U.S. patent application number 16/753645 was filed with the patent office on 2020-08-13 for chemical compounds.
This patent application is currently assigned to GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED. The applicant listed for this patent is GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED. Invention is credited to John G. CATALANO, Pek Yoke CHONG, Hamilton D. DICKSON, Martin R. LEIVERS, Jason Gordon WEATHERHEAD.
Application Number | 20200255428 16/753645 |
Document ID | 20200255428 / US20200255428 |
Family ID | 1000004823904 |
Filed Date | 2020-08-13 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200255428 |
Kind Code |
A1 |
CATALANO; John G. ; et
al. |
August 13, 2020 |
CHEMICAL COMPOUNDS
Abstract
Compounds, specifically hepatitis B virus and/or hepatitis D
virus inhibitors, more specifically compounds that inhibit HBe
antigen and HBs antigen in a subject, for the treatment of viral
infections, and methods of preparing and using such compounds.
Inventors: |
CATALANO; John G.; (Research
Triangle Park, NC) ; CHONG; Pek Yoke; (Research
Triangle Park, NC) ; DICKSON; Hamilton D.; (Research
Triangle Park, NC) ; LEIVERS; Martin R.; (Research
Triangle Park, NC) ; WEATHERHEAD; Jason Gordon;
(Research Triangle Park, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED |
Brentford, Middlesex |
|
GB |
|
|
Assignee: |
GLAXOSMITHKLINE INTELLECTUAL
PROPERTY DEVELOPMENT LIMITED
Brentford, Middlesex
GB
|
Family ID: |
1000004823904 |
Appl. No.: |
16/753645 |
Filed: |
October 5, 2018 |
PCT Filed: |
October 5, 2018 |
PCT NO: |
PCT/IB2018/057767 |
371 Date: |
April 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62568633 |
Oct 5, 2017 |
|
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|
62570509 |
Oct 10, 2017 |
|
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|
62681146 |
Jun 6, 2018 |
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62683859 |
Jun 12, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/20 20180101;
C07D 471/14 20130101 |
International
Class: |
C07D 471/14 20060101
C07D471/14; A61P 31/20 20060101 A61P031/20 |
Claims
1. A compound of Formula I ##STR00457## wherein W is N: Y is C;
wherein R.sup.1 is absent; R.sup.2 and R.sup.3 are independently
selected from hydrogen, hydroxy, halogen, cyano, amino or
substituted amino, thio or substituted thio, alkyl or substituted
alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted
cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered
heterocycloalkyl or substituted 3- to 8-membered heterocycloalkyl,
aryl or substituted aryl, heteroaryl or substituted heteroaryl,
pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; R.sup.5 is hydrogen; R.sup.8 is
hydrogen; R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22'; R.sup.9 is hydrogen; R.sup.10 is --CO.sub.2H or
a tautomer thereof; R.sup.11 is hydrogen; R.sup.12 is hydrogen;
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl
or substituted heteroaryl; R.sup.15, R.sup.15', R.sup.16 and
R.sup.16' are independently hydrogen, hydroxy, halogen, amino,
cyano, C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.15 and
R.sup.15' or R.sup.16 and R.sup.16' together form a 3- to
8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
R.sup.19, R.sup.19' and R.sup.19'' are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkyl, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone; and R.sup.20
and R.sup.21 are independently hydrogen, C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, C.sub.1-6alkenyl, C.sub.1-6alkoxy, phenyl,
C.sub.1-6alkylimidizole, C.sub.1-6alkyltriazole,
C.sub.1-6alkyltetrazole, C.sub.1-6alkylthiazole,
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone, or R.sup.20 and R.sup.21 together with
the nitrogen to which they are attached form unsubstituted
pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted
morpholinyl; or form carboxyl-substituted pyrrolidinyl,
carboxyl-substituted piperidinyl or carboxyl-substituted
morpholinyl; and R.sup.22 and R.sup.22' are independently selected
from hydrogen, oxygen, C.sub.1-6alkyl or substituted
C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl or substituted C.sub.3-8cycloalkyl,
C.sub.2-6alkenyl or substituted C.sub.2-6alkenyl, aryl or
substituted aryl, including substituted or unsubstituted
C.sub.1-6alkylimidizole, substituted or unsubstituted
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, substituted or unsubstituted
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone; --COR.sup.19, --COOR.sup.19',
--CSOR.sup.19'', --CONR.sup.20R.sup.21, or a pharmaceutically
acceptable salt thereof.
2. (canceled)
3. The compound of Formula I or pharmaceutically acceptable salt
thereof according to claim 1, wherein R.sup.6 and R.sup.7 together
form a 3- to 8-membered cycloalkyl ring, optionally substituted
with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'.
4. (canceled)
5. A compound of Formula IA or Formula IB: ##STR00458## wherein C*
is a carbon atom stereocenter which has a configuration which is
(R) or (S), w is N; Y is C; wherein R.sup.1 is absent; R.sup.2 and
R.sup.3 are independently selected from hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; R.sup.5 is
hydrogen; R.sup.8 is hydrogen; R.sup.6 and R.sup.7 together form a
3 to 8 membered cycloalkyl ring, optionally substituted with
R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'; R.sup.9 is
hydrogen; R.sup.10 is --CO.sub.2H or a tautomer thereof; R.sup.11
is hydrogen; R.sup.12 is hydrogen; alkyl or substituted alkyl,
alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl; R.sup.15,
R.sup.15', R.sup.16 and R.sup.16' are independently hydrogen,
hydroxy, halogen, amino, cyano, C.sub.1-6alkyl, or C.sub.1-6alkoxy;
or a pharmaceutically acceptable salt thereof.
6. (canceled)
7. The compound of Formula I according to claim 1 or a
pharmaceutically acceptable salt thereof, wherein: R.sup.2 and
R.sup.3 are independently selected from hydrogen, hydroxy, halogen,
cyano, amino, thio, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy; C.sub.3-8
cycloalkyl or substituted C.sub.3-8cycloalkyl; C.sub.2-8alkenyl or
substituted C.sub.2-8alkenyl, or --OR.sup.12; R.sup.6 and R.sup.7
together form a 3- to 8-membered cycloalkyl ring, optionally
substituted with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'
R.sup.12 is hydrogen; C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.3-8heterocycloalkyl or
substituted C.sub.3-8heterocycloalkyl; and R.sup.22 and R.sup.22'
are independently selected from hydrogen, oxygen, C.sub.1-6alkyl or
substituted C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted
C.sub.1-6alkoxy, C.sub.3-8cycloalkyl or substituted
C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl.
8. The compound of Formula I pharmaceutically acceptable salt
thereof according to claim 1, wherein: R.sup.15, R.sup.15',
R.sup.16 and/or R.sup.16' are independently hydrogen, hydroxy,
halogen, amino, cyano, C.sub.1-6alkyl, or C.sub.1-6alkoxy.
9. The compound of Formula I a pharmaceutically acceptable salt
thereof according to claim 8, wherein: R.sup.2 is halogen; and
R.sup.3 is OR.sup.12.
10. The compound of Formula I pharmaceutically acceptable salt
thereof according to claim 9, wherein: R.sup.15, R.sup.15',
R.sup.16 and/or R.sup.16' are independently C.sub.1-6alkyl.
11. The compound of Formula I pharmaceutically acceptable salt
thereof according to claim 1, wherein: R.sup.6 and R.sup.7 together
form a 3- to 8-membered cycloalkyl ring, optionally substituted
with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'.
12. (canceled)
13. A compound selected from the group:
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid;
(4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,-
7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyli-
c acid;
(4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4-
b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-car-
boxylic acid;
2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid;
(7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4-
b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-car-
boxylic acid;
(7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid;
(7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-ox-
o-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10--
carboxylic acid;
(4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,-
11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid;
(4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid;
2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,-
10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihyd-
ro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-1-oxo-2-(prop-1-en-2-yl)-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5-
,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-
-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
(2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-
-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihyd-
ro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihyd-
ro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid;
2',3'-Dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h-
][1,7]naphthyridine]-9'-carboxylic acid;
6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthy-
ridine-9-carboxylic acid;
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;
3'-(cyclopropylmethoxy)-2'-(difluoromethyl)-11'-fluoro-10'-oxo-5',10'-dih-
ydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic
acid;
2'-(difluoromethyl)-11'-fluoro-10'-oxo-3'-((tetrahydrofuran-3-yl)me-
thoxy)-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridin-
e]-9'-carboxylic acid;
(S)-3-(cyclopropylmethoxy)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-met-
hyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid; and
(6S)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-3-
-((tetrahydrofuran-3-yl)methoxy)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthy-
ridine-9-carboxylic acid; or a pharmaceutically acceptable salt or
tautomer thereof.
14. The compound according to claim 1 selected from: ##STR00459##
##STR00460## ##STR00461## or a pharmaceutically acceptable salt
thereof.
15-30. (canceled)
31. A method of treating or preventing a virus infection in a
subject susceptible to or suffering from the virus infection
comprising administering to the subject an inhibitor of a HBe or
HBs antigen wherein the inhibitor is a compound of Formula I
according to claim 1.
32. The method of treating or preventing a virus infection in a
subject according to claim 31, wherein the virus infection is a
hepatitis B virus infection.
33. (canceled)
34. A method of inhibiting the level of HBe or HBs antigen in a
mammal, comprising administering to said mammal a therapeutically
effective amount of a compound of Formula I according to claim 1 or
a pharmaceutically acceptable salt, solvate or hydrate thereof.
35. The method according to claim 34, wherein the mammal is a
human.
36. A pharmaceutical composition comprising a pharmaceutically
acceptable diluent and a therapeutically effective amount of a
compound as defined in Formula I according to claim 1.
37-43. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful for
treatment of HBV in animals, and more particularly for treatment of
HBV in humans.
BACKGROUND OF THE INVENTION
[0002] Hepatitis B is a viral disease transmitted parenterally by
contaminated material such as blood and blood products,
contaminated needles, sexually and vertically from infected or
carrier mothers to their offspring. In those areas of the world
where the disease is common vertical transmission at an early age
results in a high proportion of infected individuals becoming
chronic carriers of hepatitis B. It is estimated by the World
Health Organization that more than 2 billion people have been
infected worldwide, with about 4 million acute cases per year, 1
million deaths per year, and 350-400 million chronic carriers.
Approximately 25% of carriers die from chronic hepatitis,
cirrhosis, or liver cancer and nearly 75% of chronic carriers are
Asian. Hepatitis B virus (HBV) is the second most significant
carcinogen behind tobacco, causing from 60% to 80% of all primary
liver cancer. HBV is 100 times more contagious than HIV.
[0003] HBV is transmitted through percutaneous or parenteral
contact with infected blood, body fluids, and by sexual
intercourse. HBV is able to remain on any surface it comes into
contact with for about a week, e.g. table-tops, razor blades, blood
stains, without losing infectivity. However, HBV cannot cross the
skin or the mucous membrane barrier. Some break in this barrier,
which can be minimal and insignificant, is required for
transmission.
[0004] HBV is a small enveloped DNA virus belonging to the
hepadnavirus family. The virus replicates through an RNA
intermediate form by reverse transcription, which in practice
relates them to retroviruses, like HIV. Although replication takes
place in the liver, the virus spreads to the blood where viral
proteins and antibodies against them are found in infected people.
HBV is many times more infectious than HIV due to the greater
concentrations of HBV virus found in the bloodstream at any given
time.
[0005] HBV infection results in the production of two different
particles: 1) the HBV virus itself (or Dane particle) which
includes a viral capsid assembled from the HBV core antigen protein
(HBcAg) and is covered by the hepatitis B surface antigen (HBsAg)
and is capable of reinfecting cells and 2) subviral particles (or
SVPs) which are high density lipoprotein-like particles comprised
of lipids, cholesterol, cholesterol esters and the small and medium
forms of the hepatitis B surface antigen (HBsAg) which are
non-infectious. For each viral particle produced, 1,000-10,000 SVPs
are released into the blood. As such SVPs (and the HBsAg protein
they carry) represent the overwhelming majority of viral protein in
the blood. HBV infected cells also secrete a soluble proteolytic
product of the pre-core protein called the HBV e-antigen
(HBeAg).
[0006] The hepatitis D virus (HDV) uses HBsAg to form its viral
structure (Taylor, 2006, Virology, 344: 71-76) and as such, HDV
infection can only occur in subjects with concomitant HBV
infection. While the incidence of HDV co-infection in asymptomatic
HBV carriers and chronic HBV-related liver disease is low in
countries with a low incidence of HBV infection, it is a
significant complication in HBV-infected subjects in countries with
a high incidence of HBV infection and can increase the rate of
progression of liver disease to fulminant hepatitis. As such, the
clear unmet medical need in HBV infection is even more pressing in
HBV/HDV co-infected subjects.
[0007] The current conventional methods of treatment for HBV
include interferon or thymosin al-based immunotherapies and the
suppression of viral production by inhibition of the HBV polymerase
(e.g., "nucs"). HBV polymerase inhibitors are effective in reducing
viral production, but have little to no effect in rapidly reducing
HBsAg blood levels or can slowly reduce HBsAg with long term
treatment in a limited number of patients (as is the case with
tenofovir disoproxil fumarate). Interferon based immunotherapy can
achieve a reduction of both viral production and early removal of
HBsAg from the blood but only in a small percentage of treated
subjects. The generally accepted role of HBsAg in the blood is to
sequester anti-HBsAg antibodies and allow infectious viral
particles to escape immune detection which is likely one of the
reasons why HBV infection remains a chronic condition. In addition
HBsAg, HBeAg and HBcAg all have immuno-inhibitory properties as
discussed below and the persistence of these viral proteins in the
blood of patients following the administration of any of the
currently available treatments for HBV as described above is likely
having a significant impact in preventing patients from achieving
immunological control of their HBV infection.
[0008] Although the three primary HBV proteins (HBsAg, HBeAg and
HBcAg) all have immunoinhibitory properties (see below), HBsAg
comprises the overwhelming majority of HBV protein in the
circulation of HBV infected subjects. Additionally, while the
removal (via seroconversion) of HBeAg or reductions in serum
viremia are not correlated with the development of sustained
control of HBV infection off treatment, the removal of serum HBsAg
from the blood (and seroconversion) in HBV infection is a
well-recognized excellent prognostic indicator of antiviral
response on treatment which will lead to control of HBV infection
off treatment (although this only occurs in a small fraction of
patients receiving immunotherapy). Thus, while reduction of all
three major HBV proteins (HBsAg, HBeAg and HBcAg) may result in the
optimal removal of inhibitory effect, the removal of HBsAg alone
may be sufficient in and of itself to remove the bulk of the viral
inhibition of immune function in subjects with HBV infection.
[0009] Therefore, in the absence of any current treatment regimen
which can restore immunological control of HBV in a large
proportion of patients, there is a need to be provided with an
effective treatment against HBV infection and HBV/HDV co-infection
which can restore immunological control in the majority of
patients.
[0010] Hepatitis B viral infections, in conjunction with Hepatitis
D viral infections, are a continuing medical problem because, like
any rapidly-replicating infectious agent, there are continuing
mutations that help some sub-populations of HBV become resistant to
current treatment regimens. At the present time there are no
effective therapeutic agents for treating humans infected with HBV
and/or Hepatitis D virus (HDV) infections which result in
seroconversion to the virus in the body, or which effect a 90%
reduction of antigen, compared to baseline numbers before
treatment, in persons suffering from a hepatitis B viral infection.
Currently the recommended therapies for chronic HBV and/or HDV
infection by the American Association for the Study of Liver
Diseases (AASLD) and the European Association for the Study of the
Liver (EASL) include interferon alpha (INF.alpha.), pegylated
interferon alpha-2a (Peg-IFN2a), entecavir, and tenofovir. However,
typical interferon therapy is 48-weeks and results in serious and
unpleasant side effects, and HBeAg seroconversion, 24 weeks after
therapy has ceased, ranges from only 27-36%. Seroconversion of
HBsAg is even lower--only 3% observed immediately after treatment
ceases, with an increase to upwards of 12% after 5 years.
[0011] The nucleoside and nucleotide therapies entecavir and
tenofovir are successful at reducing viral load, but the rates of
HBeAg seroconversion and HBsAg loss are even lower than those
obtained using IFN.alpha. therapy. Other similar therapies,
including lamivudine (3TC), telbivudine (LdT), and adefovir are
also used, but for nucleoside/nucleotide therapies in general, the
emergence of resistance limits therapeutic efficacy.
[0012] Recent clinical research has found a correlation between
seroconversion and reductions in HBeAg (Fried et al (2008)
Hepatology 47:428) and reductions in HBsAg (Moucari et al (2009)
Hepatology 49:1151). Reductions in antigen levels may have allowed
immunological control of HBV infection because high levels of
antigens are thought to induce immunological tolerance. Current
nucleoside therapies for HBV are capable of dramatic reductions in
serum levels of HBV but have little impact on HBeAg and HBsAg
levels. Antisense therapy differs from nucleoside therapy in that
it can directly target the transcripts for the antigens and thereby
reduce serum HBeAg and HBsAg levels. But antisense therapy is
expensive and requires intravenous delivery.
[0013] Thus, there is a need in the art to discover and develop new
anti-viral therapies. More particularly, there is a need for new
anti-HBV therapies capable of increasing HBeAg and HBsAg
seroconversion rates. These serum markers are indicative of
immunological control of HBV infection and leads to an improved
prognosis, i.e. prevention of liver disease and progression to
cirrhosis, prevention of liver failure, prevention of
hepatocellular cancer (HCC), prevention of liver disease-related
transplantation, and prevention of death.
SUMMARY OF THE INVENTION
[0014] Embodiments of the present invention features compounds of
Formula I:
##STR00001##
[0015] wherein
[0016] W and Y are independently C or N, with the proviso that W
and Y are not both C; wherein
[0017] if W is C, then R.sup.1 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; and
[0018] if Y is C, then R.sup.4 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; wherein
[0019] if W is N, then R.sup.1 is absent; and
[0020] if Y is N, then R.sup.4 is absent;
[0021] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio
or substituted thio, alkyl or substituted alkyl, alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl
or substituted alkenyl; 3- to 8-membered heterocycloalkyl or
substituted 3- to 8-membered heterocycloalkyl, aryl or substituted
aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl,
--C.sub.xH.sub.2x-phenyl, --O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; R.sup.5 and R.sup.6 are independently
hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted
alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted
cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted
aryl, heteroaryl or substituted aryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0022] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0023] or R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14';
[0024] or R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22';
[0025] or R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0026] R.sup.9 is a bond, hydrogen, hydroxy, halogen, cyano, amino,
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0027] R.sup.10 is a substituent shown in Table 2 or a tautomer
thereof;
[0028] or R.sup.9 is a bond and R.sup.9 and R.sup.10 together form
an oxaborole ring;
[0029] R.sup.11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl
or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl;
heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0030] R.sup.12 is hydrogen; alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl;
[0031] R.sup.13, R.sup.13', R.sup.14 and R.sup.14' are
independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carbonyl, carboxamide, amide; or
R.sup.13 and R.sup.13' or R.sup.14 and R.sup.14' together form a 3-
to 8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring, optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0032] R.sup.15, R.sup.15', R.sup.16 and R.sup.16' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.15 and R.sup.15' or
R.sup.16 and R.sup.16' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0033] R.sup.17, R.sup.17', R.sup.18 and R.sup.18' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.17 and R.sup.18 or
R.sup.17' and R.sup.18' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0034] R.sup.19, R.sup.19' and R.sup.19'' are independently
hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone; and
[0035] R.sup.20 and R.sup.21 are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone, or R.sup.20 and
R.sup.21 together with the nitrogen to which they are attached form
unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or
unsubstituted morpholinyl; or form carboxyl-substituted
pyrrolidinyl, carboxyl-substituted piperidinyl or
carboxyl-substituted morpholinyl; and
[0036] R.sup.22 and R.sup.22' are independently selected from
hydrogen, oxygen, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl, aryl or substituted aryl, including substituted
or unsubstituted C.sub.1-6alkylimidizole, substituted or
unsubstituted C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, substituted or unsubstituted
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone; --COR.sup.19, --COOR.sup.19',
--CSOR.sup.19'', --CONR.sup.20R.sup.21,
[0037] or a pharmaceutically acceptable salt thereof.
[0038] Another embodiment provides a compound of Formula IA or
Formula IB:
##STR00002##
[0039] wherein
[0040] C* is a carbon atom stereocenter which has a configuration
which is (R) or (S);
[0041] W and Y are independently C or N, with the proviso that W
and Y are not both C;
[0042] wherein if W is C, then R.sup.1 is hydrogen, hydroxy,
halogen, cyano, amino or substituted amino, thio or substituted
thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy;
cycloalkyl or substituted cycloalkyl; alkenyl or substituted
alkenyl; 3- to 8-membered heterocycloalkyl or substituted 3- to
8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl
or substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; and
[0043] if Y is C, then R.sup.4 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; wherein
[0044] if W is N, then R.sup.1 is absent; and
[0045] if Y is N, then R.sup.4 is absent;
[0046] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio
or substituted thio, alkyl or substituted alkyl, alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl
or substituted alkenyl; 3- to 8-membered heterocycloalkyl or
substituted 3- to 8-membered heterocycloalkyl, aryl or substituted
aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl,
--C.sub.xH.sub.2x-phenyl, --O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12;
[0047] R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted aryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0048] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0049] or R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14';
[0050] or R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22';
[0051] or R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0052] R.sup.9 is a bond, hydrogen, hydroxy, halogen, cyano, amino,
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0053] R.sup.10 is a substituent shown in Table 2 or a tautomer
thereof;
[0054] or R.sup.9 is a bond and R.sup.9 and R.sup.10 together form
an oxaborole ring;
[0055] R.sup.11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl
or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl;
heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0056] R.sup.12 is hydrogen; alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl;
[0057] R.sup.13, R.sup.13', R.sup.14 and R.sup.14' are
independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carbonyl, carboxamide, amide; or
R.sup.13 and R.sup.13' or R.sup.14 and R.sup.14' together form a 3-
to 8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring, optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0058] R.sup.15, R.sup.15', R.sup.16 and R.sup.16' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.15 and R.sup.15' or
R.sup.16 and R.sup.16' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0059] R.sup.17, R.sup.17', R.sup.18 and R.sup.18' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.17 and R.sup.18 or
R.sup.17' and R.sup.18' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0060] R.sup.19, R.sup.19' and R.sup.19'' are independently
hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone; and
[0061] R.sup.20 and R.sup.21 are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone, or R.sup.20 and
R.sup.21 together with the nitrogen to which they are attached form
unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or
unsubstituted morpholinyl; or form carboxyl-substituted
pyrrolidinyl, carboxyl-substituted piperidinyl or
carboxyl-substituted morpholinyl; and
[0062] R.sup.22 and R.sup.22' are independently selected from
hydrogen, oxygen, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl, aryl or substituted aryl, including substituted
or unsubstituted C.sub.1-6alkylimidizole, substituted or
unsubstituted C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, substituted or unsubstituted
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone; --COR.sup.19, --COOR.sup.19',
--CSOR.sup.19'', --CONR.sup.20R.sup.21,
[0063] or a pharmaceutically acceptable salt thereof.
[0064] In another particular embodiment of the invention there are
provided compounds of Formula I, Formula IA or Formula IB as
described herein, including salts and prodrugs thereof,
[0065] wherein
[0066] R.sup.10 is selected from --CO.sub.2H, --B(OH).sub.2,
--NHSO.sub.2R.sup.25', --NCO.sub.2R.sup.25,
##STR00003##
[0067] wherein
[0068] R.sup.23 and R.sup.23' are independently selected from H,
alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl,
alkenyl or substituted alkenyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
##STR00004##
[0069] R.sup.24 and R.sup.24' are independently selected from H,
hydroxyl, amino or substituted amino, alkyl or substituted alkyl,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, thiol or thioalkyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl; and
[0070] R.sup.25 and R.sup.25' are independently selected from H,
OH, alkyl or substituted alkyl, cycloalkyl or substituted
cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl and
heteroaryl or substituted heteroaryl; or a pharmaceutically
acceptable salt thereof.
[0071] In another particular embodiment of the invention there are
provided compounds of Formula I, Formula IA or Formula IB,
including salts and prodrugs thereof, wherein
[0072] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.9 and R.sup.11 are as described herein;
[0073] R.sup.8 is isopropyl; and
[0074] R.sup.10 is selected from --CO.sub.2H, --B(OH).sub.2,
--NHSO.sub.2R.sup.25', --NCO.sub.2R.sup.25,
##STR00005##
[0075] wherein
[0076] R.sup.23 and R.sup.23' are independently selected from H,
alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl,
alkenyl or substituted alkenyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
##STR00006##
[0077] R.sup.24 and R.sup.24' are independently selected from H,
hydroxyl, amino or substituted amino, alkyl or substituted alkyl,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, thiol or thioalkyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl; and
[0078] R.sup.25 and R.sup.25' are independently selected from H,
OH, alkyl or substituted alkyl, cycloalkyl or substituted
cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl and
heteroaryl or substituted heteroaryl; or a pharmaceutically
acceptable salt thereof.
[0079] In another embodiment there is provided a compound of
Formula I, Formula IA or Formula IB, including salts and prodrugs
thereof, wherein
[0080] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9 and R.sup.11 are
as described;
[0081] R.sup.5, R.sup.6 and R.sup.7 are H;
[0082] R.sup.8 is isopropyl;
[0083] R.sup.10 is selected from --CO.sub.2H, --B(OH).sub.2,
--NHSO.sub.2R.sup.25', --NCO.sub.2R.sup.25,
##STR00007##
[0084] wherein
[0085] R.sup.23 and R.sup.23' are independently selected from H,
alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl,
alkenyl or substituted alkenyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
##STR00008##
[0086] R.sup.24 and R.sup.24' are independently selected from H,
hydroxyl, amino or substituted amino, alkyl or substituted alkyl,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, thiol or thioalkyl, heterocycloalkyl or substituted
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl; and
[0087] R.sup.25 and R.sup.25' are independently selected from H,
OH, alkyl or substituted alkyl, cycloalkyl or substituted
cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl and
heteroaryl or substituted heteroaryl; or a pharmaceutically
acceptable salt thereof.
[0088] In particular embodiments, there is provided a method for
the treatment of a hepatitis B infection or hepatitis B/hepatitis D
co-infection, particularly a method for the treatment of a
hepatitis B infection or hepatitis B/hepatitis D co-infection in a
human, the method comprising administering to a subject in need of
such treatment a compound of Formula I, IA or IB as described
herein.
[0089] In yet another embodiment, the present invention provides a
method for the treatment of a hepatitis B infection or hepatitis
B/hepatitis D co-infection, particularly a method for the treatment
of a hepatitis B infection or hepatitis B/hepatitis D co-infection
in a human, the method comprising administering to a subject in
need of such treatment a first pharmaceutically acceptable agent
comprising a compound of Formula I, Formula IA or Formula IB as
described herein, in combination with a second pharmaceutically
acceptable agent that stimulates immune function and a third
pharmaceutically acceptable agent comprising an antiviral
compound.
[0090] In still other embodiments, the administration of a compound
of Formula I, IA or IB as described herein inhibits the release of
hepatitis B surface antigen (HBsAg), HB core antigen protein
(HBcAg), and/or hepatitis B pre-core protein known as the HBV
e-antigen antigen (HBeAg) from infected hepatocytes.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0091] Embodiments of the present invention features compounds that
inhibit levels of HBe and/or HBs antigens in a subject infected
with hepatitis B virus, and therefore are useful for treating human
hepatitis B virus infections, and disease and symptoms associated
with such virus infections. The foregoing features of the invention
will be more readily understood by reference to the following
detailed description, taken with reference to the accompanying
Tables, in which:
[0092] Table 1 is a listing of compounds of Formula I described
herein.
[0093] Table 2 is a listing of R.sup.10 substituents for compounds
of Formula I as described herein.
[0094] Table 3 is summary of HepAD38 cells--HBsAg ELISA and
cytotoxicity assays showing EC.sub.50 values measured for a tested
compound against HBs antigens (HBsAg).
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
[0095] Throughout this application, references are made to various
embodiments relating to compounds, compositions, and methods. The
various embodiments described are meant to provide a variety of
illustrative examples and should not be construed as descriptions
of alternative species. Rather it should be noted that the
descriptions of various embodiments provided herein may be of
overlapping scope. The embodiments discussed herein are merely
illustrative and are not meant to limit the scope of the present
invention.
[0096] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only and is
not intended to limit the scope of the present invention. In this
specification and in the claims that follow, reference will be made
to a number of terms that shall be defined to have the following
meanings.
[0097] As used herein unless otherwise specified, "alkyl" refers to
a monovalent saturated aliphatic hydrocarbyl group having from 1 to
14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms
The term "alkyl" includes, by way of example, linear and branched
hydrocarbyl groups such as methyl (CH.sub.3--), ethyl
(CH.sub.3CH.sub.2--), n-propyl (CH.sub.3CH.sub.2CH.sub.2--),
isopropyl ((CH.sub.3).sub.2CH--), n-butyl
(CH.sub.3CH.sub.2CH.sub.2CH.sub.2--), isobutyl
((CH.sub.3).sub.2CHCH.sub.2--), sec-butyl
((CH.sub.3)(CH.sub.3CH.sub.2)CH--), t-butyl ((CH.sub.3).sub.3C--),
n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and
neopentyl ((CH.sub.3).sub.3CCH.sub.2--). Alkyl groups may also be
substituted, for example, with one or more alkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl,
aryl, heteroaryl, halo or haloalkyl substituents.
[0098] "Alkoxy" or "alkoxyl" refers to the group --O-alkyl wherein
alkyl is defined herein. Alkoxy includes, by way of example,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
sec-butoxy, n-pentoxy, morpholinylpropoxy, piperidinylethoxy.
Alkoxyl groups may also be substituted, for example, with one or
more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino,
aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl
substituents.
[0099] "Amino" refers to the group --NR.sup.aR.sup.b where R.sup.a
and R.sup.b are independently selected from hydrogen, hydroxy,
alkyl or substituted alkyl, alkenyl or substituted alkenyl, aryl or
substituted aryl, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, heteroaryl or
substituted heteroaryl, and wherein R.sup.a and R.sup.b are
optionally joined together with the nitrogen bound thereto to form
a heterocyclic group. When R.sup.a is hydrogen and R.sup.b is
alkyl, the amino group is sometimes referred to herein as
alkylamino or aminoalkyl. When R.sup.a and R.sup.b are alkyl, the
amino group is sometimes referred to herein as dialkylamino. When
referring to a monosubstituted amino, it is meant that either
R.sup.a or R.sup.b is hydrogen but not both. When referring to a
disubstituted amino, it is meant that neither R.sup.a nor R.sup.6
are hydrogen.
[0100] "Aryl" refers to an aromatic group of from 5 to 14 carbon
atoms and no ring heteroatoms and having a single ring (e.g.,
phenyl) or multiple condensed (fused) rings (e.g., naphthyl or
anthryl). For multiple ring systems, including fused, bridged, and
spiro ring systems having aromatic and non-aromatic rings that have
no ring heteroatoms, the term "Aryl" or "Ar" applies when the point
of attachment is at an aromatic carbon atom (e.g., 5,6,7,8
tetrahydronaphthalene-2-yl is an aryl group as its point of
attachment is at the 2-position of the aromatic phenyl ring). Aryl
groups may also be substituted, for example, with one or more
alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl,
thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl
substituents.
[0101] "Cycloalkyl" refers to a saturated or partially saturated
cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms
and having a single ring or multiple rings including fused,
bridged, and spiro ring systems. For multiple ring systems having
aromatic and non-aromatic rings that have no ring heteroatoms, the
term "cycloalkyl" applies when the point of attachment is at a
non-aromatic carbon atom (e.g.
5,6,7,8,-tetrahydronaphthalene-5-yl). The term "Cycloalkyl"
includes cycloalkenyl groups, such as cyclohexenyl. Examples of
cycloalkyl groups include, for instance, adamantyl, cyclopropyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and
cyclohexenyl. Examples of cycloalkyl groups that include multiple
bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl,
bicyclooctyl, and the like. Cycloalkyl groups may also be
substituted, for example, with one or more alkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl,
aryl, heteroaryl, halo or haloalkyl substituents.
[0102] "Halo" or "halogen" refers to fluoro, chloro, bromo, and
iodo.
[0103] "Haloalkyl" refers to substitution of alkyl groups with 1 to
9 (e.g. when the alkyl group has 3 carbon atoms, such as a t-butyl
group fully-substituted with halogen) or in some embodiments 1 to 3
halo groups (e.g. trifluoromethyl).
[0104] "Hydroxy" or "hydroxyl" refers to the group --OH.
[0105] "Heteroaryl" refers to an aromatic group of from 1 to 14
carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen,
sulfur, phosphorus, silicon and boron, and includes single ring
(e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl
and benzimidazol-6-yl). For multiple ring systems, including fused,
bridged, and spiro ring systems having aromatic and non-aromatic
rings, the term "heteroaryl" applies if there is at least one ring
heteroatom and the point of attachment is at an atom of an aromatic
ring (e.g. 1,2,3,4-tetrahydroquinolin-6-yl and
5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen
and/or the sulfur ring atom(s) of the heteroaryl group are
optionally oxidized to provide for the N-oxide (N.fwdarw.O),
sulfinyl, or sulfonyl moieties. More specifically the term
heteroaryl includes, but is not limited to, pyridyl, furanyl,
thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl,
imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl,
pyrimidinyl, purinyl, phthalazyl, naphthyl, naphthylpryidyl,
oxazolyl, quinolyl, benzofuranyl, tetrahydrobenzofuranyl,
isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl,
indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl,
quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl,
quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl,
benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl,
phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl,
phenoxazinyl, phenothiazinyl, and phthalimidyl. Heteroaryl groups
may also be substituted, for example, with one or more alkyl,
cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol,
thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0106] "Heterocyclic" or "heterocycle" or "heterocycloalkyl" or
"heterocyclyl" refers to a saturated or partially saturated cyclic
group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms
selected from nitrogen, sulfur, phosphorus or oxygen and includes
single ring and multiple ring systems including fused, bridged, and
spiro ring systems. For multiple ring systems having aromatic
and/or non-aromatic rings, the terms "heterocyclic", "heterocycle",
"heterocycloalkyl", or "heterocyclyl" apply when there is at least
one ring heteroatom and the point of attachment is at an atom of a
non-aromatic ring (e.g. 1,2,3,4-tetrahydroquinoline-3-yl,
5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In
one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of
the heterocyclic group are optionally oxidized to provide for the
N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties. More
specifically the heterocyclyl includes, but is not limited to,
tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl,
2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix
indicating the number of carbon atoms (e.g., C.sub.3-C.sub.10)
refers to the total number of carbon atoms in the portion of the
heterocyclyl group exclusive of the number of heteroatoms.
Heterocyclyl or heterocycloalkyl groups may also be substituted,
for example, with one or more alkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo
or haloalkyl substituents.
[0107] Examples of heterocycle and heteroaryl groups include, but
are not limited to, azetidine, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine,
isoindole, indole, dihydroindole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthylpyridine,
quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole,
phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine,
imidazoline, naphthalene, oxazole, oxopyrrolidine, piperidine,
piperazine, indoline, phthalimide, quinoline,
1,2,3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, cyclopentathiazole,
thiazolidine, thiophene, benzo[b]thiophene, morpholine,
thiomorpholine (also referred to as thiamorpholine), piperidine,
pyrrolidine, and tetrahydrofuranyl.
[0108] "Fused heterocyclic" or "fused heterocyclyl" refers to a 3
to 10 member cyclic substituent formed by the replacement of two
hydrogen atoms at different carbon atoms in a cycloalkyl ring
structure, as exemplified by the following cyclopentathiazole
structure:
##STR00009##
[0109] Fuse heterocycle groups may also be substituted, for
example, with one or more alkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo
or haloalkyl substituents.
[0110] "Fused aryl and fused heteroaryl" refers to a 5 to 6 member
aryl structure or heteroaryl structure fused with a 5- to 6-member
aryl, heteroaryl or cycloalkyl ring at different carbon atoms in
the aryl structure or the heteroaryl structure, which may be
substituted at one of the carbons in the fused aryl or fused
heteroaryl and connected to the core molecule at another of the
carbons, as exemplified by the following cyclopentylthiazole,
quinoline or naphthalene structures:
##STR00010##
Fused aryl and fused heteroaryl groups may also be substituted, for
example, with one or more alkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo
or haloalkyl substituents.
[0111] "Compound", "compounds", "chemical entity", and "chemical
entities" as used herein refers to a compound encompassed by the
generic formulae disclosed herein, any subgenus of those generic
formulae, and any forms of the compounds within the generic and
subgeneric formulae, including the racemates, stereoisomers, and
tautomers of the compound or compounds.
[0112] The term "heteroatom" means nitrogen, oxygen, or sulfur and
includes any oxidized form of nitrogen, such as N(O)
{N.sup.+--O.sup.-} and sulfur such as S(O) and S(O).sub.2, and the
quaternized form of any basic nitrogen.
[0113] "Oxazole" and "oxazolyl" refers to a 5-membered heterocyclic
ring containing one nitrogen and one oxygen as heteroatoms and also
contains three carbons and may be substituted at one of the three
carbons and may be connected to another molecule at another of the
three carbons, as exemplified by any of the following structures,
wherein the oxazolidinone groups shown here are bonded to a parent
molecule, which is indicated by a wavy line in the bond to the
parent molecule:
##STR00011##
[0114] "Oxopyrrolidine" and "oxopyrrolidinyl" refers to a
5-membered heterocyclic ring containing nitrogen and 4 carbons that
is substituted at one of the carbons in the heterocyclic ring by a
carbonyl and may be connected to another substituent at another
carbon in the heterocyclic ring, as exemplified by the structure
below:
##STR00012##
[0115] "Pyridine" and "pyridinyl" refers to a 6-membered heteroaryl
ring containing one nitrogen and 5 carbons that may also be
substituted at one or more of the carbons in the heteroaryl ring,
and may be connected to another substituent at another carbon in
the heteroaryl ring, as exemplified by the structures below:
##STR00013##
[0116] "Thiazole" and "thiazolyl" refers to a 5-membered heteroaryl
containing one sulfur and one nitrogen in the heteroaryl ring and 3
carbons in the heteroaryl ring that may also be substituted at one
or more of the carbons in the heteroaryl ring, and may be connected
to another substituent at another carbon in the heteroaryl ring, as
exemplified by the structures below:
##STR00014##
[0117] "Pyrimidine" and "pyrimidinyl" refers to a 6-membered
heteroaryl ring containing two nitrogens in the heteroaryl ring and
4 carbons in the heteroaryl ring that may be substituted at one or
more of the carbons in the heteroaryl ring, and may be connected to
another substituent at another carbon in the heteroaryl ring, as
exemplified by the structures below:
##STR00015##
[0118] "Racemates" refers to a mixture of enantiomers. In an
embodiment of the invention, the compounds of Formulas I, or
pharmaceutically acceptable salts thereof, are enantiomerically
enriched with one enantiomer wherein all of the chiral carbons
referred to are in one configuration. In general, reference to an
enantiomerically enriched compound or salt, is meant to indicate
that the specified enantiomer will comprise more than 50% by weight
of the total weight of all enantiomers of the compound or salt.
[0119] "Solvate" or "solvates" of a compound refer to those
compounds, as defined above, which are bound to a stoichiometric or
non-stoichiometric amount of a solvent. Solvates of a compound
includes solvates of all forms of the compound. In certain
embodiments, solvents are volatile, non-toxic, and/or acceptable
for administration to humans in trace amounts. Suitable solvates
include water.
[0120] "Stereoisomer" or "stereoisomers" refer to compounds that
differ in the chirality of one or more stereocenters. Stereoisomers
include enantiomers and diastereomers.
[0121] "Tautomer" refer to alternate forms of a compound that
differ in the position of a proton, such as enol-keto and
imine-enamine tautomers, or the tautomeric forms of heteroaryl
groups containing a ring atom attached to both a ring --NH-- moiety
and a ring .dbd.N-- moiety such as pyrazoles, imidazoles,
benzimidazoles, triazoles, and tetrazoles.
[0122] "Thio" or "thiol" refers to the group --SR where R is
selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, heterocyclic. When R is H the thio
group is sometimes referred to herein as a thiol group, and when R
is alkyl the thio group is sometimes referred to herein as a
thioalkyl group or alkylthio. The sulfur may also bound to another
carbon or atom in the same molecule to form a heterocyclic
group.
[0123] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts derived from a variety of organic
and inorganic counter ions well known in the art and include, by
way of example only, sodium, potassium, calcium, magnesium,
ammonium, and tetraalkylammonium, and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
and oxalate. Suitable salts include those described in P. Heinrich
Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts
Properties, Selection, and Use; 2002.
[0124] "Patient" or "subject" refers to mammals and includes humans
and non-human mammals.
[0125] "Treating" or "treatment" of a disease in a patient refers
to 1) preventing the disease from occurring in a patient that is
predisposed or does not yet display symptoms of the disease; 2)
inhibiting the disease or arresting its development; or 3)
ameliorating or causing regression of the disease.
[0126] Wherever dashed lines occur adjacent to single bonds denoted
by solid lines, then the dashed line represents an optional double
bond at that position. Likewise, wherever dashed circles appear
within ring structures denoted by solid lines or solid circles,
then the dashed circles represent one to three optional double
bonds arranged according to their proper valence taking into
account whether the ring has any optional substitutions around the
ring as will be known by one of skill in the art. For example, the
dashed line in the structure below could either indicate a double
bond at that position or a single bond at that position:
##STR00016##
[0127] Similarly, ring A below could be a cyclohexyl ring without
any double bonds or it could also be a phenyl ring having three
double bonds arranged in any position that still depicts the proper
valence for a phenyl ring. Likewise, in ring B below, any of
X.sup.1-X.sup.5 could be selected from: C, CH, or CH.sub.2, N, or
NH, and the dashed circle means that ring B could be a cyclohexyl
or phenyl ring or a N-containing heterocycle with no double bonds
or a N-containing heteroaryl ring with one to three double bonds
arranged in any position that still depicts the proper valence:
##STR00017##
[0128] Where specific compounds or generic formulas are drawn that
have aromatic rings, such as aryl or heteroaryl rings, then it will
understood by one of still in the art that the particular aromatic
location of any double bonds are a blend of equivalent positions
even if they are drawn in different locations from compound to
compound or from formula to formula. For example, in the two
pyridine rings (A and B) below, the double bonds are drawn in
different locations, however, they are known to be the same
structure and compound:
##STR00018##
[0129] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkyloxycarbonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--. In a term such as "--C(R.sup.x).sub.2",
it should be understood that the two Rx groups can be the same, or
they can be different if Rx is defined as having more than one
possible identity. In addition, certain substituents are drawn as
--R.sup.xR.sup.y, where the "--" indicates a bond adjacent to the
parent molecule and R.sup.y being the terminal portion of the
functionality. Similarly, it is understood that the above
definitions are not intended to include impermissible substitution
patterns (e.g., methyl substituted with 5 fluoro groups). Such
impermissible substitution patterns are well known to the skilled
artisan.
[0130] In accordance with one embodiment of the present invention,
there are provided compounds of Formula I or a salt or prodrug
thereof,
##STR00019##
[0131] wherein
[0132] W and Y are independently C or N, with the proviso that W
and Y are not both C; wherein
[0133] if W is C, then R.sup.1 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; and
[0134] if Y is C, then R.sup.4 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; wherein
[0135] if W is N, then R.sup.1 is absent; and
[0136] if Y is N, then R.sup.4 is absent;
[0137] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio
or substituted thio, alkyl or substituted alkyl, alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl
or substituted alkenyl; 3- to 8-membered heterocycloalkyl or
substituted 3- to 8-membered heterocycloalkyl, aryl or substituted
aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl,
--C.sub.xH.sub.2x-phenyl, --O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12;
[0138] R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0139] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0140] or R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14';
[0141] or R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22';
[0142] or R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0143] R.sup.9 is a bond, hydrogen, hydroxy, halogen, cyano, amino,
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0144] R.sup.10 is a substituent shown in Table 2 or a tautomer
thereof;
[0145] or R.sup.9 is a bond and R.sup.9 and R.sup.10 together form
an oxaborole ring;
[0146] R.sup.11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl
or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl;
heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0147] R.sup.12 is hydrogen; alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl;
[0148] R.sup.13, R.sup.13', R.sup.14 and R.sup.14' are
independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carbonyl, carboxamide, amide; or
R.sup.13 and R.sup.13' or R.sup.14 and R.sup.14' together form a 3-
to 8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring, optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0149] R.sup.15, R.sup.15', R.sup.16 and R.sup.16' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.15 and R.sup.15' or
R.sup.16 and R.sup.16' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0150] R.sup.17, R.sup.17', R.sup.18 and R.sup.18' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.17 and R.sup.18 or
R.sup.17' and R.sup.18' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0151] R.sup.19, R.sup.19' and R.sup.19'' are independently
hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone; and
[0152] R.sup.20 and R.sup.21 are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone, or R.sup.20 and
R.sup.21 together with the nitrogen to which they are attached form
unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or
unsubstituted morpholinyl; or form carboxyl-substituted
pyrrolidinyl, carboxyl-substituted piperidinyl or
carboxyl-substituted morpholinyl; and
[0153] R.sup.22 and R.sup.22' are independently selected from
hydrogen, oxygen, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl, aryl or substituted aryl, including substituted
or unsubstituted C.sub.1-6alkylimidizole, substituted or
unsubstituted C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, substituted or unsubstituted
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone; --COR.sup.19, --COOR.sup.19',
--CSOR.sup.19'', --CONR.sup.20R.sup.21,
[0154] or a pharmaceutically acceptable salt thereof.
[0155] One particular embodiment provides a compound according of
Formula I, Formula IA or Formula IB as described herein,
wherein:
[0156] R.sup.1 is selected from hydrogen, hydroxy, halogen, cyano,
amino, pyrrolidinyl, unsubstituted C.sub.1-6alkyl or
halo-substituted C.sub.1-6alkyl, unsubstituted C.sub.1-6alkoxy or
halo-substituted C.sub.1-6alkyoxy; C.sub.3-7cycloalkyl or
halo-substituted C.sub.3-7cycloalkyl; N-containing monocyclic
heterocycloalkyl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5 or 6; or --OR.sup.12;
[0157] R.sup.2 and R.sup.3 are independently OR.sup.12;
[0158] R.sup.4 is selected from hydrogen, hydroxy, halogen, cyano,
amino, pyrrolidinyl, unsubstituted C.sub.1-6alkyl or
halo-substituted C.sub.1-6alkyl, unsubstituted C.sub.1-6alkoxy or
halo-substituted C.sub.1-6alkyoxy; C.sub.3-7cycloalkyl or
halo-substituted C.sub.3-7cycloalkyl; N-containing monocyclic
heterocycloalkyl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5 or 6; or --OR.sup.12;
[0159] R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring
comprising one heteroatom or two or more heteroatoms, optionally
substituted with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16',
wherein the one heteroatom in the heteroalkyl ring is NR.sup.20 and
the two or more heteroatoms are selected from N, NR.sup.22, O, S,
SR.sup.22 and SR.sup.22R.sup.22'; R.sup.11 is hydrogen; R.sup.12 is
as described herein; and R.sup.15 and R.sup.16 or R.sup.15' and
R.sup.16' together form a 3- to 8-membered cycloalkyl ring or
heterocycloalkyl ring optionally substituted with oxygen, halogen,
hydroxy, amino, cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl,
C.sub.2-6alkenyl or C.sub.1-6alkoxy, wherein the heteroatom in the
heteroalkyl ring is O, N, NR.sup.22, S, SR.sup.22 or
SR.sup.22R.sup.22', or a pharmaceutically acceptable salt
thereof.
[0160] Another embodiment provides a compound of Formula I, Formula
IA or
[0161] Formula IB as described herein, R.sup.9 is as described
herein and R.sup.10 is a substituent shown in Table 2, or R.sup.9
is a bond and R.sup.9 and R.sup.10 together form an oxaborole ring;
or a pharmaceutically acceptable salt thereof.
[0162] Another particular embodiment provides a compound of Formula
I, Formula IA or Formula IB as described herein, R.sup.9 is as
described herein and R.sup.10 is a substituent shown in Table 2, or
R.sup.9 is a bond and R.sup.9 and R.sup.10 together form an
oxaborole ring; and R.sup.12 is unsubstituted C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
[0163] Another particular embodiment provides a compound of Formula
I, Formula IA or Formula IB as described herein, wherein W and Y
are as described herein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently OR.sup.12; R.sup.9 is as described herein and
R.sup.10 is a substituent shown in Table 2, or R.sup.9 is a bond
and R.sup.9 and R.sup.10 together form an oxaborole ring; and
R.sup.12 is as described herein; or a pharmaceutically acceptable
salt thereof.
[0164] Another embodiment of the invention provides a compound of
Formula I, Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof, as described herein, wherein R.sup.9 is a
bond and R.sup.9 and R.sup.10 together form an oxaborole ring.
[0165] Yet another embodiment of the invention provides a compound
of Formula I, Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof, as described herein, wherein
[0166] W and Y are as described herein;
[0167] R.sup.1 and R.sup.4, are as described;
[0168] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, halogen, cyano, amino, thio, C.sub.1-6alkyl or
substituted C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted
C.sub.1-6alkoxy; C.sub.3-8cycloalkyl or substituted
C.sub.3-8cycloalkyl; C.sub.2-8alkenyl or substituted
C.sub.2-8alkenyl; 3- to 8-membered heterocycloalkyl or substituted
3- to 8-membered heterocycloalkyl, aryl or substituted aryl,
heteroaryl or substituted heteroaryl, or --OR.sup.12;
[0169] R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino, C.sub.1-6alkyl or substituted
C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl or substituted C.sub.3-8cycloalkyl,
C.sub.2-8alkenyl or substituted C.sub.2-8alkenyl; aryl or
substituted aryl, heteroaryl or substituted aryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0170] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, C.sub.1-6alkyl or substituted
C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl or substituted C.sub.3-8cycloalkyl,
C.sub.2-8alkenyl or substituted C.sub.2-8alkenyl; aryl or
substituted aryl, heteroaryl or substituted aryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0171] or R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14';
[0172] or R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22';
[0173] or R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0174] R.sup.9 is a bond, hydrogen, hydroxy, halogen, cyano, amino,
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0175] R.sup.10 is a substituent shown in Table 2 or a tautomer
thereof;
[0176] or R.sup.9 is a bond and R.sup.9 and R.sup.10 together form
an oxaborole ring;
[0177] R.sup.11 is hydrogen, hydroxy, halogen, cyano, amino,
C.sub.1-6alkyl or substituted C.sub.1-6alkyl, C.sub.1-6alkoxy or
substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl or substituted
C.sub.3-8cycloalkyl, C.sub.2-8alkenyl or substituted
C.sub.2-8alkenyl; aryl or substituted aryl, heteroaryl or
substituted aryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0178] R.sup.12 is hydrogen; C.sub.1-6alkyl or substituted
C.sub.1-6alkyl, C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl or substituted C.sub.3-8cycloalkyl,
C.sub.3-8heterocycloalkyl or substituted C.sub.3-8heterocycloalkyl,
aryl or substituted aryl, heteroaryl or substituted heteroaryl;
and
[0179] R.sup.22 and R.sup.22' are independently selected from
hydrogen, oxygen, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl, aryl or substituted aryl, --COR.sup.19,
--COOR.sup.19', --CSOR.sup.19'', --CONR.sup.20R.sup.21.
[0180] Another embodiment of the invention provides a compound of
Formula I, Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof, as described herein, wherein W and Y are
each N.
[0181] A particular embodiment of the invention provides a compound
of Formula I, Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof, as described herein, wherein
[0182] W and Y are as described herein;
[0183] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently H or
OR.sup.12; and
[0184] R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14'.
[0185] Another particular embodiment of the invention provides a
compound of Formula I, Formula IA or Formula IB or a
pharmaceutically acceptable salt thereof, as described herein,
wherein
[0186] W and Y are as described herein;
[0187] R.sup.2 and R.sup.3 are independently H or OR.sup.12;
and
[0188] R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22'.
[0189] Another particular embodiment of the invention provides a
compound of Formula I, Formula IA or Formula IB or a
pharmaceutically acceptable salt thereof, as described herein,
wherein
[0190] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently H or
OR.sup.12; and
[0191] R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17 and R.sup.18, wherein the
heteroatom in the heterocycloalkyl ring is selected from O, N,
NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22'.
[0192] Another particular embodiment provides a compound of Formula
I, Formula IA or Formula IB as described herein, wherein R.sup.2
and R.sup.3 are independently OR.sup.12; R.sup.5 and R.sup.6
together form a 3- to 8-membered cycloalkyl ring or 3- to
8-membered heterocycloalkyl ring, optionally substituted with
R.sup.13 and R.sup.14, wherein the heteroatom in the heteroalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
R.sup.10 is a substituent shown in Table 2, or R.sup.9 is a bond
and R.sup.9 and R.sup.10 together form an oxaborole ring; R.sup.1
is H; R.sup.12 is unsubstituted C.sub.1-6alkyl; and R.sup.13 and
R.sup.14 or R.sup.13' and R.sup.14' together form a 3- to
8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring, optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heteroalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22'; or a
pharmaceutically acceptable salt thereof.
[0193] Still another particular embodiment provides a compound of
Formula I, Formula IA or Formula IB as described herein, wherein
R.sup.2 and R.sup.3 are independently OR.sup.12; R.sup.7 and
R.sup.8 together form a 3- to 8-membered ring, optionally
substituted with R.sup.17 and R.sup.18; R.sup.10 is a substituent
shown in Table 2 or R.sup.9 is a bond and R.sup.9 and R.sup.10
together form an oxaborole ring; R.sup.11 is H; R.sup.12 is
unsubstituted C.sub.1-6alkyl; and R.sup.17 and R.sup.18 or
R.sup.17' and R.sup.18' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heteroalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22'; or a
pharmaceutically acceptable salt thereof.
[0194] Another particular embodiment provides a compound of Formula
I, Formula IA or Formula IB as described herein, wherein R.sup.2
and R.sup.3 are independently OR.sup.12; and R.sup.5 and R.sup.6
together form a 3- to 8-membered cycloalkyl ring or 3- to
8-membered heterocycloalkyl ring, optionally substituted with
R.sup.13, R.sup.14, R.sup.13' and/or R.sup.14', wherein the
heteroatom in the heteroalkyl ring is O, N, NR.sup.22, S, SR.sup.22
or SR.sup.22R.sup.22', or a pharmaceutically acceptable salt
thereof.
[0195] Another particular embodiment provides a compound of Formula
I, Formula IA or Formula IB as described herein wherein R.sup.2 and
R.sup.3 are independently OR.sup.12; and R.sup.7 and R.sup.8
together form a 3- to 8-membered cycloalkyl ring or 3- to
8-membered heterocycloalkyl ring, optionally substituted with
R.sup.17, R.sup.18, R.sup.17' and/or R.sup.18', wherein the
heteroatom in the heteroalkyl ring is O, N, NR.sup.22, S, SR.sup.22
or SR.sup.22R.sup.22', or a pharmaceutically acceptable salt
thereof.
[0196] Still more particular embodiments provide compounds of
Formula I, Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof as described herein, wherein
[0197] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described;
and
[0198] (A) R.sup.5 and R.sup.6 are independently hydroxy, halogen,
cyano, amino alkyl or substituted alkyl, alkoxy or substituted
alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or
substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
[0199] --C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl
wherein x is 0, 1, 2, 3, 4, 5 or 6; or R.sup.5 and R.sup.6 together
form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered
heterocycloalkyl ring, optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14', wherein the heteroatom in the
heterocycloalkyl ring is selected from O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22'; and
[0200] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
or
[0201] (B) R.sup.5 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
[0202] --C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl
wherein x is 0, 1, 2, 3, 4, 5 or 6; and
[0203] R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring
comprising one heteroatom or two or more heteroatoms, optionally
substituted with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16',
wherein the one heteroatom in the heteroalkyl ring is NR.sup.20 and
the two or more heteroatoms are selected from N, NR.sup.22, O, S,
SR.sup.22 and SR.sup.22R.sup.22'; or
[0204] (C) R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl,
[0205] --C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl
wherein x is 0, 1, 2, 3, 4, 5 or 6; and
[0206] R.sup.7 and R.sup.8 are independently hydroxy, halogen,
cyano, amino, alkyl or substituted alkyl, alkoxy or substituted
alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or
substituted alkenyl; aryl or substituted aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6; or R.sup.7 and R.sup.8 together form a 3-
to 8-membered cycloalkyl ring or a 3- to 8-membered
heterocycloalkyl ring, optionally substituted with R.sup.17,
R.sup.18', R.sup.17 and/or R.sup.18', wherein the heteroatom in the
heterocycloalkyl ring is selected from O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22'.
[0207] In other particular embodiments, there is provided a
compound of Formula I, Formula IA, or Formula IB as described,
wherein the compound is selected from the compounds of Table 1,
wherein R.sup.10 is as described herein or a substituent shown in
Table 2, or a tautomer thereof.
[0208] In particular embodiments there is provided a compound of
Formula I or pharmaceutically acceptable salt thereof as described
herein, wherein W is N; Y is C; R.sup.1 is absent; R.sup.2 and
R.sup.3 are independently selected from hydrogen, hydroxy, halogen,
C.sub.1-6alkyl or substituted C.sub.1-6alkyl, C.sub.1-6alkoxy or
substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl or substituted
C.sub.3-8cycloalkyl, C.sub.2-8alkenyl or substituted
C.sub.2-8alkenyl, or --OR.sup.12, R.sup.4 is H; R.sup.6 and R.sup.7
together form a 3- to 8-membered cycloalkyl ring, optionally
substituted with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16';
R.sup.11 is H; and R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'
are independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy.
[0209] In a particular embodiment, there is provided a compound of
Formula I or a pharmaceutically acceptable salt thereof as
described herein, wherein W is N; Y is C: R.sup.1 is absent;
R.sup.2 is halogen; R.sup.3 is OR.sup.12; and R.sup.4 is H.
[0210] In another particular embodiment there is provided a
compound of Formula I or pharmaceutically acceptable salt thereof
as described herein, wherein W is N; Y is C; R.sup.1 is absent;
R.sup.2 is halogen and R.sup.3 is --OR.sup.12; R.sup.4 is H;
R.sup.6 and R.sup.7 together form a 3- to 8-membered cycloalkyl
ring, optionally substituted with R.sup.15, R.sup.15', R.sup.16
and/or R.sup.16'; R.sup.11 is H; and R.sup.15, R.sup.15', R.sup.16
and/or R.sup.16' are independently C.sub.1-6alkyl.
[0211] In another particular embodiment there is provided a
compound of Formula I or pharmaceutically acceptable salt thereof
as described herein, wherein: R.sup.6 and R.sup.7 together form a
3- to 8-membered cycloalkyl ring, optionally substituted with
R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16'.
[0212] In another particular embodiment there is provided a
compound of Formula I or pharmaceutically acceptable salt thereof
as described herein, wherein: R.sup.7 and R.sup.8 together form a
3- to 8-membered cycloalkyl ring or 3- to 8-membered
heterocycloalkyl ring, optionally substituted with R.sup.17 and
R.sup.18, wherein the heteroatom in the heterocycloalkyl ring is
selected from O, N, NR.sup.22, S, SR.sup.22 or
SR.sup.22R.sup.22'.
[0213] In one particular embodiment there is provided a compound
selected from the group consisting of: [0214]
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid; [0215]
(4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid; [0216]
(4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7-
,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid; [0217]
2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid; [0218]
(7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-1-
1-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-
-10-carboxylic acid; [0219]
(7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid; [0220]
(7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid; [0221]
(4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,-
11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid; [0222]
(4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydro-
cyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;
[0223]
2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,-
10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
[0224]
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0225]
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0226]
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0227]
(S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihyd-
ro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0228]
(S)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0229]
(R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0230]
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0231]
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0232]
(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0233]
(S)-6-(tert-butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0234]
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-di-
hydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0235]
(S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0236]
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0237]
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0238]
(S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5-
,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;
[0239]
(2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-
-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0240]
(2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-
-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0241]
2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihyd-
ro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0242]
2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihyd-
ro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0243]
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylic acid; [0244]
2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid; [0245]
2',3'-Dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h-
][1,7]naphthyridine]-9'-carboxylic acid; [0246]
6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthy-
ridine-9-carboxylic acid; [0247]
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;
[0248]
3'-(cyclopropylmethoxy)-2'-(difluoromethyl)-11'-fluoro-10'-oxo-5',10'-dih-
ydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic
acid; [0249]
2'-(difluoromethyl)-11'-fluoro-10'-oxo-3'-((tetrahydrofuran-3-yl)methoxy)-
-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'--
carboxylic acid; [0250]
(S)-3-(cyclopropylmethoxy)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-met-
hyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid; and [0251]
(6S)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-3-((tetrahy-
drofuran-3-yl)methoxy)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-c-
arboxylic acid; or a pharmaceutically acceptable salt or tautomer
thereof.
[0252] In one particular embodiment there is provided a compound
selected from:
##STR00020## ##STR00021## ##STR00022##
or a pharmaceutically acceptable salt thereof.
[0253] In a particular embodiment, there is provided a compound
whose structure is:
##STR00023##
or a pharmaceutically acceptable salt thereof.
[0254] In a particular embodiment, there is provided a compound
whose structure is:
##STR00024##
or a pharmaceutically acceptable salt thereof.
[0255] In a particular embodiment, there is provided a compound
whose structure is:
##STR00025##
or a pharmaceutically acceptable salt thereof.
[0256] In a particular embodiment, there is provided a compound
whose structure is:
##STR00026##
or a pharmaceutically acceptable salt thereof.
[0257] In a particular embodiment, there is provided a compound
whose structure is:
##STR00027##
or a pharmaceutically acceptable salt thereof.
[0258] In a particular embodiment, there is provided a compound
whose structure is:
##STR00028##
or a pharmaceutically acceptable salt thereof.
[0259] In a particular embodiment, there is provided a compound
whose structure is:
##STR00029##
or a pharmaceutically acceptable salt thereof.
[0260] In a particular embodiment, there is provided a compound
whose structure is:
##STR00030##
or a pharmaceutically acceptable salt thereof.
[0261] In a particular embodiment, there is provided a compound
whose structure is:
##STR00031##
or a pharmaceutically acceptable salt thereof.
[0262] In a particular embodiment, there is provided a compound
whose structure is:
##STR00032##
or a pharmaceutically acceptable salt thereof.
[0263] In a particular embodiment, there is provided a compound
whose structure is:
##STR00033##
or a pharmaceutically acceptable salt thereof.
[0264] In a particular embodiment, there is provided a compound
whose structure is:
##STR00034##
or a pharmaceutically acceptable salt thereof.
[0265] In a particular embodiment, there is provided a compound
whose structure is:
##STR00035##
or a pharmaceutically acceptable salt thereof.
[0266] In a particular embodiment, there is provided a compound
whose structure is:
##STR00036##
or a pharmaceutically acceptable salt thereof.
[0267] In accordance with one embodiment of the present invention,
there is provided a compound having the structure of Formula I, IA
or IB wherein the compounds are selected from:
##STR00037##
wherein W and Y are independently N or C, with the proviso that W
and Y are not both C, and wherein R.sup.10 is as described herein
or a substituent shown in Table 2 and
[0268] Y' is
##STR00038##
heterocycle or substituted heterocycle, heteroaryl or substituted
heteroaryl, wherein R and R' are independently alkyl or substituted
alkyl.
[0269] In particular embodiments there are provided compounds of
Formula I, IA or IB wherein the compounds are selected from:
##STR00039##
wherein W and Y are independently N or C, with the proviso that W
and Y are not both C, and wherein R.sup.10 is as described herein
or a substituent shown in Table 2.
[0270] In other particular embodiments there are provided compounds
of Formula I, IA or IB wherein the compounds are selected from:
##STR00040## ##STR00041## ##STR00042##
[0271] wherein W and Y are independently N or C, with the proviso
that W and Y are not both C, and wherein R.sup.10 is a substituent
as described herein or a substituent shown in Table 2, and R is H,
alkyl or substituted alkyl.
[0272] In another embodiment of the present invention, compounds of
Formula I, Formula IA or Formula IB are selected from:
##STR00043## ##STR00044##
[0273] wherein W and Y are independently N or C, with the proviso
that W and Y are not both C, and wherein R.sup.10 is a substituent
as described herein or a substituent shown in Table 2, and R is
hydrogen, hydroxy,
##STR00045##
heterocycloalkyl or substituted heterocycloalkyl, heteroaryl or
substituted heteroaryl, wherein R' and R'' are independently alkyl
or substituted alkyl.
[0274] In another embodiment of the present invention there is
provided a compound of Formula I, Formula IA or Formula IB as
shown:
##STR00046##
[0275] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9 and
R.sup.11 are as described, W and Y are independently N or C, with
the proviso that W and Y are not both C, and wherein R.sup.10 is as
described herein or selected from the substituents shown in Table
2, and R' and R are independently selected from hydrogen, hydroxyl,
halo, alkyl or substituted alkyl, alkylene or substituted alkylene,
carbocycle or substituted carbocycle, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl
or substituted heteroaryl, wherein said substituted R and R' groups
may be substituted with hydroxyl, halo, alkyl, alkylene,
cycloalkyl, heterocycle, aryl, heteroaryl,
##STR00047##
or R and R' together form a spiro, fused or bridged carbocylic or
heterocyclic ring.
[0276] In another embodiment of the present invention, there is
provided a compound having the structure of Formula I, IA or IB,
wherein the compound is selected from:
##STR00048## ##STR00049##
[0277] wherein W and Y are independently N or C, with the proviso
that W and Y are not both C, and wherein R.sup.10 is as described
herein or is selected from the substituents shown in Table 2, R and
R' are independently H, hydroxyl, alkyl or substituted alkyl, acyl,
ester, carbamoyl, sulfonyl urea, or urea, and wherein Z is H, OH,
NH.sub.2, SH, or substituted C, O, N or S.
[0278] In another particular embodiment, there is provided a
compound of Formula I, IA or IB as indicated:
##STR00050##
[0279] wherein R.sup.4, R.sup.5, R.sup.6, R.sup.9, and R.sup.11 are
as described, W and Y are independently N or C, with the proviso
that W and Y are not both C, and wherein R.sup.10 is as described
herein or is selected from the substituents shown in Table 2,
R.sup.1 is as described, R.sup.2 and R.sup.3 are independently
selected from:
##STR00051##
[0280] In an embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein or a pharmaceutically
acceptable salt thereof, wherein:
[0281] (A) R.sup.5 and R.sup.6 are independently hydroxy, halogen,
cyano, amino alkyl or substituted alkyl, alkoxy or substituted
alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or
substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6; or
R.sup.5 and R.sup.6 together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with R.sup.13, R.sup.13', R.sup.14 and/or R.sup.14',
wherein the heteroatom in the heterocycloalkyl ring is selected
from O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22'; and
[0282] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
or
[0283] (B) R.sup.5 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
and
[0284] R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring
comprising one heteroatom or two or more heteroatoms, optionally
substituted with R.sup.15, R.sup.15', R.sup.16 and/or R.sup.16',
wherein the one heteroatom in the heteroalkyl ring is NR.sup.20 and
the two or more heteroatoms are selected from N, NR.sup.22, O, S,
SR.sup.22 and SR.sup.22R.sup.22'; or
[0285] (C) R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted heteroaryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
and
[0286] R.sup.7 and R.sup.8 are independently hydroxy, halogen,
cyano, amino, alkyl or substituted alkyl, alkoxy or substituted
alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or
substituted alkenyl; aryl or substituted aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6; or R.sup.7 and R.sup.8 together form a 3-
to 8-membered cycloalkyl ring or a 3- to 8-membered
heterocycloalkyl ring, optionally substituted with R.sup.17,
R.sup.18', R.sup.17 and/or R.sup.18', wherein the heteroatom in the
heterocycloalkyl ring is selected from O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22'.
[0287] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB according as described herein or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the compounds of Table 1, and wherein R.sup.10 is as
described herein or is a substituent shown in Table 2, or a
tautomer thereof.
[0288] In one embodiment there is provided a method of treating or
preventing a virus infection in a subject susceptible to or
suffering from the virus infection comprising administering to the
subject an inhibitor of a HBe or HBs antigen wherein the inhibitor
is a compound of Formula I, Formula IA or Formula IB as described
herein.
[0289] In one embodiment there is provided a method of treating or
preventing a hepatitis B virus infection in a subject susceptible
to or suffering from the hepatitis B virus infection, comprising
administering to the subject an inhibitor of a HBe or HBs antigen
wherein the inhibitor is a compound of Formula I, Formula IA or
Formula IB as described herein.
[0290] In one embodiment there is provided a method of treating or
preventing a hepatitis B virus infection in a subject susceptible
to or suffering from the hepatitis B virus infection comprising
administering to the subject an inhibitor of a HBe or HBs antigen
wherein the inhibitor comprises a compound from Table 1 wherein
R.sup.10 is a substituent shown in Table 2 or tautomer thereof, or
wherein the inhibitor is a compound from Table IB.
[0291] In one embodiment there is provided a method of inhibiting
the level of HBe or HBs antigen in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I, Formula IA or Formula IB as described
herein or a pharmaceutically acceptable salt, solvate or hydrate
thereof.
[0292] In a particular embodiment, there is provided a method of
inhibiting the level of HBe or HBs antigen in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I, Formula IA or Formula IB as described
herein, or a pharmaceutically acceptable salt, solvate or hydrate
thereof, wherein the mammal is a human.
[0293] In one embodiment there is provided a pharmaceutical
composition comprising a pharmaceutically acceptable diluent and a
therapeutically effective amount of a compound of Formula I,
Formula IA or Formula IB as described herein.
[0294] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in therapy.
[0295] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in the treatment of a viral
infection.
[0296] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in the treatment of a viral infection,
wherein the viral infection is a hepatitis B viral infection.
[0297] In one embodiment there is provided use of a compound of
Formula I, Formula IA or Formula IB as described herein, or a
pharmaceutical composition thereof, in the manufacture of a
medicament for use in the treatment of a hepatitis B viral
infection in a human.
[0298] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in medical therapy.
[0299] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in the treatment of prevention of a
hepatitis B viral infection in a human.
[0300] In one embodiment there is provided a compound of Formula I,
Formula IA or Formula IB as described herein, or a pharmaceutical
composition thereof, for use in inhibiting the level of HBe or HBs
antigen in a mammal HBsAg in vitro.
[0301] Compounds described herein can exist in particular geometric
or stereoisomeric forms. The invention contemplates all such
compounds, including cis- and trans-isomers, (-)- and
(+)-enantiomers, (R)- and (S)-enantiomers, diastereomers,
(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other
mixtures thereof, such as enantiomerically or diastereomerically
enriched mixtures, as falling within the scope of the invention.
Additional asymmetric carbon atoms can be present in a substituent
such as an alkyl group. All such isomers, as well as mixtures
thereof, are intended to be included in this invention.
[0302] Optically active (R)- and (S)-isomers and d and l isomers
can be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If, for instance, a
particular enantiomer of a compound of the present invention is
desired, it can be prepared by asymmetric synthesis, or by
derivatization with a chiral auxiliary, where the resulting
diastereomeric mixture is separated and the auxiliary group cleaved
to provide the pure desired enantiomers. Alternatively, where the
molecule contains a basic functional group, such as an amino group,
or an acidic functional group, such as a carboxyl group,
diastereomeric salts can be formed with an appropriate optically
active acid or base, followed by resolution of the diastereomers
thus formed by fractional crystallization or chromatographic means
known in the art, and subsequent recovery of the pure enantiomers.
In addition, separation of enantiomers and diastereomers is
frequently accomplished using chromatography employing chiral,
stationary phases, optionally in combination with chemical
derivatization (e.g., formation of carbamates from amines).
[0303] In another embodiment of the invention, there is provided a
compound of Formula I, Formula IA or Formula IB for use in
therapy.
[0304] In another embodiment of the intention, there is provided a
compound of Formula I, Formula IA or Formula IB, for use in the
treatment of a viral infection.
[0305] In another embodiment of the invention, there is provided a
use of a compound of Formula I, Formula IA or Formula IB in the
manufacture of a medicament for use in the treatment of a viral
infection in a human.
[0306] In another embodiment of the invention, there is provided a
pharmaceutical composition comprising a pharmaceutically acceptable
diluent and a therapeutically effective amount of a compound as
defined in Formula I, Formula IA or Formula IB.
[0307] In one embodiment, the pharmaceutical formulation containing
a compound of Formula I, Formula IA or Formula IB or a salt thereof
is a formulation adapted for parenteral administration. In another
embodiment, the formulation is a long-acting parenteral
formulation. In a further embodiment, the formulation is a
nano-particle formulation.
[0308] In one embodiment, the pharmaceutical formulation containing
a compound of Formula I, Formula IA or Formula IB or a salt thereof
is a formulation adapted for oral, rectal, topical or intravenous
formulation, wherein the pharmaceutical formulation optionally
comprises any one or more of a pharmaceutically acceptable carrier,
adjuvant or vehicle.
[0309] In one embodiment, the compounds of Formula I, Formula IA or
Formula IB are formulated for oral administration, and can be
administered as a conventional preparation, for example, as any
dosage form of a solid agent such as tablets, powders, granules,
capsules and the like; an aqueous agent; an oily suspension; or a
liquid agent such as syrup and elixir. In one embodiment, the
compounds of Formula I, Formula IA or Formula IB are formulated for
parenteral administration, and can be administered as an aqueous or
oily suspension injectable, or a nasal drop. Upon preparation of a
parenteral formulation with a compound of Formula I, Formula IA or
Formula IB, conventional excipients, binders, lubricants, aqueous
solvents, oily solvents, emulsifiers, suspending agents,
preservatives, stabilizers and the like may be arbitrarily used. As
an anti-viral-drug, particularly, an oral agent is preferable. A
preparation of a compound of Formula I, Formula IA or Formula IB
may be prepared by combining (e.g. mixing) a therapeutically
effective amount of a compound of Formula I, Formula IA or Formula
IB with a pharmaceutically acceptable carrier or diluent.
[0310] Pharmaceutical formulations adapted for oral administration
may be presented as discrete units such as capsules or tablets;
powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or whips; or oil-in-water liquid
emulsions or water-in-oil liquid emulsions.
[0311] For instance, for oral administration in the form of a
tablet or capsule, the compound of Formula I, Formula IA or Formula
IB can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the
like. Powders are prepared by comminuting the compound of Formula
I, Formula IA or Formula IB to a suitable fine size and mixing with
a similarly comminuted pharmaceutical carrier such as an edible
carbohydrate, as, for example, starch or mannitol. Flavoring,
preservative, dispersing and coloring agent can also be
present.
[0312] Capsules are made by preparing a powder mixture, as
described above, and filling formed gelatin sheaths. Glidants and
lubricants such as colloidal silica, talc, magnesium stearate,
calcium stearate or solid polyethylene glycol can be added to the
powder mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0313] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like. Tablets are
formulated, for example, by preparing a powder mixture, granulating
or slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant
such as paraffin, a resorption accelerator such as a quaternary
salt and/or an absorption agent such as bentonite, kaolin or
dicalcium phosphate. The powder mixture can be granulated by
wetting with a binder such as syrup, starch paste, acadia mucilage
or solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can be run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means
of the addition of stearic acid, a stearate salt, talc or mineral
oil. The lubricated mixture is then compressed into tablets. The
compounds of the present invention can also be combined with a free
flowing inert carrier and compressed into tablets directly without
going through the granulating or slugging steps. A clear or opaque
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dyestuffs can be added to these coatings to
distinguish different unit dosages.
[0314] Oral fluids such as solutions, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added.
[0315] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The formulations of
compounds of Formula I, Formula IA or Formula IB can also be
prepared to prolong or sustain the release of the compound, as for
example by coating or embedding particulate material in polymers,
wax or the like.
[0316] The compounds of Formula I, Formula IA or Formula IB or
salts, solvates or hydrates thereof, can also be administered in
the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine or phosphatidylcholines.
[0317] The compounds of Formula I, Formula IA or Formula IB or
salts, solvates or hydrates thereof, may also be delivered by the
use of monoclonal antibodies as individual carriers to which the
compound molecules are coupled. The compounds may also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include polyvinylpyrrolidone, pyrancopolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds may
be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked
or amphipathic block copolymers of hydrogels.
[0318] Pharmaceutical formulations adapted for transdermal
administration may be presented as discrete patches intended to
remain in intimate contact with the epidermis of the recipient for
a prolonged period of time. For example, the compounds of Formula
I, Formula IA or Formula IB may be delivered from a patch by
iontophoresis as generally described in Pharmaceutical Research,
3(6), 318 (1986).
[0319] Pharmaceutical formulations adapted for topical
administration may be formulated as ointments, creams, suspensions,
lotions, powders, solutions, pastes, gels, sprays, aerosols or
oils. When formulated in an ointment, the active ingredient may be
employed with either a paraffinic or a water-miscible ointment
base. Alternatively, the active ingredient may be formulated in a
cream with an oil-in-water cream base or a water-in-oil base.
[0320] Pharmaceutical formulations adapted for rectal
administration may be presented as suppositories or as enemas.
[0321] Pharmaceutical formulations adapted for nasal administration
wherein the carrier is a solid include a coarse powder having a
particle size for example in the range 20 to 500 microns which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid, for administration as a nasal spray or as
nasal drops, include aqueous or oil solutions of the active
ingredient.
[0322] Pharmaceutical formulations adapted for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurized
aerosols, nebulizers or insufflators.
[0323] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0324] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations described herein may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavouring agents.
[0325] A therapeutically effective amount of a compound of Formula
I, Formula IA or Formula IB will depend upon a number of factors
including, for example, the age and weight of the human or other
animal, the precise condition requiring treatment and its severity,
the nature of the formulation, and the route of administration, and
will ultimately be at the discretion of the attendant physician or
veterinarian. An effective amount of a salt or hydrate thereof may
be determined as a proportion of the effective amount of the
compound of Formula I, Formula IA or Formula IB or salts, solvates
or hydrates thereof per se.
[0326] Embodiments of the present invention provide administration
of a compound of Formula I, Formula IA or Formula IB to a healthy
or virus-infected patient, either as a single agent or in
combination with (a) another agent that is effective in treating or
preventing hepatitis B virus of hepatitis D virus, (b) another
agent that improves immune response and robustness, or (c) another
agent that reduces inflammation and/or pain.
[0327] The compounds of Formula I, Formula IA or Formula IB or
salts, solvates or hydrates thereof, are believed to have activity
in preventing, halting or reducing the effects of hepatitis B virus
by inhibiting the HBe and/or HBs antigens, thereby interfering with
or preventing the virus from remaining in the host cell and
rendering the virus unable to replicate.
[0328] Accordingly, there is provided a method of treating a
hepatitis B virus and/or hepatitis D virus by administering a
therapeutically effective amount of a compound of Formula I,
Formula IA or Formula IB to a mammal, or a pharmaceutically
acceptable salt, solvate or hydrate thereof. In one embodiment, the
mammal is a human.
[0329] In another aspect of the present invention, there is
provided a method of reducing HBe and/or HBs antigens in a mammal
by administering to said mammal a therapeutically effective amount
of a compound of Formula I, Formula IA or Formula IB or a
pharmaceutically acceptable salt, solvate or hydrate thereof. In
one embodiment, the mammal is a human.
[0330] In other embodiments, the compounds of the present invention
may be used in combination with one or more antiviral therapeutic
agents or anti-inflammatory agents useful in the prevention or
treatment of viral diseases or associated pathophysiology. Thus,
the compounds of the present invention and their salts, solvates,
or other pharmaceutically acceptable derivatives thereof, may be
employed alone or in combination with other antiviral or
anti-inflammatory therapeutic agents.
[0331] The compounds of the present invention and any other
pharmaceutically active agent(s) may be administered together or
separately and, when administered separately, administration may
occur simultaneously or sequentially, in any order. The amounts of
the compounds of the present invention and the other
pharmaceutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect. The administration in combination of a
compound of the present invention and salts, solvates, or other
pharmaceutically acceptable derivatives thereof with other
treatment agents may be in combination by administration
concomitantly in: (1) a unitary pharmaceutical composition
including both compounds; or (2) separate pharmaceutical
compositions each including one of the compounds.
[0332] Alternatively, the combination may be administered
separately in a sequential manner wherein one treatment agent is
administered first and the other second or vice versa. Such
sequential administration may be close in time or remote in time.
The amounts of the compound(s) of Formula I, Formula IA or Formula
IB or salts thereof and the other pharmaceutically active agent(s)
and the relative timings of administration will be selected in
order to achieve the desired combined therapeutic effect.
[0333] More particularly, embodiments provide a method as described
comprising administering an additional agent selected from an
antiviral agent, an antibiotic, an analgesic, a non-steroidal
anti-inflammatory (NSAID) agent, an antifungal agent, an
antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent,
or an immunosuppressant agent. In certain embodiments, the
antiviral agent is an anti-hepatitis B agent or an anti-hepatitis C
agent. Still more particularly, the additional agent is
administered as part of a single dosage form of said pharmaceutical
formulation, or as a separate dosage form.
[0334] The present invention is directed to compounds, compositions
and pharmaceutical compositions that have utility as novel
treatments and/or preventative therapies for virus infections.
While not wanting to be bound by any particular theory, it is
thought that the present compounds are able to inhibit the levels
of HBe and HBs antigens in a subject infected with hepatitis B
virus or suffering from a chronic hepatitis B viral infection. By
reducing the levels of HBe and HBs antigens in a subject infected
with hepatitis B virus, compounds described herein are effective at
treating hepatitis B infections, and secondary disorders such as
liver cirrhosis, liver failure and liver cancer which are often
associated with hepatitis B virus infections.
[0335] Therefore, in another embodiment of the present invention,
there is provided a method of treating or preventing a hepatitis B
virus infection in a subject suffering from the HBV infection
comprising administering to the subject an inhibitor of HBe and/or
HBs antigens, wherein the inhibitor is a compound of Formula I,
Formula IA or Formula IB.
[0336] In another embodiment of the present invention, there is
provided a method of treating a hepatitis B virus infection and/or
a hepatitis D virus infection in a subject suffering from the virus
infection comprising administering to the subject compound from
Table 1.
[0337] In some embodiments, provided is a method for treating a
viral infection in a subject mediated at least in part by a virus
in the hepatitis B family and or the hepatitis D family, comprising
administering to the subject a composition comprising a compound of
any of Formula I, Formula IA or Formula IB, or a pharmaceutically
acceptable salt thereof.
[0338] In yet another aspect, another embodiment of the present
invention provides a method of inhibiting progression of a viral
infection in a subject at risk for infection with a hepatitis B
virus and/or a hepatitis D virus, comprising administering to the
subject a therapeutically effective amount of the compound of
Formula I, Formula IA or Formula IB, or a pharmaceutically
acceptable salt thereof.
[0339] In yet another aspect, another embodiment of the present
invention provides a method of preventing a viral infection in a
subject at risk for infection from a hepatitis B virus and/or a
hepatitis D virus comprising administering to the subject a
therapeutically effective amount of the compound of Formula I or
Formula IA, or a pharmaceutically acceptable salt thereof.
[0340] In yet another aspect, another embodiment of the present
invention provides a method of treating a virus infection in a
subject suffering from said virus infection, comprising
administering to the subject a therapeutically effective amount of
the compound of Formula I, Formula IA or Formula IB, or a
pharmaceutically acceptable salt thereof.
[0341] Compounds, methods and pharmaceutical compositions for
treating viral infections, by administering compounds of Formula I,
Formula IA or Formula IB in therapeutically effective amounts are
disclosed. Methods for preparing compounds of Formula I, Formula IA
or Formula IB and methods of using the compounds and pharmaceutical
compositions thereof are also disclosed. In particular, the
treatment and prophylaxis of viral infections such as those caused
by hepatitis B and/or hepatitis D are disclosed.
[0342] In other embodiments, the compounds described herein are
useful for treating infections in a subject wherein the infection
is caused by a multi-drug resistant strain of the hepatitis B virus
and/or a hepatitis D virus.
[0343] In further embodiments, the compound of the present
invention, or a pharmaceutically acceptable salt thereof, is chosen
from the compounds set forth in Table 1.
EXAMPLES
[0344] Synthetic Schemes
[0345] The compounds of the present invention having Formula I,
Formula IA or Formula IB
##STR00052##
[0346] or corresponding pharmaceutically acceptable salts thereof,
are prepared using conventional organic syntheses, wherein:
[0347] C* is a carbon atom stereocenter which has a configuration
which is (R) or (S);
[0348] W and Y are independently C or N, with the proviso that W
and Y are not both C; wherein
[0349] if W is C, then R.sup.1 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; and
[0350] if Y is C, then R.sup.4 is hydrogen, hydroxy, halogen,
cyano, amino or substituted amino, thio or substituted thio, alkyl
or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or
substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to
8-membered heterocycloalkyl or substituted 3- to 8-membered
heterocycloalkyl, aryl or substituted aryl, heteroaryl or
substituted heteroaryl, pyrrolidinyl, --C.sub.xH.sub.2x-phenyl,
--O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12; wherein
[0351] if W is N, then R.sup.1 is absent; and
[0352] if Y is N, then R.sup.4 is absent;
[0353] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio
or substituted thio, alkyl or substituted alkyl, alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl
or substituted alkenyl; 3- to 8-membered heterocycloalkyl or
substituted 3- to 8-membered heterocycloalkyl, aryl or substituted
aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl,
--C.sub.xH.sub.2x-phenyl, --O--C.sub.xH.sub.2x-phenyl, or
--(C.sub.1-6alkyl)N--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2,
3, 4, 5, 6; or --OR.sup.12;
[0354] R.sup.5 and R.sup.6 are independently hydrogen, hydroxy,
halogen, cyano, amino alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl or
substituted aryl, --C.sub.xH.sub.2x-phenyl or
--O--C.sub.xH.sub.2x-phenyl wherein x is 0, 1, 2, 3, 4, 5 or 6;
[0355] R.sup.7 and R.sup.8 are independently hydrogen, hydroxy,
halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl
or substituted alkenyl; aryl or substituted aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0356] or R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14';
[0357] or R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22';
[0358] or R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0359] R.sup.9 is a bond, hydrogen, hydroxy, halogen, cyano, amino,
alkyl or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, alkenyl or substituted
alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0360] R.sup.10 is a substituent shown in Table 2 or a tautomer
thereof;
[0361] or R.sup.9 is a bond and R.sup.9 and R.sup.10 together form
an oxaborole ring;
[0362] R.sup.11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl
or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or
substituted alkoxy; cycloalkyl or substituted cycloalkyl;
heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl,
--C.sub.xH.sub.2x-phenyl or --O--C.sub.xH.sub.2x-phenyl wherein x
is 0, 1, 2, 3, 4, 5 or 6;
[0363] R.sup.12 is hydrogen; alkyl or substituted alkyl, alkoxy or
substituted alkoxy, cycloalkyl or substituted cycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, aryl or
substituted aryl, heteroaryl or substituted heteroaryl;
[0364] R.sup.13, R.sup.13', R.sup.14 and R.sup.14' are
independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carbonyl, carboxamide, amide; or
R.sup.13 and R.sup.13' or R.sup.14 and R.sup.14' together form a 3-
to 8-membered cycloalkyl ring or 3- to 8-membered heterocycloalkyl
ring, optionally substituted with oxygen, halogen, hydroxy, amino,
cyano, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0365] R.sup.15, R.sup.15', R.sup.16 and R.sup.16' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.15 and R.sup.15' or
R.sup.16 and R.sup.16' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0366] R.sup.17, R.sup.17', R.sup.18 and R.sup.18' are
independently hydrogen, hydroxy, halogen, amino, cyano,
C.sub.1-6alkyl, or C.sub.1-6alkoxy; or R.sup.17 and R.sup.18 or
R.sup.17' and R.sup.18' together form a 3- to 8-membered cycloalkyl
ring or 3- to 8-membered heterocycloalkyl ring, optionally
substituted with oxygen, halogen, hydroxy, amino, cyano,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or
C.sub.1-6alkoxy, wherein the heteroatom in the heterocycloalkyl
ring is O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22';
[0367] R.sup.19, R.sup.19' and R.sup.19'' are independently
hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone; and
[0368] R.sup.20 and R.sup.21 are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, phenyl, C.sub.1-6alkylimidizole,
C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, C.sub.1-6alkyloxazole,
C.sub.1-6alkyldioxazole; C.sub.1-6alkyloxazolidone, or R.sup.20 and
R.sup.21 together with the nitrogen to which they are attached form
unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or
unsubstituted morpholinyl; or form carboxyl-substituted
pyrrolidinyl, carboxyl-substituted piperidinyl or
carboxyl-substituted morpholinyl; and
[0369] R.sup.22 and R.sup.22' are independently selected from
hydrogen, oxygen, C.sub.1-6alkyl or substituted C.sub.1-6alkyl,
C.sub.1-6alkoxy or substituted C.sub.1-6alkoxy, C.sub.3-8cycloalkyl
or substituted C.sub.3-8cycloalkyl, C.sub.2-6alkenyl or substituted
C.sub.2-6alkenyl, aryl or substituted aryl, including substituted
or unsubstituted C.sub.1-6alkylimidizole, substituted or
unsubstituted C.sub.1-6alkyltriazole, C.sub.1-6alkyltetrazole,
C.sub.1-6alkylthiazole, substituted or unsubstituted
C.sub.1-6alkyloxazole, C.sub.1-6alkyldioxazole;
C.sub.1-6alkyloxazolidone; --COR.sup.19, --COOR.sup.19',
--CSOR.sup.19'', --CONR.sup.20R.sup.21,
[0370] or a pharmaceutically acceptable salt thereof.
[0371] Other embodiments provide compounds of Formula I, Formula IA
or Formula IB or a pharmaceutically acceptable salt thereof as
described herein, wherein:
[0372] R.sup.5 and R.sup.6 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring, wherein
the heteroatom in the heterocycloalkyl ring is O, N, NR.sup.22, S,
SR.sup.22 or SR.sup.22R.sup.22', wherein the 3- to 8-membered
heterocycloalkyl ring is optionally substituted with R.sup.13,
R.sup.13', R.sup.14 and/or R.sup.14'.
[0373] Other particular embodiments provide compounds of Formula I,
Formula IA or Formula IB or a pharmaceutically acceptable salt
thereof as described herein, wherein:
[0374] R.sup.6 and R.sup.7 together form a 3- to 8-membered
cycloalkyl ring or heterocycloalkyl ring comprising one heteroatom
or two or more heteroatoms, optionally substituted with R.sup.15,
R.sup.15', R.sup.16 and/or R.sup.16', wherein the one heteroatom in
the heteroalkyl ring is NR.sup.20 and the two or more heteroatoms
are selected from N, NR.sup.22, O, S, SR.sup.22 and
SR.sup.22R.sup.22'.
[0375] Other particular embodiments provide compounds of Formula I,
Formula IA or Formula IB or a pharmaceutically acceptable salt
thereof as described herein, wherein:
[0376] R.sup.7 and R.sup.8 together form a 3- to 8-membered
cycloalkyl ring or 3- to 8-membered heterocycloalkyl ring,
optionally substituted with R.sup.17, R.sup.17', R.sup.18 and/or
R.sup.18', wherein the heteroatom in the heterocycloalkyl ring is
O, N, NR.sup.22, S, SR.sup.22 or SR.sup.22R.sup.22'.
[0377] Suitable synthetic routes are depicted below in the
following general reaction schemes. The skilled artisan will
appreciate that if a substituent described herein is not compatible
with the synthetic methods described herein, the substituent may be
protected with a suitable protecting group that is stable to the
reaction conditions. The protecting group may be removed at a
suitable point in the reaction sequence to provide a desired
intermediate or target compound. Suitable protecting groups and the
methods for protecting and de-protecting different substituents
using such suitable protecting groups are well known to those
skilled in the art; examples of which may be found in T. Greene and
P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John
Wiley & Sons, NY (1999). In some instances, a substituent may
be specifically selected to be reactive under the reaction
conditions used. Under these circumstances, the reaction conditions
convert the selected substituent into another substituent that is
either useful as an intermediate compound or is a desired
substituent in a target compound.
Abbreviations
[0378] In describing the examples, chemical elements are identified
in accordance with the Periodic Table of the Elements.
Abbreviations and symbols utilized herein are in accordance with
the common usage of such abbreviations and symbols by those skilled
in the chemical arts. The following abbreviations are used herein:
[0379] AcOH acetic acid [0380] Ac.sub.2O acetic anhydride [0381] aq
aqueous [0382] B4
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1-yl)p-
ropanoic acid [0383] BOC (Boc)N-tert-butoxycarbonyl or
tert-butyloxycarbonyl [0384] CBz carboxybenzyl [0385] dba
dibenzylideneacetone or dibenzalacetone [0386] DCE dichloroethane
[0387] DCM dichloromethane [0388] DCM/EA dichloromethane/ethanol
[0389] DDQ 2,3-dichloro-5,6-dicyanobenzoquinone [0390] DIPEA (or
DIEA) N,N-diisopropylethylamine, or Hunig's base [0391] DME
dimethoxyethane [0392] DMEM Dulbecco's Modified Eagle Medium [0393]
DMF dimethylformamide [0394] DMP Dess-Martin periodinane [0395]
DMSO-d6 deuterated dimethylsulfoxide [0396] DMSO dimethylsulfoxide
[0397] DPPA diphenyl phosphoryl azide [0398] EC.sub.50 50%
effective concentration [0399] EDTA ethylenediaminetetraacetic acid
[0400] Et ethyl [0401] Et.sub.2O diethyl ether [0402] EtOH ethanol
[0403] EtOAc, EA, AcOEt ethyl acetate [0404] GlutaMAX.TM. cell
culture supplement from Life Technologies [0405] h hour(s) [0406]
HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [0407]
HPLC high performance liquid chromatography [0408] IC.sup.50 50%
inhibition concentration [0409] iPrOH isopropyl alcohol or
isopropanol [0410] LCMS Liquid chromatography mass spectroscopy
[0411] LDA lithium di-isopropyl amide [0412] Me methyl [0413] MeOH
methanol [0414] NBS N-bromosuccinimide [0415] NCS
N-chlorosuccinimide [0416] NIS N-iodosuccinimide [0417] NXS
N-halosuccinimide [0418] NaBH(OAc).sub.3 sodium
triacetoxyborohydride [0419] NMR Nuclear Magnetic Resonance
spectroscopy [0420] Pd.sub.2(dba).sub.3
Tris(dibenzylideneacetone)dipalladium(0) [0421] PE petroleum ether
[0422] PPh.sub.3 triphenylphosphine [0423] Pr propyl [0424] RB
round bottom [0425] rt or r.t. room temperature [0426] RT retention
time [0427] SFC supercritical fluid chromatography [0428]
SO.sub.3pyr sulfur trioxide pyridine complex--formula
C.sub.5H.sub.5NSO.sub.3 [0429] SPhos 2-dicyclohexyl
phosphine-2',6'-dimethoxybiphenyl or
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl) [0430] t-BuOMe
methyl t-butyl ether [0431] T3P 1-Propanephosphonic anhydride
solution,
2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
[0432] TFA trifluoroacetic acid [0433] THF tetrahydrofuran [0434]
uv ultraviolet
[0435] Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without further purification.
Unless otherwise indicated, all temperatures are expressed in
.degree. C. (degrees Centigrade). Unless otherwise indicated, all
reactions are conducted under an inert atmosphere at ambient
temperature.
[0436] All temperatures are given in degrees Celsius, all solvents
are highest available purity and all reactions run under anhydrous
conditions in an argon (Ar) or nitrogen (N.sub.2) atmosphere where
necessary.
[0437] The following examples illustrate the invention. These
examples are not intended to limit the scope of the present
invention, but rather to provide guidance to the skilled artisan to
prepare and use the compounds, compositions, and methods of the
present invention.
[0438] While particular embodiments of the present invention are
described, the skilled artisan will appreciate that various changes
and modifications can be made without departing from the spirit and
scope of the invention.
[0439] As used herein the symbols and conventions used in these
processes, schemes and examples are consistent with those used in
the contemporary scientific literature, for example, the Journal of
the American Chemical Society or the Journal of Biological
Chemistry. Unless otherwise noted, all starting materials were
obtained from commercial suppliers and used without further
purification.
[0440] All references to ether are to diethyl ether; brine refers
to a saturated aqueous solution of NaCl. Unless otherwise
indicated, all temperatures are expressed in .degree. C. (degrees
Centigrade). All reactions are conducted under an inert atmosphere
at room temperature unless otherwise noted, and all solvents are
highest available purity unless otherwise indicated.
[0441] .sup.1H NMR (hereinafter also "NMR") spectra were recorded
on a Varian Unity-400 spectrometer. Chemical shifts are expressed
in parts per million (ppm, .delta. units). Coupling constants are
in units of hertz (Hz). Splitting patterns describe apparent
multiplicities and are designated as s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), m (multiplet), br
(broad).
[0442] Flash chromatography was run over Merck Silica gel 60
(230-400 mesh), or using a Teledyne Isco Combiflash.RTM. Companion
with normal phase, disposable Redi-Sep.RTM. flash columns. Mass
spectra were run on an open access LC-MS system using electrospray
ionization. The analytical low-resolution mass spectra (MS) were
recorded on Waters SQD instrument with UPLC analysis was conducted
on a Phenomenex.RTM. Kinetex.RTM. 1.7 um, 2.1.times.50 mm XB-C18
column at 40CSQ using a gradient elution method. Solvent A: 0.2%
formic acid (FA) in water; Solvent B: 0.15% FA in acetonitrile;
1%-99% Solvent B gradient over 1.1 minutes and holding steady at
99% solvent B for another 0.4 minutes, at 1 ml/min flow rate.
[0443] Synthetic Preparation of Compounds
[0444] General Protocols for Making Compounds as Described Herein
are Shown Below in Schemes 1-15.
##STR00053## ##STR00054##
[0445] Particular compounds disclosed herein may be made according
to Scheme 1. For example, compound 4 can be prepared by reacting
compound 1 with an appropriately substituted 4-pyranone, as shown,
in acetic acid or ethanol, with heat. Reductive cyclisation of 2 by
treatment of compound 2 with Pd(II) catalyst with an appropriate
base such as potassium acetate in an appropriate solvent such as
N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF) at
90-120.degree. C., yields fused tricyclic carboxylate compound 3.
Compound 3 is then subjected to hydrolysis of the ester under acid
or base conditions to yield the carboxylic acid 4. Further chemical
manipulation of the carboxylic acid can lead to additional R.sup.10
groups.
[0446] Alternatively, compounds described herein may be prepared
according to Scheme 2.
##STR00055##
[0447] wherein X is Br or I, and W, Y, R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are as described herein.
[0448] As shown in Scheme 2, compound 2 can be prepared by reacting
compound 1 with an appropriately substituted 4-pyranone, as shown,
in acetic acid or ethanol, with heat. Reductive cyclisation of 2 by
treatment of compound 2 with Pd(II) catalyst with an appropriate
base such as potassium acetate in an appropriate solvent such as
N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF) at
90-120.degree. C., yields fused tricyclic carboxylate compound 3.
Compound 3 is then subjected to hydrolysis of the ester under acid
or base conditions to yield the carboxylic acid 4. As with Scheme
1, further chemical manipulation of the carboxylic acid can lead to
additional R.sup.10 groups.
##STR00056## ##STR00057##
Example 1 Preparation A (Compound 220)
(4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-
-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
##STR00058##
[0449] Step 1:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanone
##STR00059##
[0451] A flask was charged with a stir bar,
5-bromo-2-chloro-3-methoxypyridine (16.5 g, 74.2 mmol),
tris(dibenzylideneacetone)dipalladium(0) (1.02 g, 1.11 mmol),
xantphos (1.16 g, 2.00 mmol), and sodium tert-butoxide (12.6 g, 131
mmol). The flask was purged with a stream of nitrogen for 30
minutes. Tetrahydrofuran (THF) (300 ml) was degassed with nitrogen
for 30 minutes. 2,2-dimethylcyclopentan-1-one (11.2 ml, 89 mmol)
was added to the degassed tetrahydrofuran (THF) (300 ml) and this
solution added to the nitrogen-purged flask that contained the
initial substrate. The mixture was heated to reflux under nitrogen
for 3 hours. The mixture was allowed to cool to room temperature
and filtered through a silica plug over nitrogen. The plug was
washed with tetrahydrofuran and the filtrate concentrated. The
residue was dissolved in minimal dichloromethane and injected onto
a silica column. The column was eluted 1 minute with hexanes and
then a quick gradient (3 minutes) to 20% ethyl acetate/hexanes, and
then isocratic at 20% ethyl acetate/hexanes until the product
eluted. Fractions were concentrated to give
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
(10.7 g, 42.1 mmol, 56.8% yield) as an oil. LCMS (ESI) m/z 254.2
(M+1).
Step 2:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanamine
(trans/cis mixture)
##STR00060##
[0453] A stirring mixture of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
(trans/cis mixture) (10.7 g, 42.2 mmol) and ammonium acetate (32.5
g, 422 mmol) in methanol (200 mL) was degassed with a stream of
nitrogen for 25 minutes. Sodium cyanoborohydride (5.30 g, 84 mmol)
was added and the mixture heated at 65.degree. C. over the weekend.
The reflux condenser was removed and the oil bath heated to
80.degree. C., allowing the reaction mixture to concentrate to
.about.70% of original volume over 4 hours. The reflux condenser
was attached again and the mixture heated at strong reflux
overnight (oil bath at 80.degree. C.). The mixture was concentrated
and the residue slurried in .about.300 mL of dichloromethane. The
mixture was stirred vigorously for .about.30 minutes. Solids were
filtered off and the filter cake washed with dichloromethane. The
filtrate was concentrated to give 22 g of crude
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(trans/cis mixture). The crude material was purified by silica
chromatography eluting with a gradient of 0% to 10% 2M
ammonia/methanol in dichloromethane. Fractions were concentrated to
give
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(trans/cis mixture) (9.04 g, 35.5 mmol, 84% yield). LCMS (ESI) m/z
255.2 (M+1).
Step 3:
5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(trans/cis mixture)
##STR00061##
[0455] Boron tribromide (6.71 mL, 71.0 mmol) was added slowly
dropwise to a vigorously stirring solution of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(trans/cis mixture) (9.04 g, 35.5 mmol) in 1,2-dichloroethane (DCE)
(175 mL). The mixture was stirred at room temperature for 30
minutes and then heated at 70.degree. C. overnight. The mixture was
cooled in an ice bath and then carefully quenched with slow
addition of methanol. Additional methanol (100 mL) was added. The
mixture was warmed to room temperature, stirred for 30 minutes, and
concentrated to leave .about.17 g of crude
5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (trans/cis
mixture). Water (200 mL) was added to the crude material and
stirred with a stir bar. Potassium carbonate (24.5 g, 177 mmol) was
added slowly and carefully portion-wise in order to control
effervescence. The mixture was stirred for 10 minutes after
complete addition of the potassium carbonate. The aqueous mixture
was tested with pH paper to assure that the mixture was basic. The
aqueous mixture was extracted 1 time with 100 mL of
dichloromethane. LC-MS indicated only impurities in the organic
layer and only
5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (trans/cis
mixture) in the aqueous layer. The organic phase was discarded and
the aqueous layer transferred from the separatory funnel to a round
bottom flask before Iodine (18.0 g, 71.0 mmol) was added. The
mixture was stirred overnight at room temperature. Excess sodium
sulfite (.about.4 eq) was added portion wise.
2-Methyltetrahydrofuran (100 mL) was added and the mixture stirred.
Excess acetic acid was added carefully to neutralize the aqueous
layer while controlling effervescence. Solid sodium chloride was
added to the aqueous phase. The mixture was extracted 3 times with
2-methyltetrahydrofuran. The combined organic layers were washed 2
times with brine. The organic phase was dried over sodium sulfate
and concentrated to give 12.6 g of crude material. The material was
purified by silica chromatography eluting with a gradient of 0% to
20% 2M ammonia/methanol in dichloromethane. Fractions were
concentrated to give
5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(trans/cis mixture) (6.6 g, 18 mmol, 50.7% yield). LCMS (ESI) m/z
367.1 (M+1).
Step 4: Ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (trans/cis
mixture)
##STR00062##
[0457]
5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(trans/cis mixture) (6.6 g, 18 mmol) and ethyl
4-oxo-4H-pyran-3-carboxylate (3.94 g, 23.4 mmol) in acetic acid
(150 mL) were stirred at 100.degree. C. for 3 hours. The mixture
was allowed to cool to room temperature and concentrated to dryness
under vacuum. Toluene was added and rotovaped several times to help
get rid of remaining acetic acid. Final evaporation gave crude
ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate. LCMS (ESI) m/z 517.1 (M+1).
Crude ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopenty-
l)-4-oxo-1,4-dihydropyridine-3-carboxylate was dissolved in
N,N-dimethylformamide (DMF) (75 mL) before potassium carbonate
(12.4 g, 90 mmol) and 1-bromo-3-methoxypropane (4.05 mL, 36.0 mmol)
were added. The mixture was allowed to stir at room temperature for
15 minutes and then was heated to 60.degree. C. for 1 hour. The
reaction mixture was cooled in an ice bath and quenched with water.
A solid precipitated. The mixture was extracted 3 times with ethyl
acetate. A solid was floating at the phase interface and so the
mixture was extracted 1 time with dichloromethane. Solids dissolved
and product was observed in the organic phase. The combined organic
layers were washed 2 times with 5% lithium chloride, washed 1 time
with brine, dried over sodium sulfate, and concentrated. The
residue was slurried in ethyl ether and the precipitate collected
by filtration. The solid was air dried to give ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (racemic trans)
(5.21 g, 8.85 mmol, 49.1% yield) as a pale tan solid. LCMS (ESI)
m/z 589.2 (M+1). The filtrate was concentrated and the residue
purified by silica chromatography eluting with a gradient or 0% to
10% methanol in dichloromethane. Fractions were concentrated to
give ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (trans/cis mixture)
(2.59 g, 3.08 mmol, 17.1% yield, 70% pure). LCMS (ESI) m/z 589.2
(M+1).
Step 5: Ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(trans/cis mixture)
##STR00063##
[0459] A round bottom flask containing a stir bar, ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (trans/cis mixture)
(5.57 g, 9.46 mmol), potassium acetate (4.64 g, 47.3 mmol), and
palladium(II) bromide (0.504 g, 1.89 mmol) was purged with nitrogen
for 20 minutes using a septum with needle-in/needle-out.
N,N-Dimethylformamide (DMF) (75 mL) was purged with nitrogen for 20
minutes before being added to the reaction vessel. The reaction
vessel was placed into an oil bath that was preheated to
100.degree. C. and the mixture stirred overnight. The mixture was
allowed to cool to room temperature and filtered through a pad of
celite. The celite pad was washed with dichloromethane and the
filtrate concentrated. The residue was purified by silica
chromatography eluting with a gradient of 0% to 10% methanol in
dichloromethane. Fractions were concentrated to give ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,5,6,7,7a,11-hexahydro-
cyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(trans/cis mixture) (3.15 g, 6.83 mmol, 72.2% yield) as a pale tan
solid. LCMS (ESI) m/z 461.3 (M+1).
Step 6:
(4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,5,6,-
7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyli-
c acid
##STR00064##
[0461] To a solution of ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(trans/cis mixture) (3.15 g, 6.83 mmol) in 1,4-dioxane (40 mL) was
added a solution of lithium hydroxide monohydrate (1.434 g, 34.2
mmol) in water (30 mL). The mixture was heated at 70.degree. C. for
3 hours. LC-MS indicated complete conversion to the desired racemic
cis product. The mixture was allowed to cool to room temperature
and diluted with 0.5M hydrochloric acid (100 mL). The precipitate
was collected by filtration and the filter cake thoroughly washed
with water. The filter cake was air dried for several hours with
vacuum on a Buchner funnel until solids no longer appeared moist by
visual inspection. The filter cake was dissolved in 150 mL of
dichloromethane. Full dissolution required stirring for several
minutes. The solution was dried over sodium sulfate and
concentrated to give
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis) (2.6 g, 6.01 mmol, 88% yield).
[0462] The racemate was purified in several batches using the
following conditions: Column=Chiralpak IC, 10 mm.times.250 mm (5u);
Mobile phase=3:1 MeOH/EtOH+0.1% TFA; Flow rate=10 mLl/min;
Injection volume=500 uL (30 mg/mL conc., DCM used as injection
solvent); Collection wavelength=254 nm. Fractions corresponding to
peak 1 were concentrated. The residues were slurried in ethyl
ether, sonicated, stirred for 10 minutes, and then the stirring
mixture cooled in an ice bath. Solids were collected by vacuum
filtration, air dried, and dried under high vacuum to give
(4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7-
,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (1.24 g, 2.87 mmol, 42% yield) as white solids. LCMS (ESI) m/z
433.2 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.62
(s, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 4.72 (d, J=8.98 Hz, 1H),
4.19-4.39 (m, 2H), 3.94 (td, J=8.68, 3.32 Hz, 1H), 3.51 (t, J=6.05
Hz, 2H), 3.26 (s, 3H), 2.35-2.46 (m, 1H), 2.19-2.31 (m, 1H), 2.03
(quin, J=6.25 Hz, 2H), 1.55-1.67 (m, 1H), 1.40-1.50 (m, 1H), 1.15
(s, 3H), 0.40 (s, 3H).
##STR00065## ##STR00066##
Example 1 Preparation B (Compound 220)
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-
-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
##STR00067##
[0463] Step 1:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
##STR00068##
[0465] To a solution of 5-bromo-2-chloro-3-methoxypyridine (100 g,
449 mmol) in THF (2 L) was added NaOtBu (76.02 g, 791 mmol),
Xantphos (7.01 g, 12.1 mmol) and 2,2-dimethylcyclopentan-1-one
(65.56 g, 584.6 mmol). The reaction mixture was degassed with
nitrogen for 30 minutes. Pd.sub.2(dba).sub.3 was added to the
reaction and the reaction mixture was stirred at 70.degree. C. for
3 h. After completion of the reaction, the reaction mixture was
filtered through silica gel (60-120) pad and washed with THF. The
solvent was removed under reduced pressure and the crude product
was purified by column chromatography (230-400 silica gel) using
0-30% ethyl acetate in petroleum ether as an eluent. Fractions were
collected and concentrated to afford the title compound (61 g, 54%
yield), LCMS (ESI) m/z 253.9 (M+1).
Step 2:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(trans/cis mixture)
##STR00069##
[0467] To a solution of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
(60 g, 236.5 mmol) in methanol (1.2 L) was added NH.sub.4OAc (182
g, 2365 mmol).The reaction mixture was degassed with nitrogen for
30 minutes. NaBH.sub.3CN was added (29.7 g, 473 mmol) to the
reaction mixture and the reaction mixture was stirred at 65.degree.
C. for 3 days. After completion of the reaction, the solvent was
removed under reduced pressure to afford the crude title compound
(55 g). LCMS (ESI) m/z: 255.7 (M+1). This was taken for next step
without further purification.
Step 3: Preparation of
5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(trans/cis mixture)
##STR00070##
[0469] To a solution of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(60 g, 236 mmol) in 1,2-Dichloroethane (DCE) (1300 mL), BBr.sub.3
(22.27 mL, 236 mmol) was added and the reaction mixture was stirred
at 70.degree. C. for 16 h. After completion of the reaction,
methanol (1.5 L) was added to reaction mixture slowly dropwise at
0.degree. C. and stirred at room temperature for 30 minutes. The
reaction mixture was concentrated and the residue was taken in
water (1 L) and adjusted the pH at basic using potassium carbonate
(325 g, 2355 mmol). The aqueous layer was washed with DCM (200 mL).
To the aqueous layer iodine (120 g, 471 mmol) was added and stirred
at room temperature for 16 h. After completion of the reaction,
sodium sulfite (200 g) was added to quench the excess Iodine.
Acetic acid (250 mL) was added and extracted with 2-methyl THF (2*1
L). The organic layer was separated and dried over sodium sulfate.
The solvent was removed under reduced pressure and the crude
product was triturated with 20% dichloromethane in hexane (2*600
mL). The solid obtained was filtered and dried to afford the title
compound (35 g, 21.89% yield). LCMS (54%) (ESI) m/z: 367 (M+1).
Step 4: Ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate (trans/cis mixture)
##STR00071##
[0471] A suspension of
5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (87
g, 237 mmol), ethyl 4-oxo-4H-pyran-3-carboxylate (45.9 g, 273 mmol)
and acetic acid (1.8 L) was stirred at 100.degree. C. for 3 h.
After completion of the reaction, the reaction mixture was
concentrated and co-evaporated with toluene (4*200 mL) and the
residue was purified by column chromatography (230-400 silica gel)
using 10-15% MeOH in DCM as an eluent. Fractions were collected and
concentrated to afford the title compound (51 g, 22% yield) as dark
brown solid. LCMS (53%) (ESI) m/z: 517 (M+1).
Step 5: Ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (trans/cis
mixture)
##STR00072##
[0473] To a solution of ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate (51 g, 99 mmol) in
N,N-Dimethylformamide (580 mL) was added K2CO3 (68.2 g, 493 mmol)
and 1-bromo-3-methoxypropane (30.2 g, 197 mmol). The reaction
mixture was stirred at 60.degree. C. for 1 h. After completion of
the reaction, the reaction mixture was quenched with ice cold water
(1500 mL) and extracted with DCM (2 L). The combined organic layers
were washed with brine (500 mL), dried over Na2SO4 and
concentrated. The crude was purified by column chromatography
(230-400 silica gel) using 0.about.10% Methanol in DCM as an
eluent. Fractions were collected and concentrated to afford the
title compound (52 g, 84% yield). LCMS (ESI) m/z: 588.8 (M+1).
Step 6: Ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(trans/cis mixture)
##STR00073##
[0475] To a solution of ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)
pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carbox-
ylate (52 g, 88 mmol) in N, N-Dimethylformamide (550 mL) was added
potassium acetate (43.3 g, 442 mmol). The reaction mixture was
degassed with nitrogen for 20 minutes. Palladium(II) bromide (4.70
g, 17.66 mmol) was added to the reaction mixture and the reaction
mixture was stirred at 100.degree. C. for 16 h. After completion of
the reaction, the reaction mixture was filtered through celite and
washed with DCM. The organic phase was washed with water (250 mL),
dried over Na2SO4 and concentrated. The crude was purified by
column chromatography (230-400 silica gel) using 2-5% MeOH in DCM
as an eluent. Fractions were collected and concentrated to afford
the title compound (20 g, 42% yield). LCMS (ESI) m/z: 461.1
(M+1).
Step 7:
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid
##STR00074##
[0477] To a solution of Ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7] naphthyridine-10-carboxylate (17.5
g, 38 mmol) in 1.4-Dioxane (150 mL) and water (150 mL) was added
lithium hydroxide.H.sub.2O (7.9 g, 190.14 mmol). The reaction
mixture was heated to 70.degree. C. for 2 h. After completion of
the reaction, the reaction mixture was concentrated and the residue
was taken in DCM (250 mL). 1.5 N HCl was added to this mixture
until pH=6. The organic layer was separated and dried over
Na.sub.2SO.sub.4 and concentrated to get 15 g (yield: 91%) of
racemic mixture. This racemic mixture was purified by prep. HPLC
using to afford the title compound (5.5 g, 73% yield) as pale
yellow solid. Chiral HPLC method: Chiral pak IC (21*250), 5 mics,
Mobile phase A: 0.1% TFA in Methanol, B: 0.1% TFA in Ethanol;
A:B:75:25, Flow rate: 25 ml/min. First peak rt: 5.4. .sup.1H NMR
400 MHz, DMSO-d.sub.6: .delta. 8.62 (s, 1H), 7.63 (s, 1H), 7.43 (s,
1H), 4.73 (d, J=8.96 Hz, 1H), 4.33-4.28 (m, 2H), 3.95-3.94 (m, 1H),
3.53-3.50 (m, 2H), 3.27 (s, 3H), 2.39-2.38 (m, 1H), 2.28-2.27 (m,
1H), 2.04-2.01 (m, 2H), 1.61-1.60 (m, 1H), 1.47-1.44 (m, 1H), 1.15
(s, 3H), 0.40 (s, 3H). LCMS (ESI) m/z: 432.9 (M+1).
Example 2 (Compound 221)
(4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-
-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
##STR00075##
[0478] Step 1:
(4b,7a)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11--
hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
[0479]
2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-he-
xahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis) (500 mg) was purified by chiral chromatography.
Column=Chiralpak IC, 10 mm.times.250 mm (5u), Mobile phase=3:1
MeOH/EtOH+0.1% TFA, Flow rate=10 mL/min, Injection volume=500 uL
(30 mg/mL conc.); DCM used as injection solvent, Collection
wavelength=254 nm. Peak 2 was concentrated to give
(4bS,7aR)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (190 mg, 0.438 mmol, 38% yield) as a white solid. LCMS (ESI)
m/z 433.3 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.59 (s, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 4.69 (d, J=8.98 Hz, 1H),
4.18-4.36 (m, 2H), 3.84-3.96 (m, 1H), 3.48 (t, J=6.25 Hz, 2H), 3.23
(s, 3H), 2.30-2.43 (m, 1H), 2.18-2.28 (m, 1H), 2.00 (quin, J=6.15
Hz, 2H), 1.53-1.64 (m, 1H), 1.37-1.48 (m, 1H), 1.12 (s, 3H), 0.37
(s, 3H).
Example 3: (Compound 222)
(4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,-
7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
##STR00076##
[0480] Step 1:
(4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7-
,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
[0481] A reaction vial containing a stir bar,
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (81 mg, 0.19 mmol), potassium carbonate (103 mg, 0.748 mmol),
cyclopropylboronic acid (32.1 mg, 0.374 mmol), and
tetrakis(triphenylphosphine)palladium(0) (43.2 mg, 0.037 mmol) was
purged thoroughly with a stream of nitrogen (needle in/needle out).
1,4-Dioxane (2 mL) was added and the reaction vial placed into a
heating block that was preheated to 100.degree. C. The mixture was
heated at 100.degree. C. overnight. The reaction mixture was
allowed to cool to room temperature and then diluted with
2-methyltetrahydrofuran and water. Acetic acid was added slowly and
carefully (effervescence) until the aqueous phase was neutralized.
The mixture was extracted 2 times with 2-methyltetrahydrofuran. The
combined organic layers were washed with brine and concentrated.
The residue was purified by medium pressure reverse phase
chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100%
gradient). Fractions were combined and concentrated until a white
precipitate was observed. A small amount of acetonitrile was added
and the solution became clear. The solution was lyophilized to give
(4bR,7aS)-2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7-
,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (67 mg, 0.151 mmol, 81% yield) as a white powder. LCMS (ESI)
m/z 439.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.54 (s, 1H), 7.46 (s, 1H), 7.31 (s, 1H), 4.64 (d, J=8.98 Hz, 1H),
4.08-4.33 (m, 2H), 3.79-3.91 (m, 1H), 3.50 (t, J=6.25 Hz, 2H), 3.24
(s, 3H), 2.39-2.45 (m, 1H), 2.16-2.38 (m, 2H), 2.01 (quin, J=6.15
Hz, 2H), 1.51-1.63 (m, 1H), 1.32-1.45 (m, 1H), 1.12 (s, 3H),
0.92-1.05 (m, 4H), 0.34 (s, 3H).
Example 4: (Compound 223)
2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexa-
hydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis)
##STR00077##
[0482] Step 1:
2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis)
[0483] A reaction vial containing a stir bar, ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(racemic cis) (200 mg, 0.434 mmol), potassium carbonate (240 mg,
1.74 mmol), cyclopropylboronic acid (74.5 mg, 0.868 mmol), and
tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) was
purged thoroughly with a stream of nitrogen (needle in/needle out).
1,4-Dioxane (4 mL) was added and the reaction vial placed into a
heating block that was preheated to 100.degree. C. The mixture was
heated at 100.degree. C. for 3 hours. Additional cyclopropylboronic
acid (74.5 mg, 0.868 mmol) and
tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) were
added and the mixture continued to heat at 100.degree. C. for 2
hours. The mixture was allowed to cool and was filtered through a
celite plug. The celite plug was washed with ethyl acetate. The
filtrate was concentrated to give crude ethyl
2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hex-
ahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate.
The crude intermediate was dissolved in methanol (2 mL) before a
solution of lithium hydroxide monohydrate (182 mg, 4.34 mmol) in
water (2 mL) was added. The mixture was heated at 60.degree. C. for
3 hours and cooled to room temperature. The mixture was purified by
medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were lyophilized to give
2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,5,6,7,7a,11-hexa-
hydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis) (50 mg, 0.114 mmol, 26.3% yield) as a pale tan
powder. LCMS (ESI) m/z 439.3 (M+1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.54 (s, 1H), 7.46 (s, 1H), 7.31 (s, 1H),
4.64 (d, J=8.98 Hz, 1H), 4.11-4.28 (m, 2H), 3.79-3.91 (m, 1H), 3.50
(t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.39-2.45 (m, 1H), 2.16-2.38 (m,
2H), 1.96-2.04 (m, 2H), 1.51-1.64 (m, 1H), 1.34-1.44 (m, 1H), 1.12
(s, 3H), 0.93-1.06 (m, 4H), 0.34 (s, 3H).
##STR00078##
Example 5: (Compound 224)
(7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b-
,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carb-
oxylic acid
##STR00079##
[0484] Step 1:
(7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4-
b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-car-
boxylic acid
[0485] Potassium tert-butoxide (13.3 mg, 0.119 mmol) was added to a
solution of
(4bR,7aS)-2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7-
,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (13 mg, 0.030 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL) at
room temperature and stirred overnight. The mixture was injected
onto a medium pressure reverse phase column and eluted
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were lyophilized to give
(7aR)-2-cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4-
b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-car-
boxylic acid (single isomer) (6 mg, 0.013 mmol, 43.6% yield) as an
off-white powder. LC-MS and NMR were consistent with desired
product. LCMS (ESI) m/z 455.3 (M+1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.68 (s, 1H), 7.50 (s, 2H), 6.11 (s, 1H),
4.62 (s, 1H), 4.12-4.35 (m, 2H), 3.51 (t, J=6.05 Hz, 2H), 3.24 (s,
3H), 2.57-2.68 (m, 1H), 2.11-2.24 (m, 1H), 2.02 (quin, J=6.15 Hz,
2H), 1.56-1.70 (m, 1H), 1.13-1.26 (m, 4H), 0.97-1.10 (m, 4H), 0.24
(s, 3H).
Example 6: (Compound 225)
(7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,-
7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyli-
c acid
##STR00080##
[0486] Step 1:
(7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid
[0487] Potassium tert-butoxide (15.5 mg, 0.139 mmol) was added to a
solution of
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (15 mg, 0.035 mmol) in dimethyl sulfoxide (DMSO) (1 mL) at
room temperature and stirred for 2 hours. The mixture was injected
onto a medium pressure reverse phase column and eluted
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were lyophilized to give
(7aR)-2-chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid (7 mg, 0.015 mmol, 44.6% yield) as a white powder. LCMS
(ESI) m/z 449.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.74 (s, 1H), 7.78 (s, 1H), 7.44 (s, 1H), 6.28 (s, 1H), 4.70
(s, 1H), 4.18-4.43 (m, 2H), 3.49 (t, J=6.25 Hz, 2H), 3.24 (s, 3H),
2.59-2.73 (m, 1H), 2.21 (dt, J=13.47, 8.88 Hz, 1H), 2.01 (quin,
J=6.15 Hz, 2H), 1.58-1.71 (m, 1H), 1.21-1.29 (m, 1H), 1.18 (s, 3H),
0.27 (s, 3H).
Example 7: (Compound 226)
(7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,-
7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyli-
c acid
##STR00081##
[0488] Step 1:
(7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid
[0489] Sodium hydride (60% in mineral oil) (1.87 mg, 0.047 mmol)
was added to a stirring solution of
(7aR)-2-chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6-
,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxyl-
ic acid (7 mg, 0.016 mmol) and methyl iodide (2.9 .mu.l, 0.047
mmol) in N,N-dimethylformamide (DMF) (0.5 mL). The mixture was
stirred for 2 hours. The mixture was heated to 80.degree. C. for 2
hours. The mixture was allowed to cool to room temperature and
quenched with water. The mixture stirred for 20 minutes. The
mixture was injected onto a medium pressure reverse phase
chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100%
gradient). Fractions were lyophilized to give
(4bS,7aR)-2-chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,-
5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carbo-
xylic acid as an off-white powder. LCMS (ESI) m/z 463.2 (M+1).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.79 (s, 1H), 7.78
(s, 1H), 7.46 (s, 1H), 4.92 (s, 1H), 4.26-4.42 (m, 2H), 3.49 (t,
J=6.25 Hz, 2H), 3.24 (s, 3H), 2.94 (s, 3H), 2.66 (dt, J=13.56, 6.68
Hz, 1H), 2.19-2.33 (m, 1H), 2.01 (quin, J=6.15 Hz, 2H), 1.63-1.74
(m, 1H), 1.28-1.40 (m, 1H), 1.19 (s, 3H), 0.29 (s, 3H).
Example 8 (Compound 227) and Example 9 (Compound 228)
(4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid
(4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydroc-
yclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid
##STR00082##
[0491] A mixture of
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,1-
1-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (61 mg, 0.141 mmol) in sodium hydroxide (2M) (4 mL, 8 mmol)
was heated at 150.degree. C. in a microwave reactor for 1 hour. The
mixture was injected onto a medium pressure reverse phase column
and eluted (C18/acetonitrile/water/0.1% formic acid/0% to 100%
gradient). 2 sets of fractions were lyophilized separately to
give:
[0492] Example 8:
(4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,-
11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (20 mg, 0.048 mmol, 34% yield). LCMS (ESI) m/z 415.2 (M+1).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.15-11.71 (m,
1H), 8.53 (s, 1H), 7.44 (s, 1H), 6.97-7.27 (m, 1H), 4.61 (d, J=8.98
Hz, 1H), 4.00-4.19 (m, 2H), 3.73 (br. s., 1H), 3.45 (t, J=6.05 Hz,
2H), 3.23 (s, 3H), 2.11-2.33 (m, 2H), 1.96 (quin, J=6.25 Hz, 2H),
1.50-1.61 (m, 1H), 1.31-1.45 (m, 1H), 1.11 (s, 3H), 0.42 (s,
3H).
[0493] Example 9:
(4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydro-
cyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (8
mg, 0.022 mmol, 15.6% yield). LCMS (ESI) m/z 361.1 (M+1). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.85 (br. s, 1H), 8.57 (s,
1H), 7.37 (s, 1H), 7.24 (s, 1H), 4.66 (d, J=8.98 Hz, 1H), 3.80-3.94
(m, 1H), 2.25-2.43 (m, 2H), 1.94-2.08 (m, 1H), 1.52-1.64 (m, 1H),
1.38-1.49 (m, 1H), 1.11 (s, 3H), 0.37 (s, 3H).
Example 10: (Compound 229)
2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,1-
0-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00083##
[0494] Step 1:
4-(Benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one
##STR00084##
[0496] A flask was charged with a stir bar,
5-bromo-2-chloro-3-methoxypyridine (5.8 g, 26 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.358 g, 0.391 mmol), and
sodium tert-butoxide (4.41 g, 45.9 mmol). The flask was purged with
a stream of nitrogen before 4-(benzyloxy)-3,3-dimethylbutan-2-one
(5.45 g, 26.4 mmol) in tetrahydrofuran (THF) (100 ml) was added.
The mixture was heated to reflux for 3 hours. The mixture was
allowed to cool to room temperature and diluted with water. The
mixture was extracted 3 times with ethyl acetate. The combined
organic layers were washed with brine, dried over sodium sulfate,
and concentrated. The residue was purified by silica chromatography
eluting with a gradient of 0% to 50% ethyl acetate in hexanes. The
fractions were concentrated to give
4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one
(5.62 g, 16.2 mmol, 62% yield) as a pale yellow oil. LCMS (ESI) m/z
348.2 (M+1). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.70
(d, J=1.95 Hz, 1H), 7.21-7.39 (m, 5H), 7.01 (d, J=1.56 Hz, 1H),
4.49 (s, 2H), 3.79 (s, 5H), 3.52 (s, 2H), 1.22 (s, 6H).
Step 2:
4-(Benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-
-2-amine
##STR00085##
[0498] A mixture of
4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one
(3 g, 8.6 mmol) and ammonium acetate (9.97 g, 129 mmol) in methanol
(50 mL) were stirred at room temperature overnight. Sodium
cyanoborohydride (1.08 g, 17.3 mmol) was added and the mixture
heated at 60.degree. C. overnight. The mixture was allowed to cool
to room temperature, concentrated to -15 mL, quenched with 1M
sodium hydroxide, and extracted 3 times with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate, and concentrated to give crude
4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amin-
e (2.84 g, 5.62 mmol, 65% yield). LCMS (ESI) m/z 349.3 (M+1).
Step 3:
5-(2-Amino-4-hydroxy-3,3-dimethylbutyl)-2-chloropyridin-3-ol
##STR00086##
[0500] Boron tribromide (2.66 mL, 28.1 mmol) was added dropwise to
a solution of
4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amin-
e (2.84 g, 5.62 mmol) in 1,2-dichloroethane (DCE) (100 mL) at
0.degree. C. The mixture was allowed to warm to room temperature
and stirred for 4 hours. An oily solid precipitated on the bottom
of the flask. The solids were scraped off the walls of the flask
and the mixture stirred vigorously at room temperature overnight.
An oily solid precipitate coated the bottom of the flask. The
liquid phase was decanted and poured into ice. The precipitate in
the original reaction flask was slurried in fresh
1,2-dichloroethane (DCE) (100 mL) and stirred while 1 mL (.about.2
eq) of fresh boron tribromide was added dropwise at room
temperature. The mixture was heated at 70.degree. C. for 4 hours
and then allowed to cool to room temperature. The mixture was
cooled with an ice bath, quenched with slow careful addition of 100
mL of methanol, warmed to room temperature, and stirred for 1 hour.
The mixture was concentrated and the residue purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/0% to 20% gradient). Fractions were lyophilized to give
5-(2-amino-4-hydroxy-3,3-dimethylbutyl)-2-chloropyridin-3-01 (910
mg, 3.72 mmol, 66.2% yield) as a white powder. LCMS (ESI) m/z 245.2
(M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.80 (d,
J=1.95 Hz, 1H), 7.59 (br. s., 3H), 7.25 (d, J=1.95 Hz, 1H),
3.31-3.38 (m, 2H), 3.19-3.29 (m, 1H), 2.92-3.02 (m, 1H), 2.53-2.63
(m, 1H), 0.95 (s, 3H), 0.90 (s, 3H).
Step 4:
5-(2-Amino-4-hydroxy-3,3-dimethylbutyl)-2-chloro-6-iodopyridin-3-o-
l
##STR00087##
[0502] Iodine (233 mg, 0.919 mmol) was added to a stirring mixture
of 5-(2-amino-4-hydroxy-3,3-dimethylbutyl)-2-chloropyridin-3-ol
(225 mg, 0.919 mmol) and potassium carbonate (381 mg, 2.76 mmol) in
water (10 mL). The mixture was stirred at room temperature for 2
hours. Solid sodium sulfite was added portion wise to the mixture
until color dissipated. The aqueous mixture was injected onto a
medium pressure reverse phase C18 column and then eluted with
acetonitrile/water/0.1% formic acid/0% to 50% gradient. Combined
fractions were lyophilized to give
5-(2-amino-4-hydroxy-3,3-dimethylbutyl)-2-chloro-6-iodopyridin-3-ol
(164 mg, 0.443 mmol, 48.1% yield) as a white solid. LCMS (ESI) m/z
371.0 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.23
(s, 1H), 7.20 (s, 1H), 3.13-3.41 (m, 2H), 2.70-2.88 (m, 2H),
2.29-2.39 (m, 1H), 0.92 (s, 3H), 0.84 (s, 3H).
Step 5: Ethyl
1-(4-acetoxy-1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan--
2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00088##
[0504]
5-(2-Amino-4-hydroxy-3,3-dimethylbutyl)-2-chloro-6-iodopyridin-3-ol
(164 mg, 0.443 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (83 mg,
0.494 mmol) in acetic acid (4 mL) were stirred at 100.degree. C.
for 4 hours. The mixture was allowed to cool to room temperature
and concentrated. The residue was purified by medium pressure
reverse phase chromatography (C18/acetonitrile/water/0.1% formic
acid/0% to 100% gradient). 2 sets of fractions were concentrated
separately to give ethyl
1-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-4-hydroxy-3,3-dimethylbutan--
2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (83 mg, 0.16 mmol,
36% yield) and ethyl
1-(4-acetoxy-1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan--
2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (27 mg, 0.048 mmol,
11% yield). LCMS (ESI) m/z 563.2 (M+1).
Step 6: Ethyl
1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dim-
ethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00089##
[0506] Ethyl
1-(4-acetoxy-1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan--
2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (27 mg, 0.048 mmol),
potassium carbonate (26.5 mg, 0.192 mmol), and
1-bromo-3-methoxypropane (19 mg, 0.124 mmol) were stirred at room
temperature overnight. The mixture was quenched with water and
extracted 2 times with ethyl acetate. The combined organic layers
were washed with brine, washed with 5% lithium chloride (aq), and
concentrated. The residue was purified by medium pressure reverse
phase chromatography (C18/acetonitrile/water/0.1% formic acid/10%
to 100% gradient). Fractions were lyophilized to give ethyl
1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3-
,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (15
mg, 0.024 mmol, 49.2% yield) as a white powder. LCMS (ESI) m/z
635.9 (M+1).
Step 7:
2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-
-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid
##STR00090##
[0508] A round bottom flask containing a stir bar, ethyl
1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dim-
ethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (14 mg,
0.022 mmol), potassium acetate (4.33 mg, 0.044 mmol), and
palladium(II) bromide (1.2 mg, 4.4 .mu.mol) was purged with
nitrogen for 15 minutes. N,N-Dimethylacetamide (DMA) (1 mL) was
purged with nitrogen for 5 minutes before being added to the
reaction vessel. The reaction vessel was placed into an oil bath
that was preheated to 90.degree. C. and the mixture stirred for 3
hours. The mixture was allowed to cool to room temperature,
filtered through celite, and the filtrate purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/10% to 100% gradient). Fractions were combined and
basified with 1M sodium hydroxide. The mixture was heated at
60.degree. C. overnight, cooled to room temperature, and
concentrated. The residue was dissolved in water and acidified to
pH=3-4 with 1M hydrochloric acid. The mixture was purified by
medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient).
Fractions were lyophilized to give
2-chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (3
mg, 6.9 .mu.mol, 31% yield). LCMS (ESI) m/z 437.2 (M+1).
[0509] General Scheme 6 for Preparation of Compounds of Examples
11-25
##STR00091##
Example 11 (Compound 230)
(S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-py-
rido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00092##
[0510] Step 1:
(R)--N--((S)-1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide
##STR00093##
[0512] A solution of
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (2.54 g,
10.50 mmol), (R)-2-methylpropane-2-sulfinamide (2.55 g, 21.00 mmol)
and Ti(OEt).sub.4 (5.99 g, 26.3 mmol) in toluene (8.5 mL) was
stirred for 10 mins at 60.degree. C. and the vessel was then
evacuated. The reaction mixture was stirred at 60.degree. C. under
vacuum for 24 h. The vessel was re-pressurized with nitrogen and
toluene (5 mL) and THF (35 mL) were added. A solution of LiBH.sub.4
(15.8 mL, 2M in THF, 31.5 mmol) was added slowly. The reaction
mixture was stirred at RT overnight. The reaction mixture was
diluted with THF (130 mL) and brine (3 mL), stirred for 30 mins,
and then filtered through celite. The filtrate was evaporated and
purified by silica gel chromatography (0-100% EtOAc/hexanes) to
afford
(R)--N--((S)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide (2.58 g, 71%) as the major
diastereomer. LCMS (m/z, ES+)=346.9, 348.1 (M+1).
Step 2: (S)-5-(2-Amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol
##STR00094##
[0514] A solution of
(R)--N--((S)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide (2.56 g, 7.38 mmol) in
1,2-dichloroethane (36.9 mL) was stirred at 0.degree. C. Boron
tribromide (4.88 mL, 51.7 mmol) was added slowly. The reaction
mixture was removed from the cooling bath and stirred overnight at
RT. The solution was cooled to 0.degree. C. and quenched by careful
addition of MeOH. The resulting suspension was evaporated. EtOAc
was added and the solid was collected by filtration, washed with
EtOAc, and dried to afford
(S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol, as the bis
HBr salt. (2.89 g, quant.) LCMS (m/z, ES+)=229.1, 231.1 (M+1).
Step 3: (S)-tert-Butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
##STR00095##
[0516] Triethylamine (0.95 mL, 6.85 mmol) was added to a stirred
suspension of
(S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol. 2HBr (1.36
g, 3.42 mmol) and Boc-anhydride (0.87 mL, 3.73 mmol) in THF (34.2
mL) and the reaction mixture was stirred at 60.degree. C. for 1 h
and then evaporated to dryness. The solid was suspended in diethyl
ether, isolated by filtration and then partitioned between EtOAc
and water. The aqueous layer was extracted with CH.sub.2Cl.sub.2
(4.times.) and the combined organic phases were dried
(Na.sub.2SO.sub.4), filtered and evaporated to provide
(S)-tert-butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(assumed quant.). LCMS (m/z, ES+)=329.6, 331.2 (M+1).
Step 4: (S)-tert-Butyl
(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbama-
te
##STR00096##
[0518] Iodine (0.87 g, 3.42 mmol) was added to a stirred solution
of tert-butyl
(S)-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(1.13 g, 3.42 mmol) and K.sub.2CO.sub.3 (1.42 g, 10.26 mmol) in
water (8.6 mL) and 1,4-dioxane (8.6 mL). The reaction mixture was
stirred overnight at rt. More iodine (0.20 g, 0.79 mmol) and
K.sub.2CO.sub.3 (0.40 g, 7.23 mmol) were added and the reaction
mixture was heated at 40.degree. C. for 5 h. Solid Na.sub.2SO.sub.3
was added while stirring until the solution was no longer dark
brown. The solution was diluted with brine and EtOAc. The aqueous
phase was extracted with EtOAc. The combined organic layers were
dried (Na.sub.2SO.sub.4), filtered and evaporated to provide
(S)-tert-butyl
(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbama-
te as a yellow foam (1.56 g, quant.). LCMS (m/z, ES+)=455.1, 457.1
(M+1).
Step 5: (S)-tert-Butyl (1-(6-chloro-2-iodo-5-(3-methoxypropoxy)
pyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
##STR00097##
[0520] A solution of tert-butyl
(S)-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)car-
bamate (0.83 g, 1.84 mmol), K.sub.2CO.sub.3 (0.76 g, 5.51 mmol),
and 1-bromo-3-methoxypropane (0.56 g, 3.67 mmol) in DMF (12.2 mL)
was heated at 80.degree. C. for 3 h. The reaction mixture was
evaporated to dryness and the residue was taken up in
CH.sub.2Cl.sub.2 and H.sub.2O. The aqueous phase was extracted
CH.sub.2Cl.sub.2 (2.times.) and the combined organic layers were
dried (Na.sub.2SO.sub.4), filtered, and evaporated to afford
tert-butyl
(S)-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbut-
an-2-yl)carbamate (0.97 g, quant.) as an off-white solid. LCMS
(m/z, ES+)=527.2, 529.2 (M+1).
Step 6: (S)-Ethyl
1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-
-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00098##
[0522] 4 M Hydrogen chloride in dioxane (6.89 mL, 27.5 mmol) was
added to a solution of tert-butyl
(S)-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbut-
an-2-yl)carbamate (967 mg, 1.84 mmol) in CH.sub.2Cl.sub.2 (7 mL).
The reaction mixture was stirred at rt for 3 h and evaporated to
dryness. The solid was dissolved in CH.sub.2Cl.sub.2 (1 mL) and
Et.sub.3N (1 mL) and then evaporated to dryness. The residue was
taken up in saturated NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous
phase was extracted with CH.sub.2Cl.sub.2 (2.times.) and the
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and evaporated to afford
(S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbuta-
n-2-amine. A solution of the above amine and ethyl
4-oxo-4H-pyran-3-carboxylate (340 mg, 2.02 mmol) in acetic acid
(18.4 mL) was stirred at 100.degree. C. for 7 h. The reaction
mixture was evaporated to dryness and the residue was purified by
reverse phase chromatography (10-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford ethyl
(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dim-
ethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (593 mg,
56%) as a tan solid. LCMS (m/z, ES+)=577.7, 579.2 (M+1).
Step 7: (S)-Ethyl
6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrid-
o[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00099##
[0524] A flask containing of ethyl
(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylb-
utan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.59 g, 1.03
mmol), potassium acetate (0.20 g, 2.06 mmol), and palladium(II)
bromide (0.055 g, 0.21 mmol) was purged with nitrogen. Degassed
N,N-dimethylacetamide (DMA) (10.3 mL) was added and the reaction
mixture was heated at 90.degree. C. for 24 h. The solvent was
removed by evaporation and the residue was purified by reverse
phase chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1% formic
acid)) to afford ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (326 mg, 71%) as an
off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.18
(s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 4.40 (q, J=7.0 Hz, 2H),
4.13-4.26 (m, 2H), 3.93 (d, J=6.6 Hz, 1H), 3.62 (m, 2H), 3.42-3.51
(m, 1H), 3.38 (s, 3H), 3.17-3.25 (m, 1H), 2.15 (quin, J=6.0 Hz,
2H), 1.41 (t, J=7.2 Hz, 3H), 0.86 (s, 9H); LCMS (m/z, ES+)=449.3,
451.3 (M+1).
Step 8:
(S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihyd-
ro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00100##
[0526] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (42 mg, 0.094 mmol) in
1M LiOH (1.7 mL) and MeOH (1.7 mL) was stirred at 50.degree. C. for
1.5 h. 1M Citric acid (2 mL) was added and the reaction mixture was
stirred for several mins. The white solid was collected by
filtration, washed with water, and dried to afford
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (35.5 mg, 90%) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
16.31 (s, 1H), 8.81 (s, 1H), 7.75 (s, 1H), 7.30 (s, 1H), 4.68 (d,
J=6.3 Hz, 1H), 4.19-4.32 (m, 2H), 3.40-3.60 (m, 4H), 3.26 (s, 3H),
2.04 (quin, J=6.2 Hz, 2H), 0.75 (s, 9H); LCMS (m/z, ES+)=421.3,
423.2 (M+1).
Example 12 (Compound 231)
(S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00101##
[0527] Step 1: (S)-tert-Butyl
(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-
-2-yl)carbamate
##STR00102##
[0529] A solution of tert-butyl
(S)-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)car-
bamate (0.73 g, 1.60 mmol), K.sub.2CO.sub.3 (0.66 g, 4.78 mmol),
and (bromomethyl)cyclopropane (0.43 g, 3.19 mmol) in DMF (10.6 mL)
was heated at 80.degree. C. for 3 h. The reaction mixture was
evaporated to dryness and the residue was taken up in
CH.sub.2Cl.sub.2 and H.sub.2O. The aqueous phase was extracted with
CH.sub.2Cl.sub.2 (2.times.) and the combined organic layers were
dried (Na.sub.2SO.sub.4), filtered, and evaporated to afford
tert-butyl
(S)-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylb-
utan-2-yl)carbamate (0.81 g, quant.) as an off-white solid. LCMS
(m/z, ES+)=508.8, 511.1 (M+1).
Step 2: (S)-Ethyl
1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbut-
an-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00103##
[0531] 4 M Hydrogen chloride in dioxane (5.98 mL, 23.9 mmol) was
added to a solution of tert-butyl
(S)-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylb-
utan-2-yl)carbamate (812 mg, 1.60 mmol) in CH.sub.2Cl.sub.2 (6 mL).
The reaction mixture was stirred at rt for 3 h and evaporated to
dryness. The solid was dissolved in CH.sub.2Cl.sub.2 (1 mL) and
Et.sub.3N (1 mL) and then evaporated to dryness. The residue was
taken up in saturated NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous
phase was extracted with CH.sub.2Cl.sub.2 (2.times.) and the
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and evaporated to afford
(S)-1-(6-chloro-2-iodo-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbu-
tan-2-amine. LCMS (m/z, ES+)=409.1, 411.1 (M+1).
[0532] A solution of the above amine and ethyl
4-oxo-4H-pyran-3-carboxylate (295 mg, 1.76 mmol) in acetic acid
(16.0 mL) was stirred at 100.degree. C. for 7 h. The reaction
mixture was evaporated to dryness and the residue was purified by
reverse phase chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford ethyl
(S)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-d-
imethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (453 mg,
51%) as a tan solid. LCMS (m/z, ES+)=559.4, 561.1 (M+1).
Step 3: (S)-Ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00104##
[0534] A flask containing ethyl
(S)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethy-
lbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.45 g, 0.81
mmol), potassium acetate (0.16 g, 1.62 mmol), and palladium(II)
bromide (0.043 g, 0.16 mmol) was purged with nitrogen. Degassed
N,N-dimethylacetamide (DMA) (8.1 mL) was added and the reaction
mixture was heated at 90.degree. C. for 24 h. The solvent was
removed by evaporation and the residue was taken up in
CH.sub.2Cl.sub.2 and water and filtered through celite. The organic
phase was evaporated to dryness and the residue was purified by
reverse phase chromatography (10-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford ethyl
(S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (216 mg, 62%) as an
off-white solid. LCMS (m/z, ES+)=431.2, 433.2 (M+1); >97% e.e.
by chiral HPLC.
Step 4:
(S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00105##
[0536] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (52.7 mg, 0.12
mmol), Pd(PPh.sub.3).sub.4 (28 mg, 0.024 mmol), potassium carbonate
(34 mg, 0.25 mmol), and trimethylboroxine (46 mg, 0.37 mmol) in
1,4-dioxane (0.61 mL) was heated at 100.degree. C. overnight. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered
through celite. The filtrate was evaporated and the residue was
purified by reverse phase chromatography (5-100%
CH.sub.3CN/H.sub.2O (0.1% formic acid)) to afford (S)-ethyl
6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (36.5 mg, 73%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.18 (s, 1H), 7.56 (s, 1H),
6.80 (s, 1H), 4.40 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 3.39-3.48 (m,
1H), 3.10-3.18 (m, 1H), 2.50 (s, 3H), 1.41 (t, J=7.0 Hz, 3H), 0.69
(m, 2H), 0.40 (m, 2H); LCMS (m/z, ES+)=411.4 (M+1).
[0537] A solution of the above ester in 1 M LiOH (0.9 mL) and MeOH
(0.9 mL) was heated at 50.degree. C. for 1.5 h. 1M citric acid (1.2
mL) was added and the reaction mixture was stirred for 15 mins. The
solid was collected by filtration, washed with water, and dried to
afford
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (27.7 mg, 59%
for 2 steps) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 16.53 (br. s., 1H), 8.77 (s, 1H), 7.44 (s., 1H), 7.42
(s, 1H), 4.58-4.69 (m, 1H), 3.98 (m, 2H), 3.46-3.55 (m, 2H), 2.43
(s, 3H), 1.22-1.36 (m, 1H), 0.73 (s, 9H), 0.65-0.55 (m, 2H),
0.33-0.44 (m, 2H); LCMS (m/z, ES+)=383.2 (M+1).
Example 13 (Compound 232)
(S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-py-
rido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00106##
[0539] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (47.7 mg, 0.11 mmol),
Pd(PPh.sub.3).sub.4 (25 mg, 0.021 mmol), potassium carbonate (29
mg, 0.21 mmol), and trimethylboroxine (40 mg, 0.32 mmol) in
1,4-dioxane (0.53 mL) was heated at 100.degree. C. overnight. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered
through celite. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford (S)-ethyl
6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrid-
o[1,2-h][1,7]naphthyridine-9-carboxylate (41.3 mg, 91%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.17 (s, 1H),
7.27 (s, 1H), 6.86 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 4.05-4.17 (m,
2H), 3.91 (d, J=6.6 Hz, 1H), 3.63-3.55 (m, 2H), 3.49-3.41 (m, 1H),
3.38 (s, 3H), 3.15 (d, J=16.8 Hz, 1H), 2.46 (s, 3H), 2.12 (quin,
J=6.1 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 0.84 (s, 9H); LCMS (m/z,
ES+)=429.4 (M+1).
[0540] A solution of the above ester in 1 M LiOH (1 mL) and MeOH (1
mL) was heated at 50.degree. C. for 1.5 h. 1M citric acid (1.2 mL)
was added and the reaction mixture was stirred for 15 mins. The
solid was collected by filtration, washed with water, and dried to
afford
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (27.6 mg, 65% for
2 steps) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 16.53 (s, 1H), 8.77 (s, 1H), 7.46 (s, 1H), 7.44 (s,
1H), 4.64 (d, J=6.3 Hz, 1H), 4.09-4.23 (m, 2H), 3.47-3.56 (m, 3H),
3.38-3.32 (m, 1H), 3.26 (s, 3H), 2.42 (s, 3H), 2.02 (quin, J=6.2
Hz, 2H), 0.74 (s, 9H); LCMS (m/z, ES+)=401.2 (M+1).
Example 14 (Compound 233)
(S)-6-(tert-Butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydr-
o-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00107##
[0542] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (53 mg, 0.12 mmol),
Pd(PPh.sub.3).sub.4 (28 mg, 0.025 mmol), potassium carbonate (51
mg, 0.37 mmol), and cyclopropylboronic acid (21 mg, 0.25 mmol) in
1,4-dioxane (1.2 mL) was heated at 100.degree. C. overnight. The
reaction mixture was diluted with CH.sub.2CO.sub.2 and filtered
through celite. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford (S)-ethyl
6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (53.3 mg, 99%) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.14 (s,
1H), 7.42 (s, 1H), 6.77 (s, 1H), 4.38 (q, J=7.3 Hz, 2H), 3.88 (m,
J=6.8, 2.1 Hz, 2H), 3.43 (dd, J=16.8, 7.0 Hz, 1H), 3.11 (d, J=16.8
Hz, 1H), 2.56-2.47 (m, 1H), 1.39 (t, J=7.0 Hz, 3H), 1.35-1.29 (m,
1H), 1.22-1.29 (m, 1H), 1.04-1.19 (m, 2H), 0.93-1.01 (m, 2H), 0.82
(s, 9H), 0.63-0.73 (m, 2H), 0.44-0.38 (m, 2H); LCMS (m/z,
ES+)=437.4 (M+1).
[0543] A solution of the above ester in 1 M LiOH (1.2 mL) and MeOH
(1.2 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (1.5
mL) was added and the reaction mixture was stirred for 15 mins. The
solid was collected by filtration, washed with water, and dried to
afford
(S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-5,10-dihyd-
ro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (38.8 mg,
77% for 2 steps) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 16.53 (s, 1H), 8.76 (s, 1H), 7.38 (s,
1H), 7.35 (s, 1H), 4.62 (d, J=6.3 Hz, 1H), 4.05-3.94 (m, 2H),
3.42-3.55 (m, 1H), 3.30-3.28 (m, 1H), 1.26-1.44 (m, 1H), 0.93-1.06
(m, 4H), 0.72 (s, 9H), 0.65-0.59 (m, 2H), 0.43-0.5 (m, 2H); LCMS
(m/z, ES+)=409.2 (M+1).
Example 15 (Compound 234)
(S)-6-(tert-Butyl)-2-cyclo
propyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naph-
thyridine-9-carboxylic acid
##STR00108##
[0545] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (46 mg, 0.10 mmol),
Pd(PPh.sub.3).sub.4, (24 mg, 0.020 mmol), potassium carbonate (42
mg, 0.31 mmol), and cyclopropylboronic acid (18 mg, 0.21 mmol) in
1,4-dioxane (1.0 mL) was heated at 100.degree. C. overnight. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered
through celite. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford (S)-ethyl
6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (43.6 mg, 94%) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.16 (s,
1H), 7.45 (s, 1H), 6.83 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 4.13 (m,
2H), 3.89 (d, J=6.6 Hz, 1H), 3.62 (m, 2H), 3.39-3.46 (m, 1H), 3.38
(s, 3H), 3.13 (d, J=16.8 Hz, 1H), 2.40-2.50 (m, 1H), 2.15 (quin,
J=6.1 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 1.14-1.22 (m, 1H), 1.04-1.12
(m, 1H), 0.93-1.02 (m, 2H), 0.83 (s, 9H); LCMS (m/z, ES+)=455.5
(M+1).
[0546] A solution of the above ester in 1 M LiOH (1.2 mL) and MeOH
(1.2 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (1.5
mL) was added and the reaction mixture was stirred for 15 mins. The
solid was collected by filtration, washed with water, and dried to
afford
(S)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-
-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (27.2 mg,
62%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 16.53 (s, 1H), 8.76 (s, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 4.62
(d, J=6.3 Hz, 1H), 4.11-4.24 (m, 2H), 3.42-3.57 (m, 4H), 3.26 (s,
3H), 2.41-2.46 (m, 1H), 2.05 (quin, J=6.2 Hz, 2H), 0.94-1.06 (m,
4H), 0.73 (s, 9H); LCMS (m/z, ES+)=427.2 (M+1).
Example 16 (Compound 235)
(R)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00109##
[0547] Step 1:
(S)--N--((R)-1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide and
(S)--N--((S)-1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide
##STR00110##
[0549] A solution of
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (2.56 g,
10.57 mmol), (S)-2-methylpropane-2-sulfinamide (2.56 g, 21.14
mmol), Ti(OEt).sub.4 (6.03 g, 26.4 mmol) in toluene (8.5 mL) was
stirred for 10 mins at 60.degree. C. and the vessel was then
evacuated. The reaction mixture was stirred at 60.degree. C. under
vacuum for 24 h. The vessel was re-pressurized with nitrogen,
toluene (5 mL) and Ti(OEt).sub.4 (2.4 g, 10.5 mmol) were added and
the reaction mixture was stirred under vacuum for 4 h. The vessel
was re-pressurized with nitrogen, toluene (5 mL) was added and the
reaction mixture was stirred under vacuum for another 3 h. The
thick reaction mixture was then taken up in THF (70.5 mL),
additional Ti(OEt).sub.4 (2.4 g, 10.5 mmol) was added, and the
solution was cooled to -30.degree. C. NaBH.sub.4 (1.20 g, 31.7
mmol) was added portion wise. The reaction mixture was then allowed
to warm slowly to rt overnight. The reaction mixture was diluted
with THF (130 mL) and brine (3 mL), stirred for 30 mins, and then
filtered through celite. The filtrate was evaporated and purified
by silica gel chromatography to afford the two diastereomers.
[0550] Major diastereomer is a white solid:
(S)--N--((R)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide (1.8 g, 50%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.81 (d, J=2.0 Hz, 1H), 7.40 (d, J=2.0 Hz,
1H), 3.97 (s, 3H), 3.26 (m, 1H), 3.06-3.15 (m, 2H), 2.72 (dd,
J=14.8, 8.2 Hz, 1H), 1.17 (s, 9H), 0.99 (s, 9H); LCMS (m/z,
ES+)=346.8, 348.5 (M+1).
[0551] Minor diastereomer is a clear oil:
(S)--N--((S)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide (1.2 g, 33%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.77 (d, J=1.6 Hz, 1H), 7.07 (d, J=1.6 Hz,
1H), 3.93 (s, 3H), 3.19-3.33 (m, 2H), 3.02 (dd, J=14.1, 2.7 Hz,
1H), 2.55 (dd, J=14.1, 10.5 Hz, 1H), 1.08 (s, 9H), 0.98 (s, 9H);
LCMS (m/z, ES+)=346.8, 348.0 (M+1).
Step 2: (R)-5-(2-Amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol
##STR00111##
[0553] A solution of
(S)--N--((R)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-
-methylpropane-2-sulfinamide (1.82 g, 5.26 mmol) in
1,2-dichloroethane (26.3 mL) was stirred at 0.degree. C. Boron
tribromide (3.48 mL, 36.8 mmol) was added slowly. The reaction
mixture was removed from the cooling bath and stirred overnight at
RT. The solution was cooled to 0.degree. C. and quenched by careful
addition of MeOH. The resulting suspension was evaporated. EtOAc
was added and the solid was collected by filtration, washed with
EtOAc, and dried to afford
(S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol, as the bis
HBr salt. (2.1 g, quant.) LCMS (m/z, ES+)=229.2, 231.2 (M+1).
Step 3: (R)-tert-Butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
##STR00112##
[0555] A stirred suspension of
(R)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol. 2HBr (1.0
g, 2.51 mmol) and Boc-anhydride (0.80 g, 3.67 mmol) in THF (25.1
mL) was stirred at 60.degree. C. for 1.5 h. THF (10 mL) and
triethylamine (0.35 mL, 2.51 mmol) were added and the reaction
mixture was stirred for another 30 mins. Additional triethylamine
(0.35 mL, 2.51 mmol) was added and the reaction mixture was stirred
at 60.degree. C. for 1 h. The solution was then evaporated to
dryness. The solid was suspended in diethyl ether, isolated by
filtration and washed with additional diethyl ether. The solid was
taken up in EtOAc and washed with dilute aqueous NaHCO.sub.3, and
brine. The organic phase was dried (Na.sub.2SO.sub.4), filtered and
evaporated to provide (R)-tert-butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(1.01 g, 99%) as a light yellow solid. LCMS (m/z, ES+)=329.2, 331.2
(M+1).
Step 4: (R)-tert-Butyl
(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbama-
te
##STR00113##
[0557] Iodine (0.64 g, 2.51 mmol) was added to a stirred solution
of tert-butyl
(R)-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(0.83 g, 2.51 mmol) and K.sub.2CO.sub.3 (1.04 g, 7.53 mmol) in
water (6.3 mL) and 1,4-dioxane (6.3 mL). The reaction mixture was
stirred at RT for 1.5 h.
[0558] Solid Na2SO3 was added while stirring until the solution was
no longer dark brown. The solution was diluted with brine and
EtOAc. The aqueous phase was extracted with EtOAc. The combined
organic phases were dried (Na2SO4), filtered and evaporated to
provide (R)-tert-butyl
(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbama-
te as a yellow foam (0.38 g, 34%). LCMS (m/z, ES+)=455.4, 457.1
(M+1).
Step 5: (R)-tert-Butyl
(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-
-2-yl)carbamate
##STR00114##
[0560] A solution of tert-butyl
(R)-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)car-
bamate (0.3819 g, 0.840 mmol), K.sub.2CO.sub.3 (0.35 g, 2.52 mmol),
and (bromomethyl)cyclopropane (0.23 g, 1.68 mmol) in DMF (5.6 mL)
was heated at 80.degree. C. for 3 h. The reaction mixture was
evaporated to dryness and the residue was taken up in
CH.sub.2Cl.sub.2 and H.sub.2O. The aqueous phase was extracted
CH.sub.2Cl.sub.2 (2.times.) and the combined organic layers were
dried (Na.sub.2SO.sub.4), filtered, and evaporated to afford
tert-butyl
(R)-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylb-
utan-2-yl)carbamate (415.4 mg, 97%) as an off-white solid. LCMS
(m/z, ES+)=509.2, 511.2 (M+1).
Step 6: Ethyl
(R)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethy-
lbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00115##
[0562] 4 M Hydrogen chloride in dioxane (3.06 mL, 12.25 mmol) was
added to a solution of tert-butyl
(R)-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylb-
utan-2-yl)carbamate (0.42 g, 0.82 mmol) in CH.sub.2Cl.sub.2 (3 mL).
The reaction mixture was stirred at rt for 3 h and evaporated to
dryness. The solid was dissolved in CH.sub.2Cl.sub.2 (1 mL) and
Et.sub.3N (1 mL), stirred, and then evaporated to dryness. The
residue was taken up in saturated NaHCO.sub.3 and CH.sub.2Cl.sub.2.
The aqueous phase was extracted with CH.sub.2Cl.sub.2 (2.times.)
and the combined organic layers were dried (Na.sub.2SO.sub.4),
filtered, and evaporated to afford
(R)-1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbu-
tan-2-amine. A solution of the above amine and ethyl
4-oxo-4H-pyran-3-carboxylate (151 mg, 0.90 mmol) in acetic acid
(8.2 mL) was stirred at 100.degree. C. for 7 h. The reaction
mixture was evaporated to dryness and the residue was purified by
reverse phase chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford ethyl
(R)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-d-
imethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (389 mg,
85%) as a light tan solid. LCMS (m/z, ES-)=575.2, 577.2 (M-1).
Step 7: (R)-Ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00116##
[0564] A flask containing of ethyl
(R)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethy-
lbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.39 g, 0.70
mmol), potassium acetate (0.14 g, 1.39 mmol), and palladium(II)
bromide (0.037 g, 0.14 mmol) was purged with nitrogen. Degassed
N,N-dimethylacetamide (DMA) (7.0 mL) was added and the reaction
mixture was heated at 90.degree. C. for 24 h. The solution was
purified by reverse phase chromatography (10-100%
CH.sub.3CN/H.sub.2O (0.1% formic acid)) to afford ethyl
(R)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihy-
dro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (167 mg, 56%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.18 (s, 1H), 7.49
(s, 1H), 6.96 (s, 1H), 4.40 (q, J=7.3 Hz, 2H), 3.96 (d, J=7.0 Hz,
2H), 3.93 (d, J=6.6 Hz, 1H), 3.46 (dd, J=17.0, 6.8 Hz, 1H), 3.19
(d, J=16.8 Hz, 1H), 1.41 (t, J=7.0 Hz, 3H), 1.30-1.37 (m, 1H), 0.85
(s, 9H), 0.76-0.70 (m, 2H), 0.41-0.48 (m, 2H); LCMS (m/z,
ES-)=429.4, 431.4 (M-1).
Step 8:
(R)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-di-
hydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00117##
[0566] A solution of ethyl
(R)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (33 mg, 0.077 mmol),
NaB(OMe).sub.4 (36 mg, 0.23 mmol), tBuXPhos (6.5 mg, 0.015 mmol)
and Pd.sub.2(dba).sub.3 (7.0 mg, 7.66 .mu.mol) in DMF (0.77 mL) was
heated at 80.degree. C. for 2 h. The reaction mixture was filtered
through celite and the celite was rinsed with EtOAc and
CH.sub.2Cl.sub.2. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford ethyl
(R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (27 mg, 83%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.17 (s, 1H), 7.42
(s, 1H), 6.80 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 4.05 (s, 3H),
3.94-3.85 (m, 3H), 3.42 (dd, J=16.6, 6.8 Hz, 1H), 3.09 (d, J=16.8
Hz, 1H), 1.37-1.40 (t, J=7.2 Hz, 4H), 1.27-1.37 (m, 1H), 0.85 (s,
9H), 0.66-0.75 (m, 2H), 0.42-0.37 (m, 2H); LCMS (m/z, ES+)=427.4
(M+1).
[0567] A solution of the above ester in 1 M LiOH (1 mL) and MeOH (1
mL) was heated at 50.degree. C. for 2 h. The reaction mixture was
filtered through an acrodisc filter to remove fine particulates and
1M citric acid (1 mL) was added to the clear filtrate. The
precipitate was collected by filtration, washed with water, and
dried to afford
(R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (19 mg, 62% for
2 steps) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 16.53 (s, 1H), 8.77 (s, 2H), 7.40 (s, 2H), 7.36 (s,
2H), 4.62 (d, J=6.8 Hz, 1H), 3.97 (s, 3H), 3.96-3.89 (m, 2H),
3.49-3.40 (m, 1H), 1.22-1.32 (m, 1H), 0.75 (s, 9H), 0.57-0.65 (m,
2H), 0.31-0.40 (m, 2H); LCMS (m/z, ES+)=399.2 (M+1).
Example 17 (Compound 236)
(S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00118##
[0569] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (52 mg, 0.12 mmol),
NaB(OMe).sub.4 (57 mg, 0.36 mmol), tBuXPhos (10.3 mg, 0.024 mmol)
and Pd.sub.2(dba).sub.3 (11.0 mg, 0.012 mmol) in DMF (1.2 mL) was
heated at 80.degree. C. for 2 h. The reaction mixture was filtered
through celite and the celite was rinsed with EtOAc and
CH.sub.2Cl.sub.2. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford ethyl
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (32 mg, 62%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.17 (s, 1H), 7.44
(s, 1H), 6.80 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.89
(m, 3H), 3.42 (dd, J=16.8, 7.0 Hz, 1H), 3.09 (d, J=16.4 Hz, 1H),
1.40 (t, J=7.0 Hz, 3H), 1.31-1.37 (m, 1H), 0.84 (s, 9H), 0.68-0.75
(m, 2H), 0.36-0.43 (m, 2H); LCMS (m/z, ES+)=427.4 (M+1).
[0570] A solution of the above ester in 1 M LiOH (0.75 mL) and MeOH
(0.75 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (0.75
mL) was added to the reaction mixture and the precipitate was
collected by filtration, washed with water, and dried to afford
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (26.5 mg, 55%
for 2 steps) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 16.11 (s, 1H), 8.45 (s, 1H), 7.65 (s, 1H), 6.83 (s,
1H), 4.08 (s, 3H), 4.04 (d, J=6.8 Hz, 1H), 3.92 (m, 2H), 3.48 (dd,
J=17.1, 7.3 Hz, 1H), 3.16 (d, J=17.1 Hz, 1H), 1.31-1.43 (m, 1H),
0.86 (s, 9H), 0.69-0.78 (m, 2H), 0.41 (m, 2H); LCMS (m/z,
ES+)=399.3 (M+1).
Example 18 (Compound 237)
(S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00119##
[0572] The demethylated product was formed as a by-product of the
reaction that produced ethyl
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate and was collected
as mixed fractions that were combined. Re-purification by reverse
phase chromatography (10-100% CH.sub.3CN/H.sub.2O (0.1% formic
acid)) afforded (S)-ethyl
6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (8.3 mg,
17%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.18 (s, 1H),
6.85 (s, 1H), 6.55 (s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.83-3.97 (m,
3H), 3.33 (dd, J=16.8, 6.6 Hz, 1H), 2.95 (d, J=17.2 Hz, 1H),
1.33-1.42 (m, 4H), 0.65-0.74 (m, 2H), 0.40 (m, 2H); LCMS (m/z,
ES+)=413.3 (M+1).
[0573] A solution of the above ester in 1 M LiOH (0.5 mL) and MeOH
(0.5 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (0.5
mL) was added to the reaction mixture and the solution was purified
by reverse phase chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-5,10-di-
hydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (6.4 mg,
14% for 2 steps) as a yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 15.72 (br. s., 1H), 8.44 (s, 1H), 7.38 (s,
1H), 6.66 (s, 1H), 4.04 (d, J=4.9 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H),
3.40-3.53 (m, 1H), 3.04 (d, J=17.1 Hz, 1H), 1.34-1.45 (m, 1H), 0.89
(s, 9H), 0.77-0.72 (m, 2H), 0.47-0.42 (m, 2H); LCMS (m/z,
ES+)=385.2 (M+1).
Example 19 (Compound 238)
(S)-6-(tert-Butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00120##
[0575] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (46.8 mg, 0.10 mmol),
NaB(OMe).sub.4 (49 mg, 0.31 mmol), tBuXPhos (8.9 mg, 0.021 mmol)
and Pd.sub.2(dba).sub.3 (9.6 mg, 0.010 mmol) in DMF (1.0 mL) was
heated at 80.degree. C. for 2 h. The reaction mixture was filtered
through celite and the celite was rinsed with CH.sub.2Cl.sub.2. The
filtrate was evaporated and the residue was re-subjected to the
reaction conditions with more reagents: NaB(OMe).sub.4 (49 mg, 0.31
mmol), tBuXPhos (8.9 mg, 0.021 mmol) and Pd.sub.2(dba).sub.3 (9.6
mg, 0.010 mmol) in DMF (1.0 mL) at 80.degree. C. for another 3 h.
The reaction mixture was filtered through celite and the celite was
rinsed with CH.sub.2Cl.sub.2. The filtrate was evaporated and the
residue was purified by silica gel chromatography (0-100% (3:1
EtOAc:EtOH) in hexanes) to afford ethyl
(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylate as a tan solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.18 (s, 1H), 7.44
(s, 1H), 6.86 (s, 1H), 4.40 (q, J=7.3 Hz, 2H), 4.19-4.12 (m, 2H),
4.05 (s, 3H), 3.90 (d, J=6.6 Hz, 1H), 3.61-3.55 (m, 2H), 3.42 (dd,
J=16.8, 7.0 Hz, 1H), 3.37 (s, 3H), 3.11 (d, J=16.8 Hz, 1H), 2.15
(quin, J=6.2 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 0.86 (s, 9H); LCMS
(m/z, ES+)=445.0 (M+1).
[0576] A solution of the above ester in 1 M LiOH (0.75 mL) and MeOH
(0.75 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (0.75
mL) was added to the reaction mixture and the solution was purified
by reverse phase chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford
(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihy-
dro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (19.6 mg,
45% for 2 steps) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 16.12 (s, 1H), 8.46 (s, 1H), 7.65 (s, 1H),
6.90 (s, 1H), 4.24-4.13 (m, 2H), 4.06 (s, 1H), 3.63-3.55 (m, 2H),
3.49 (dd, J=16.6, 6.3 Hz, 1H), 3.38 (s, 3H), 3.18 (d, J=17.1 Hz,
1H), 2.16 (quin, J=6.1 Hz, 2H), 0.87 (s, 9H); LCMS (m/z, ES+)=417.2
(M+1).
Example 20 (Compound 239)
(S)-6-(tert-Butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00121##
[0578] The demethylated product was formed as a by-product of the
reaction that produced ethyl
(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylate and was collected as
mixed fractions that were combined and subjected to hydrolysis
conditions without further purification. A solution of the ester in
1 M LiOH (0.5 mL) and MeOH (0.5 mL) was heated at 50.degree. C. for
2 h. 1M citric acid (0.5 mL) was added to the reaction mixture and
the solution was purified by reverse phase chromatography (5-100%
CH.sub.3CN/H.sub.2O (0.1% formic acid)) to afford
(S)-6-(tert-butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H--
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (3.4 mg, 8% for 2
steps) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 15.76 (br. s., 1H), 8.42 (s, 1H), 7.47 (s, 1H), 6.70 (s, 1H),
4.20 (t, J=6.1 Hz, 2H), 4.04 (d, J=6.3 Hz, 1H), 3.61-3.76 (m, 2H),
3.48 (dd, J=17.1, 6.8 Hz, 1H), 3.41 (s, 3H), 3.04 (d, J=17.1 Hz,
1H), 2.21 (quin, J=6.0 Hz, 2H), 0.89 (s, 9H); LCMS (m/z, ES+)=403.2
(M+1).
Example 21 (Compound 240)
(S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dih-
ydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00122##
[0579] Step 1: (S)-Ethyl
6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydr-
o-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00123##
[0581] A solution of ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-p-
yrido[1,2-h][1,7]naphthyridine-9-carboxylate (88.4 mg, 0.20 mmol),
potassium isopropenyltrifluoroborate (58 mg, 0.39 mmol), sodium
carbonate (63 mg, 0.59 mmol) and Pd(PPh.sub.3).sub.4 (23 mg, 0.020
mmol) in ethanol (2.0 mL) was stirred at 80.degree. C. overnight.
The reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered
through celite. The filtrate was evaporated and the residue was
purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in
hexanes) to afford ethyl
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-di-
hydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (87.5 mg,
98%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 8.18 (s, 1H), 7.54 (s, 1H), 7.00 (s, 1H), 5.91 (s, 1H), 5.54
(s, 1H), 4.39 (q, J=7.0 Hz, 2H), 4.07-4.22 (m, 2H), 3.93 (d, J=6.6
Hz, 1H), 3.61-3.56 (m, 2H), 3.48 (dd, J=17.0, 6.8 Hz, 1H), 3.37 (s,
3H), 3.19 (d, J=16.8 Hz, 1H), 2.25 (s, 3H), 2.13 (quin, J=6.1 Hz,
2H), 1.40 (t, J=7.2 Hz, 3H), 0.85 (s, 9H); LCMS (m/z, ES+)=455.9
(M+1).
Step 2:
(S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)--
6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid
##STR00124##
[0583] The title compound was isolated as a side-product by
base-promoted hydrolysis during an oxidation reaction of ethyl
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-di-
hydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (30.3 mg,
0.067 mmol) with trimethylsulfoxonium iodide (31 mg, 0.14 mmol) and
KOtBu (15 mg, 0.13 mmol) in DMSO (0.64 mL) and THF (0.27 mL).
Purification of the reaction mixture by reverse phase
chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1% formic acid))
afforded
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-di-
hydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (4.8 mg,
17%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 16.16 (s, 1H), 8.47 (s, 1H), 7.78 (s, 1H), 7.04 (s, 1H), 5.95
(s, 1H), 5.59 (s, 1H), 4.26-4.12 (m, 2H), 4.07 (d, J=6.8 Hz, 1H),
3.62-3.57 (m, 2H), 3.53 (dd, J=17.3, 7.1 Hz, 1H), 3.38 (s, 3H),
3.26 (d, J=17.1 Hz, 1H), 2.26 (s, 3H), 2.15 (quin, J=6.0 Hz, 2H),
0.87 (s, 9H); LCMS (m/z, ES+)=427.3 (M+1).
Example 22: (Compound 241)
(S)-6-(tert-Butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00125##
[0585] A solution of ethyl
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-di-
hydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (11.9 mg,
0.026 mmol) and 10% Pd/C (catalytic) in MeOH (1 mL) was stirred
under 60 psi H.sub.2 for 1.5 h. The reaction mixture was filtered
through celite and evaporated to dryness to afford the crude
(S)-ethyl
6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-py-
rido[1,2-h][1,7]naphthyridine-9-carboxylate, which was used without
further purification.
[0586] A solution of the above ester in 1 M LiOH (0.7 mL) and MeOH
(0.7 mL) was heated at 50.degree. C. for 2 h. 1M citric acid (0.8
mL) was added and the reaction mixture was stirred for 15 mins. The
precipitate was collected by filtration, washed with water, and
dried to afford
(S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6-
H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (9.3 mg, 83%
for two steps) as an off-white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 16.26 (s, 1H), 8.46 (s, 1H), 7.83 (s, 1H),
6.91 (s, 1H), 4.08-4.21 (m, 2H), 4.05 (d, J=6.8 Hz, 1H), 3.66-3.58
(m, 2H), 3.41-3.55 (m, 2H), 3.38 (s, 3H), 3.22 (d, J=17.1 Hz, 1H),
2.14 (quin, J=6.0 Hz, 2H), 1.27 (d, J=6.8 Hz, 6H), 0.85 (s, 9H);
LCMS (m/z, ES+)=429.3 (M+1).
Example 23: (Compound 243)
(S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihy-
dro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00126##
[0587] Step 1: Ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate
##STR00127##
[0589] A solution of ethyl 3-oxobutanoate (3.64 g, 28 mmol) in 20
mL THF was added by syringe pump (dropwise) to a vessel containing
NaH (60% dispersion in mineral oil) (1.176 g, 29.4 mmol) that was
cooled at 0.degree. C. during the addition. The reaction mixture
was stirred at RT for 1 h after addition was complete, and then
cooled back down to 0.degree. C. A solution of 3-chloroacryloyl
chloride (3.50 g, 28 mmol) in 20 mL THF was slowly added to the
cooled reaction mixture by syringe pump over 1 h. After addition
was complete, the reaction mixture was stirred at RT overnight and
then heated under reflux for 2.5 h. The reaction mixture was
diluted with water and extracted with Et.sub.2O (4.times.) and
CH.sub.2Cl.sub.2 (2.times.). The combined organic extracts were
dried (Na.sub.2SO.sub.4), filtered, evaporated and purified by
silica gel chromatography (0-100% EtOAc/hexanes) to afford ethyl
2-methyl-4-oxo-4H-pyran-3-carboxylate (2.65 g, 52%) as a brown
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.66 (d,
J=5.9 Hz, 1H), 6.36 (d, J=5.9 Hz, 1H), 4.39 (q, J=7.3 Hz, 2H), 2.38
(s, 3H), 1.38 (t, J=7.2 Hz, 3H); LCMS (m/z, ES+)=183.1 (M+1).
Step 2: (S)-Ethyl
1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-
-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00128##
[0591] A solution of
(S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbuta-
n-2-amine, Hydrochloride (196 mg, 0.42 mmol) and ethyl
2-methyl-4-oxo-4H-pyran-3-carboxylate (0.23 g, 1.27 mmol) in HOAc
(4.2 mL) was stirred at 100.degree. C. for 10 h. The reaction
mixture was evaporated to dryness, taken up in CH.sub.2Cl.sub.2 and
saturated NaHCO.sub.3 and stirred for 1 h. The organic layer was
isolated, dried (Na.sub.2SO.sub.4), filtered and evaporated. The
residue was stirred with additional ethyl
2-methyl-4-oxo-4H-pyran-3-carboxylate (200 mg, 1.10 mmol) in HOAc
(4.2 mL) at 100.degree. C. overnight. The reaction mixture was
evaporated to dryness and the residue was purified by reverse phase
chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1% formic acid)) to
afford ethyl
(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dim-
ethylbutan-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate
(67.4 mg, 27%) as a brown solid. LCMS (m/z, ES+)=591.2, 593.2
(M+1).
Step 3: (S)-Ethyl
6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00129##
[0593] A flask containing ethyl
(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylb-
utan-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (67.4
mg, 0.11 mmol), potassium acetate (22 mg, 0.23 mmol), and
palladium(II) bromide (6.1 mg, 0.023 mmol) was purged with
nitrogen. Degassed DMF (1.1 mL) was added and the reaction mixture
was heated at 90.degree. C. for 24 h. The solution was cooled to
RT, additional palladium(II) bromide (6.1 mg, 0.023 mmol) was added
and the reaction mixture was heated at 90.degree. C. for another 6
h. The solvent was removed by evaporation and the residue was
purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in
hexanes) to afford ethyl
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (12.1 mg,
23%) as a brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.48 (s, 1H), 7.00 (s, 1H), 4.34-4.45 (m, 3H), 4.13-4.24 (m, 2H),
3.65-3.58 (m, 2H), 3.31-3.41 (m, 4H), 3.15 (d, J=16.8 Hz, 1H), 2.45
(s, 3H), 2.12-2.19 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.80 (s, 9H);
LCMS (m/z, ES+)=463.3, 465.3 (M+1).
Step 4:
(S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6-
,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid
##STR00130##
[0595] A solution of (S)-ethyl
6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (12.1 mg, 0.026
mmol) in 1M LiOH (0.5 mL) and MeOH (0.5 mL) was heated at
50.degree. C. for 2 h and then 60.degree. C. for 2 h. 1M citric
acid (0.7 mL) was added to the reaction mixture. The solution was
evaporated to dryness and the residue was purified by reverse phase
chromatography (5-90% CH.sub.3CN/H.sub.2O (0.1% formic acid)) to
afford
(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (7.0 mg,
62%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 17.61 (br. s., 1H), 7.82 (s, 1H), 7.05 (s, 1H), 4.81 (d, J=5.4
Hz, 1H), 4.15-4.28 (m, 2H), 3.67-3.57 (m, 2H), 3.49-3.41 (m, 1H),
3.38 (s, 3H), 3.25 (d, J=17.6 Hz, 1H), 3.18 (s, 3H), 2.17 (quin,
J=6.0 Hz, 2H), 0.81 (s, 9H); LCMS (m/z, ES+)=435.2, 437.2
(M+1).
Example 24: (Compound 243)
(S)-6-(tert-Butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihy-
dro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00131##
[0596] Step 1: (S)-tert-Butyl
(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)car-
bamate
##STR00132##
[0598] A solution of tert-butyl
(S)-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)car-
bamate (2.18 g, 4.79 mmol), K.sub.2CO.sub.3 (1.99 g, 14.38 mmol),
(bromomethyl)benzene (0.86 mL, 7.19 mmol) in DMF (32.0 mL) was
heated at 80.degree. C. for 3 h. The reaction mixture was
evaporated to dryness and the residue was taken up in
CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.) and the combined organic phases were
dried (Na.sub.2SO.sub.4), filtered, and evaporated to afford
tert-butyl
(S)-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl-
)carbamate (assumed quant), which was taken on to the next step
without further purification. LCMS (m/z, ES+)=545.4, 547.0
(M+1).
Step 2: Ethyl
(S)-1-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2--
yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00133##
[0600] HCl (4M in dioxane) (11.98 mL, 47.9 mmol) was added to a
solution of tert-butyl
(S)-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl-
)carbamate (2.61 g, 4.79 mmol) in CH.sub.2Cl.sub.2 (6 mL) and the
reaction mixture was stirred at RT for 3 h. The mixture was
evaporated to dryness and the residue was taken up in saturated
NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous layer was extracted
with CH.sub.2Cl.sub.2 (2.times.) and the combined organic phases
were dried (Na.sub.2SO.sub.4), filtered, and evaporated to give a
brown oil.
[0601] A solution of the above amine and ethyl
4-oxo-4H-pyran-3-carboxylate (0.89 g, 5.27 mmol) in HOAc (24 mL)
was stirred at 100.degree. C. for 7 h. The reaction mixture was
evaporated, the residue was taken up in CH.sub.2Cl.sub.2 and
saturated NaHCO.sub.3, and the solution was stirred vigorously for
30 mins. The aqueous phase was extracted with CH.sub.2Cl.sub.2
(5.times.10 mL), and the combined organic phases were dried
(Na.sub.2SO.sub.4), filtered, evaporated and purified by silica gel
chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to afford ethyl
(S)-1-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2--
yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.39 g, 49%) as a
brown solid. LCMS (m/z, ES+)=596.1, 597.2 (M+1).
Step 3: Ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1-
,2-h][1,7]naphthyridine-9-carboxylate
##STR00134##
[0603] A flask containing ethyl
(S)-1-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2--
yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.39 g, 2.34 mmol),
potassium acetate (460 mg, 4.68 mmol), and palladium(II) bromide
(125 mg, 0.47 mmol) was purged with nitrogen. Degassed DMF (23.4
mL) was added and the reaction mixture was heated at 90.degree. C.
for 24 h. The solvent was removed by evaporation and the residue
was dissolved in CH.sub.2Cl.sub.2, filtered through celite and
purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in
hexanes) to afford ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1-
,2-h][1,7]naphthyridine-9-carboxylate (706 mg, 65%) as a brown
solid. LCMS (m/z, ES+)=467.3, 469.3 (M+1).
Step 4: Ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,-
2-h][1,7]naphthyridine-9-carboxylate
##STR00135##
[0605] A solution of ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1-
,2-h][1,7]naphthyridine-9-carboxylate (0.34 g, 0.74 mmol),
trifluoro(vinyl)-14-borane potassium salt (0.20 g, 1.48 mmol),
sodium carbonate (0.24 g, 2.22 mmol) and Pd(PPh.sub.3).sub.4 (85
mg, 0.074 mmol) in EtOH (7.4 mL) was stirred at 80.degree. C.
overnight. The reaction mixture was diluted with CH.sub.2Cl.sub.2,
filtered through celite, and evaporated. The residue was purified
by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in hexanes)
to afford ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,-
2-h][1,7]naphthyridine-9-carboxylate (251 mg, 74%) as an off-white
foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.21 (s, 1H),
7.39-7.73 (m, 7H), 7.00 (s, 1H), 6.59 (d, J=6.6 Hz, 1H), 5.54 (d,
J=10.5 Hz, 1H), 5.09-5.24 (m, 2H), 4.40 (q, J=7.0 Hz, 2H),
3.90-4.01 (m, 1H), 3.39-3.55 (m, 1H), 3.13-3.24 (m, 1H), 1.41 (t,
J=7.0 Hz, 3H), 0.84 (s., 9H); LCMS (m/z, ES+)=459.1, 460.4
(M+1).
Step 5: (S)-Ethyl
6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-6,10-dihydro-5H-pyrido[-
1,2-h][1,7]naphthyridine-9-carboxylate
##STR00136##
[0607] To a solution of ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,-
2-h][1,7]naphthyridine-9-carboxylate (251 mg, 0.55 mmol) in THF
(5.5 mL) and water (1.4 mL) at 0.degree. C. was added potassium
osmate dihydrate (20.2 mg, 0.055 mmol) followed by sodium periodate
(468 mg, 2.19 mmol). After addition was complete, the reaction
mixture was stirred at RT for 2 h. The reaction mixture was diluted
with CH.sub.2Cl.sub.2 and water, stirred, and filtered through
celite. The combined organic phases were dried (Na.sub.2SO.sub.4),
filtered, evaporated, and purified by silica gel chromatography
(0-100% 3:1 (EtOAc/EtOH) in CH.sub.2Cl.sub.2) to afford ethyl
(S)-3-(benzyloxy)-6-(tert-butyl)-2-formyl-10-oxo-5,10-dihydro-6H-pyrido[1-
,2-h][1,7]naphthyridine-9-carboxylate (assumed quant.). LCMS (m/z,
ES+)=461.3 (M+1).
[0608] A solution of the above aldehyde and 10% Pd/C (catalytic) in
EtOH (20 mL) was stirred under 60 psi H.sub.2 overnight. The
reaction mixture was filtered through celite and evaporated to
afford ethyl
(S)-6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (122.1 mg, 60%), which
was taken onto the next step without purification. LCMS (m/z,
ES+)=373.3 (M+1).
Step 6: Ethyl
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00137##
[0610] 1-Bromo-3-methoxypropane (44.3 .mu.l, 0.39 mmol) was added
to a solution of ethyl
(S)-6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (122.1 mg, 0.33 mmol)
and potassium carbonate (136 mg, 0.98 mmol) in DMF (3.3 mL) and the
reaction mixture was stirred at RT overnight. Additional potassium
carbonate (100 mg, 0.72 mmol) and 1-bromo-3-methoxypropane (44.3
.mu.l, 0.39 mmol) were added and the reaction mixture was heated at
40.degree. C. for 2.5 h, and then stirred at RT overnight. The
solvent was evaporated and the residue was diluted with
CH.sub.2Cl.sub.2 and brine. The organic layer was dried
(Na.sub.2SO.sub.4), filtered, evaporated, and purified by silica
gel chromatography (0-100% 3:1 (EtOAc/EtOH) in CH.sub.2Cl.sub.2) to
afford ethyl
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (62.8
mg, 43%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 8.18 (s, 1H), 7.44 (s, 1H), 6.98 (s, 1H), 4.72 (s, 2H), 4.39
(q, J=7.2 Hz, 2H), 4.22-4.12 (m, 2H), 3.90-4.06 (m, 2H), 3.61-3.53
(m, 3H), 3.37 (s, 3H), 3.21 (d, J=16.8 Hz, 1H), 2.11 (quin, J=6.0
Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.83 (s, 9H); LCMS (m/z,
ES+)=445.3 (M+1).
Step 7:
(S)-6-(tert-Butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5-
,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid
##STR00138##
[0612] A solution of ethyl
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (29 mg, 0.065
mmol) in 1M LiOH (0.65 mL) and MeOH (0.65 mL) was heated at
50.degree. C. for 2 h. 1M citric acid (1 mL) was added and the
reaction mixture was evaporated to dryness. The residue was
purified by reverse phase chromatography (5-90% CH.sub.3CN/H.sub.2O
(0.1% formic acid)) to afford
(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dih-
ydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (18.5 mg,
68%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 15.96 (s, 1H), 8.49 (s, 1H), 7.74 (s, 1H), 7.02 (s, 1H), 4.79
(d, J=4.4 Hz, 2H), 4.14-4.27 (m, 2H), 4.10 (d, J=6.3 Hz, 1H), 3.90
(t, J=4.9 Hz, 1H), 3.62-3.53 (m, 3H), 3.37 (s, 3H), 3.29 (d, J=17.1
Hz, 1H), 2.13 (quin, J=5.9 Hz, 2H), 0.86 (s, 9H); LCMS (m/z,
ES-)=415.3 (M-1).
Example 25: (Compound 244)
(S)-6-(tert-Butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00139##
[0613] Step 1: Ethyl
4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate
##STR00140##
[0615] DMF-DMA (5.70 mL, 42.5 mmol) was added to a solution of
ethyl 4-(benzyloxy)-3-oxobutanoate (6.70 g, 28.4 mmol) in toluene
(30 mL) and the reaction mixture was stirred overnight and
evaporated to dryness. The residue was purified by silica gel
chromatography (0-100% EtOAc in hexanes) to afford ethyl
4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate (6.78 g,
82%) as a yellow oil. LCMS (m/z, ES+)=292.6 (M+1).
Step 2: Ethyl 5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate
##STR00141##
[0617] Ethyl formate (10.2 mL, 126 mmol) was slowly added to a
suspension of potassium tert-butoxide (3.54 g, 31.6 mmol) in 24 mL
THF at 0.degree. C. After addition was complete, the reaction
mixture was stirred for another 15 mins at 0.degree. C. and a
solution of ethyl
4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate (4.6 g,
15.8 mmol) in 24 mL THF was added dropwise using an addition
funnel. After addition was complete, the reaction mixture was
removed from the ice bath and stirred at RT overnight. 1 M HCl (50
mL) was added and the solution was extracted with EtOAc (2.times.).
The combined organic phases were dried (Na.sub.2SO.sub.4),
filtered, evaporated, and purified by silica gel chromatography
(0-100% EtOAc in hexanes) to afford ethyl
5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate (1.48 g, 34%) as a light
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.41
(s, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 5H), 5.12 (s, 2H), 4.37 (q,
J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H); LCMS (m/z, ES+)=275.5
(M+1).
Step 3: (S)-Ethyl
5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-
-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00142##
[0619] A solution of the
(S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbuta-
n-2-amine, hydrochloride (0.402 g, 0.87 mmol) and ethyl
5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate (0.38 g, 1.37 mmol) in
HOAc (8.7 mL) was stirred at 100.degree. C. for 10 h. The reaction
mixture was evaporated to dryness, taken up in CH.sub.2Cl.sub.2 and
saturated NaHCO.sub.3 and stirred for 1 h. The aqueous layer was
extracted with CH.sub.2Cl.sub.2 and EtOAc (2.times.). The combined
organic phases were dried (Na.sub.2SO.sub.4), filtered and
evaporated. The residue was dissolved in EtOH (8 mL) and heated at
80.degree. C. overnight. The reaction mixture was evaporated to
dryness and the residue was purified by reverse phase
chromatography (5-100% CH.sub.3CN/H.sub.2O (0.1% formic acid)) to
afford ethyl
(S)-5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-
-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
(89.8 mg, 15%) as a brown solid. LCMS (m/z, ES+)=683.7, 685.7
(M+1).
Step 4: (S)-Ethyl
11-(benzyloxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-d-
ihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00143##
[0621] A flask containing ethyl
(S)-5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-
-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
(89.8 mg, 0.13 mmol), potassium acetate (26 mg, 0.26 mmol), and
palladium(II) bromide (7.0 mg, 0.03 mmol) was purged with nitrogen.
Degassed DMF (1.3 mL) was added and the reaction mixture was heated
at 90.degree. C. for 24 h. The reaction mixture was filtered
through celite, the solvent was removed by evaporation and the
residue was purified by silica gel chromatography (0-100% 3:1
(EtOAc/EtOH) in hexanes) to afford ethyl
(S)-11-(benzyloxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (47.9
mg, 66%) as a brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 8.15 (s, 1H), 7.73 (d, J=6.2 Hz, 2H), 7.28-7.36 (m, 3H), 6.94
(s, 1H), 5.26 (br. s., 2H), 4.35 (q, J=6.4 Hz, 2H), 4.21-4.10 (m,
2H), 3.82-3.92 (m, 1H), 3.56-3.67 (m, 2H), 3.46-3.37 (m, 1H), 3.39
(s, 3H), 2.98 (d, J=16.0 Hz, 1H), 2.13 (quin, J=5.9 Hz, 2H),
1.40-1.31 (m, 3H), 0.71 (s, 9H); LCMS (m/z, ES+)=555.4, 557.3
(M+1).
Step 5: (S)-Ethyl
11-(benzyloxy)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6-
,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00144##
[0623] A solution of ethyl
(S)-11-(benzyloxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (47.9
mg, 0.086 mmol), Pd(PPh.sub.3).sub.4 (20 mg, 0.017 mmol), potassium
carbonate (36 mg, 0.26 mmol), and cyclopropylboronic acid (15 mg,
0.17 mmol) in 1,4-dioxane (0.9 mL) was heated at 100.degree. C. for
2 days. The reaction mixture was diluted with CH.sub.2Cl.sub.2 and
filtered through celite. The filtrate was evaporated and the
residue was purified by reverse phase chromatography (5-100%
CH.sub.3CN/H.sub.2O (0.1% formic acid)) to afford (S)-ethyl
11-(benzyloxy)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6-
,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (14.7
mg, 30%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.18 (s, 1H), 7.66 (d, J=7.0 Hz, 2H), 7.27-7.20 (m,
3H), 6.82 (s, 1H), 5.45 (d, J=10.9 Hz, 1H), 5.21 (d, J=10.9 Hz,
1H), 4.46-4.38 (m, 2H), 4.04-4.20 (m, 2H), 3.89 (d, J=5.5 Hz, 1H),
3.65-3.56 (m, 2H), 3.38 (s, 3H), 3.30 (dd, J=16.0, 6.2 Hz, 1H),
3.03 (d, J=16.0 Hz, 1H), 2.39-2.49 (m, 1H), 2.13 (quin, J=6.1 Hz,
2H), 1.42 (t, J=7.2 Hz, 3H), 1.07-1.15 (m, 1H), 0.96-1.04 (m, 1H),
0.88-0.96 (m, 1H), 0.80-0.86 (m, 1H), 0.77 (s, 9H); LCMS (m/z,
ES+)=561.8 (M+1).
Step 6:
(S)-6-(tert-Butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-1-
0-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid
##STR00145##
[0625] A solution of ethyl
(S)-11-(benzyloxy)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-o-
xo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate
(14.7 mg, 0.026 mmol) and 10% Pd/C (catalytic) in MeOH (5 mL) was
stirred under 1 atm H.sub.2 for 1.5 h. The reaction mixture was
filtered through celite and evaporated to dryness. The residue was
taken up in MeOH (0.5 mL) and 1M LiOH (0.5 mL) and the solution was
heated at 50.degree. C. for 2 h. 1M citric acid (1.5 mL) was added,
the mixture was evaporated to dryness and the residue was purified
by reverse phase chromatography (5-90% CH.sub.3CN/H.sub.2O (0.1%
formic acid)) to afford
(S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5-
,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
(6.3 mg, 54%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 15.79 (s, 1H), 13.96 (s, 1H), 8.28 (s, 1H), 7.08 (s,
1H), 4.25-4.16 (m, 2H), 4.06 (d, J=6.3 Hz, 1H), 3.58-3.69 (m, 2H),
3.51 (dd, J=17.1, 6.8 Hz, 1H), 3.39 (s, 3H), 3.25 (d, J=17.1 Hz,
1H), 2.49-2.59 (m, 1H), 2.18 (quin, J=6.1 Hz, 2H), 1.06-1.19 (m,
4H), 0.84 (s, 9H); LCMS (m/z, ES+)=443.7 (M+1).
[0626] General Scheme 7 for Preparation of Compounds Such as
Examples 26, 27
##STR00146## ##STR00147##
[0627] Specific Synthetic Scheme 8 for Compounds of Example
26,2
##STR00148## ##STR00149##
Example 26: (Compound 245)
(2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro--
6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid-Isomer-1
Example 27: (Compound 246)
(2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro--
6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid-Isomer-2
##STR00150##
[0628] Step 1: Methyl 6-chloro-5-hydroxynicotinate
##STR00151##
[0630] To a solution of methyl 5-hydroxynicotinate (100 g, 0.65
mol) in DMF (1000 mL), NCS (130.5 g, 0.97 mol) was added and the
reaction mixture was heated to 80.degree. C. for 16 h. The reaction
mixture was cooled to room temperature and the solvent was removed
under reduced pressure. The residue was taken in EtOAc (2 L) and
washed with saturated sodium chloride solution (500 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The
crude product was purified by column chromatography on 230-400
silica gel using 0-30% ethyl acetate in petroleum ether as an
eluent. Fractions were collected and concentrated to afford the
title compound as yellow oil (60 g, 49% yield), LCMS (ESI) m/z
187.9 (M+1).
Step 2: 2-Chloro-5-(hydroxymethyl)pyridin-3-ol
##STR00152##
[0632] A solution of methyl 6-chloro-5-hydroxynicotinate (60 g,
0.32 mol) in THF (600 mL) was added dropwise to Lithium aluminium
hydride (160 ml, 0.32 mol, 2.0 M in THF) at -50.degree. C. under
nitrogen atmosphere. The reaction mixture was stirred at
-25.degree. C. for 2 h. EtOAc (1000 mL), water (50 ml) and
saturated aq. sodium potassium tartrate solution (500 ml) were
added to the reaction mixture dropwise at -25.degree. C. The
mixture was filtered through celite pad, washed with 20% MeOH in
DCM (500 mL). The filtrate was concentrated on reduced pressure to
afford as title compound (40 g, 80% yield) as an off-white solid.
LCMS (ESI) m/z 157.9 (M-H).
Step 3: 2-Chloro-5-(hydroxymethyl)-6-iodopyridin-3-ol
##STR00153##
[0634] To a solution of 2-chloro-5-(hydroxymethyl)pyridin-3-ol (3.5
g, 22.01 mmol) in THF (35 mL), water (35 mL), K.sub.2CO.sub.3 (6.1
g, 44.24 mmol) and Iodine (5.84 g, 23.11 mmol) were added and the
reaction mixture was stirred at room temperature for 2 h. The
reaction mixture was cooled to 00.degree. C. and quenched with aq.
sodium sulfite solution (50 mL). Ethyl acetate (150 mL) was added
to it, organic layer was separated and discarded. The aqueous layer
was acidified with 1.5N aq. HCl solution up to the pH=6 and
extracted with ethyl acetate (150 mL). The organic layer was
separated, washed with water (25 mL) and dried over sodium
sulphate. Solvent was removed under reduced pressure to afford the
title compound as off white solid (4 g, 64.5% yield). LCMS (ESI)
m/z: 283.7 (M-H).
Step 4: (6-Chloro-2-iodo-5-methoxypyridin-3-yl)methanol
##STR00154##
[0636] To a solution of
2-chloro-5-(hydroxymethyl)-6-iodopyridin-3-ol (4 g, 14.03 mmol) in
acetonitrile (50 mL), K.sub.2CO.sub.3 (3.87 g, 28.06 mmol) and
methyl iodide (MeI) (5.97 g, 42.10 mmol) were added and the
reaction mixture was heated to 80.degree. C. for 2 h in a sealed
tube. The reaction mixture was quenched with water (100 mL),
acidified with 1.5N HCl (pH=6) and extracted with ethyl acetate
(150 mL). The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The crude was purified by column
chromatography on 230-400 silica gel using 0-30% ethyl acetate in
petroleum ether as an eluent. Fractions were collected and
concentrated to afford the title compound as off-white solid (3.3
g, 80% yield). LCMS (ESI) m/z: 299.8 (M+1).
Step 5: 3-(Bromomethyl)-6-chloro-2-iodo-5-methoxypyridine
##STR00155##
[0638] To a solution of
(6-chloro-2-iodo-5-methoxypyridin-3-yl)methanol (2.2 g, 7.35 mmol)
in DCM (20 mL) was added CBr.sub.4 (3.6 g, 11.35 mmol) and
PPh.sub.3 (2.3 g, 8.82 mmol) in THF (20 mL). The reaction mixture
was stirred at room temperature for 6 h. Solvent was removed under
reduced pressure to get crude product. This was purified by column
chromatography on silica gel 60-120 mesh using 0-20% EtOAc in
petroleum ether as an eluent. Fractions were collected and
concentrated to afford the title compound as off-white solid (2.4
g, 92% yield). LCMS (ESI) m/z: 363.6 (M+H).
Step 6: Ethyl
2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoate
##STR00156##
[0640] To a solution of diisopropylamine (2.43 mL, 17.38 mmol) in
dry THF (20 mL) was added n-BuLi (10.86 mL, 17.38 mmol, 1.6M in
Hexane) dropwise at -78.degree. C. The reaction mixture was stirred
at same temperature for 30 min. Ethyl 2,3-dimethylbutanoate (2.3 g,
16.57 mmol) in THF (20 mL) was added to the reaction mixture and
the reaction mixture was stirred at -78.degree. C. for 1 h.
3-(bromomethyl)-6-chloro-2-iodo-5-methoxypyridine (3 g, 8.28 mmol)
in THF (20 mL) was added dropwise at same temperature and the
reaction mixture was warmed to room temperature and stirred at room
temperature for 1 h. The reaction mixture was cooled to 0.degree.
C., quenched with saturated NH.sub.4Cl solution (50 mL), diluted
with water (20 mL) and extracted with EtOAc (3.times.50 mL). The
combined organic layers were washed with brine (20 mL), dried over
anhydrous Na.sub.2SO.sub.4 and filtered. Solvents were removed
under reduced pressure to get crude product. The crude product was
purified by column chromatography on silica gel 230-400 mesh using
0-10% EtOAc in Petroleum ether as an eluent. Fractions were
collected and concentrated to afford the title compound as yellow
oil (3 g, 85% yield). LCMS (ESI) m/z: 426 (M+H).
Step 7:
2-((6-Chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbuta-
noic acid
##STR00157##
[0642] To a solution of ethyl
2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoate
(3 g, 7.05 mmol) in DMSO (9 mL), 5M NaOH solution (21.6 mL, 98.11
mmol) was added and the reaction mixture was stirred at 120.degree.
C. for 6 h. The reaction mixture was cooled to 0.degree. C.,
acidified with concentrated HCl till pH=1. After diluting with
water (50 mL) it was extracted with EtOAc (2.times.100 L). The
combined organic layers were washed with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed
under reduced pressure to get the crude product. The crude product
was purified by column chromatography on 230-400 silica gel using
0-10% MeOH in DCM to afford
2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoic
acid (500 mg, 18% yield) (LCMS (ESI) m/z: 397.8 (M+1)).
Step 8:
1-(6-Chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-amin-
e
##STR00158##
[0644] To a solution of
2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoic
acid (1 g, 2.5 mmol) in toluene (30 mL), triethylamine (0.57 g, 5.5
mmol) and diphenyl phosphoryl azide (1.52 g, 5.5 mmol) were added
and the reaction mixture was stirred at 80.degree. C. for 2 h. The
reaction mixture was cooled to room temperature and concentrated
HCl (8.4 mL) was added to the reaction mixture dropwise over 30 min
at 0.degree. C. The reaction mixture was stirred at 60.degree. C.
for 2 h. The reaction mixture was cooled to 0.degree. C. and
basified with 1N aqueous NaOH solution until pH=10. The reaction
mixture was diluted with water (20 mL) and extracted with EtOAc
(2.times.50 mL). The combined organic layers were washed with brine
(20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to get a brown gummy solid. This was purified by
column chromatography on 230-400 silica using 0-3% MeOH in DCM to
afford the title compound as yellow oil (800 mg, 87% yield). LCMS
(ESI) m/z: 368.8 (M+1).
Step 9: Ethyl
1-(1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-yl)-4-ox-
o-1,4-dihydropyridine-3-carboxylate
##STR00159##
[0646] To a solution of
1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-amine
(800 mg, 2.17 mmol) in acetic acid (25 mL), ethyl
4-oxo-4H-pyran-3-carboxylate (0.547 g, 3.2 mmol) was added and the
reaction mixture was stirred at 100.degree. C. for 8 h. The
reaction mixture was cooled to room temperature, the solvent was
removed under reduced pressure and the residue was purified by
column chromatography on 230-400 silica gel using 0-10% MeOH in DCM
as an eluent. Fractions were collected and concentrated to afford
the title compound (400 mg, 35% yield) as brown solid. LCMS (ESI)
m/z: 518.7 (M+1).
Step 10: Ethyl
2-chloro-6-isopropyl-3-methoxy-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-
-h][1,7]naphthyridine-9-carboxylate
##STR00160##
[0648] To a solution of ethyl
1-(1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-yl)-4-ox-
o-1,4-dihydropyridine-3-carboxylate (300 mg, 0.57 mmol) in N,
N-Dimethylformamide (7.5 mL) was added potassium acetate (283 mg,
2.89 mmol). The reaction mixture was degassed with nitrogen for 20
minutes. Palladium (II) bromide (30 mg, 0.11 mmol) was added to the
reaction mixture was stirred at 90.degree. C. for 16 h. The
reaction mixture was cooled to room temperature, filtered through
celite and washed with DCM. The solvents were removed under reduced
pressure and the crude was purified by column chromatography on
230-400 silica gel using 0-10% MeOH in DCM as an eluent. Fractions
were collected and concentrated to afford the title compound (150
mg, 68% yield) as brown solid. LCMS (ESI) m/z: 390.9 (M+1).
Step 11:
2-Chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-py-
rido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00161##
[0650] To a solution of ethyl
2-chloro-6-isopropyl-3-methoxy-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-
-h][1,7]naphthyridine-9-carboxylate (150 mg, 0.38 mmol) in
1,2-Dichloroethane (DCE) (6.45 mL), BBr.sub.3 (288 mg, 1.15 mmol)
was added and the reaction mixture was stirred at 70.degree. C. for
16 h. The reaction mixture was cooled to -10.degree. C., methanol
(15 mL) was added to reaction mixture dropwise and then stirred at
room temperature for 30 minutes. The reaction mixture was
concentrated to get the crude compound (150 mg) as a brown solid.
LCMS (ESI) m/z: 348.9 (M+1). This crude product was taken for next
step.
Step 12:
Methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-ox-
o-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1
and
Methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2
##STR00162##
[0652] To a solution of
2-chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-
-h][1,7]naphthyridine-9-carboxylic acid (150 mg, 0.43 mmol) in DMF
(2 mL), K.sub.2CO.sub.3 (594 mg, 4.3 mmol) and
(bromomethyl)cyclopropane (464 mg, 3.44 mmol) were added and the
reaction mixture was stirred at 80.degree. C. for 5 h. The reaction
mixture was cooled to room temperature, the solvent was removed
under reduced pressure and the residue was stirred with MeOH (10
mL) at room temperature for 30 min. Solvent was removed under
reduced pressure and diluted with DCM (20 mL). Organic layer was
washed with water (15 mL) and dried over anhydrous sodium sulphate,
filtered and concentrated under reduced pressure to get the
compound as mixture of isomers which was separated by chiral
supercritical fluid chromatography (SFC). Collected fractions of
Isomer-1 (first elution peak) and Isomer-2 (second elution peak)
were concentrated under reduced pressure to get
methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-d-
ihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1
(50 mg, 28% yield) as off white solid LCMS (ESI) m/z: 417.9 (M+1)
and
methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-d-
ihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2
(50 mg, 28% yield) as off white solid. LCMS (ESI) m/z: 417.9
(M+1).
Step 13:
(2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-
-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid-Isomer-1
##STR00163##
[0654] To a solution of
methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-d-
ihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1
(50 mg, 0.11 mmol) in Methanol (2 ml) and H.sub.2O (0.5 ml),
lithium hydroxide (25 mg, 0.59 mmol) was added and the reaction
mixture was stirred at room temperature for 2 h. The solvents were
removed under reduced pressure and the residue was taken in water
(3 mL) and acidified with 1.5 N HCl up to pH 3. The obtained solid
was filtered, washed with water (5 ml), dried under vacuum and
purified by prep-HPLC to get the title compound (15 mg, yield
31.2%) as off-white solid. LCMS (ESI) m/z: 403.1 (M+1). 1H NMR; 400
MHz, DMSO-d6: .delta. ppm 8.57 (s, 1H), 7.72 (s, 1H), 7.39 (s, 1H),
4.10-4.07 (m, 2H), 3.36-3.35 (m, 2H), 1.91-1.84 (m, 1H), 1.70 (s,
3H), 1.35-1.25 (m, 1H), 0.85-0.82 (m, 3H), 0.65-0.63 (m, 5H),
0.42-0.39 (m, 2H).
Step 13 A:
2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,1-
0-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid-Isomer-2
##STR00164##
[0656] To a solution of methyl
2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro--
6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2 (50 mg,
0.11 mmol) in Methanol (2 ml) and H.sub.2O (0.5 ml), lithium
hydroxide (25 mg, 0.59 mol) was added and the reaction mixture was
stirred at room temperature for 2 h. The solvents were removed
under reduced pressure and the residue was taken in water (3 mL)
and acidified with 1.5 N HCl up to pH 3. The obtained solid was
filtered, washed with water (5 ml), dried under vacuum for 16 h to
get the title compound as off-white solid (30 g, yield 62%). LCMS
(ESI) m/z: 402.9 (M+1). 1H NMR; 400 MHz, DMSO-d6: .delta. ppm 8.57
(s, 1H), 7.71 (s, 1H), 7.39 (s, 1H), 4.09-4.08 (m, 2H), 3.39-3.38
(m, 2H), 1.90-1.87 (m, 1H), 1.70 (s, 3H), 1.32-1.28 (m, 1H),
1.11-1.07 (m, 3H), 0.83-0.81 (m, 5H), 0.63-0.62 (m, 2H).
Example 28: (Compound 247)
2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydr-
o-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid-Isomer-1
##STR00165##
[0657] Example 29: (Compound 248)
2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydr-
o-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid-Isomer-2
##STR00166##
[0659] General Synthetic Scheme 9 for Compounds Such as Example
28,29:
##STR00167##
[0660] Specific Synthetic Scheme 10 for Compounds of Example 28,
29:
##STR00168##
Step 1:
Methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-
-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer--
1 and
Methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-ox-
o-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2
##STR00169##
[0662] To a stirred solution of methyl
2-chloro-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-
-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (570 mg, 1.311 mmol)
in 1,4-Dioxane (11.4 mL), was added potassium carbonate (362 mg,
2.62 mmol) and purged with Nitrogen for 5 min. Cyclopropylboronic
acid (225 mg, 2.62 mmol) was added followed by Pd(PPh.sub.3).sub.4
(303 mg, 0.262 mmol) and purged with nitrogen for 5 min. The
reaction mixture was heated to 100.degree. C. in a sealed tube for
16 h. The reaction mixture was concentrated completely under
reduced pressure and the residue was diluted with DCM (100 mL),
washed with water (40 mL), brine (40 mL). The organic layer was
separated, dried over sodium sulfate and concentrated and the crude
was purified by Isolera.TM. silica chromatography and eluted with
3% MeOH in DCM. Collected fractions were concentrated completely to
get the compound as mixture of isomers. Then the compound was
purified by preparative HPLC followed by chiral SFC. Collected
fractions of Isomer-1 (first elution peak) and Isomer-2 (second
elution peak) were concentrated separately under reduced pressure
to get
methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-0-oxo-5,10-
-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1
(60 mg, yield 10.3%) as colorless oil and
methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,1-
0-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2
(90 mg, 13.97% yield) as colorless oil. LCMS (ESI) m/z: 441.0
(M+1).
Step 2:
2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,1-
0-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid-Isomer-1
##STR00170##
[0664] To a solution of
methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,1-
0-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1
(60 mg, 0.136 mmol) in methanol (2.4 mL) was added LiOH (16.31 mg,
0.681 mmol) and water (0.60 mL) at room temperature and the
reaction mixture was stirred at rt for 2 h. Solvents from the
reaction mixture were removed under reduced pressure and the
residue was dissolved in water (2 ml). This solution was acidified
with 1.5N HCl up to pH 6 at 0.degree. C. The solid obtained was
filtered, washed with water, n-pentane and dried to get the title
compound as pale brown solid (15 mg, 25.3%). LCMS (ESI) m/z: 427.2
(M+1). 1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.54 (s, 1H), 7.44
(s, 2H), 4.19-4.18 (m, 2H), 3.53 (t, J=6 Hz, 2H), 3.29-3.37 (m,
5H), 2.05 (t, J=6 Hz, 2H), 1.84-1.82 (m, 1H), 1.68 (s, 3H),
1.03-1.01 (m, 4H), 0.82 (d, J=6.5 Hz 3H), 0.61 (d, J=6.6 Hz,
3H).
Step 2A:
2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,-
10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic
acid-Isomer-2
##STR00171##
[0666] To a solution of
methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,1-
0-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-2
(90 mg, 0.204 mmol) in Methanol (3.6 mL) was added LiOH (24.46 mg,
1.021 mmol) and Water (0.90 mL) at room temperature and the
reaction mixture was stirred at rt for 2 h. Solvents from the
reaction mixture were removed under reduced pressure and the
residue was dissolved in water (2 ml). This solution was acidified
with 1.5N HCl up to pH 6 at 0.degree. C. The solid obtained was
filtered, washed with water, n-pentane and dried to get the title
compound as pale brown solid (26 mg, 29.3%). LCMS (ESI) m/z: 427.2
(M+1). 1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.53 (s, 1H), 7.44
(s, 2H), 4.25-4.12 (m, 2H), 3.56-3.52 (m, 2H), 3.23-3.18 (m, 5H),
2.10-2.01 (m, 3H), 1.81-1.62 (m, 4H), 1.05-0.99 (m, 4H), 0.85-0.81
(m, 3H), 0.65-0.61 (m, 3H).
##STR00172## ##STR00173##
[0667] Compound 249 can be prepared according to the general
synthetic procedure outlined in Scheme 11 above, and as described
in detail below.
Example 30 (Compound 249 (racemic))
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyri-
do[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00174##
[0668] Step 1:
1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one
##STR00175##
[0670] A flask was charged with a stir bar, xantphos (0.225 g,
0.388 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.198 g,
0.216 mmol), and sodium tert-butoxide (2.43 g, 25.3 mmol). The
flask was purged with a stream of nitrogen before a solution of
5-bromo-2-chloro-3-methoxypyridine (3.2 g, 14.4 mmol) and
3,3-dimethylbutan-2-one (2.16 ml, 17.3 mmol) in tetrahydrofuran
(THF) (50 ml) was added. The mixture was heated at reflux
overnight. The mixture was allowed to cool to room temperature and
diluted with water. The mixture was extracted 3 times with ethyl
acetate. The combined organic layers were washed with brine, dried
over sodium sulfate, and concentrated to give
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (3.07 g,
12.7 mmol, 88% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 7.74 (d, J=1.56 Hz, 1H), 7.10 (d, J=1.56 Hz, 1H), 3.89 (s, 3H),
3.77 (s, 2H), 1.20 (s, 9H).
Step 2:
1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine
##STR00176##
[0672] A mixture of
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (3.07 g,
12.7 mmol) and ammonium acetate (14.7 g, 191 mmol) in methanol (50
mL) were stirred for 1 hour at room temperature before sodium
cyanoborohydride (2.00 g, 31.8 mmol) was added portionwise. The
mixture was stirred over the weekend at room temperature before
being basified with 1M sodium hydroxide. The mixture was extracted
3 times with dichloromethane. The combined organic layers were
washed with brine, dried over sodium sulfate, and concentrated to
give 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine
(2.82 g) as a clear oil. The material was purified by reverse phase
medium pressure chromatography (C18/acetonitrile/water/0.1% formic
acid/0% to 100% gradient). Fractions were combined, basified with
1M sodium hydroxide, and extracted 3 times with ethyl acetate.
Combined organic layers were washed with brine, dried over sodium
sulfate, and concentrated to give
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (1.45
g, 5.97 mmol, 47.0% yield) as a clear oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.83 (d, J=1.56 Hz, 1H), 7.08 (d, J=1.56
Hz, 1H), 3.90 (s, 3H), 2.91 (dd, J=13.48, 2.15 Hz, 1H), 2.62 (dd,
J=10.94, 1.95 Hz, 1H), 2.22 (dd, J=13.48, 11.13 Hz, 1H), 1.12-1.36
(m, 2H), 0.98 (s, 9H). LCMS(ES.sup.+)(m/z): 243, 245 (M+1).
Step 3: 5-(2-Amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol
##STR00177##
[0674] Boron tribromide (2.82 mL, 29.9 mmol) was added dropwise to
a solution of
1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (1.45
g, 5.97 mmol) in 1,2-dichloroethane (DCE) (30 mL) at 0.degree. C.
The mixture was allowed to warm to room temperature and stirred
overnight. LC-MS showed significant conversion to desired product,
but starting material was still present. Solids that had formed
overnight were broken up and the mixture stirred an additional 24
hours at room temperature. The mixture was cooled to 0.degree. C.
and quenched with careful dropwise addition of methanol. After
excess BBr.sub.3 had been fully quenched, additional methanol (100
mL) was added. The mixture was stirred for 1 hour and concentrated.
The residue was purified by medium pressure reverse phase
chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100%
gradient). Fractions were lyophilized to give
5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-01 (1.33 g, 5.81
mmol, 97% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.21 (s, 1H), 7.83-8.16 (m, 2H), 7.74 (d,
J=1.95 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 2.82-3.02 (m, 2H),
2.35-2.43 (m, 1H), 0.94 (s, 9H). LCMS(ES.sup.+)(m/z): 229, 231
(M+1).
Step 4: tert-Butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
##STR00178##
[0676] di-tert-Butyl dicarbonate (1.52 g, 6.98 mmol) was added to a
stirring mixture of
5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol (1.33 g, 5.81
mmol) and triethylamine (2.43 mL, 17.4 mmol) in
N,N-dimethylformamide (DMF) (30 mL). The mixture was stirred at
room temperature for 1 hour. LC-MS showed minimal conversion. The
solids never fully dissolved. Tetrahydrofuran (THF) (50 mL) was
added and the solids went into solution. The mixture was stirred
for 2 hours, concentrated, and the residue purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/10% to 100% gradient). Fractions were concentrated and
then the residue lyophilized (acetonitrile/water) to give
tert-butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(1.04 g, 3.16 mmol, 54.4% yield). .sup.1H NMR (400 MHz, Temp.=80 C,
DMSO-d.sub.6) .delta. ppm 9.81-10.14 (m, 1H), 7.68 (d, J=1.56 Hz,
1H), 7.15 (d, J=1.56 Hz, 1H), 6.13-6.46 (m, 1H), 3.24-3.46 (m, 1H),
2.76 (dd, J=14.05, 2.34 Hz, 1H), 2.31-2.42 (m, 1H), 1.21 (br. s.,
9H), 0.91 (s, 9H). LCMS(ES.sup.+)(m/z): 329, 331 (M+1).
Step 5: tert-Butyl
(1-(2-bromo-6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbam-
ate
##STR00179##
[0678] Under nitrogen, a solution of N-bromosuccinimide (471 mg,
2.65 mmol) in 2 mL of DMF was added slowly dropwise to a 0.degree.
C. solution of tert-butyl
(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate
(791 mg, 2.405 mmol) in N,N-dimethylformamide (DMF) (25 mL) and the
mixture stirred in a reaction vial that was protected from light by
aluminum foil. The cold bath was maintained between -25 C and -20 C
for 30 minutes. The mixture was allowed to warm to room temperature
and stirred overnight. The mixture was quenched with water and
extracted 3 times with ethyl acetate. The combined organic layers
were washed with brine and concentrated. The residue was purified
by medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 60% gradient, then
isocratic 60%, then 60% to 100% gradient). Fractions were
concentrated to give tert-butyl
(1-(2-bromo-6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbam-
ate (485 mg, 1.19 mmol, 49.5% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.81 (br. s., 1H), 7.23 (s, 1H), 6.60
(d, J=10.15 Hz, 1H), 3.35-3.50 (m, 1H), 2.73-2.89 (m, 1H),
2.18-2.37 (m, 1H), 1.15 (s, 9H), 0.83-0.91 (m, 9H).
LCMS(ES.sup.+)(m/z): 407, 409, 411 (M+1).
Step 6:
1-(2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimeth-
ylbutan-2-amine
##STR00180##
[0680] (Bromomethyl)cyclopropane (0.231 mL, 2.38 mmol) was added to
a stirring mixture of tert-butyl
(1-(2-bromo-6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbam-
ate (485 mg, 1.19 mmol) and potassium carbonate (658 mg, 4.76 mmol)
in N,N-dimethylformamide (DMF) (5 mL). The mixture was stirred at
room temperature overnight. The mixture was quenched with water and
extracted 2 times with ethyl acetate. The combined organic layers
were washed with 5% lithium chloride, washed with brine, dried over
sodium sulfate, and concentrated to give crude tert-butyl
(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbuta-
n-2-yl)carbamate. The intermediate was dissolved in dichloromethane
(DCM) (5.00 mL) before hydrogen chloride (4M in dioxane) (5 mL, 20
mmol) was added. The mixture was stirred for 4 hours and
concentrated to give a white solid. Saturated sodium bicarbonate
was added and the mixture extracted 2 times with ethyl acetate. The
combined organic layers were dried over sodium sulfate and
concentrated to give
1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-
-2-amine (423 mg, 1.17 mmol, 98% yield) as a clear oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.62 (s, 1H), 3.96 (d, J=7.03
Hz, 2H), 2.89 (dd, J=12.88, 1.95 Hz, 1H), 2.43-2.46 (m, 1H),
2.20-2.33 (m, 1H), 1.19-1.36 (m, 3H), 0.92 (s, 9H), 0.52-0.66 (m,
2H), 0.26-0.42 (m, 2H). LCMS(ES.sup.+)(m/z): 361, 363, 365
(M+1).
Step 7: Ethyl
1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbu-
tan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00181##
[0682]
1-(2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethy-
lbutan-2-amine (375 mg, 1.04 mmol) and ethyl
4-oxo-4H-pyran-3-carboxylate (174 mg, 1.04 mmol) in acetic acid (10
mL) were stirred at 100.degree. C. for 4 hours. The mixture was
allowed to cool to room temperature and concentrated. The residue
was purified by medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient).
Fractions were concentrated and the residue lyophilized
(water/acetonitrile) to give ethyl
1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbu-
tan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (420 mg, 0.821
mmol, 79% yield) as a white powder. LCMS(ES.sup.+)(m/z): 511, 513,
515 (M+1).
Step 8: Ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate
##STR00182##
[0684] A reaction vial containing a stir bar, ethyl
1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbu-
tan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (395 mg, 0.772
mmol), potassium acetate (151 mg, 1.543 mmol), and
chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II)
(79 mg, 0.15 mmol) was purged with nitrogen for 15 minutes.
N,N-Dimethylacetamide (DMA) (8 mL) was purged with nitrogen for 5
minutes before being added to the reaction vial. The reaction vial
was placed into a heating block that was preheated to 90.degree. C.
and the mixture stirred overnight. The reaction mixture was allowed
to cool to room temperature, filtered through a cotton plug, and
purified by reverse phase medium pressure chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were concentrated and the residue azeotroped with
acetonitrile to help remove any remaining water. The residue was
dissolved in dichloromethane and hexanes before being concentrated
to give ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (140 mg, 0.325 mmol,
42.1% yield) as a pale yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.38 (s, 1H), 7.66 (s, 1H), 6.90 (s, 1H),
4.40 (d, J=6.25 Hz, 1H), 4.21 (q, J=7.03 Hz, 2H), 3.99-4.10 (m,
2H), 3.37-3.50 (m, 1H), 3.31-3.37 (m, 1H), 1.22-1.37 (m, 4H), 0.74
(s, 9H), 0.59-0.67 (m, 2H), 0.34-0.45 (m, 2H). LCMS(ES.sup.+)(m/z):
431, 433 (M+1).
Step 9:
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid
##STR00183##
[0686] A solution of lithium hydroxide monohydrate (1.6 mg, 0.039
mmol) in water (1 mL) was added to a solution of ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (2.0 mg, 3.9 .mu.mol) in
methanol (1 mL) and the mixture heated at 60.degree. C. for 3
hours. The mixture was allowed to cool to room temperature and was
purified by medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were concentrated and the residue dried to give
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylic acid (1.2 mg, 2.9
.mu.mol, 77% yield) as a white solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. ppm 8.70 (br. s., 1H), 7.54 (br. s., 1H),
7.47 (br. s., 1H), 4.44-4.55 (m, 1H), 3.97-4.14 (m, 2H), 3.39-3.61
(m, 2H), 1.33 (br. s., 1H), 1.12 (br. s., 1H), 0.83 (s, 9H),
0.63-0.71 (m, 2H), 0.34-0.50 (m, 2H). LCMS(ES.sup.+)(m/z): 403, 405
(M+1).
Example 30-a (Compound 249 Isomer 1)
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyri-
do[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 1)
##STR00184##
[0687] Step 1: Ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1)
##STR00185##
[0689] Racemic ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (153 mg) was purified by
chiral chromatography using the following conditions:
Column=Chiralpak IC, 10 mm.times.250 mm (5u); Mobile phase=95:5
MeCN/H2O+0.1% formic acid; Flow rate=10 mL/min: Injection
volume=300 uL (18 mg/mL conc.); Collection wavelength: 254 nm.
Fractions were concentrated to give ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1) (48 mg).
LCMS(ES.sup.+)(m/z): 431, 433 (M+1).
Step 2:
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer
1)
##STR00186##
[0691] A solution of lithium hydroxide monohydrate (38.8 mg, 0.925
mmol) in water (2 mL) was added to a solution of ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1) (48 mg, 0.092
mmol) in methanol (2 mL) and the mixture heated at 60.degree. C.
for 3 hours. The mixture was cooled to room temperature and
acidified with 3 mL of 1M hydrochloric acid. Solids were collected
by filtration. The filtrate was injected onto a medium pressure
reverse phase column. The collected solid was dissolved in DMF and
injected onto the reverse phase column. The column was eluted
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were lyophilized to give
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 1) (33 mg,
0.082 mmol, 89% yield) as a white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.75 (br. s., 1H), 7.66 (s, 1H), 7.24
(br. s., 1H), 4.55-4.68 (m, 1H), 3.93-4.10 (m, 2H), 3.39-3.54 (m,
2H), 1.27 (d, J=5.08 Hz, 1H), 0.70 (s, 9H), 0.55-0.62 (m, 2H),
0.30-0.39 (m, 2H). LCMS(ES.sup.+)(m/z): 403, 405 (M+1).
Example 30-b (Compound 249 Isomer 2)
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyri-
do[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 2)
##STR00187##
[0692] Step 1: Ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2)
##STR00188##
[0694] Racemic ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (153 mg) was purified by
chiral chromatography using the following conditions:
Column=Chiralpak IC, 10 mm.times.250 mm (5u); Mobile phase=95:5
MeCN/H2O+0.1% formic acid; Flow rate=10 mL/min: Injection
volume=300 uL (18 mg/mL conc.); Collection wavelength: 254 nm.
Fractions were concentrated to give ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2) (46 mg).
LCMS(ES.sup.+)(m/z): 431, 433 (M+1).
Step 2:
6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-
-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer
2)
##STR00189##
[0696] A solution of lithium hydroxide monohydrate (37.2 mg, 0.886
mmol) in water (2 mL) was added to a solution of ethyl
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2) (46 mg, 0.089
mmol) in methanol (2 mL) and the mixture heated at 60.degree. C.
for 3 hours. The mixture was allowed to cool to room temperature
and was acidified with 3 mL of 1M hydrochloric acid. Solids were
collected by filtration. The filtrate was injected onto a medium
pressure reverse phase column. The collected solid was dissolved in
DMF and also injected onto the reverse phase column. The column was
eluted (C18/acetonitrile/water/0.1% formic acid/10% to 100%
gradient). Fractions were lyophilized to give
6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyr-
ido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 2) (34 mg,
0.084 mmol, 95% yield) as a white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.76 (s, 1H), 7.67 (s, 1H), 7.25 (s, 1H),
4.63 (d, J=6.64 Hz, 1H), 3.96-4.11 (m, 2H), 3.33-3.54 (m, 2H),
1.19-1.33 (m, 1H), 0.70 (s, 9H), 0.56-0.62 (m, 2H), 0.30-0.42 (m,
2H). LCMS(ES.sup.+)(m/z): 403, 405 (M+1).
##STR00190##
Example 31 (Compound 250)
2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane--
1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid
##STR00191##
[0697] Step 1: 6-Bromo-2-chloro-5-methylpyridin-3-ol
##STR00192##
[0699] 6-Bromo-5-methylpyridin-3-ol (10.4 g, 55.3 mmol) and NCS
(8.12 g, 60.8 mmol) in N,N-dimethylformamide (DMF) (150 mL) were
heated at 80.degree. C. for 2 hours. The mixture was allowed to
cool to room temperature, quenched with brine, and extracted 3
times with ethyl acetate. The combined organic layers were washed
with 5% lithium chloride, washed with brine, dried over sodium
sulfate, and concentrated. The residue was purified by silica
chromatography eluting with a gradient of 0% to 50% ethyl acetate
in hexanes. Fractions were concentrated to give
6-bromo-2-chloro-5-methylpyridin-3-ol (7.85 g, 35.3 mmol, 63.8%
yield) as a white powder. LCMS(ES.sup.+)(m/z): 222, 224, 226
(M+1).
Step 2:
2-Bromo-6-chloro-5-(cyclopropylmethoxy)-3-methylpyridine
##STR00193##
[0701] 6-Bromo-2-chloro-5-methylpyridin-3-ol (1.1 g, 4.9 mmol),
potassium carbonate (2.73 g, 19.8 mmol), and
(bromomethyl)cyclopropane (1.01 mL, 10.4 mmol) in
N,N-dimethylformamide (DMF) (10 mL) were stirred at room
temperature overnight. The mixture was diluted with water and
extracted 2 times with ethyl acetate. The combined organic layers
were washed with 5% lithium chloride, washed with brine, dried over
sodium sulfate, and concentrated to give
2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-methylpyridine (1.18 g,
4.27 mmol, 86% yield) as a white solid. LCMS(ES.sup.+)(m/z): 276,
278, 280 (M+1).
Step 3:
2-Bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine
##STR00194##
[0703] N-Bromosuccinimide (0.801 g, 4.50 mmol) and AIBN (0.049 g,
0.30 mmol) were added to a stirring solution of
2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-methylpyridine (1.0 g,
3.0 mmol) in carbon tetrachloride (15 mL). The mixture was heated
at 85.degree. C. for 5 hours. Additional AIBN (0.049 g, 0.300 mmol)
was added and the mixture allowed to heat overnight. The mixture
was allowed to cool to room temperature and solids collected by
filtration. The filtrate was quenched with water and extracted 2
times with dichloromethane. The combined organic layers were washed
with brine, dried over sodium sulfate, and concentrated. The
residue was purified by silica chromatography eluting with 10%
ethyl acetate in hexanes. Fractions were concentrated to give
2-bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine
(730 mg, 1.23 mmol, 60% pure, 41% yield). The material was
.about.60:40 mixture of desired product/starting material.
LCMS(ES.sup.+)(m/z): 354, 356, 358 (M+1).
Step 4: Ethyl
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
ecarboxylate
##STR00195##
[0705] n-Butyllithium (2.5 M in hexanes) (1.04 mL, 2.59 mmol) was
added dropwise to a -78.degree. C. solution of diisopropylamine
(0.369 mL, 2.59 mmol) in tetrahydrofuran (THF) (10 mL). The mixture
was allowed to warm to room temperature and stirred for 15 minutes.
The mixture was cooled to -78.degree. C. before ethyl
cyclobutanecarboxylate (0.317 mL, 2.46 mmol) was added dropwise.
The mixture was warmed to 0.degree. C. and stirred for 15 minutes.
A solution of
2-bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine
(730 mg, 1.23 mmol) in tetrahydrofuran (THF) (3.33 mL) was added
dropwise. The mixture was stirred an additional 10 minutes at
0.degree. C. and then quenched with saturated ammonium chloride.
The mixture was extracted 2 times with ethyl acetate. The combined
organic layers were washed with brine, dried over sodium sulfate,
and concentrated. The residue was purified by medium pressure
reverse phase chromatography (C18/acetonitrile/water/0.1% formic
acid/10% to 100% gradient). Fractions were concentrated to give
ethyl
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
e-1-carboxylate (350 mg, 0.869 mmol, 70.5% yield) as an oil.
LCMS(ES.sup.+)(m/z): 402, 404, 406 (M+1).
Step 5:
1-((2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyc-
lobutanecarboxylic acid
##STR00196##
[0707] A solution of lithium hydroxide monohydrate (365 mg, 8.69
mmol) in water (3 mL) was added to a solution of ethyl
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
e-1-carboxylate (350 mg, 0.869 mmol) in 1,4-dioxane (5 mL) and the
mixture heated at 60.degree. C. for 4 hours. The mixture was
allowed to cool to room temperature, quenched with saturated
ammonium chloride and extracted 3 times with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium
sulfate, and concentrated to give
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
e-1-carboxylic acid (325 mg, 0.867 mmol, quantitative) as a white
solid. LCMS(ES.sup.+)(m/z): 374, 376, 378 (M+1).
Step 6:
1-((2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyc-
lobutanamine and
5-((1-aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol
##STR00197##
[0709] Diphenyl phosphorazidate (0.394 mL, 1.83 mmol) was added
dropwise to a 0.degree. C. stirring mixture of
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
e-1-carboxylic acid (311 mg, 0.830 mmol) and triethylamine (0.255
mL, 1.83 mmol) in toluene (10 mL). The mixture was allowed to warm
to room temperature and stirred for 15 minutes before being heated
at 80.degree. C. for 1 hour. LC-MS showed clean conversion to
2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-((1-isocyanatocyclobutyl)methyl-
)pyridine. The mixture was allowed to cool to room temperature
before a 5N hydrogen chloride (5 mL, 25 mmol) and 1,4-dioxane (10
mL) were added. The mixture was heated at 80.degree. C. with
vigorous stirring for 3 hours. The mixture was concentrated and the
residue purified by medium pressure reverse phase chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Two
sets of fractions were concentrated separately to give the
following products:
[0710] 5-((1-aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol
(170 mg, 0.583 mmol, 70.2% yield). LCMS(ES.sup.+)(m/z): 291, 293,
295 (M+1)
[0711]
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cycl-
obutan-1-amine (50 mg, 0.145 mmol, 17.43% yield).
LCMS(ES.sup.+)(m/z): 345, 347, 349 (M+1).
Step 7: Ethyl 4-oxo-4H-pyran-3-carboxylate
##STR00198##
[0713] Ethyl formate (23.6 ml, 292 mmol) was slowly added to a
suspension of KOtBu (6.06 g, 54.0 mmol) in 50 mL of THF at
0.degree. C. The reaction mixture for stirred for 15 mins at
0.degree. C. and a pre-cooled (0.degree. C.) solution of ethyl
2-((dimethylamino)methylene)-3-oxobutanoate (5 g, 27.0 mmol) in 45
mL of THF was added by cannula transfer. After addition was
complete, the solution was removed from the cooling bath, stirred
at rt overnight, and quenched by addition of 1M aqueous HCl (80
mL). The mixture was extracted with EtOAc (3.times.25 mL) and
CH.sub.2Cl.sub.2 (5.times.25 mL). The organic layers were pooled,
dried (Na.sub.2SO.sub.4), filtered, evaporated, and purified by
silica gel chromatography (0-100% EtOAc/hexanes) to afford ethyl
4-oxo-4H-pyran-3-carboxylate (1.8994 g, 41.8% yield) as a brown
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.47 (d, J=0.78
Hz, 1H), 7.72 (dd, J=5.86, 0.78 Hz, 1H), 6.47 (d, J=5.86 Hz, 1H),
4.37 (q, J=7.29 Hz, 2H), 1.38 (t, J=7.03 Hz, 3H). LCMS (ESI) m/z:
169.05 (M+1).sup.+.
Step 8: Ethyl
1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobu-
tyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
##STR00199##
[0715] 5-((1-Aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol
(170 mg, 0.583 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (98 mg,
0.58 mmol) in acetic acid (5 mL) were stirred at 100.degree. C. for
4 hours. The mixture was allowed to cool to room temperature and
concentrated. The residue was diluted in toluene and the mixture
concentrated to remove remaining acetic acid. The residue was
dissolved in N,N-dimethylformamide (DMF) (2 mL) before potassium
carbonate (322 mg, 2.33 mmol) and (bromomethyl)cyclopropane (0.113
mL, 1.17 mmol) were added. The mixture was stirred at room
temperature for 6 hours to give a crude mixture of ethyl
1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)c-
yclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate in DMF. In a
separate reaction flask,
1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-
-1-amine (50 mg, 0.145 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate
(24.3 mg, 0.145 mmol) in acetic acid (1 mL) were stirred at
100.degree. C. overnight. The mixture was allowed to cool to room
temperature and then combined with the former crude mixture of
ethyl
1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobu-
tyl)-4-oxo-1,4-dihydropyridine-3-carboxylate in DMF disclosed
above. The mixture was diluted with water and extracted 2 times
with ethyl acetate. The combined organic layers were washed with 5%
lithium chloride, washed with brine, dried over sodium sulfate, and
concentrated. The residue was purified by medium pressure reverse
phase chromatography (C18/acetonitrile/water/0.1% formic acid/10%
to 100% gradient). Fractions were concentrated until cloudy.
Acetonitrile was added to fully dissolve and the solution
lyophilized to give ethyl
1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobu-
tyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg, 0.202 mmol,
26% yield) as a pale yellow solid. LCMS(ES.sup.+)(m/z): 495, 497,
499 (M+1).
Step 9: Ethyl
2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate
##STR00200##
[0717] A reaction vial containing a stir bar, ethyl
1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobu-
tyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg, 0.202 mmol),
potassium acetate (39.6 mg, 0.403 mmol), and
chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II)
(20.7 mg, 0.040 mmol) was purged with nitrogen for 15 minutes.
N,N-Dimethylacetamide (DMA) (2 mL) was purged with nitrogen for 5
minutes before being added to the reaction vial. The reaction vial
was placed into a heating block that was preheated to 90.degree. C.
and the mixture stirred overnight. The reaction mixture was allowed
to cool to room temperature, filtered through a cotton plug, and
purified by reverse phase medium pressure chromatography
(C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient).
Fractions were lyophilized to give ethyl
2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate (30 mg, 0.072
mmol, 35.9% yield) as an off-white solid. LCMS(ES.sup.+)(m/z): 415,
417 (M+1).
Step 10:
2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyc-
lobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic
acid
##STR00201##
[0719] A solution of lithium hydroxide monohydrate (25.2 mg, 0.600
mmol) in water (1 mL) was added to a solution of ethyl
2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate (30 mg, 0.060
mmol) in methanol (1 mL) and the mixture heated at 60.degree. C.
for 3 hours. The mixture was allowed to cool to room temperature
and acidified with 1M hydrochloric acid. The mixture was diluted
with DMF to dissolve the sample and then purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/10% to 100% gradient). Combined fractions were
lyophilized to give
2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-
-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid (22 mg,
0.056 mmol, 94% yield) as an off-white powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.79 (s, 1H), 7.68 (s, 1H), 7.27 (s,
1H), 4.07 (d, J=7.03 Hz, 2H), 3.44 (s, 2H), 2.61-2.75 (m, 2H),
2.00-2.12 (m, 2H), 1.78-1.95 (m, 2H), 1.25-1.37 (m, 1H), 0.57-0.68
(m, 2H), 0.33-0.40 (m, 2H). LCMS(ES.sup.+)(m/z): 387, 389
(M+1).
Example 32 (Compound 251)
2',3'-Dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h]-
[1,7]naphthyridine]-9'-carboxylic acid
##STR00202##
[0720] Step 1:
2',3'-Dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h-
][1,7]naphthyridine]-9'-carboxylic acid
##STR00203##
[0722]
2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclo-
butane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid (10
mg, 0.026 mmol) and sodium methoxide (0.5M in methanol) (0.517 mL,
0.259 mmol) were heated at 65.degree. C. for 2 hours. Dioxane (0.5
mL) was added and the mixture heated to 100.degree. C. The vial was
left uncapped initially so that most the methanol distilled off.
The reaction vial was capped and stirred at 100.degree. C. for 1.5
hours. The mixture was allowed to cool to room temperature,
acidified with 1N HCl, and purified by medium pressure reverse
phase chromatography (C18/acetonitrile/water/0.1% formic acid/10%
to 100% gradient). Fractions lyophilized to give
2',3'-dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h-
][1,7]naphthyridine]-9'-carboxylic acid (1.5 mg, 4.03 .mu.mol,
15.6% yield) as a white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 8.90 (s, 1H), 7.65 (s, 1H), 6.93 (s, 1H), 4.08 (s, 3H),
3.97 (s, 3H), 3.26 (s, 2H), 2.57-2.75 (m, 2H), 2.15-2.29 (m, 2H),
2.00-2.12 (m, 2H). LCMS(ES.sup.-)(m/z): 341 (M-1)-.
##STR00204## ##STR00205##
##STR00206## ##STR00207##
Example 33 (Compound 252)
6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyr-
idine-9-carboxylic acid
##STR00208##
[0723] Step 1: 2-Chloro-5,6-dimethylnicotinonitrile
##STR00209##
[0725] A mixture of 2-hydroxy-5,6-dimethylnicotinonitrile (10 g,
67.5 mmol) in POCl.sub.3 (100 ml) was refluxed for 10 h and was
concentrated. The residue was basified with 10% NaOH aqueous
solution and filtered. The filter cake was washed with H.sub.2O.
The filtrate was extracted with DCM (200 mL.times.2). The organic
layers were combined, washed with brine (200 mL), dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to give 9.8 g crude
2-chloro-5,6-dimethylnicotinonitrile as a yellow solid. LCMS (ESI)
m/z: 167.1, 169.1 (M/M+2).sup.+.
Step 2: 2-Chloro-5,6-dimethylnicotinaldehyde
##STR00210##
[0727] To a -78.degree. C. solution of
2-chloro-5,6-dimethylnicotinonitrile (1.6 g, 9.6 mmol) in DCM (20
ml), DIBAL-H (5.76 ml, 2 mol/L in hexane) was added. The resulting
mixture was stirred at the same temperature for 2 h. The reaction
was quenched by adding ice water. Then the mixture was acidified
with 1N HCl to pH=-6 and extracted with DCM (100 mL.times.2). The
organic layers were combined, washed with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to give 1.5 g crude
2-chloro-5,6-dimethylnicotinaldehyde as a white solid. LCMS (ESI)
m/z: 170.1, 172.1 (M/M+2).sup.+.
Step 3: 2-Chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine
##STR00211##
[0729] A mixture of 2-chloro-5,6-dimethylnicotinaldehyde (1.5 g,
8.84 mmol), ethane-1,2-diol (1.1 g, 17.68 mmol), PPTS (444.3 mg,
1.768 mmol) in toluene (20 ml) was refluxed for 12 h. The reaction
mixture was cooled to r. t. and extracted with EtOAc (100
mL.times.2). The organic layers were combined, washed with aqueous
NaHCO.sub.3 solution (50 mL), dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The residue was purified by flash column
chromatography (silica gel, 0-50% EtOAc in PE) to afford
2-chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine (1.35 g, 71.5%
yield) as a colorless oil. LCMS (ESI) m/z: 214.1, 216.1
(M/M+2).sup.+.
Step 4:
1-(3-(1,3-Dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-
-one
##STR00212##
[0731] A mixture of
2-chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine (1.35 g, 6.32
mmol), 3-methylbutan-2-one (653 mg, 7.58 mmol), Pd(dtbpf)Cl.sub.2
(411.9 mg, 0.632 mmol) and t-BuONa (1.52 g, 15.8 mmol) in THF (20
ml) was heated at 60.degree. C. for 3 h. The reaction mixture was
cooled to r. t. and filtered. The filtrate was concentrated and the
residue was purified by the flash column chromatography (silica
gel, 0-70% EtOAc in PE) to afford
1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-one
(231 mg, 14% yield) as a yellow solid. LCMS (ESI) m/z: 264.3
(M+1).sup.+.
Step 5:
1-(3-(1,3-Dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-
-amine
##STR00213##
[0733] To a solution of
1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-one
(231 mg, 0.878 mmol) in MeOH (10 ml) was added NH.sub.4OAc (683.1
mg, 8.78 mmol) at room temperature. After the mixture being stirred
for 30 mins, NaBH.sub.3CN (82.8 mg, 1.317 mmol) was added to the
mixture at 0.degree. C. Then the resulting mixture was stirred at
50.degree. C. for 10 h. The reaction mixture was cooled to r. t.
and concentrated. The residue was diluted with H.sub.2O (20 ml),
basified to ph.about.10 with 10% NaOH solution. The aqueous mixture
was extracted with DCM (2.times.). The organic layers were
combined, washed with brine (30 ml), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
236 mg crude
1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-amine.
LCMS (ESI) m/z: 265.3 (M+1).sup.+.
Step 6: 7-Isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine
##STR00214##
[0735] To a solution of
1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-amine
(70 mg, 0.264 mmol) in THF (10 mL), 10% HCl aqueous solution (2 mL)
was added. The resulting mixture was heated at 50.degree. C. for 10
h. After being cooled to rt, the mixture was concentrated. The
residue was purified by column chromatography (silica gel, 0-10%
MeOH in DCM) to give
7-isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine (20 mg,
37.3% yield). LCMS (ESI) m/z: 203.27 (M+1).sup.+.
Step 7: Ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,1-f][1-
,6]naphthyridine-9-carboxylate
##STR00215##
[0737] A solution of
7-isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine (20 mg,
0.099 mmol) and ethyl 2-(ethoxymethylene)-3-oxo-butanoate (55.86
mg, 0.3 mmol) in EtOH (5 mL) was heated at 85.degree. C. for 10 h.
After being cooled to room temperature, the mixture was
concentrated. The residue was purified by column chromatography
(silica gel, 0-10% MeOH in DCM) to give ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,-
1-f][1,6]naphthyridine-9-carboxylate (20 mg, 58.9% yield). LCMS
(ESI) m/z: 343.2 (M+1).sup.+.
Step 8: Ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthy-
ridine-9-carboxylate
##STR00216##
[0739] To a solution of ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,1-f][1-
,6]naphthyridine-9-carboxylate (20 mg, 0.058 mmol) in DME (5 mL)
was added p-chloranil (12.3 mg, 0.05 mmol). The mixture was heated
at 80.degree. C. for 3 h. After being cooled to r. t., the mixture
was concentrated. The residue was purified by column chromatography
(silica gel, 0-10% MeOH in DCM) to afford ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthy-
ridine-9-carboxylate (15 mg, 76% yield). LCMS (ESI) m/z: 341.2
(M+1).sup.+.
Step 9:
6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]-
naphthyridine-9-carboxylic acid
##STR00217##
[0741] To a solution of ethyl
6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthy-
ridine-9-carboxylate (15 mg, 0.044 mmol) in MeOH (5 ml), NaOH (7
mg, 0.176 mmol) dissolved in H.sub.2O (1 ml) was added. The
resulting mixture was stirred at room temperature for 2 h. The
reaction mixture was acidified to ph.about.5 with 1N HCl. Then the
mixture was diluted with EtOAc (20 mL) and H.sub.2O (20 mL), and
then extracted with EtOAc (20 mL.times.2). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated.
The residue was purified by reverse phase HPLC (C18 column, 5%-100%
MeCN in H.sub.2O, with 0.1% formic acid in H.sub.2O) to give
6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]na-
phthyridine-9-carboxylic acid (5 mg, 36.3% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.87 (s, 1H), 8.25 (s,
1H), 7.43 (s, 1H), 4.63-4.58 (m, 1H), 3.56-3.50 (m, J=16.8, 5.3 Hz,
1H), 3.18 (d, J=16.6 Hz, 1H), 2.48 (s, 3H), 2.31 (s, 3H), 1.64-1.57
(m, 1H), 0.84 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H). LCMS (ESI)
m/z: 313.2 (M+1).sup.+.
Example 34 (Compound 253)
2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydro-
cyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid
(racemic cis)
##STR00218##
[0742] Step 1:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanone
##STR00219##
[0744] A flask was charged with a stir bar,
5-bromo-2-chloro-3-methoxypyridine (9.9 g, 44 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.611 g, 0.668 mmol),
xantphos (0.695 g, 1.202 mmol), and sodium tert-butoxide (7.5 g, 78
mmol). The flask was purged with a stream of nitrogen before
2,2-dimethylcyclopentan-1-one (8.38 ml, 66.8 mmol) in
tetrahydrofuran (THF) (200 ml) was added. The mixture was heated to
reflux for 3 hours. The mixture was allowed to cool to room
temperature, filtered, and the filter cake washed with ethyl
acetate. The filtrate was diluted with additional ethyl acetate,
washed with brine, concentrated, and the residue purified by silica
chromatography eluting with a gradient of 0% to 30% ethyl acetate
in hexanes. Fractions were concentrated to give
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
(4.6 g, 18 mmol, 41% yield) as an oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.82 (d, J=1.56 Hz, 1H), 7.13 (d, J=1.95
Hz, 1H), 3.91 (s, 3H), 3.36-3.47 (m, 1H), 2.45 (m, 1H), 1.96-2.17
(m, 2H), 1.79-1.92 (m, 1H), 1.18 (s, 3H), 1.07 (s, 3H).
LCMS(ES.sup.+)(m/z): 254.2 (M+1).
Step 2:
5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanamine
(cis/trans isomers)
##STR00220##
[0746] A mixture of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one
(4.6 g, 18 mmol) and ammonium acetate (21 g, 270 mmol) in methanol
(75 mL) were stirred at room temperature for 1 hour. Sodium
cyanoborohydride (2.28 g, 36.3 mmol) was added and the mixture
heated at 60.degree. C. overnight and then at 65.degree. C. for an
additional 24 hours. The mixture was allowed to cool to room
temperature, concentrated to .about.20 mL, quenched with 1M sodium
hydroxide, and extracted 3 times with 2-methyltetrahydrofuran. The
combined organic layers were washed with brine, dried over sodium
sulfate, and concentrated. The residue was purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/0% to 100% gradient). Fractions were concentrated to
give
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(2.63 g, 10.3 mmol, 57% yield) as a mixture of cis/trans isomers.
LCMS(ES.sup.+)(m/z): 255.2 (M+1).
Step 3: 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol
(cis/trans isomers)
##STR00221##
[0748] Boron tribromide (4.82 mL, 51.0 mmol) was added slowly
dropwise to a vigorously stirring solution of
5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine
(2.6 g, 10.2 mmol) (cis/trans isomers). The mixture was heated at
70.degree. C. overnight. The mixture was allowed to cool to room
temperature and then cooled to 0.degree. C. The mixture was
carefully quenched with slow addition of methanol. An additional 50
mL of methanol was added and the mixture stirred for 30 minutes
before being concentrated. The residue was purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/0% to 100% gradient). Fractions were lyophilized to
give 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol
(cis/trans isomers) (2.17 g, 9.01 mmol, 88% yield) as a white
solid. LCMS(ES.sup.+)(m/z): 241.2 (M+1).
Step 4:
5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(racemic cis) and
5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(racemic trans)
##STR00222##
[0750] Iodine (2.29 g, 9.01 mmol) was added to a stirring mixture
of 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (2.17
g, 9.01 mmol) and potassium carbonate (3.74 g, 27.0 mmol) in water
(40 mL). The mixture was stirred at room temperature for 2 hours.
Solid sodium sulfite (2.39 g, 18.9 mmol) was added portion wise and
the mixture stirred for 30 minutes. The aqueous mixture was
adjusted to pH=.about.3 with 3N hydrochloric acid. The mixture was
filtered. LC-MS showed the solid contained a small amount of
product, but was discarded. The wash was concentrated to .about.50
mL and injected onto a medium pressure reverse phase C18 ISCO
column that was eluted with acetonitrile/water/0.1% formic acid/0%
to 100% gradient. 2 sets of fractions were lyophilized
separately.
[0751] Peak
1=5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(racemic trans) (1.17 g, 3.19 mmol, 35% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.23 (s, 1H), 7.26 (s, 1H),
2.99-3.15 (m, 2H), 2.05-2.19 (m, 1H), 1.51-1.64 (m, 2H), 1.22-1.35
(m, 1H), 1.09 (s, 3H), 0.95 (s, 3H). LCMS(ES.sup.+)(m/z): 367.1
(M+1).
[0752] Peak
2=5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(racemic cis contaminated with .about.20% racemic trans) (924 mg,
2.01 mmol, 22% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.27 (s, 1H), 7.20 (s, 1H), 3.41-3.53 (m, 1H), 3.28 (d, J=5.86
Hz, 1H), 2.07-2.19 (m, 1H), 1.81-1.95 (m, 1H), 1.68-1.77 (m, 1H),
1.47-1.57 (m, 1H), 1.14 (s, 3H), 1.08 (s, 3H). LCMS(ES.sup.+)(m/z):
367.1 (M+1).
Step 5: Ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate (racemic cis)
##STR00223##
[0754]
5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol
(racemic cis) (924 mg, 2.02 mmol) (contaminated with .about.20%
trans) and ethyl 4-oxo-4H-pyran-3-carboxylate (466 mg, 2.77 mmol)
in acetic acid (13 mL) were stirred at 100.degree. C. for 4 hours.
The mixture was allowed to cool to room temperature, diluted with
water, and extracted 2 times with dichloromethane. Brine was added
to the aqueous phase and the mixture extracted 2 more times with
dichloromethane. The combined organic layers were washed with
brine, dried over sodium sulfate, and concentrated. The residue was
purified by silica chromatography eluting with a gradient of 0% to
10% methanol in dichloromethane. Fractions were concentrated to
give ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate (racemic cis) (346 mg, 0.670
mmol, 33% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.92 (br. s., 1H), 7.78 (d, J=1.95 Hz, 1H), 7.43 (dd, J=7.81, 2.34
Hz, 1H), 7.07 (s, 1H), 6.04 (d, J=7.42 Hz, 1H), 4.54 (d, J=7.42 Hz,
1H), 4.03-4.17 (m, 2H), 3.82-3.95 (m, 1H), 2.15-2.27 (m, 2H), 1.99
(dt, J=13.66, 7.22 Hz, 1H), 1.74-1.87 (m, 1H), 1.24-1.31 (m, 3H),
1.14-1.23 (m, 3H), 0.92 (s, 3H). LCMS(ES.sup.+)(m/z): 517.1
(M+1).
Step 6: Ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (racemic cis)
##STR00224##
[0756] Ethyl
1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-o-
xo-1,4-dihydropyridine-3-carboxylate (racemic cis) (346 mg, 0.670
mmol), potassium carbonate (463 mg, 3.35 mmol), and
1-bromo-3-methoxypropane (205 mg, 1.34 mmol) in
N,N-dimethylformamide (DMF) (5 mL) were stirred at room temperature
overnight. The mixture was quenched with water and extracted 3
times with ethyl acetate. The combined organic layers were washed
with brine and concentrated. The residue was purified by
chromatography to give ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (341 mg, 0.579
mmol, 86% yield). LCMS(ES.sup.+)(m/z): 589.2 (M+1).
Step 7: Ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(racemic cis)
##STR00225##
[0758] A septum-capped round bottom flask containing a stir bar,
ethyl
1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclo-
pentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (341 mg, 0.579
mmol), potassium acetate (114 mg, 1.16 mmol), and palladium(II)
bromide (30.8 mg, 0.116 mmol) was purged with nitrogen for 15
minutes. N,N-Dimethylacetamide (DMA) (5 mL) was purged with
nitrogen for 5 minutes before being added to the reaction vessel.
The reaction vessel was placed into an oil bath that was preheated
to 90.degree. C. and the mixture stirred for 4 hours. The reaction
mixture was allowed to cool to room temperature, diluted with ethyl
acetate, and filtered through a cotton plug. The mixture was washed
with brine, dried over sodium sulfate, and concentrated. The
residue was purified by silica chromatography eluting with a
gradient of 0% to 10% methanol in dichloromethane. Fractions were
concentrated. Desired product was isolated, but a significant
amount of DMA remained. The product was further purified by medium
pressure reverse phase chromatography (C18/acetonitrile/water/0.1%
formic acid/10% to 100% gradient). Fractions were concentrated to
give ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,5,6,7,7a,11-hexahydro-
cyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(racemic cis) (150 mg, 0.325 mmol, 56% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.21 (s, 1H), 7.55 (s, 1H), 7.00 (s,
1H), 4.43 (d, J=8.98 Hz, 1H), 4.15-4.31 (m, 4H), 3.79-3.88 (m, 1H),
3.47 (t, J=6.05 Hz, 2H), 3.23 (s, 3H), 2.27-2.38 (m, 1H), 2.12-2.25
(m, 1H), 1.99 (quin, J=6.15 Hz, 2H), 1.50-1.60 (m, 1H), 1.35-1.45
(m, 1H), 1.24 (t, J=7.22 Hz, 3H), 1.11 (s, 3H), 0.39 (s, 3H).
LCMS(ES.sup.+)(m/z): 461.3 (M+1).
Step 8:
2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-1-oxo-4b,5,6,7,7a,11-he-
xahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic
acid (racemic cis)
##STR00226##
[0760] A solution of lithium hydroxide monohydrate (113 mg, 2.70
mmol) in water (2 mL) was added to a solution of ethyl
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate
(racemic cis) (150 mg, 0.270 mmol) in methanol (3 mL) and the
mixture heated at 65.degree. C. for 1 hour. The mixture was allowed
to cool, diluted with water, acidified with 1M HCl, and extracted 3
times with 2-methyltetrahydrofuran. The combined organic layers
were washed with brine and concentrated. The residue was purified
by silica chromatography eluting with a gradient of 0% to 10%
methanol in dichloromethane. Fractions were concentrated to give
2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydr-
ocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid
(racemic cis) (95 mg, 0.219 mmol, 81% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.62 (s, 1H), 7.63
(s, 1H), 7.43 (s, 1H), 4.72 (d, J=9.37 Hz, 1H), 4.21-4.39 (m, 2H),
3.89-3.99 (m, 1H), 3.51 (t, J=6.05 Hz, 2H), 3.26 (s, 3H), 2.33-2.44
(m, 1H), 2.19-2.31 (m, 1H), 1.96-2.08 (m, 2H), 1.55-1.66 (m, 1H),
1.40-1.51 (m, 1H), 1.15 (s, 3H), 0.40 (s, 3H). LCMS(ES.sup.+)(m/z):
433.3 (M+1).
[0761] Additional general synthetic protocols for making compounds
as described herein are shown below in Scheme 15.
##STR00227## ##STR00228##
Biological Examples
Example 35--Compound Treatment in Primary Human Hepatocytes
Infected with HBV
[0762] HBV-Ag Inhibitors
[0763] Vials of cryopreserved primary human hepatocytes were placed
in a 37.degree. C. water bath just until thawed. The cells were
pooled, resuspended gently in differentiation medium (Williams
medium containing differentiation supplement, GlutaMax-1.TM., and
penicillin/streptomycin) and counted using a hemacytometer. The
cells were pelleted by centrifugation at 1000.times.g for 10 min
and resuspended to a density of 5.5.times.105 cells/mL in
differentiation medium. 100 .mu.L of cell suspension were plated in
each well of collagen-coated 96-well plates. The plates were
incubated at 37.degree. C. and 5% CO.sub.2 for 2 days prior to
infection.
[0764] HBV stocks were prepared by ultrafiltration of media from
HepG2.2.15 cell cultures. To prepare a working virus stock with a
multiplicity of infection (MOI) of 100, HBV stock was added to
differentiation medium containing 4% polyethylene glycol to achieve
a concentration of 5.5.times.107 HBV DNA copies/mL. The cell media
was replaced with 100 .mu.L of the working virus stock in columns
1-11 and with differentiation medium in column 12. The plates were
incubated at 37.degree. C. and 5% CO.sub.2 for approximately 24
hr.
[0765] Compounds were resuspended in DMSO and serially diluted
3-fold in DMSO to make a 10-point dilution series at 200.times. the
final desired concentrations. Columns 11 and 12 contained DMSO.
Using a Biomek FX, 2.5 .mu.L of each compound dilution was stamped
into 96-well U-bottom plates, making 3 copies. The compound plates
were sealed and stored at -20.degree. C. After equilibration to
room temperature, the compound plates were diluted 200 fold with
assay medium (differentiation medium plus 1 mM ABT). The media on
the cell plates was replaced with 150 .mu.L of the diluted
compounds. The final highest compound concentration was 20 .mu.M.
The plates were incubated at 37.degree. C. and 5% CO.sub.2. The
compound treatments were repeated at days 4 and 9 following the
initial treatment. Readouts were done of HBsAg and HBeAg ELISAs at
days 9 and 14.
[0766] At Days 9 after the initial treatment, the media was
transferred from each cell plate to a U-bottom plate and stored at
-80.degree. C. At Day 14 after the initial treatment, the cell
plates were washed once with PBS and stored at -80.degree. C.
[0767] HBs Ag ELISA
[0768] Frozen plates containing the collected media were
equilibrated to room temperature in a biosafety cabinet for
approximately 30 min. The HBsAg ELISA kit was used according to the
manufacturer's directions. Briefly, the ELISA plates and solutions
were equilibrated to room temperature for approximately 1 hr and
the plates were washed once with 300 .mu.L 1.times. wash buffer.
100 .mu.L 1.times. enzyme conjugate solution, 120 .mu.L PBS
containing 10% FBS, and 30 .mu.L collected media were placed in
each well. The assay plates were sealed and incubated at 37.degree.
C. for approximately 2 hr. The plates were washed 4 times with 195
mL 1.times. wash buffer and dried thoroughly inverted on paper
towels. 195 .mu.L of chromagen/substrate solution were added to
each well and incubated at room temperature for approximately 5
min. 100 .mu.L of stop solution were added to each well and the
plates were read on a Molecular Devices SpectraMax.RTM. 384 Plus
Microplate Reader at 450 nm. IC.sub.50s were determined using
GraphPad Prism: Four-parameter logistic curve with equation
Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((Log
IC50-X)*HillSlope)).
[0769] HBe Ag ELISA
[0770] Frozen plates containing the collected media were
equilibrated to room temperature in a biosafety cabinet for
approximately 30 min. The HBeAg ELISA kit was used according to the
manufacturer's directions. Briefly, the ELISA plates and solutions
were equilibrated to room temperature for approximately 1 hr and
the plates were washed once with 300 .mu.L 1.times. wash buffer. 80
.mu.L PBS containing 10% FBS, and 20 .mu.L collected media were
placed in each well. The assay plates were sealed and incubated at
37.degree. C. for approximately 1 hr. The plates were washed twice
with 300 mL 1.times. wash buffer and dried thoroughly inverted on
paper towels. 100 .mu.L 1.times. enzyme conjugate solution was
placed in each well. The assay plates were sealed and incubated at
37.degree. C. for at least 1 hr. The plates were washed 3 times
with 300 mL 1.times. wash buffer and dried thoroughly inverted on
paper towels. 100 .mu.L chromagen/substrate solution were added to
each well and incubated at room temperature for approximately 5
min. 100 .mu.L of stop solution were added to each well and the
plates were read on a Molecular Devices SpectraMax 384 Plus
Microplate Reader at 450 nm.
[0771] Data Analysis
[0772] IC.sub.50s were determined using GraphPad Prism:
Four-parameter logistic curve with equation
Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((Log
IC50-X)*HillSlope)). IC.sub.50 values for 50% reduction in HBs and
HBe antigens for tested compounds are shown in Table 1 for days 9
and 14. As can be seen from the IC.sub.50 values, the tested
compounds exhibited 50% inhibition of HBe and HBs antigens at
values between less than .about.0.22 .mu.M and 0.0069 .mu.M.
[0773] The embodiments of the invention described above are
intended to be merely exemplary; numerous variations and
modifications will be apparent to those skilled in the art. All
such variations and modifications are intended to be within the
scope of the present invention as defined in any appended
claims.
Example 36 HepAD38 Cells--HBsAg ELISA and Cytotoxicity Assays
[0774] HepAD38 cells are maintained in collagen-coated flasks in
cell culture medium (DMEM/F12 containing 10% fetal bovine serum
(FBS), GlutaMax-1, penicillin/streptomycin, non-essential amino
acids, Na pyruvate, 250 .mu.g/mL geneticin, and 1 .mu.g/mL
doxycycline). Compound solutions are prepared in DMSO and compound
are serially diluted for final concentrations of 4000, 1000, 250,
62.5, 15.6, 3.91, 0.977, 0.244, 0.061, and 0.015 .mu.M. The cells
are then trypsinized and the cells are plate at 10,000 cells per
well. Incubate plates are incubated at 37.degree. C., 5% CO.sub.2
for 4 days. Media is replaced with new media with compound
treatment. The plates are then incubated at 37.degree. C., 5%
CO.sub.2 for an additional 3 days for a total treatment time of 7
days. For antiviral response, HBsAg was measured using the HBsAg
ELISA kit (International Immuno-diagnostics) with instructions
provided. 100 uL of cell media samples was used for ELISA. The
absorbance was read on the Spectramax.RTM. 384 plate reader
(Molecular Devices) at 450 nm. For cell toxicity, the cells were
used for CellTiter-Glo.RTM. Luminescent Cell Viability Assay
reagent (Promega). The luminescence was read on Envision Multilabel
Reader (Perkin Elmer). The data was analyzed compared to the DMSO
control.
% inhibition=(1-(unknown/high control))*100
[0775] The average % inhibition values from duplicate assay plates
are then plotted in GraphPad Prism to determine one IC value:
Four-parameter logistic curve with equation
Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((Log
IC50-X)*HillSlope))
pIC.sub.50=log(-IC.sub.50 in M)
TABLE-US-00001 TABLE 1 Example/ Scheme Compound No. No. Structure
Name 1 220 ##STR00229##
(4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-
dimethyl-11-oxo-4b,5,6,7,7a,11- hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 2 221 ##STR00230##
(4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-
7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 3 222 ##STR00231##
(4bR,7aS)-2-Cyclopropyl-3-(3- methoxypropoxy)-7,7-dimethyl-11-oxo-
4b,5,6,7,7a,11- hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 4 223 ##STR00232##
2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-
dimethyl-11-oxo-4b,5,6,7,7a,11- hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid (racemic cis) 5 224
##STR00233## (7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-
methoxypropoxy)-7,7-dimethyl-11-oxo- 4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 6 225 ##STR00234##
(7aR)-2-Chloro-4b-hydroxy-3-(3-
methoxypropoxy)-7,7-dimethyl-11-oxo- 4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 7 226 ##STR00235##
(7aR)-2-Chloro-4b-methoxy-3-(3-
methoxypropoxy)-7,7-dimethyl-11-oxo- 4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 8 227 ##STR00236##
(4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-
7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 9 228 ##STR00237##
(4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl- 11-oxo-4b,5,6,7,7a,11-
hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 10 229 ##STR00238##
2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-
(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 11 230
##STR00239## (S)-6-(tert-butyl)-2-chloro-3-(3-
methoxypropoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 12 231
##STR00240## (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-
methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 13 232 ##STR00241##
(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-
methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 14 233 ##STR00242##
(S)-6-(tert-butyl)-2-cyclopropyl-3-
(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 15 234
##STR00243## (S)-6-(tert-butyl)-2-cyclopropyl-3-(3-
methoxypropoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 16 235
##STR00244## (R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-
methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 17 236 ##STR00245##
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-
methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 18 237 ##STR00246##
(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-
hydroxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 19 238 ##STR00247##
(S)-6-(tert-butyl)-2-methoxy-3-(3-
methoxypropoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 20 239
##STR00248## (S)-6-(tert-butyl)-2-hydroxy-3-(3-
methoxypropoxy)-10-oxo-6,10-dihdyro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 21 240
##STR00249## (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-
oxo-2-(prop-1-en-2-yl)-6,10-dihdyro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 22 241
##STR00250## (S)-6-(tert-butyl)-2-isopropyl-3-(3-
methoxypropoxy)-10-oxo-6,10-dihydro-5H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 23 242
##STR00251## (S)-6-(tert-butyl)-2-chloro-3-(3-
methoxypropoxy)-8-methyl-10-oxo-6,10-
dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9- carboxylic acid 24
243 ##STR00252## (S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-
methoxypropoxy)-10-oxo-5,10-dihydro-6H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 25 244
##STR00253## (S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-
(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-
pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid 26 245
##STR00254## (2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-
6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 27 246 ##STR00255##
(2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-
6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid 28 247 ##STR00256##
2-cyclopropyl-6-isopropyl-3-(3-
methoxypropoxy)-6-methyl-10-oxo-5,10-
dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9- carboxylic acid 29
248 ##STR00257## 2-cyclopropyl-6-isopropyl-3-(3-
methoxypropoxy)-6-methyl-10-oxo-5,10-
dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9- carboxylic acid 30
249 ##STR00258## 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-
10-oxo-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid (isomers 1 and 2) 31 250
##STR00259## 2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-
5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-
h][1,7]naphthyridine]-9'-carboxylic acid 32 251 ##STR00260##
2',3'-Dimethoxy-10'-oxo-5',10'-
dihydrospiro[cyclobutane-1,6'-pyrido[1,2-
h][1,7]naphthyridine]-9'-carboxylic acid 33 252 ##STR00261##
6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-
6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid 34 253
##STR00262## 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-
11-oxo-4b,5,6,7,7a,11- hexahydrocyclopenta[f]pyrido[1,2-
h][1,7]naphthyridine-10-carboxylic acid 35 254 ##STR00263##
3'-(cyclopropylmethoxy)-2'-(difluoromethyl)-
11'-fluoro-10'-oxo-5',10'-
dihydrospiro[cyclobutane-1,6'-pyrido[1,2-
h][1,7]naphthyridine]-9'-carboxylic acid 36 255 ##STR00264##
2'-(difluoromethyl)-11'-fluoro-10'-oxo-3'-
((tetrahydrofuran-3-yl)methoxy)-5',10'-
dihydrospiro[cyclobutane-1,6'-pyrido[1,2-
h][1,7]naphthyridine]-9'-carboxylic acid 37 256 ##STR00265##
(S)-3-(cyclopropylmethoxy)-2-(difluoromethyl)-
11-fluoro-6-isopropyl-6-methyl-10-oxo-6,10-
dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9- carboxyli acid 38 257
##STR00266## (6S)-2-(difluoromethyl)-11-fluoro-6-isopropyl-
6-methyl-10-oxo-3-((tetrahydrofuran-3-
yl)methoxy)-6,10-dihydro-5H-pyrido[1,2-
h][1,7]naphthyridine-9-carboxylic acid
TABLE-US-00002 TABLE 2 R.sup.10 = R.sup.10 = R.sup.10 = R.sup.10 =
##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271##
##STR00272## ##STR00273## ##STR00274## --OH ##STR00275##
##STR00276## ##STR00277## --OR.sup.a ##STR00278## ##STR00279##
##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284##
##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289##
##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294##
##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299##
##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304##
##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309##
##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314##
##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319##
##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324##
##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329##
##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334##
##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339##
##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344##
##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349##
##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354##
##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359##
##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364##
##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369##
##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374##
##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379##
##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384##
##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389##
##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394##
##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399##
##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404##
##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409##
##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414##
##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419##
##STR00420## --CO.sub.2H --B(OH).sub.2 --NHSO.sub.2R.sup.25'
--NCO.sub.2R.sup.25 wherein R.sup.a, R.sup.a' and R.sup.a'' are
independently selected from hydroxy, alky or substituted alkyl,
cycloalkyl or substituted cycloalkyl, heterocycloalkyl or
substituted heterocycloalky, aryl or substituted aryl, heteroaryl
or substituted heteroaryl; with the proviso that R.sup.a is not
hydroxy when linked to an oxygen group R.sup.b, R.sup.b' and
R.sup.b'' are independently selected from hydrogen, halo, hydroxy,
alkyl, or substituted alkyl, alkoxy or substituted alkoxy,
cycloalkyl or substituted cycloalkyl, heterocycloalkyl or
substituted heterocycloalky, thio or thioalkyl, amino or
substituted amino, aryl or substituted aryl, heteroaryl or
substituted aryl; R.sup.25 and R.sup.25' are independently selected
from H, OH, alkyl or substituted alkyl, cycloalkyl or substituted
cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or
substituted heterocycloalkyl, aryl or substituted aryl and
heteroaryl or substituted heteroaryl; and wherein the above
substituents for R.sup.10 may exist as tautomers of the structures
shown.
TABLE-US-00003 TABLE 3 Hep AD38, HBsAg and Cell tox Data -
EC.sub.50 (.eta.M) HepAD38, HBsAg (EC50, Example No. Compound No.
.mu.M) Cell tox (EC50, .eta.M) 1 ##STR00421## ++++ - 2 ##STR00422##
++ - 3 ##STR00423## ++++ - 4 ##STR00424## ++++ - 5 ##STR00425## +++
- 6 ##STR00426## ++ - 7 ##STR00427## ++ - 8 ##STR00428## + - 9
##STR00429## + - 10 ##STR00430## +++ - 11 ##STR00431## ++++ - 12
##STR00432## ++++ - 13 ##STR00433## ++++ - 14 ##STR00434## ++++ -
15 ##STR00435## ++++ - 16 ##STR00436## + - 17 ##STR00437## ++++ -
18 ##STR00438## + - 19 ##STR00439## ++++ - 20 ##STR00440## + - 21
##STR00441## ++++ - 22 ##STR00442## ++++ - 23 ##STR00443## + - 24
##STR00444## +++ - 25 ##STR00445## ++++ - 26 ##STR00446## +++ - 27
##STR00447## + - 28 ##STR00448## ++++ - 29 ##STR00449## ++ - 30
##STR00450## +++ - 30-A ##STR00451## ++++ - 30-B ##STR00452## + -
31 ##STR00453## +++ - 32 ##STR00454## ++ - 33 ##STR00455## + - 34
##STR00456## +++ - wherin: - >4000 .eta.M (4 .mu.M) (cell tox) +
.gtoreq.0.1 .mu.M ++ <0.1 .mu.M, and .gtoreq.0.01 .mu.M +++
<0.01 .mu.M, and .gtoreq.0.001 .mu.M ++++ <0.001 .mu.M
* * * * *