 3H), 3.41-3.32 (m,
1H), 2.22-2.06 (m, 2H), 1.87-1.67 (m, 1H), 1.46 (s, 9H),1.23-1.19
(d, 3H), 1.08-1.02 (m, 2H) 0.76-0.62 (m, 2H).(MS ES: m/z 462) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (R)-1-((S)-pyrrolidine-3-yl)ethyl)carbamic acid
tert-butyl ester using General Method A.
[1027] (qq)
6-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-7-yl)octahydropyrrolo[3,4-b]pyridine-1-carboxylic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.61-7.55 (d, 1H), 5.16 (bs, 2H), 4.52 (bs, 0.5H), 4.48 (bs, 0.5H),
4.95-3.38 (m, 6H), 2.40 (s, 3H), 2.36-1.83(m, 3H),1.46 (s, 9H),
1.21-1.17 (m, 5H), 0.65-0.57 (m, 2H), from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and octahydropyrrolo[3,4-b]pyridine-5-carboxylic acid
tert-butyl ester using General Method A.
[1028] (rr)
[(trans)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamic
acid tert-butyl ester (MS ES: m/z 478 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (trans-4-methylpyrrolidin-3-ylmethyl)carbamic
acid tert-butyl ester (Kuniyoshi M., Seigo S., Keiji H., Takayoshi
I., Eur. Pat. Appl. EP 208210, 1987) using General Method A.
[1029] (ss)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroq-
uinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 462 (MH+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (4-methylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (Kuniyoshi M., Seigo S., Keiji H., Takayoshi I.,
Eur. Pat. Appl. EP 208210, 1987) using General Method A.
[1030] (tt)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-4-methylpyrrolidin-3-yl]carbamic acid tert-butyl
ester (MS ES: m/z 464 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (4-methylpyrrolidin-3-yl)carbamic acid tert-butyl
ester (Di Cesare P., Bouzard D., Essiz M., Jacquet J. P., Ledoussai
B., Kiechet J. R., Remuzon P. et al., J. Med. Chem., 1992,35:4205)
using General Method A.
[1031] (uu)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)morpholin-3-ylmethyl]carbamic acid tert-butyl ester
(MS ES: m/z 480 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and 1-(morpholin-3-ylmethyl)carbamic acid tert-butyl
ester (Araki K., Kuroda T., Uemori S., Moriguchi A., Ikeda Y.,
Hirayama F., Yokoyama Y. et al., J. Med. Chem., 1993,36:1356) using
General Method A.
[1032] (vv)
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)piperidin-3-ylmethyl]carbamic acid tert-butyl ester
(MS ES: m/z 478 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and 1-piperidin-3-ylmethylcarbamic acid tert-butyl
ester (Hilpert K., et al., J. Med. Chem., 1994;37(23):3889-3901)
using General Method A.
[1033] (ww)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS ES: m/z 492 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and [1-(4-methylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (A5g) using General Method A.
[1034] (xx)
[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoli-
n-7-yl)-3-methylpyrrolidin-3-yl]]carbamic acid tert-butyl ester
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.61 (d, 1H), 5.15 (s,
2H), 4.74 (s, 1H), 3.71-3.37 (m, 6H), 2.45-2.20 (m, 4H), 1.45 (s,
12H), 1.21-1.08 (m, 2H), 0.61 (d, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 3-methylpyrrolidin-3-ylcarbamic acid tert-butyl
ester (Yoshida T., Yamamoto Y., Orita H., Kakiuchi M., Takahashi
Y., Itakura M., Kado N. et al., Chem. Pharm. Bull.,
1996;44[7]:1376-1386) using General Method A
[1035] (yy)
3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1-yl-1H-quinazoline--
2,4-dione (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.61-7.54 (d,
1H), 5.15 (bs, 2H), 3.51-3.40 (m, 5H), 2.39 (s, 3H), 2.01-1.95 (m,
4H), 1.21-1.11 (m, 2H), 0.67-0.62 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and pyrrolidine using General Method A.
[1036] (zz)
3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1-yl-1H-quinazoline-
-2,4-dione (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.49-7.42
(d, 1H), 5.13 (bs, 2H), 3.66-3.54 (m, 4H), 3.50 (s, 3H), 3.42-3.31
(m, 1H), 2.02-1.92 (m, 4H), 1.17-1.07 (m, 2H), 0.69-0.61 (m, 2H))
from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and pyrrolidine using General Method A.
[1037] (aaa)
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxyethyl-1-methyl)-pyrrolidin--
1-yl]-8-methyl-1H-quinazoline-2,4-dione (.sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.59 (d, 1H), 5.15 (s, 2H), 3.68-3.53 (m, 2H),
3.44-3.31 (m, 3H), 2.42 (s, 3H), 2.00-1.82 (m, 2H), 1.58 (s, 1H),
1.28 (s, 6H), 1.20-1.10 (m, 2H), 1.00-0.80 (m, 1H), 0.66-0.60 (m,
2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 1-methyl-1-pyrrolidin-3-yl-ethanol (Example A5n)
using General Method A.
[1038] (bbb)
3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin--
1-yl]-8-methoxy-1H-quinazoline-2,4-dione (.sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.50 (d, 1H), 5.14 (s, 2H), 3.86-3.70 (m, 2H),
3.49 (s, 3H), 3.60-3.30 (m, 3H), 2.40-2.22 (m, 1H), 2.00-1.80 (m,
2H), 1.30 (s, 6H), 1.09-0.85 (m, 2H), 0.75-0.57 (m, 2H)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and 1-methyl-1-pyrrolidin-3-yl-ethanol (Example A5n)
using General Method A.
[1039] (ccc)
1-[(R)-1-(3-(S)-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[3-(1-methylamino-
ethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione (MS ES: m/z 376
(MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione
(Example 24e) and methyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine
using General Method A.
[1040] (ddd)
1-[(R)-1-(3-(S)-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)-pyrrolidin-1-
-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione (MS ES: m/z 406
(MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and ethyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine
(Domagala J. M., Hagen S. E., Joannides T., Kiely J. S., Laborde
E., Schroeder M. C., Sesnie J. A., et al., J. Med. Chem.,
1993;36[7]:871-882) using General Method A.
[1041] (eee)
3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)-pyrrolidin-1-yl]-6-
-fluoro-8-methyl-1H-quinazoline-2,4-dione (MS ES: m/z 390
(MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and ethyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine
using General Method A.
[1042] (fff)
3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-
-fluoro-8-methoxy-1H-quinazoline-2,4-dione (MS ES: m/z 390
(MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dion-
e (Example 24d) and 1-methyl-3-azabicyclo[3.2.0]hept-6-ylamine (Kim
C. S., Kim J. W., Lee J. M., Youn Y. S., Shin Y. J., Lee K. H., Kim
J. H. WO 94/15933) using General Method A.
[1043] (ggg)
3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1-
H-quinazoline-2,4-dione (MS ES: m/z 350 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and azetidin-3-ylmethylamine (Okada T., Ezumi K.,
Yamakawa M., Sato H., Tsuji T., Tsushima T., Motokawa K., Komatsu
Y., Chem. Pharm. Bull., 1993;41:126-131) using General Method
A.
[1044] (hhh)
3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy--
1H-quinazoline-2,4-dione (MS ES: m/z 378 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and piperidin-4-ylmethylamine using General Method
A.
[1045] (iii)
[(cis)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamic acid
tert-butyl ester (MS ES: m/z 482 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (cis-4-fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester [A5k)] using General Method A.
[1046] (jjj)
[(trans)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-te-
trahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamic
acid tert-butyl ester (MS ES: m/z 482 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (trans-4-methylpyrrolidin-3-ylmethyl)carbamic
acid tert-butyl ester [A51] using General Method A.
[1047] (kkk)
[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
quinazolin-7-yl)-(1-amino-5-azaspiro[2.4]hept-5-yl)]carbamic acid
tert-butyl ester (MS APCI: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 14d) and 1-amino-5-aza-spiro[2.4]hept-5-yl)]carbamic acid
tert-butyl ester (Li Q., Chu D. T. W., Claiborne A., Cooper C. S.,
Lee C. M., Raye K., Berst K. B., et al., J. Med. Chem.,
1996;39[16]:3070-3088) using General Method C.
[1048] (lll)
[1-(3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluo-
ro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl]carbamic
acid tert-butyl ester (MS APCI: m/z 518 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 24d) and (3a-aminomethyloctahydro-isoindol-2-yl)carbamic
acid tert-butyl ester (Ma Z., Chu D. T. W., Cooper C. S., Li Q.,
Fung A. K. L., Wang S., Shen L. L., et al., J. Med. Chem.,
1999;42(20):4202-4213) using General Method C.
[1049] (mmm)
3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-
-methyl-1H-quinazoline-2,4-dione (MS APCI: m/z 502 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and 3a-aminomethyloctahydroisoindol-2-ylcarbamic
acid-tert-butyl ester (Ma Z., Chu D. T. W., Cooper C. S., Li Q.,
Fung A. K. L., Wang S., Shen L. L., et al., J. Med. Chem.,
1999;42(20);4202-4213) using General Method C.
[1050] (nnn)
{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid
tert-butyl ester (MS APCI: m/z 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(Example 14d) and ((R)-(S)-1-pyrrolidin-3-yl)ethylcarbamic acid
tert-butyl ester (J. Het. Chem., 1992;29:1481) using General Method
C.
[1051] (ooo)
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-propyl}-carbamic acid
tert-butyl ester (MS: m/e 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and (1-pyrrolidin-3-yl-propyl)-carbamic acid
tert-butyl ester (Kimura Y., Atarashi S., Takahashi M., Hayakkawa
I., Chem. Pharm. Bull., 1994;42:1442) using General Method A.
[1052] (ppp)
{(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)pyrrolidin-3-yl]-ethyl}-methyl-carbamic
acid dimethylethyl ester (MS: m/e 476 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and methyl-(R)-((S)-1-pyrrolidin-3-yl)ethylamine
(Plummer J. S., Emery L. A., Stier M. A., Suto M. J., Tetrahedron
Lett., 1993;34(47):7529-7532) using General Method A.
[1053] (qqq)
{1-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
roquinazolin-7-yl)-5-aza-spiro[2.4]hept-7-yl]ethyl}carbamic acid
tert-butyl ester (MS CI: m/e 488 (MH.sup.+)) from
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(Example 24e) and [1-(5-aza-spiro[2.4]hept-7-yl)ethyl]carbamic acid
tert-butyl ester (Example A5a) using General Method A.
EXAMPLE 29
(7,8-Difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4yl)-oxoacetaldehyde
oxime
[1054] ##STR251##
[1055] A solution of 8.27 g (50 mmol) of chloral hydrate in 125 mL
of water is treated with 112.8 g (0.35 mmol) of sodium sulfate
decahydrate. The mixture is stirred and treated with a solution of
7,8-difluoro-3-methyl-3,4-dihydro-2H-benz[1,4]oxazine (Chem. Pharm.
Bull., 1984;32:4907) hydrochloride (prepared by dissolving 8.26 g
(44.6 mmol) of the free base in 50 mmol of concentrated
hydrochloric acid in 70 mL of 50% aqueous ethanol). The reaction is
stirred and a solution of 9.8 g (140 mmol) of hydroxylamine
hydrochloride in 50 mL of water is added. After heating at 75 to
80.degree. C. for 3 hours, the reaction is stirred at room
temperature overnight. The resulting precipitate is removed by
filtration, washed with water, and the wet filter cake is dissolved
in dichloromethane. The organic solution is washed with water,
dried (MgSO.sub.4), decolorized with charcoal, filtered and
concentrated in vacuo to give 10.5 g of the title compound, mp
188-190.degree. C.
EXAMPLE 30
Synthesis of
6,7-Difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthlylene-1,2-dione
[1056] ##STR252##
[1057] A solution of 45 mL of 98% sulfuric acid in 18 mL of water
is heated to 50.degree. C. to 60.degree. C. and treated portionwise
over 30 minutes with 10.5 g (41 mmol) of
(7,8-difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4-yl)oxoacetaldehyde
oxime (Example 29). After the addition is complete, the reaction is
heated to 80.degree. C. for 15 minutes and poured onto 200 mL of
ice and water. The mixture is stirred until the ice melts and the
solid is removed by filtration, washed with water and the wet
filter cake is dissolved in dichloromethane. The organic solution
is washed with water (2.times.200 mL), dried (MgSO.sub.4), filtered
and concentrated in vacuo affording 7.1 g of the title compound, mp
169-171.degree. C.
EXAMPLE 31
Synthesis of
7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic
acid
[1058] ##STR253##
[1059] A suspension of 6.9 g (28.8 mmol) of
6,7-difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1,2-dione
(Example 30) in 250 mL of 4.5% aqueous sodium hydroxide is treated
dropwise with 16.4 mL of 30% hydrogen peroxide over 1 hour. The
reaction is filtered to remove a trace of insoluble material and
the filtrate is acidified to pH 4.5 with acetic acid. After cooling
to 5.degree. C., the precipitate is removed by filtration, washed
with water and dried in vacuo to give 5.5 g of the title compound,
mp 200-202.degree. C.
EXAMPLE 32
Synthesis of Anthranilic Esters
(a)
7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic
acid methyl ester
[1060] ##STR254##
[1061] A solution of 2.1 g (9.1 mmol) of
7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic
acid (Example 31) in 50 mL of methanol is cooled to 0.degree. C.
and saturated with hydrogen chloride gas. The reaction is stirred
at room temperature for 18 hours, recooled to 0.degree. C. and
resaturated with hydrogen chloride gas. After stirring an
additional 24 hours at room temperature, the solvent is removed in
vacuo and the residue is partitioned between dichloromethane/5%
aqueous sodium bicarbonate (200:100 mL). The organic layer is
separated, washed with 5% aqueous sodium bicarbonate, water, dried
(MgSO.sub.4), filtered, and concentrated in vacuo affording 1.9 g
of the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.27 (bs,
1H), 7.24 (m, 1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.62
(m, 1H), 1.22 (d, 3H).
(b) Synthesis of
5,6-Difluoro-2-methyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic
acid methyl ester
[1062] ##STR255##
[1063] A solution of 8.0 g (33.7 mmol) of
5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester
(Example 33) in 100 mL of glacial acetic acid is treated with 2.15
g of platinum on carbon (0.8 g of active catalyst+62.8% water) and
then shaken in a hydrogen atmosphere at temperatures of 24.degree.
C. to 29.degree. C. and pressures of 23.9 to 46.6 psi for 3 hours.
The catalyst is removed by filtration and the solvent is removed in
vacuo at 50.degree. C. The residue is triturated with water (50 mL)
and extracted with dichloromethane (2.times.200 mL). The combined
organic layers are stirred with 5% sodium bicarbonate solution,
washed with water, dried (MgSO.sub.4), filtered and evaporated in
vacuo. The residue is chromatographed over flash grade silica gel
(230-400 mesh) eluting with dichloromethane to give 5.6 g of the
title compound as a light yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.66 (bs, 1H), 7.49 (m, 1H), 3.82 (s, 3H), 3.46 (m,
1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H).
EXAMPLE 33
Synthesis of 5,6-Difluoro-2-methylquinoline-8-carboxylic acid
methyl ester
[1064] ##STR256##
[1065] In a stainless steel reactor, a solution of 9.53 g (36.9
mmol) of 8-bromo-5,6-difluoro-2-methylquinoline (Chem. Pharm.
Bull., 1996;44:642), 6.8 g (67.6 mmol) of triethylamine, 0.67 g
(3.0 mmol) of palladium (II) acetate, 1.28 g (3.1 mmol) of
1,3-bis(diphenyl-phosphino)propane in 90 mL of dimethylformamide
and 65 mL of methanol is flushed with nitrogen gas and pressurized
to 550 psi with carbon monoxide. The reaction is rocked and heated
to 75.degree. C. for 24 hours, cooled to room temperature and
evaporated in vacuo. The residue is triturated with water (50 mL)
and extracted with dichloromethane (2.times.200 mL). The combined
organic layers are washed with water (2.times.50 mL), dried
(MgSO.sub.4), filtered and evaporated in vacuo. The residue is
chromatographed over flash grade silica gel (230-400 mesh) eluting
with dichloromethane (200 mL), then dichloromethane/ethyl acetate
(90:10) to give 8.0 g of the title compound, mp 99-101.degree.
C.
EXAMPLE 34
Synthesis of 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinic
acid ethyl ester
[1066] ##STR257##
[1067] A solution of 8.7 g (34.8 mmol) of
2-chloro-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester (J.
Med. Chem., 1993;36:2676) and 5.7 g (100 mmol) of cyclopropylamine
in 100 mL of acetonitrile is heated at reflux for 18 hours. After
TLC showed the presence of unreacted starting material, 4.12 g (72
mmol) of cyclopropylamine is added and the reaction mixture is
refluxed for 48 hours. The solvent is removed in vacuo and the
residue is partitioned between dichloromethane (250 mL) and water
(100 mL). The organic layer is washed with water, dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The residue is
chromatographed over flash grade silica gel (230-400 mesh) eluting
with dichloromethane to give 6.5 g of the title compound, mp
67-69.degree. C.
EXAMPLE 35
Synthesis of
1-Cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-
e-7-thiosulfonic acid
[1068] ##STR258##
[1069] A solution of 0.65 g (2.4 mmol) of
1-cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-di-
one (Example 23e) in 20 mL of formic acid is treated with 1.83 g
(19.5 mmol) of urea-hydrogen peroxide and the reaction mixture is
stirred at room temperature overnight. The resulting precipitate is
removed by filtration, washed with water, ethyl acetate and dried
in vacuo to give 0.63 g of the title compound, mp 300-302.degree.
C.
EXAMPLE 36
Synthesis of
{8-Chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrroli-
din-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester
[1070] ##STR259##
[1071] A solution of
(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin--
3-yl)carbamic acid tert-butyl ester (Example 14, 0.37 g, 0.97 mmol)
in acetonitrile (20 mL) is added pyrrolidin-3-yl-methylamine (0.115
g, 1.16 mmol) and triethylamine (2.7 mL, 19.3 mmol). After
refluxing for 20 hours, the reaction mixture is cooled to room
temperature and diluted with ethyl acetate. The organic layer is
washed with saturated sodium bicarbonate, water, and brine. The
organic layer is dried over MgSO.sub.4, filtered, and the filtrate
concentrated. The resulting residue is redissolved in methylene
chloride (10 mL) at 0.degree. C. and while stirring, triethylamine
(0.33 mL, 2.34 mmol) and methanesulfonyl chloride (0.072 mL, 0.94
mmol) is added. After 2 hours, the reaction mixture is diluted with
ethyl acetate and washed with saturated sodium bicarbonate, water,
and brine. The organic layer is dried over MgSO.sub.4, filtered,
and the filtrate concentrated and the product is purified via flash
column chromatography (1:1 EtOAc/hexanes) to afford
{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrroli-
din-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid
tert-butyl ester (0.043 g). MS CI: m/e 446 ((MH.sup.+)-Boc).
Amine Side Chain Synthesis
EXAMPLE A1
(a) 5-Benzyl-5-azaspiro[2,4]heptan-1-carboxylic acid ethyl
ester
[1072] ##STR260##
[1073] A solution of cyclopropylidene acetic acid ethyl ester (192
g, 1520 mmol [Salaun J., Bennani F., Compain J. C., Fadel A.,
Ollivier J. J,. Org Chem., 1980;45(21):4129-3415]) and
N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (572 g, 2410
mmol [Gerlach K., Hoffmann H. M. R., Wartchow R. J., Chem. Soc.,
Perkin Trans. 11, 1998(22):3867-3872]) in dichloromethane (5.5 L)
was treated with a solution of 1.0N trifluoroacetic acid in
dichloromethane (80 mL) and the reaction is stirred at ambient
temperature for 30 minutes. The solvent is then evaporated at
reduced pressure and the product purified by Kugelrohr distillation
(277 g). MS CI: m/z 260 (MH.sup.+).
EXAMPLE A2
(a) Synthesis of 1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)ethanone
[1074] ##STR261##
[1075] A solution (-78.degree. C.) of
5-benzyl-5-azaspiro[2.4]heptane-7-carboxylic acid ethyl ester
(Example A1a, 8.15 g, 31.4 mmol) in diethyl ether (200 mL) under a
nitrogen atmosphere is treated with methyllithium (1.4 M in diethyl
ether, 22.4 mL, 31.4 mmol) over a period of 10 minutes. After 1
hour, reaction mixture is warmed to -10.degree. C. and quenched
with saturated aqueous ammonium chloride. The mixture is poured
into a separatory funnel and the organic layer is washed with
saturated aqueous ammonium chloride, water, and brine. The organic
layer is then dried with MgSO.sub.4, filtered, and the filtrate
concentrated. The resulting residue is purified via flash column
chromatography (1% triethylamine/7% isopropanol/92%
CH.sub.2Cl.sub.2) to afford the title compound (3.93 g). MS CI: m/z
230 (MH.sup.+).
EXAMPLE A3
(a) Synthesis of 1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)ethanone
oxime
[1076] ##STR262##
[1077] 1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone (Example A2a,
3.93 g, 17.1 mmol) and hydroxylamine hydrochloride (1.78 g, 25.7
mmol) are stirred in pyridine (10 mL) at 90.degree. C. After 20
hours, the reaction mixture is diluted with ethyl acetate and the
organic layer is washed with saturated NaHCO.sub.3, water, and
brine. The organic layer is dried with MgSO.sub.4, filtered, and
the filtrate concentrated to afford
1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime as an oil (3.07
g). MSCI: m/z 245 (MH.sup.+).
General Method A
[1078] A solution of substrate, hydroxylamine hydrochloride (1.2
eq.), sodium acetate (0.9 eq.) in ethanol is stirred at room
temperature for 2 hours. The solvent is removed in vacuo and the
residue is partitioned between ethyl acetate and saturated sodium
chloride solution. The aqueous is re-extracted with ethyl acetate
and the combined extracts are dried over Na.sub.2SO.sub.4, filtered
and concentrated under vacuum to afford the title compound.
[1079] The compounds below were prepared according to General
Method A.
[1080] (b) 1-(1-Benzylpiperidin-3-yl)ethanone oxime (.sup.1H NMR
(200 MHz, CDCl.sub.3): .delta. 7.48-7.28 (m, 5H), 3.92-3.68 (m,
2H), 3.28-3.0 (m, 4H), 2.88-2.62 (m, 2H), 2.38-1.72 (m, 3H),
1.3-1.18 (m, 3H)) from 1-(1-benzylpiperidin-3-yl)ethanone (Example
A23).
[1081] (c) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone oxime
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.68-7.30 (m, 5H),
6.60-5.80 (bs, 1H), 3.80-2.38 (m, 6H), 1.90 (s, 3H), 1.38-0.96 (m,
7H)) from 1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone (Example
A18b).
[1082] (d) 1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethanone oxime
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.41-7.15 (m, 5H),
3.78-3.44 (m, 3H), 2.98-2.80 (m, 1H), 2.75-2.39 (m, 3H), 2.35-2.08
(m, 2H), 1.90 (m, 3H), 1.18-0.95 (m, 3H)) from
1-(1-benzyl-4-methylpyrrolidin-3-yl)ethanone (Example A23b).
EXAMPLE A4
(a) Synthesis of
1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)-ethyl]carbamic acid
tert-butyl ester
[1083] ##STR263##
[1084] To a solution of
1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime (Example A3a,
2.90 g, 11.9 mmol) in methanol (100 mL) is added Raney-Nickel (2
g). Hydrogen is introduced to the reaction mixture at high pressure
(48 psi) for 20 hours and the reaction mixture is filtered through
celite, washed with methanol, and the combined filtrates
concentrated in vacuo. The resulting residue is redissolved in
dichloromethane (25 mL) and treated with di-tert-butyl dicarbonate
(3.24 g, 14.9 mmol). After 1 hour, the mixture is concentrated and
the product purified via flash column chromatography (1%
triethylamine/7% isopropanol/92% dichloromethane) to afford
[1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)-ethyl]carbamic acid
tert-butyl ester (1.47 g). MS CI: m/z 331 (MH.sup.+).
General Method A
[1085] Di-tert-butyl dicarbonate (0.69 g, 0.3 mmol) is added to a
solution of amine in methanol (4 mL) at 0.degree. C. After stirring
at room temperature for 2 hours, the mixture is concentrated and
the residue is purified by chromatography (SiO.sub.2, ethyl
acetate/hexanes) to afford the title carbamic esters.
General Method B
[1086] An ice-cold solution of substrate in 2:1 methanol and water
is treated with di-tert-butyl dicarbonate (1.25 eq.). The resulting
solution is stirred at room temperature for 18 hours and extracted
with dichloromethane. The organic extracts are washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum. The residue is purified by flash column chromatography
(ethyl acetate/hexanes) to afford the title compounds.
General Method C
[1087] To a solution of substrate in dichloromethane is added
di-tert-butyl dicarbonate (2 eq.) and triethylamine (2 eq.). The
resulting mixture is stirred at room temperature for 18 hours and
diluted with water. The organic extract is washed with water,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue is then purified by column chromatography to
afford the title compound.
[1088] Examples A4b-A4m are prepared according to General Methods
A, B, and C.
[1089] (b)
3-(1-tert-Butoxycarbonylaminoethyl)-3-methoxypyrrolidine-1-carboxylic
acid benzyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.37-7.29 (m, 5H), 5.13 (s, 2H), 4.70 (bs, 1H), 3.91-3.22 (m, 8H),
2.03-1.75 (m, 2H), 1.43 (s, 9H), 1.16-1.11 (m, 3H)) from
3-(1-aminoethyl)-3-methoxypyrrolidine-1-carboxylic acid benzyl
ester (Example A13a) using General Method A.
[1090] (c)
3-(1-tert-Butoxycarbonylaminoethyl)-3-fluoropyrrolidine-1-carboxylic
acid benzyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.35
(s, 5H), 5.13 (s, 2H), 4.79 (d, 1H), 3.97-3.26 (m, 5H), 2.17-1.75
(m, 2H), 1.44 (s, 9H), 1.24 (d, 3H)) from
3-(1-aminoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester
(Example A13b) using General Method A.
[1091] (d) (1-Benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)carbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.35-7.17 (m, 5H), 5.78 (bs, 1H), 3.56 (s, 2H), 3.32 (s, 3H), 3.27
(s, 2H), 3.21-3.12 (m, 2H), 2.71-2.62 (m, 1H), 2.54-2.30 (m, 3H),
1.78-1.54 (m, 2H), 1.46 (s, 9H)) from
(1-benzyl-3-methoxymethylpyrrolidin-3-yl)methylamine (Example A13c)
using General
Method B.
[1092] (e) [1-(1-Benzylpiperidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.3
(s, 5H), 4.46-4.30 (m, 1H), 3.62-3.42 (m, 4H), 2.94-2.62 (m, 3H),
2.0-1.0 (m, 8H), 1.44 (s, 9H)) from
1-(1-benzylpiperidin-3-yl)ethylamine (Example A13d) using General
Method C.
[1093] (f) [1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): Isomer-1:
.delta. 7.36-7.22 (m, 5H), 3.82-3.38 (m, 2H), 2.98-1.78 (m, 5H),
1.52-1.0 (m, 19H); Isomer-2: .delta. 7.35-7.25 (m, 5H), 4.35-4.18
(m, 1H), 3.70-3.45 (m, 2H), 2.90-1.54 (m, 6H), 1.43 (s, 9H),
1.18-0.92 (m, 9H)) from
1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethylamine (Example A13e)
using General Method C.
[1094] (g) [1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.38-7.13 (m, 5H), 3.71-3.32 (m, 4H), 3.08-1.53 (m, 6H), 1.52-1.31
(m, 9H), 1.14-0.94 (m, 6H). MS ES: m/z 319 (MH.sup.+)) from
1-(1-benzyl-4-methylpyrrolidin-3-yl)ethylamine (Example A13f) using
General Method C.
[1095] (h) (5-Benzyl-5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid
tert-butyl ester (MS ES: m/z 317 (MH.sup.+)) from
1-(5-benzyl-5-azaspiro[2,4]hept-7-yl)methylamine (Example A13g)
using General Method C.
[1096] (i) (1-Benzyl-3-hydroxypyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (MS ES: m/z 307 (MH.sup.+)) from
3-aminomethyl-1-benzylpyrrolidin-3-ol (Grohe K., Schriewer M.,
Haller I., Metzger K., Endermann R., Zeiler H., EP 0326916) using
General Method C.
[1097] (j) [3-(1
Phenylethyl)-3-azabicyclo[3.1.0]hex-1-ylmethylcarbamic acid
tert-butyl ester (MS ES: m/z 317 (ME.sup.+)) from
1-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hex-1-yl]methylamine
(Example A13h) using General Method C.
[1098] (k) (1,3-Dibenzylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (MS El+: m/z 381 (MH.sup.+)) using
1-(1,3-dibenzylpyrrolidin-3-yl)methylamine (Example A13i) using
General Method C.
[1099] (l) (1-Benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.30
(s, 5H), 5.04 (m, 1H), 5.04(m, 1H), 4.77 (m, 1H), 3.63 (s, 2H),
3.20 (t, 2H), 2.86-3.00 (m, 2H), 2.76 (d, 1H), 2.20-2.60 (m, 2H),
1.45 (s, 9H)) from (1-benzyl-4-fluoropyrrolidin-3yl)methylamine
(Bouzard D., Di Cesare P., Essiz M., Jacquet J. P., Kiechel J. R.,
Remuzon P., Weber A., et al., J. Med. Chem., 1990;33:1344-1352)
using General Method C.
[1100] (m) cis-(1-Benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.30 (s, 5H), 5.04 (m, 1H), 4.77 (m, 1H), 3.63 (s, 2H), 3.20 (t,
2H), 3.00-2.86 (m, 2H), 2.76 (d, 1H), 2.60-2.20 (m, 2H), 1.45 (s,
9H)) from cis-(1-benzyl-4-fluoro-pyrrolidin-3-yl)methylamine
(Matsumoto J., Nakano J., Chiba K., Minamida A., Nishimura Y., Jpn.
Kokai Tokkyo Koho, 1987; 11 pp., JP 62072660, A2 19870403) using
General Method C.
[1101] (n) trans-(1-Benzyl-4-fluoropyrrolidin-3-ylmethylcarbamic
acid tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.30 (s, 5H), 5.25 (m, 1H), 4.77 (m, 1H), 3.85 (s, 2H), 3.55 (t,
2H), 3.40-2.40 (m, 5H), 1.47 (s, 9H) from
trans-(1-benzyl-4-fluoropyrrolidin-3-yl)methylamine (Matsumoto J.,
Nakano J., Chiba K., Minamida A., Nishimura Y., Jpn. Kokai Tokkyo
Koho, 1987;11 pp., JP 62072660, A2 19870403) using General Method
C.
[1102] (o) (1-Benzyl-3-phenylpyrrolidine-3-ylmethyl)carbamic acid
tert-butyl ester (MS ES: m/z 367 (MH.sup.+)) from
(1-benzyl-3-phenylpyrrolidine-3-yl)methylamine ester (Hagen S.,
Domagala J. M., Heifetz C. L., Sanchez J. P., Solomon M., J. Med.
Chem., 1990;33:849-854) using General Method C.
EXAMPLE A5
(a) Synthesis of [1-(5-Azaspiro[2.4]hept-7-yl)ethyl]carbamic acid
tert-butyl ester
[1103] ##STR264##
[1104] A solution of
[1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethyl]carbamic acid
tert-butyl ester (Example A4a, 1.47 g) in methanol (30 mL) in a
Parr shaker is treated with 10% palladium on carbon (0.5 g) and
hydrogen introduced (50 psi) for 24 hours. The reaction mixture is
filtered through celite, washed with methanol, and the combined
filtrate concentrated in vacuo to afford the title compound. MS CI:
m/z 241 (MH.sup.+).
General Method A
[1105] To a solution of substrate in methanol is added ammonium
formate (5 eq.) and 10% palladium on charcoal (0.75 wt. vol. eq.).
After 2 hours at reflux, the reaction mixture is cooled, diluted
with dichloromethane and filtered. The filtrate is concentrated to
afford the title compound.
[1106] Examples A5b-A5o are prepared using General Method A.
[1107] (b) [1-(3-Methoxypyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 5.30
(bs, 1H), 5.03 (dd, 1H), 3.92 (bs, 1H), 3.28-2.82 (m, 7H),
1.97-1.72 (m, 2H), 1.44 (s, 9H), 1.19-1.14 (m, 3H)) from
3-(1-tert-butoxycarbonylaminoethyl)-3-methoxypyrrolidine-1-carboxylic
acid benzyl ester (Example A4b) using General Method A.
[1108] (c) [1-(3-Fluoropyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 4.89
(d, 1H), 3.95-3.61 (m, 1H), 3.21-2.70 (m, 4H), 2.11-1.53 (m, 1H),
1.44 (s, 9H), 1.26 (d, 3H)) from
3-(1-tert-butoxycarbonylaminoethyl)-3-fluoropyrrolidine-1-carbo-
xylic acid benzyl ester (Example A4c) using General Method A.
[1109] (d) (3-Methoxymethylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 5.25
(bs, 1H), 3.35 (s, 3H), 3.30 (s, 2H), 3.27-3.15 (m, 2H), 3.09-2.94
(m, 2H), 2.78 (s, 2H), 1.68-1.56 (m, 2H), 1.45 (s, 9H). (MS ES: m/z
245 (MH.sup.+)) from
(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (Example A4d) using General Method A.
[1110] (e) (1-Piperidin-3-ylethyl)carbamic acid tert-butyl ester
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 4.52-4.32 (m, 1H),
3.68-3.18 (m, 4H), 2.74-2.42 (m, 1H), 2.02-1.2 (m, 5H), 1.44 (s,
9H), 1.30-1.04 (m, 3H)) from
[1-(1-benzylpiperidin-3-yl)ethyl]carbamic acid tert-butyl ester
(Example A4e) using General Method A.
[1111] (f) [1-(4,4-Dimethylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): 6.28-5.85 (bs,
1H), 4.75 (d, 1H), 3.92-1.80 (m, 6H), 1.43 (s, 9H), 1.30-1.0 (9H))
from [1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (Example A4f).
[1112] (g) [1-(4-Methylpyrrolidin-3-yl)ethyl]carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
4.88-4.40 (m, 1H), 4.02-3.38 (m, 4H), 3.25-2.75 (m, 2H), 2.46-1.88
(m, 2H), 1.44 (s, 9H), 1.31-1.04 (m, 6H)) from
[1-(1-benzyl-4-methylpyrrolidin-3-yl)ethyl]carbamic acid tert-butyl
ester (Example A4g).
[1113] (h) (5-Azaspiro[2,4]hept-7-ylmethyl)carbamic acid tert-butyl
ester (MS ES: m/z 227 (MH.sup.+)) from
(5-benzyl-5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid tert-butyl
ester (Example A4h).
[1114] (i) (3-Hydroxypyrrolidin-3-ylmethyl)carbamic acid tert-butyl
ester (MS ES: m/z 217 (MH.sup.+)) using
(1-benzyl-3-hydroxypyrrolidin-3-ylmethyl)carbamic acid tert-butyl
ester (Example A4i).
[1115] (j) (3-Azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acid
tert-butyl ester (MS ES: m/z 213 (MH.sup.+)) using
[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hex-1-ylmethylcarbamic acid
tert-butyl ester (Example A4j).
[1116] (k) cis-(4-Fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
5.60-5.00 (m, 4H), 3.60-3.10 (m, 4H), 3.00 (t, 1H), 2.75-2.30 (m,
1H), 1.44 (s, 9H)) using
cis-(1-benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (Example A4l).
[1117] (l) trans-(4-Fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
6.60-5.70 (m, 2H), 5.25 (bs, 0.5H), 4.98 (bs, 0.5H), 3.70-2.90 (m,
5H) 2.90-2.50 (m, 1H), 1.44 (s, 9H)) using
trans-(1-benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid
tert-butyl ester (Example A4m).
[1118] (m) 3-Hydroxy-4-hydroxymethylpyrrolidine (.sup.1H NMR (200
MHz, DMSO-d.sub.6): .delta. 5.50-4.30 (bs, 3H), 4.30-1.50 (m, 8H))
using 1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (Jaeger E.,
Biel J. H., J. Org. Chem., 1965;30:740-744).
[1119] (n) 1-Methyl-1-pyrrolidin-3-yl-ethanol (MS ES: m/z 130
(MH.sup.+)) from 2-(1-benzylpyrrolidin-3-yl)propan-2-ol (Example
A25).
[1120] (o) (3-benzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl
ester (mp 183-185.degree. C.) from
(1,3-dibenzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester
(Example A4K).
[1121] (p) A5p (3-Phenylpyrrolidine-3-ylmethyl)carbamic acid
tert-butyl ester (MS APCI: m/z 277 (MH.sup.+)) from
(1-benzyl-3-phenylpyrrolidine-3-ylmethyl)carbamic acid tert-butyl
ester (Example A4o).
EXAMPLE A6
Synthesis of 1-Benzylpyrrolidin-3-one oxime
[1122] ##STR265##
[1123] To a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.71 mmol)
in pyridine (5 mL) is added hydroxylamine hydrochloride (0.59 g,
8.57 mmol). After stirring at 90.degree. C. for 5 hours, the
reaction mixture is diluted with ethyl acetate and washed with
saturated sodium bicarbonate, water, and brine. The organic layer
is dried over MgSO.sub.4, filtered, and filtrate concentrated to
afford 1-benzylpyrrolidin-3-one oxime (1.11 g) as an oil. MS CI:
m/z 191 (MH.sup.+).
EXAMPLE A7
Synthesis of Pyrrolidin-3-one oxime
[1124] ##STR266##
[1125] In a Parr shaker, 1-benzylpyrrolidin-3-one oxime (1.5 g) in
methanol (20 mL) is treated with 20% palladium on carbon (0.5 g)
under Hydrogen pressure (50 psi) for 24 hours. The mixture is then
filtered through Celite, washed with methanol, and the combined
filtrate concentrated in vacuo to afford the title compound as an
oil (1.2 g). MS CI: m/e 101 (M.sup.++1).
EXAMPLE A8
Synthesis of 3-Ethylidenepyrrolidine-1-carboxylic acid benzyl
ester
[1126] ##STR267##
[1127] Under an inert atmosphere, sodium-hydride (0.160 g, 7 mmol)
and ethyltriphenylphosphonium bromide (2 g, 5.4 mmol) are mixed in
dry dimethyl sulfoxide (10 mL) and stirred for 40 minutes.
3-Oxopyrrolidine-1-carboxylic acid benzyl ester (1.18 g, 5.4 mmol
(J. Med. Chem., 1992;35:1392)) in dry dimethyl sulfoxide (5 mL) is
added to the reaction and the mixture is stirred at 70.degree. C.
for 3 hours. The reaction is cooled, diluted with cold water and
extracted with ethyl acetate. The organic phase is washed with
brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue is
purified by column chromatography (65:35 hexanes/ethyl acetate) to
afford the title compound (0.650 g) as a viscous oil.
[1128] .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.37-7.28 (m,
5H), 5.40-5.32 (m, 1H), 5.15 (s, 2H), 3.97 (bs, 2H), 3.60-3.44 (m,
2H), 2.49 (bs, 2H), 1.65-1.60 (m, 3H).
EXAMPLE A9
Synthesis of 2-Methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic
acid benzyl ester
[1129] ##STR268##
[1130] A solution of 3-ethylidenepyrrolidine-1-carboxylic acid
benzyl ester (Example A8, 0.65 g, 2.8 mmol) and
3-chloroperoxybenzoic acid (0.86 g, 5 mmol) in dichloromethane (15
mL) is stirred at room temperature for 3 hours. The excess peracid
is decomposed by the addition of 10% sodium sulfite. The organic
layer is washed with 5% sodium bicarbonate solution, dried over
Na.sub.2SO.sub.4 and evaporated. The residue is purified by column
chromatography (1:1 hexanes/ethyl acetate) to afford the title
compound (0.310 g). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
7.36-7.26 (m, 5H), 5.14 (s, 2H), 3.73-3.55 (m, 3H), 3.34 (d. 1H),
3.20-3.13 (m, 1H), 2.26-2.11 (m, 1H), 1.90-1.62 (m, 1H), 1.33 (d,
3H).
EXAMPLE A10
Synthesis of 3-(1-Aminoethyl)-3-hydroxypyrrolidine-1-carboxylic
acid benzyl ester
[1131] ##STR269##
[1132] A solution of
2-methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acid benzyl
ester (Example A9, 0.31 g, 1.25 mmol) in methanol (10 mL) and
ammonium hydroxide (7 mL) is heated in a sealed tube at 100.degree.
C. for 16 hours. After cooling, the reaction mixture is dissolved
ethyl acetate, washed with water, dried over Na.sub.2SO.sub.4 and
evaporated to afford the title compound (0.340 g).
[1133] .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.33-7.26 (m,
5H), 5.28 (bs, 2H), 5.07(s, 2H), 3.56-3.16(m, 5H), 2.03-1.76 (m,
2H), 1.15 (d, 3H).
EXAMPLE A11
Synthesis of
3-Hydroxy-3-{1-[(2-hydroxybenzylidene)amino]ethyl}pyrrolidine-1-carboxyli-
c acid benzyl ester
[1134] A solution of
3-(1-aminoethyl)-3-hydroxypyrrolidine-1-carboxylic acid benzyl
ester (Example A10, 0.34 g, 0.93 mmol) and salicylaldehyde (0.147
g, 1.2 mmol) in dry ethanol (5 mL) is refluxed for 3 hours. After
evaporation of the solvent, the residue is purified by column
chromatography (30:70:0.01 ethyl acetate/hexanes/ammonium
hydroxide) to afford the title compound (0.12 g).
[1135] .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.39 (s, 1H),
7.41-7.25 (m, 7H), 6.97-6.85 (m, 2H), 5.09 (s, 2H), 3.65-3.34 (m,
5H), 2.01-1.87 (m, 2H), 1.37-1.32 (m, 3H).
EXAMPLE A12
Synthesis of
3-Methoxy-3-{1-[(2-methoxybenzylidene)amino]ethyl}pyrrolidine-1-carboxyli-
c acid benzyl ester
[1136] To a stirred solution of
3-hydroxy-3-{1-[(2-hydroxybenzylidene)amino]-ethyl}pyrrolidine-1-carboxyl-
ic acid benzyl ester (Example A11, 0.120 g, 0.33 mmol) in
tetrahydrofuran (5 mL) at 0.degree. C. is added 0.024 g (1 mmol) of
sodium hydride. The mixture is stirred at room temperature for 2
hours and methyl iodide (3 mL) is added and stirring was continued
overnight. After evaporation, ethyl acetate and water are added to
the residue. The organic layer is separated, dried over
Na.sub.2SO.sub.4 and concentrated to afford the title compound
(0.125 g). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 8.70 (s, 1H),
7.95 (d, 1H), 7.41-7.32 (m, 6H), 7.01-6.88 (m, 2H), 5.09 (s, 2H),
3.86 (s, 3H), 3.72-3.22 (m, 8H), 2.33-1.73 (m, 2H), 1.27-1.24 (m,
3H).
EXAMPLE A13
(a) Synthesis of 3-(1-Aminoethyl)-3-methoxypyrrolidine-1-carboxylic
acid benzyl ester
[1137] ##STR270##
[1138] A solution of
3-methoxy-3-{1-[(2-methoxybenzylidene)amino]ethyl-pyrrolidine-1-carboxyli-
c acid benzyl ester (Example A12, 0.120 g, 0.3 mmol) in 3 M
hydrogen chloride in methanol (1 mL) is heated at 40.degree. C.
overnight. The reaction is basified, extracted with ethyl acetate
and the organic layer is dried over Na.sub.2SO.sub.4. After
concentration, the residue is purified by column chromatography
(20:80 methanol/dichloromethane) to afford the title compound
(0.060 g).
[1139] .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.38-7.29 (m,
5H), 5.12 (s, 2H), 3.64-3.19 (m, 8H), 2.47 (bs, 2H), 2.07-1.80 (m,
2H), 1.16-1.10 (m, 3H).
(b) 3-(1-Aminoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl
ester
[1140] ##STR271##
[1141] A solution of
3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester
(Example A16, 0.16 g, 0.5 mmol) in methanol (10 mL) is treated with
Raney nickel (100 mg, wet weight) and shaken in a hydrogen
atmosphere at room temperature and at 55 psi for 17 hours. The
catalyst is removed by filtration through Celite, and the solvent
is removed in vacuo to afford the title compound (0.12 g). .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta. 7.30 (s, 5H), 5.12 (s, 2H),
3.84-3.22 (m, 5H), 2.23-1.79 (m, 4H), 1.20 (d, 3H).
(c) 1-(1-Benzyl-3-methoxymethylpyrrolidin-3-yl)methylamine
[1142] ##STR272##
[1143] Hydrazine hydrate (85% solution in water, 0.372 g, 6.32
mmol) is added to a solution of
2-(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione
(Example A20, 1.581 g, 4.34 mmol) in ethanol (50 mL). The resulting
mixture is refluxed for 4.5 hours, cooled and acidified with
concentrated hydrochloric acid. The precipitate is removed by
filtration and the filtrate is concentrated in vacuo. The residue
is dissolved in ethanol/water (2:1) and the insoluble material is
removed by filtration. The filtrate is basified to pH 10 with 1N
sodium hydroxide solution and extracted with dichloromethane. The
combined organic extracts are dried over Na.sub.2SO.sub.4, filtered
and concentrated under vacuum to afford the title compound (0.910
g). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.41-7.15 (m, 5H),
3.57 (s, 2H), 3.33 (s, 3H), 3.30 (s, 2H), 2.71 (s, 2H), 2.64-2.51
(m, 2H), 2.42-2.24 (m, 2H), 1.68-1.52 (m, 2H), 1.38-1.10 (m,
2H).
General Method A
[1144] Lithium aluminium hydride (2 eq.) is slowly added to a
solution of oxime, nitrile, or amide derivative in dry
tetrahydrofuran. After the addition is complete, the mixture is
refluxed for 2 to 6 hours, cooled in an ice bath and quenched with
saturated sodium sulfate solution. The solid is removed by
filtration and the filtrate is concentrated in vacuo to afford the
title compound.
[1145] Examples A13d-i are prepared according to General Method
A.
[1146] (d) 1-(1-Benzylpiperidin-3-yl)ethylamine (.sup.1H NMR (200
MHz, DMSO-d.sub.6): .delta. 7.38-7.18 (m, 5H), 3.52-3.22 (m, 2H),
2.82-2.58 (m, 3H), 1.92-0.75 (m, 10H)) from
1-(1-benzylpiperidin-3-yl)ethanone oxime (Example A3b).
[1147] (e) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethylamine
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.36-7.22 (m, 5H),
3.66-3.42 (m, 2H), 2.94-2.10 (m, 5H), 1.32-0.88 (m, 10H)) from
1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone oxime (Example
A3c).
[1148] (f) 1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethylamine (.sup.1H
NMR (200 MHz, CDCl.sub.3): .delta. 7.38-7.11 (m, 5H), 3.63-3.12 (m,
2H), 2.78-2.27 (m, 5H), 2.23-1.18 (m, 4H), 1.10-0.78 (m, 6H)) from
1-(1-benzyl-4-methylpyrrolidin-3-yl)ethanone oxime (Example
A3d).
[1149] (g) 1-(5-Benzyl-5-azaspiro[2,4]hept-7-yl)methylamine
(.sup.1H NMR (CDCl.sub.3): .delta. 7.36-7.21 (m, 5H), 3.68-3.53 (m,
2H), 3.1 (dd, 1H), 2.61-2.38 (m, 5H), 2.1-1.92 (m, 1H), 1.29 (bs,
2H), 0.72-0.32 (m, 4H)) from
5-benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid amide (Example
A24).
[1150] (h)
1-[3-(1-Phenylethyl)-3-azabicyclo[3.1.0]hex-1-yl]methylamine (MS
ES: m/z 217 (MH.sup.+)) from
3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile
(Takemura M., Kimura Y., Kawakami K., EP 0807630).
[1151] (i) 1,3-Dibenzyl-3-pyrrolidinemethanamine (MS El: m/z 281
(MH.sup.+)) from 1,3-dibenzyl-3-pyrrolidine carboxamide (Example
A29).
EXAMPLE A14
Synthesis of 3-Fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic
acid benzyl ester
[1152] ##STR273##
[1153] A solution of 0.247 g, (1 mmol) of
2-methyl-1-oxa-5-azaspiro[2,4]-heptane-5-carboxylic acid benzyl
ester (Example A9) in dichloromethane (3 mL) is added to a
polypropylene flask containing 0.5 mL of hydrogen fluoride-pyridine
at -40.degree. C. The reaction is allowed to come to room
temperature and stirring is continued for 3 hours. The reaction
mixture is poured into an aqueous ice-cold ammonium hydroxide
solution (30 mL) and extracted with dichloromethane. The organic
layer is dried, filtered and concentrated to afford the title
compound (0.267 g). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.35
(s, 5H), 5.13 (s, 2H), 3.96-3.34 (m, 5H), 2.20-1.98 (m, 3H),
1.33-1.26 (m, 3H).
EXAMPLE A15
Synthesis of
3-Fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic b
acid benzyl ester
[1154] To a -10.degree. C. solution of
3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl
ester (Example A14, 0.267 g, 1.00 mmol), triethylamine (0.4 g, 4
mmol) and dichloromethane (10 mL) is added methanesulfonyl chloride
(0.229 g, 2.00 mmol). The mixture is stirred at room temperature
for 2 hours and concentrated in vacuo. The residue is partitioned
between ethyl acetate and water. The organic layer is dried over
Na.sub.2SO.sub.4 and concentrated to afford the title compound
(0.330 g). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.36 (s, 5H),
5.14 (s, 2H), 4.99-4.81 (m, 1H), 3.76-3.37 (m, 4H), 3.06 (s, 3H),
2.25-1.96 (m, 2H), 1.52-1.47 (m, 3H).
EXAMPLE A16
Synthesis of 3-(1-Azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid
benzyl ester
[1155] To a solution of
3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid
benzyl ester (Example A15, 0.25 g, 0.72 mmol) in
N,N-dimethylformamide (5 mL) is added sodium azide (0.13 g, 2
mmol). The reaction mixture is heated at 120.degree. C. overnight.
The mixture is diluted with water and extracted with ethyl acetate.
The extracts are washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to afford the title compound (0.160 g). .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta. 7.28 (s, 5H), 5.08 (s, 2H),
3.80-3.25 (m, 5H), 2.13-1.75 (m, 2H), 1.40 (d, 3H).
EXAMPLE A17
Synthesis of 2-Methoxymethylacrylic acid ethyl ester
[1156] ##STR274##
[1157] A solution of ethyl .alpha.-(bromomethyl)acrylate (0.99 g,
5.1 mmol [Villieras J., Rambaud M., Synthesis, 1982:924-926]) in
methanol (10 mL) is added to an ice-cold solution of sodium
methoxide (0.33 g, 6.1 mmol) in methanol (50 mL). The suspension is
refluxed for 21 hours, cooled, diluted with water and extracted
with dichloromethane. The organic extracts are dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The
resulting residue is purified by flash column chromatography (1:5
ethyl acetate/hexanes) to afford the title compound (0.211 g).
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 6.33-6.26 (m, 1H),
5.88-5.80 (m, 1H), 4.23 (q, 2H), 4.19-4.10 (m, 2H), 3.41 (s, 3H),
1.31 (t, 3H).
EXAMPLE A18
General Method A
[1158] A solution of substrate and
N-(methoxymethyl)-N-(trimethyl-silylmethyl)benzylamine (1.3 eq.) in
dichloromethane at 0.degree. C. is treated with trifluoroacetic
acid (0.07 eq). The mixture is stirred at room temperature for 3
hours, diluted with dichloromethane and washed successively with a
saturated NaHCO.sub.3 solution and brine. The organic extracts are
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum to afford the title compounds.
[1159] The examples below (Example A18a-e) were prepared according
to General Method A.
[1160] (a) 1-Benzyl-3-methoxymethylpyrrolidine-3-carboxylic acid
ethyl ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.45-7.16
(m, 5H), 4.19 (q, 2H), 3.78-3.67 (m, 2H), 3.55 (s, 2H), 3.31 (s,
3H), 3.11-2.92 (m, 1H), 2.89-2.49 (m, 2H), 2.42-2.21 (m, 2H),
1.99-1.78 (m, 1H), 1.26 (t, 3H)) from 2-methoxymethylacrylic acid
ethyl ester (Example A17).
[1161] (b) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone
(.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.36-7.22 (m, 5H), 3.60
(d, 2H), 3.05-2.20 (m, 5H), 2.15 (s, 3H), 1.30 (s, 3H), 0.96 (s,
3H)) from mesityl oxide.
[1162] (c) 1-Benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl
ester (.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.44-7.13 (m,
5H), 4.21-4.04 (q, 1H), 3.71-3.49 (m, 3H), 2.94-2.71 (m, 3H),
2.61-2.41 (m, 2H), 2.28-2.04 (m, 1H), 1.32-1.18 (t, 3H), 1.16-1.04
(d, 3H). MS ES: m/z 248 (MH.sup.+)) from ethyl crotonate.
[1163] (d) Pyrrolidine-3-carboxylic acid tert-butyl ester (MS ES:
m/z 172 (MH.sup.+)) from tert-butylacrylate.
[1164] (e) Ethyl1,3-dibenzyl-3-pyrrolidinecarboxylic acid (MS El+:
m/z 324 (MH.sup.+)) from ethyl-2-phenylmethylacrylic acid
(Vassiliou S., Mucha A., Cuniasse P., Georgiadis D.,
Lucet-Levannier K., Beau F., Kannan R, et al., J. Med. Chem.,
1999;42(14):2610-2620).
EXAMPLE A19
Synthesis of (1-Benzyl-3-methoxymethylpyrrolidin-3-yl)methanol
[1165] ##STR275##
[1166] A solution of
1-benzyl-3-methoxymethylpyrrolidine-3-carboxylic acid ethyl ester
(Example A18a, 2.30 g, 8.3 mmol) in anhydrous tetrahydrofuran (10
mL) is added dropwise to an ice-cold suspension of lithium aluminum
hydride (0.821 g, 22 mmol) in tetrahydrofuran (50 mL). The
resulting mixture is stirred at room temperature for 18 hours,
cooled and quenched by the sequential dropwise addition of 1N
sodium hydroxide and water. The solids are removed by filtration,
re-suspended in hot tetrahydrofuran and filtered. The combined
filtrates are concentrated in vacuo and the residue is partitioned
between dichloromethane and water. The organic extracts are dried
over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to
afford the title compound (1.71 g). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.41-7.17 (m, 5H), 3.84-3.43 (m, 4H), 3.34 (s,
2H), 3.32 (s, 3H), 2.85-2.60 (m, 2H), 2.54-2.14 (m, 3H), 1.98-1.50
(m, 2H).
EXAMPLE A20
2-(1-Benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione
[1167] ##STR276##
[1168] A solution of
(1-benzyl-3-methoxymethylpyrrolidin-3-yl)methanol (Example A19,
1.71 g, 7.27 mmol), triphenylphosphine (2.16 g, 8.22 mmol),
phthalimide (1.14 g, 7.73 mmol), and anhydrous tetrahydrofuran is
cooled to 0.degree. C. and treated with diethyl azodicarboxylate
(1.62 g, 9.31 mmol). The resulting mixture is stirred at room
temperature for 18 hours and concentrated under vacuum. The residue
is purified by flash column chromatography (1:5 ethyl
acetate/hexanes) to afford the title compound, (0.58 g) as a solid.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.91-7.80 (m, 2H),
7.78-7.66 (m, 2H), 7.39-7.11 (m, 5H), 3.95-3.72 (m, 2H), 3.65-3.40
(m, 2H), 3.31 (s, 2H), 3.27 (s, 3H), 2.72-2.34 (m, 4H), 2.02-1.82
(m, 1H), 1.76-1.56 (m, 1H). MS ES: m/z 365 (MH.sup.+).
EXAMPLE A21
Synthesis of 1-Benzylpiperidine-3-carboxylic acid benzyl ester
[1169] ##STR277##
[1170] To a solution added of nipecotic acid (8.0 g, 61.9 mmol) in
N,N-dimethylformamide (80 mL) is benzyl bromide (31.8 g, 186 mmol)
and potassium carbonate (42.8 g, 310 mmol). The mixture is heated
at 70.degree. C. for 18 hours and diluted with ethyl acetate and
water. The organic extract is washed with 1.0 M hydrochloric acid,
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by column
chromatography (1:7 ethyl acetate/hexanes) to afford the title
compound (8.6 g). .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.
7.27-7.42 (m, 10H), 5.07 (s, 2H), 3.45 (s, 2H), 2.88-2.49 (m, 3H),
2.32-1.32 (m, 6H).
EXAMPLE A22
Synthesis of 1-Benzylpiperidine-3-carboxylic acid
[1171] ##STR278##
[1172] To a solution 3.0 g (9.7 mmol) of
1-benzylpiperidine-3-carboxylic acid benzyl ester (Example A21) in
methanol (20 mL) was added 1N sodium hydroxide (20 mL), and the
reaction is stirred at room temperature for 18 hours. The methanol
is removed in vacuo and the basic aqueous solution is acidified to
pH 4 with 1.0 M hydrochloric acid. After washing with ethyl
acetate, the aqueous acid layer is lyophilized. The solid is
suspended in methanol (10 mL), stirred for 10 minutes and filtered.
The filtrate is evaporated in vacuo to afford the title compound
(2.0 g). .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 7.38-7.23 (m,
5H), 3.58 (s, 2H), 2.98-2.40 (m, 3H), 2.30-1.25 (m, 6H).
EXAMPLE A23
General procedure A
[1173] Methyl lithium (1.1 eq.) is added dropwise to a -70.degree.
C. solution of substrate in tetrahydrofuran (15 mL). The resulting
mixture is stirred at -70.degree. C. for 1 hour, and then warmed to
room temperature for 18 hours. The reaction is diluted with ice
water and ether and the organic layer is separated. The aqueous
layer is extracted with ether and the combined extracts are dried
with Na2SO.sub.4 and concentrated in vacuo to afford the title
compound.
[1174] The following compounds are prepared according to general
procedure A.
[1175] (a) 1-(1-Benzylpiperidin-3-yl)ethanone (.sup.1H NMR (200
MHz, DMSO-d.sub.6): .delta. 7.38-7.22 (m, 5H), 3.45 (s, 2H),
2.85-2.48 (m, 3H), 2.05 (s, 3H), 2.16-1.06 (m, 6H)) from
1-benzylpiperidine-3-carboxylic acid (Example A22).
[1176] (b) 1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethanone (.sup.1H
NMR (200 MHz, CDCl.sub.3): .delta. 7.42-7.18 (m, 5H), 3.71-3.45 (m,
3H), 2.89-2.33 (m, 5H), 2.16 (s, 3H), 1.12 (d, 3H)) from
1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester (Example
A18c).
EXAMPLE A24
Synthesis of 5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid
amide
[1177] ##STR279##
[1178] 5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid amide
(3.32 g) is prepared from
5-benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid (Example A28b,
5.0 g, 21.64 mmol) in dichloromethane by conversion to the acid
chloride using oxalyl chloride (5.0 mL, 65 mmol) and
N,N-dimethylformamide (3 drops). The mixture is allowed to stir for
2 hours then concentrate in vacuo. The residue is redissolved in
dichloromethane and the mixture is again concentrated in vacuo. The
residue is dissolved in ether and treated with a solution of
ammonia in ether. After 1 hour, the mixture is concentrated in
vacuo to provide the title compound. .sup.1H NMR (CDCl.sub.3):
.delta. 7.6 (bs, 1H), 7.38-7.23 (m, 5H), 5.42 (bs, 1H), 3.75-3.57
(m, 2H), 3.19 (d, 1H), 2.83-2.64 (m, 2H), 2.4 (d, 2H), 0.96-0.58
(m, 4H).
EXAMPLE A25
Synthesis of 2(1-Benzylpyrrolidin-3-yl)propan-2-ol
[1179] To a 5.degree. C. solution of
1-benzylpyrrolidine-3-carboxylic acid ethyl ester (0.467 g, 2.0
mmol) in tetrahydrofuran (25 mL) is added an etherial solution of
methylmagnesium bromide (3.3 mL, 10 mmol). The reaction mixture is
stirred at room temperature for 2 hours, cooled to 0.degree. C. and
saturated aqueous ammonium chloride (10 mL) is added followed by
water (10 mL). The mixture is extracted with ethyl acetate
(2.times.100 mL) and the combined organic extracts are washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum to afford the title compound (0.43 g). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 7.30-7.22 (m, 5H), 3.59 (s, 2H), 3.0 (bs, 1H),
2.80-2.66 (m, 2H), 2.48-2.30 (m, 2H), 2.20-2.05 (m, 1H), 1.94-1.80
(m, 2H), 1.19 (s, 3H), 1.16 (s, 3H).
EXAMPLE A26
Synthesis of 2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic
acid tert-butyl ester
[1180] ##STR280##
[1181] 2-Benzyloctahydropyrrolo[3,4-c]pyridine (21.6 g, 100 mmol
[Himmler T., Petersen U., Bremm K-D., Endermann R., Stegemann M.,
Wetzstein H-G., 1995, U.S. Pat. No. 5,578,604] is dissolved in 1000
mL of dichloromethane containing triethylamine (16.7 mL, 120 mmol).
Then di-t-butyldicarbonate (22.6 g, 120 mmol) is added and the
mixture is stirred at room temperature for 18 hours. The organic
layer is washed with saturated NaHCO.sub.3, brine, dried, and
concentrated to provide 30 g of the title compound as an oil; MS
El+: 318 (MH.sup.+).
EXAMPLE A27
Synthesis of octahydropyrrolo[3,4-c]pyridine-5-carboxylic acid
tert-butyl ester
[1182] ##STR281##
[1183] 2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic acid
tert-butyl ester (Example A26, 24.98 g, 78.8 mmol) in 400 mL of
methanol is treated with 2.5 g of 20% Pd/C and shaken for 20.5
hours under 50 PSI of hydrogen. The solution is filtered and
concentrated to afford 17.8 g of the title compound as a solid. MS
APCI: m/z 228 (MH.sup.+).
EXAMPLE A28
(a) Synthesis of 1,3-Dibenzylpyrrolidine-3-carboxylic acid
[1184] ##STR282##
[1185] To a solution of 1,3-dibenzylpyrrolidine-3-carboxylic acid
ethyl ester (Example A18e, 13.1 g, 41 mmol) in 250 mL of methanol
is added 2N NaOH (46 mL, 92 mmol) and the reaction is heated to
reflux for 24 hours. The solution is cooled, concentrated,
redissolved in water and extracted with ether. The pH of the
aqueous layer is adjusted to 7 and the precipitated solid is
collected, to give 9.3 g of the title compound, MS El+: m/z 296
(MH.sup.+), mp 209-210.degree. C.
[1186] (b) 5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid (MS
ES: m/z 232) from 5-benzyl-7-ethoxycarbonyl-5-azaspiro[2,4]heptane
(A1) using the method of Example A28a
EXAMPLE A29
Synthesis of 1,3-Dibenzylpyrrolidine-3-carboxylic acid amide
[1187] ##STR283##
[1188] A mixture of 1,3-dibenzylpyrrolidine-3-carboxylic acid
(Example A28, 4.0 g, 13.5 mmol), 1,1'-carbonyldiimidazole (2.42 g,
14.9 mmol), and triethylamine (2.08 mL, 14.9 mmol) in
tetrahydrofuran (100 mL) is heated at reflux for 1.5 hours. The
solution is cooled, poured into NH.sub.4OH (300 mL), and stirred
for 18 hours. The mixture is extracted with chloroform, the organic
layer is washed with water, dried, and concentrated to afford 4.13
g of the title compound as an oil; MS El+: m/z 295 (MH.sup.+).
EXAMPLE A30
Synthesis of (3-Phenylpyrrolidin-3-yl)carbamic acid tert-butyl
ester
[1189] ##STR284##
[1190] (1-Benzyl-3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl
ester (Hagen S. E., Domagala J. M., Heifetz C. L., Sanchez J. P.,
Solomon M., J. Med. Chem., 1990;33(2):849-854) (2.79 g, 7.9 mmol)
in 100 mL of methanol is treated with 1.0 g of 20% Pd/C and shaken
for 17 hours under 50 psi of hydrogen. The solution is filtered and
concentrated to afford 2.07 g of the title compound as a foam; MS
EI+: m/z 263 (MH.sup.+).
[1191] The compounds of the present invention are potent inhibitors
of bacterial growth both in animals and on surfaces, and also are
inhibitors of bacterial enzymes. The invention compounds have been
evaluated in a number of standard in vitro and in vivo assays
routinely used by those in the antibacterial art to measure
antibacterial activity of test compounds.
Antibacterial Assay
[1192] The compounds of the present invention are tested against an
assortment of Gram negative and Gram positive organisms using
standard microtitration techniques (Cohen et al., Antimicrob.
Agents Chemother., 1985;28:766; Heifetz et al., Antimicrob. Agents
Chemother, 1974;6:124). The results of the evaluation of
representative 3-aminoquinazolin-2,4-diones of Formula I are shown
in Table 2 and compared to two 3-hydroxyquinazolin-2,4-diones.
DNA Gyrase Assay
[1193] The effects of invention compounds on the activity of DNA
gyrase is determined in the supercoiling inhibition assay,
following reaction conditions recommended by the enzyme supplier
(Lucent, Ltd., Leicester, UK). Reactions are performed in buffer G
(35 mM Tris-HCl (pH 7.5), 24 mM KCl, 4 mM MgCl.sub.2, 2 mM DTT, 1.8
mM spermidine, 1 mM ATP, 0.1 mg/mL bovine serum albumin). Relaxed
plasmid pBR322 (0.25 .mu.g, Lucent, Ltd., Leicester, UK) is reacted
with 1 U E. coli gyrase (Lucent, Ltd., Leicester, UK), in the
absence or presence of test compounds, for 30 minutes at 37.degree.
C. Reactions are stopped by the addition of SDS and proteinase K to
respective final concentrations of 1% and 0.5 mg/mL. After an
additional 30 minutes at 37.degree. C., one-tenth volume of
10.times. loading buffer (0.3% bromophenol blue, 16% Ficoll, 10 mM
Na.sub.2HPO.sub.4) is added, and reactions are loaded onto agarose
gels and electrophoresed. The concentration of representative
invention compounds of Formula I inhibiting 50% of the supercoiling
activity of DNA gyrase is given as an IC.sub.50 and recorded in
Table 2. TABLE-US-00003 TABLE 2 Antibacterial and E. coli gyrase
Activities Minimum Inhibitory Concentrations .mu.g/mL E. coli Gram
Negatives Gram Positives gyrase E. coli E. coli E. coli E. faecalis
S. aureus S. pyogenes IC.sub.50 Compound Number or Structure MC4100
B90 Tol C RB1 29213 C203 (.mu.M) 1 2.0 1.0 0.25 1.0 0.5 0.13 1.0 2
16.0 4.0 2.0 >64 >64 >64 26.0 7 2.0 0.5 0.25 8.0 8.0 4.0
1.3 9 2.0 1.0 0.5 32.0 16.0 16.0 3.0 11 2.0 0.5 0.25 8.0 8.0 4.0
11.0 12 16.0 0.25 0.13 4.0 2.0 8.0 2.1 14 4.0 0.25 0.5 8.0 8.0 4.0
2.4 ##STR285## 1.0 0.25 0.25 4.0 4.0 2.0 0.9 ##STR286## 8.0 2.0 1.0
64.0 32.0 32.0 5.0
[1194] The in vivo activity of invention compounds is evaluated
according to the procedure of Miller et al., Proc. Soc. Exp. Biol.
Med., 1944;57:261. The median protective dose (PD.sub.50) is
determined in mice given lethal systemic infections. Two
3-aminoquinazolin-2,4-diones of the invention are compared to a
3-hydroxyquinazolin-2,3-dione, and the results are presented in
Table 3. The results establish the unexpected superiority of the
3-amino invention compounds compared to similar 3-hydroxy analogs.
TABLE-US-00004 TABLE 3 In Vivo Median Protective Dose (PD.sub.50)
in Mice PD50 Compound Number or Structure Organism (mg/kg) 1 S.
pyogenes 12 10 E. coli 72 ##STR287## S. pyogenes >100
Cross Resistance Antibacterial Assay
[1195] The compounds of the present invention are tested against an
assortment of ciprofloxacin resistant E. coli and S. aureus
organisms described below using standard microtitration techniques
(Cohen, et al., Antimicrob. Agents Chemother, 1985;28:766; Heifetz,
et al., Antimicrob. Agents Chemother., 1974;6:124). The results of
the evaluation are shown in Table 4 and compared to two
3-hydroxyquinazolin-2,4-diones.
E. coli and S. aureus Organisms:
[1196] E. coli JL4: E. coli W3110+Tol C.sup.- (Tol C pump deficient
strain with E. coli W3 110 background) [1197] E. coli LLM-1:
Isogenic to E. coli JL4 with a D87G mutation (aspartic acid to
glycine at position 87) in the QRDR (quinolone resistance
determining region) [1198] S. aureus UC-76: Typical sensitive
laboratory strain (Wild type) [1199] S. aureus 2552: Isogenic to S.
aureus UC-76, with upregulated norA pump [1200] S. aureus 2554:
Isogenic to S. aureus 2552, with point mutation at position 80 of
grlA.subunit
[1201] S. aureus 2558: Isogenic to S. aureus 2554, with point
mutation at position 84 of gyrA subunit TABLE-US-00005 TABLE 4
Antibacterial Activities Against Ciprofloxacin Resistant Strains
Minimum Inhibitory Concentrations .mu.g/mL E. coli E. coli S.
aureus S. aureus S. aureus S. aureus Compound Number of Structure
JL4 LLM1 UC-76 2552 2554 2558 1 0.13 0.5 0.13 1 1 1 3 0.5 1 1 2 2 4
12 0.06 0.25 1 1 1 2 ##STR288## 0.25 4 4 32 32 >64 ##STR289##
0.5 2 4 >64 >64 >64
[1202] The quinolone mimics provided by this invention display
Gram-negative and Gram-positive activity. The compounds also show
inhibition of bacterial DNA gyrase/activity. The compounds
demonstrate in vivo protective activity in mice and are not highly
cytotoxic to mammalian cells, thus indicating selectivity for
bacteria. The compounds of Formula I are thus useful for treating
and preventing bacterial disease and growth in both animals and on
surfaces. The compounds can be applied to wood and metal surfaces,
for instance, to eliminate bacterial growth. The compounds can be
administered to animals such as humans, horses, dogs, sheep, and
cattle to prevent and treat bacterial infections.
[1203] The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms
for convenient administration to animals. Thus, the compounds of
the present invention can be administered by injection, that is,
intravenously, intramuscularly, intracutaneously, subcutaneously,
intraduodenally, or intraperitoneally. Also, the compounds of the
present invention can be administered by inhalation, for example,
intranasally. Additionally, the compounds of the present invention
can be administered transdermally. It will be obvious to those
skilled in the art that the following dosage forms may comprise as
the active component, either a compound of Formula I or a
corresponding pharmaceutically acceptable salt of a compound of
Formula I. The formulations typically will comprise from about 1 to
about 95 percent by weight of the active invention compound. The
compounds can be dissolved or suspended in liquids, such as
ethanol, and applied to wood or metal surfaces to prevent and/or
kill bacterial growth.
[1204] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.
[1205] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[1206] In tablets, the active component is mixed with the carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired.
[1207] The powders and tablets preferably contain from five or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as a
carrier providing a capsule in which the active component with or
without other carriers, is surrounded by a carrier, which is thus
in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges
can be used as solid dosage forms suitable for oral
administration.
[1208] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[1209] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water propylene glycol solutions.
For parenteral injection liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[1210] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents as
desired.
[1211] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or, synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents.
[1212] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[1213] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is divided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[1214] The quantity of invention compound in a unit dose
preparation may be varied or adjusted from 0.1 mg to 100 mg,
preferably from 0.5 mg to 100 mg, according to the particular
application and the potency of-the active component as determined
by a skilled physician. The composition can, if desired, also
contain other compatible therapeutic agents.
[1215] In therapeutic use as agents for the treatment of infections
caused by a bacteria, the compounds utilized in the pharmaceutical
method of this invention are administered at the initial dosage of
about 0.01 mg to about 500 mg/kg daily. A daily dose range of about
0.01 mg to about 100 mg/kg is preferred. The dosages, however, may
be varied depending upon the requirements of the patient, the
severity of the condition being treated, and the particular
compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the medical art.
Generally, treatment is initiated with smaller dosages which are
less than the optimum dose of the compound. Thereafter, the dosage
is increased by small increments until the optimum effect under the
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day, if
desired.
[1216] The following additional examples illustrate typical
formulations for use according to the invention.
EXAMPLE 37
[1217] TABLE-US-00006 1. Tablet Formulation Ingredient Amount (mg)
Compound No. 10 50 Cornstarch (mix) 15 Cornstarch (paste) 5 Lactose
50 Calcium stearate 2 Dicalcium phosphate 28 150
[1218] Compound 10 is blended to uniformity with the cornstarch
mix, lactose, and dicalcium phosphate. The cornstarch paste is
prepared as a 10% aqueous paste, and it is blended to uniformity
with the other mixture. The wet granulation is passed through a
standard 8-mesh screen. The wet granules are dried and then blended
to uniformity with the calcium stearate and pressed into a tablet.
Such tablets are administered orally to patients suffering from
bacterial infections at the rate of from one to about four times a
day. TABLE-US-00007 2. Capsule Formulation Ingredients Amount (mg)
Compound No. 25 120 Lactose USP 150 Starch 100 Magnesium stearate 5
150
[1219] The ingredients are blended to uniformity and packed into a
soft gelatin capsule. The capsules are administered at the rate of
one to two per day to a patient infected with bacteria resistant to
commercially available quinolone antibiotics. TABLE-US-00008 3.
Liquid Preparation Ingredient Amount Compound No. 18 500 mg Water
1000 mL
[1220] The compound is dissolved in water, and the solution is
sprayed onto wood surfaces and in shower stalls to control and
eliminate bacterial growth.
[1221] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
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