U.S. patent application number 13/526995 was filed with the patent office on 2012-10-11 for process for synthesizing phosphonic and phosphinic acid compounds.
Invention is credited to Luigi Anzalone, IIias K. Dorziotis, Penina Feibush, Stefan Horns, Neelakandha S. Mani, Daniel J. Pippel, Frank J. Villani, JR..
Application Number | 20120259130 13/526995 |
Document ID | / |
Family ID | 40567690 |
Filed Date | 2012-10-11 |
United States Patent
Application |
20120259130 |
Kind Code |
A1 |
Anzalone; Luigi ; et
al. |
October 11, 2012 |
PROCESS FOR SYNTHESIZING PHOSPHONIC AND PHOSPHINIC ACID
COMPOUNDS
Abstract
The present invention is directed to an improved process for
synthesizing phosphonic and phosphinic acid chymase inhibitor
compounds.
Inventors: |
Anzalone; Luigi; (West
Chester, PA) ; Pippel; Daniel J.; (Del Mar, CA)
; Mani; Neelakandha S.; (San Diego, CA) ; Feibush;
Penina; (Ambler, PA) ; Dorziotis; IIias K.;
(Somerville, NJ) ; Horns; Stefan; (Schaffhausen,
DE) ; Villani, JR.; Frank J.; (Perkasie, PA) |
Family ID: |
40567690 |
Appl. No.: |
13/526995 |
Filed: |
June 19, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12288044 |
Oct 16, 2008 |
8222431 |
|
|
13526995 |
|
|
|
|
60999115 |
Oct 16, 2007 |
|
|
|
Current U.S.
Class: |
549/6 |
Current CPC
Class: |
C07F 9/6541 20130101;
C07F 9/65583 20130101; C07F 9/572 20130101; C07F 9/65586 20130101;
C07F 9/3808 20130101; C07F 9/5728 20130101; C07F 9/65517 20130101;
C07F 9/657181 20130101; A61P 11/00 20180101; C07F 9/59 20130101;
C07F 9/4006 20130101; C07F 9/655354 20130101; C07F 9/6561 20130101;
C07F 9/301 20130101; C07F 9/60 20130101 |
Class at
Publication: |
549/6 |
International
Class: |
C07F 9/6553 20060101
C07F009/6553 |
Claims
1. A process for preparing a compound of Formula (I) and a salt
thereof: ##STR00019## wherein ##STR00020## is selected from the
group consisting of heteroaryl and benzo fused heterocyclyl,
optionally substituted with R.sup.2 and R.sup.3; R.sup.2 is one to
three substituents independently selected from the group consisting
of C.sub.1-4alkyl, methoxy, C.sub.2-6alkoxy,
--OCH.sub.2--C.sub.2-6alkenyl, NH.sub.2, --NH(C.sub.1-6alkyl),
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and
nitro, wherein said C.sub.1-4alkyl, C.sub.2-6alkenyl and
C.sub.2-6alkoxy substituents of R.sup.2 are optionally substituted
with a substituent independently selected from the group consisting
of --NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxy; R.sup.11 and R.sup.12 are substituents independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl, and
aryl; wherein said C.sub.1-6alkyl substituent of R.sup.11 or
R.sup.12 is optionally substituted with substituent selected from
the group consisting of hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
and --NR.sup.15R.sup.16; R.sup.15 and R.sup.16 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl, and aryl, and said R.sup.15 and R.sup.16 are
optionally taken together with the atoms to which they are attached
to form a ring of five to seven members; R.sup.3 is one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
--OCH.sub.2(C.sub.2-6)alkenyl, NH.sub.2, --NH(C.sub.1-6alkyl),
--N(C.sub.1-6)dialkyl, --NHC(.dbd.O)Cy,
--N(C.sub.1-6alkyl)C(.dbd.O)Cy, --C(.dbd.O)C.sub.1-4alkoxy,
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C.sub.1-6alkyl)cyclo alkyl, --C(.dbd.O)NHCy,
--C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)NR.sup.19R.sup.20, halogen, hydroxy, nitro, cyano, aryl
and aryloxy, wherein said C.sub.1-6alkyl and C.sub.1-6alkoxy are
optionally substituted with one to three substituents independently
selected from the group consisting of --NR.sup.21R.sup.22,
--NHcycloalkyl, --N(C.sub.1-6alkyl)cycloalkyl, --NHCy,
--N(C.sub.1-6alkyl)Cy, --NHC(O)--C.sub.1-6alkyl-C.sub.1-6alkoxy,
aryl, heteroaryl, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.)(C.sub.1-4)alkoxy, and
--C(.dbd.O)Cy, wherein each instance of said C.sub.2-6alkenyl is
optionally substituted on a terminal carbon with aryl or
--C(.dbd.O)NR.sup.27R.sup.28, and wherein said aryl and cycloalkyl
are optionally substituted with one to three substituents
independently selected from R.sup.14; R.sup.14 is independently
hydrogen, C.sub.1-6alkyl, C.sub.1-6 alkoxy, C.sub.2-6alkenyl,
C.sub.1-6alkylthio, --NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy,
halogen, hydroxy, or nitro, and any one of the foregoing
C.sub.1-6alkyl- or C.sub.1-6alkoxy-containing substituents of
R.sup.14 is optionally substituted on a terminal carbon atom with a
substituent selected from --NR.sup.29R.sup.30, aryl, heteroaryl,
one to three halogen atoms, or hydroxy; R.sup.17, R.sup.18,
R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 are substituents independently selected from
the group consisting of hydrogen, C.sub.1-6alkyl and aryl, wherein
C.sub.1-6alkyl and aryl are each optionally substituted with
hydroxy, aryl, aryloxy, --C(.dbd.O)-aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; and said R.sup.17 and R.sup.18, R.sup.19 and
R.sup.20, R.sup.21 and R.sup.22, R.sup.23 and R.sup.24 or R.sup.25
and R.sup.26 are optionally taken together with the atoms to which
they are attached to form a ring of five to seven members; R.sup.27
and R.sup.28 are independently hydrogen; C.sub.1-6alkyl optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, --NH(C.sub.1-6alkyl) or --N(C.sub.1-6)dialkyl; or aryl;
and said R.sup.27 and R.sup.28 are optionally taken together with
the atoms to which they are attached to form a ring of five to
seven members; R.sup.29 and R.sup.30 are independently hydrogen;
C.sub.1-6alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; or aryl; and R.sup.29 and R.sup.30 are
optionally taken together with the atoms to which they are attached
to form a ring of five to seven members; Cy is a heterocyclyl
optionally substituted with a substituent selected from the group
consisting of oxo, C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy, --C.sub.1-6alkyl-aryl,
--C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl and heterocyclyl, wherein aryl and the aryl
portion of --C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)aryl and
--SO.sub.2aryl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, hydroxy, NH.sub.2,
--NH(C.sub.1-6alkyl), and --N(C.sub.1-6)dialkyl; and wherein
heterocyclyl is optionally substituted with aryl, one to three
halogen atoms, or one to three oxo substituents; and, wherein
heterocyclyl is optionally spiro-fused to said Cy; R.sup.5 is
selected from the group consisting of hydrogen or C.sub.1-3alkyl
optionally substituted with NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, C.sub.1-6alkylcarbonyloxy-,
C.sub.1-6alkoxycarbonyloxy-, C.sub.1-6alkylcarbonylthio-,
(C.sub.1-6)alkylaminocarbonyl-, di(C.sub.1-6)alkylaminocarbonyl-,
one to three halogens, or hydroxy; and said aryl is optionally
substituted with C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio-, C.sub.2-6alkenyl, NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively,
when R.sup.6 is C.sub.1-8alkoxy, said R.sup.5 and R.sup.6 are taken
together with the atoms to which they are attached to form a 5-8
membered monocyclic ring, provided that R.sup.5 is other than
C.sub.1-3alkyl substituted with di(C.sub.1-6)alkylamino-carbonyl-
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is OH,
and Z--R.sup.4 is 5-chloro-benzothiophen-3-yl; and provided that
R.sup.5 is other than C.sub.1-3alkyl substituted with
C.sub.1-6alkylcarbonylthio- when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is CH.sub.3, and Z--R.sup.4 is
5-chloro-benzothiophen-3-yl; R.sup.6 is selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-8alkoxy, heteroaryl, aryl,
and hydroxy; wherein C.sub.1-6alkyl is optionally substituted on a
terminal carbon atom with a substituent selected from
C.sub.1-3alkoxy, aryl, or hydroxy; and C.sub.1-8alkoxy is
optionally substituted on a terminal carbon atom with a substituent
independently selected from the group consisting of
C.sub.1-6alkylcarbonyloxy- and di(C.sub.1-6)alkylaminocarbonyl-;
and wherein heteroaryl and aryl are optionally substituted with one
to three substituents independently selected from the group
consisting of aryl, hydroxy, C.sub.1-6alkoxy, and halogen; Z is a
bicyclic aryl or bicyclic heteroaryl; wherein aryl and heteroaryl
are optionally substituted with the group R.sup.4; R.sup.4 is one
to three substituents selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo and cyano,
wherein said C.sub.1-6alkyl, C.sub.2-6alkenyl and C.sub.1-6alkoxy
are optionally substituted with a substituent independently
selected from the group consisting of --NR.sup.33R.sup.34, aryl,
one to three halogen atoms and hydroxy, and wherein said aryl is
optionally substituted with a substituent independently selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, aryl, halogen, hydroxy, and nitro; and R.sup.31,
R.sup.32, R.sup.33 and R.sup.34 are substituents independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl, and
aryl, wherein alkyl is optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; and said R.sup.31 and R.sup.32 or R.sup.33
and R.sup.34 are optionally taken together with the atoms to which
they are attached to form a ring of five to seven members;
comprising the steps of: Step 1. reacting a Compound A1 (wherein
R.sup.5 is C.sub.1-3alkyl) with a Compound A2, wherein Compound A1
and Compound A2 are present in a first ratio, in toluene, to
provide a Compound A3 (wherein R.sup.5 is C.sub.1-3alkyl),
representative of a compound of Formula (I): ##STR00021## wherein
in the first ratio, the amount of Compound A1 exceeds the amount of
Compound A2 by about 0.2 equivalents; and Step 2. reacting the
Compound A3 (wherein R.sup.5 is C.sub.1-3alkyl) in the presence of
TMSBr, in acetonitrile and optionally present pyridine, wherein
TMSBr and Compound A3 are in a second ratio, and wherein TMSBr and
pyridine, when pyridine is present, are in a third ratio, to
provide a Compound A4 (wherein R.sup.5 is hydrogen), representative
of a compound of Formula (I): ##STR00022## wherein the second ratio
of TMSBr:Compound A3 is in a range of about 2.5:1 to about 2:1; and
wherein the third ratio of TMSBr:pyridine, when pyridine is
present, is in a range of from about 1:1 to about 1:2.
2. The process of claim 1, further comprising the step of: Step 3.
reacting the Compound A4 (wherein R.sup.5 is hydrogen) with a
cationic salt-forming compound, in a solvent mixture, wherein the
solvents in the mixture are in a fourth ratio, to provide a
Compound A5 as a salt, representative of a compound Formula (I),
wherein the salt is obtained by direct crystallization:
##STR00023##
3. The process of claim 2, wherein an amount of Compound A1 is in a
range of from about 1.2 equivalents to about 1 equivalent and an
amount of Compound A2 is in a range of from about 1 equivalent to
about 0.8 equivalents according to said first ratio.
4. The process of claim 1, wherein the ratio of TMSBr:Compound A3
is in a range of about 2.5:1 to about 2:1, according to said second
ratio, and wherein the third ratio of TMSBr:pyridine is in a range
of about 1:1 to about 1:2.
5. The process of claim 1, wherein in the third ratio of
TMSBr:pyridine is about 1:2.
6. The process of claim 1, wherein the ratio of TMSBr:Compound A3
is in a range of about 2.5:1 to about 2:1, according to said second
ratio, wherein pyridine is not present.
7. The process of claim 2, wherein the salt of the compound of
claim 1 is a choline salt precipitated from a solvent mixture of
MeOH and EtOAc, wherein the solvents are in said fourth ratio of
about 1:3 MeOH:EtOAc.
8. The process of claim 1, wherein the compound is selected from
the group consisting of:
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-3-yl-vinylcarbamoyl)-met-
hyl]-phosphonic acid,
[(benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-ph-
osphonic acid,
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylthiocarbamoyl)-methyl]--
phosphonic acid,
[(benzo[b]thiophen-5-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl-
]-phosphonic acid,
[naphthalen-1-yl-(quinolin-3-ylcarbamoyl)-methyl]-phosphonic acid,
[(benzo[b]thiophen-6-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid,
[(benzo[b]thiophen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphoni-
c acid,
[(2-amino-benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-
-yl)-methyl]-phosphonic acid,
[naphthalen-1-yl-(quinolin-6-ylcarbamoyl)-methyl]-phosphonic acid,
[(indan-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,
[naphthalen-1-yl-(quinolin-2-ylcarbamoyl)-methyl]-phosphonic acid,
[(1H-indol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,
[(benzo[1,3]dioxol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid,
[(isoquinolin-3-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid,
[(5-chloro-benzo[b]thiophen-3-yl)-(2-phenyl-trans-cyclopropylcarbam-
oyl)-methyl]-methyl-phosphinic acid,
[(benzofuran-2-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-meth-
yl-phosphinic acid,
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-met-
hyl]-methyl-phosphinic acid,
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-met-
hyl]-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)ester,
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)ester,
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-met-
hyl]-phosphonic acid bis-(tert-butylcarbonyloxymethyl)ester,
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-met-
hyl]-phosphonic acid (tert-butylcarbonyloxymethyl)ester,
(E)-2-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-ylvinylcarbamoyl)-me-
thyl]-1,3,2-dioxaphosphorinane 2-oxide, and
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-met-
hyl]-phosphonic acid (isopropyloxycarbonyloxymethyl)ester.
Description
[0001] This application is a divisional of nonprovisional
application Ser. No. 12/288,044, filed on Oct. 16, 2008, which
claims the benefit of priority from provisional application U.S.
Ser. No. 60/999,115, filed on Oct. 16, 2007.
FIELD OF THE INVENTION
[0002] The present invention is directed to an improved process for
synthesizing phosphonic and phosphinic acid compounds. More
particularly, the process is amenable to an efficient, large scale
synthesis, produces a salt form of a compound by direct
crystallization and minimizes the formation of impurities.
SUMMARY OF THE INVENTION
[0003] The present invention is directed to a process for preparing
a compound of Formula (I):
##STR00001##
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, Z, n and Ring
A are as defined herein.
[0004] The present invention provides a process that is amenable to
an efficient, large scale synthesis, obtains a salt form of the
compound of Formula (I) by direct crystallization and avoids the
formation of impurities, thus resulting in an improved yield.
[0005] The compound of Formula (I) has been disclosed in commonly
assigned United States Patent Publication 2005/0176769 and referred
to therein as a compound of Formula (Ia), which Publication is
incorporated herein by reference in its entirety and for all
purposes.
[0006] The present invention is also directed to a process for
preparing a compound of Formula (Ia) and intermediates thereof:
##STR00002##
[0007] The compound of Formula (Ia),
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarba-
moyl]-methyl}-methyl-phosphinic acid, has also been disclosed in
U.S. Patent Publication 2005/0176769 and referred to therein as
Compound 17 and synthesized as in Example 6 of same.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The present invention is directed to a process for preparing
a compound of Formula (I) and a salt thereof:
##STR00003##
wherein
##STR00004##
is independently selected from the group consisting of aryl,
heteroaryl, and benzo fused heterocyclyl, optionally substituted
with R.sup.2 and R.sup.3; [0009] R.sup.2 is one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, methoxy, C.sub.2-6alkoxy,
--OCH.sub.2--C.sub.2-6alkenyl, NH.sub.2, --NH(C.sub.1-6alkyl),
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and
nitro, [0010] wherein said C.sub.1-4alkyl, C.sub.2-6alkenyl and
C.sub.2-6alkoxy substituents of R.sup.2 are optionally substituted
with a substituent independently selected from the group consisting
of --NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxy; [0011] R.sup.11 and R.sup.12 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl, and aryl; wherein said C.sub.1-6alkyl substituent
of R.sup.11 or R.sup.12 is optionally substituted with a
substituent selected from the group consisting of hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, and --NR.sup.15R.sup.16; [0012]
R.sup.15 and R.sup.16 are substituents independently selected from
the group consisting of hydrogen, C.sub.1-6alkyl, and aryl, and
said R.sup.15 and R.sup.16 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; [0013] R.sup.3 is one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.1-6alkoxy, --OCH.sub.2(C.sub.2-6)alkenyl,
NH.sub.2, --NH(C.sub.1-6alkyl), --N(C.sub.1-6)dialkyl,
--NHC(.dbd.O)Cy, --N(C.sub.1-6alkyl)C(.dbd.O)Cy,
--C(.dbd.O)C.sub.1-4alkoxy, --C(.dbd.O)NR.sup.17R.sup.18,
--C(.dbd.O)NHcycloalkyl, --C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl,
--C(.dbd.O)NHCy, --C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)NR.sup.19R.sup.20, halogen, hydroxy, nitro, cyano, aryl
and aryloxy, [0014] wherein said C.sub.1-6alkyl and C.sub.1-6alkoxy
are optionally substituted with one to three substituents
independently selected from the group consisting of
--NR.sup.21R.sup.22, --NHcycloalkyl, --N(C.sub.1-6alkyl)cycloalkyl,
--NHCy, --N(C.sub.1-6alkyl)Cy,
--NHC(O)--C.sub.1-6alkyl-C.sub.1-6alkoxy, aryl, heteroaryl,
halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)(C.sub.1-4)alkoxy, and
--C(.dbd.O)Cy, [0015] wherein each instance of said
C.sub.2-6alkenyl is optionally substituted on a terminal carbon
with aryl or --C(.dbd.O)NR.sup.27R.sup.28, and [0016] wherein said
aryl and cycloalkyl are optionally substituted with one to three
substituents independently selected from R.sup.14; [0017] R.sup.14
is independently hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.2-6alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro, and [0018] any
one of the foregoing C.sub.1-6alkyl- or C.sub.1-6alkoxy-containing
substituents of R.sup.14 is optionally substituted on a terminal
carbon atom with a substituent selected from --NR.sup.29R.sup.30,
aryl, heteroaryl, one to three halogen atoms, or hydroxy; [0019]
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl and aryl, wherein C.sub.1-6alkyl and aryl are each
optionally substituted with hydroxy, aryl, aryloxy,
--C(.dbd.O)-aryl, --C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2,
--NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; and said R.sup.17
and R.sup.18, R.sup.19 and R.sup.20, R.sup.21 and R.sup.22,
R.sup.23 and R.sup.24 or R.sup.25 and R.sup.26 are optionally taken
together with the atoms to which they are attached to form a ring
of five to seven members; [0020] R.sup.27 and R.sup.28 are
independently hydrogen; C.sub.1-6alkyl optionally substituted with
hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2,
--NH(C.sub.1-6alkyl) or --N(C.sub.1-6)dialkyl; or aryl; and said
R.sup.27 and R.sup.28 are optionally taken together with the atoms
to which they are attached to form a ring of five to seven members;
[0021] R.sup.29 and R.sup.30 are independently hydrogen;
C.sub.1-6alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; or aryl; and R.sup.29 and R.sup.30 are
optionally taken together with the atoms to which they are attached
to form a ring of five to seven members; [0022] Cy is a
heterocyclyl optionally substituted with a substituent selected
from the group consisting of oxo, C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy, --C.sub.1-6alkyl-aryl,
--C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl and heterocyclyl, [0023] wherein aryl and the aryl
portion of --C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)aryl and
--SO.sub.2aryl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, hydroxy, NH.sub.2,
--NH(C.sub.1-6alkyl) and --N(C.sub.1-6)dialkyl; and wherein
heterocyclyl is optionally substituted with aryl, one to three
halogen atoms, or one to three oxo substituents; and, wherein
heterocyclyl is optionally spiro-fused to said Cy; [0024] R.sup.5
is selected from the group consisting of hydrogen or C.sub.1-3alkyl
optionally substituted with NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, C.sub.1-6alkylcarbonyloxy-,
C.sub.1-6alkoxycarbonyloxy-, C.sub.1-6alkylcarbonylthio-,
(C.sub.1-6)alkylaminocarbonyl-, di(C.sub.1-6)alkylaminocarbonyl-,
one to three halogens, or hydroxy; and said aryl is optionally
substituted with C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio-, C.sub.2-6alkenyl, NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively,
when R.sup.6 is C.sub.1-8alkoxy, said R.sup.5 and R.sup.6 are taken
together with the atoms to which they are attached to form a 5-8
membered monocyclic ring, [0025] provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with
di(C.sub.1-6)alkylamino-carbonyl- when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z--R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio-
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z--R.sup.4 is 5-chloro-benzothiophen-3-yl; [0026]
R.sup.6 is selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-8alkoxy, heteroaryl, aryl, and hydroxy; wherein
C.sub.1-6alkyl is optionally substituted on a terminal carbon atom
with a substituent selected from C.sub.1-3alkoxy, aryl, or hydroxy;
and C.sub.1-8alkoxy is optionally substituted on a terminal carbon
atom with a substituent independently selected from the group
consisting of C.sub.1-6alkylcarbonyloxy- and
di(C.sub.1-6)alkylaminocarbonyl-; and wherein heteroaryl and aryl
are optionally substituted with one to three substituents
independently selected from the group consisting of aryl, hydroxy,
C.sub.1-6alkoxy, and halogen; [0027] Z is a bicyclic aryl or
bicyclic heteroaryl; wherein aryl and heteroaryl are optionally
substituted with the group R.sup.4; [0028] R.sup.4 is one to three
substituents selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.1-6alkoxy, aryl(C.sub.2-6)alkenyl, halogen,
--C(.dbd.O)Cy, --C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo
and cyano, [0029] wherein said C.sub.1-6alkyl, C.sub.2-6alkenyl and
C.sub.1-6alkoxy are optionally substituted with a substituent
independently selected from the group consisting of
--NR.sup.33R.sup.34, aryl, one to three halogen atoms and hydroxy,
and [0030] wherein said aryl is optionally substituted with a
substituent independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, halogen, hydroxy,
and nitro; and [0031] R.sup.31, R.sup.32, R.sup.33 and R.sup.34 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, and aryl, wherein C.sub.1-6alkyl is
optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl) or
--N(C.sub.1-6)dialkyl; and said R.sup.31 and R.sup.32 or R.sup.33
and R.sup.34 are optionally taken together with the atoms to which
they are attached to form a ring of five to seven members; [0032]
according to Scheme A, comprising the steps of:
##STR00005## ##STR00006##
[0033] An example of the present invention includes a process
wherein in the first ratio of Compound A1 and Compound A2, the
amount of Compound A1 exceeds the amount of Compound A2 by about
0.2 equivalents.
[0034] An example of the present invention includes an amount of
Compound A1 in a range of from about 1.2 equivalents to about 1
equivalent and an amount of Compound A2 in a range of from about 1
equivalent to about 0.8 equivalents according to said first
ratio.
[0035] An example of the present invention includes TMSBr in a
range of about 2.5:1 TMSBr:Compound A3 to about 2:1 TMSBr:Compound
A3, according to said second ratio, and pyridine is present in a
range of about 1:1 TMSBr:pyridine to about 1:2 TMSBr:pyridine
according to said third ratio.
[0036] An example of the present invention includes a process
wherein in the third ratio, TMSBr and pyridine are about 1:2
TMSBr:pyridine.
[0037] An example of the present invention includes TMSBr in a
range of about 2.5:1 TMSBr:Compound A3 to about 2:1 TMSBr:Compound
A3, according to said second ratio, wherein pyridine is not
present.
[0038] An example of the present invention includes a process
wherein the cationic salt of the compound of Formula (I) is a
choline salt precipitated from a solvent mixture of MeOH and EtOAc,
wherein the solvents are in said fourth ratio of about 1:3
MeOH:EtOAc.
[0039] The foregoing Scheme A and the other schemes shown herein
are offered by way of illustration; the invention should not be
construed as being limited by the chemical reactions and conditions
expressed. The methods for preparing the various starting materials
used in the schemes are within the skill of persons versed in the
art.
[0040] The present invention is also directed to a process for
preparing a compound of Formula (I) disclosed in commonly assigned
U.S. Patent Publication 2005/0176769 selected from the group
consisting of:
TABLE-US-00001 Cpd Name 1
[(5-chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-me-
thyl- phosphinic acid, 2
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 3
[(5-chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 4
(E)-{(5-chloro-1-methyl-1H-indol-3-yl)-[2-(4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 5
[(5-methyl-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 6
(E)-{(5-chloro-1-methyl-1H-indol-3-yl)-[2-(3-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 7
(E)-{(5-chloro-1-methyl-1H-indol-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 8
[(4-{[1-(naphthalene-2-carbonyl)-piperidine-4-carbonyl]-amino}-naphthale-
n- 2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, 9
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 10
[(5-fluoro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 11
[(5-fluoro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 12
(E)-[[2-(4-amino-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3-y-
l)- methyl]-phosphonic acid, 13
[(5-bromo-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 14
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-styrylcarbamoyl-methyl]-methyl-
phosphinic acid, 15
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 16
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4,5-trifluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 17
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 18
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-styrylcarbamoyl-methyl]-phosphoni-
c acid, 19
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-fluoro-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 20
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
methyl-phosphinic acid, 21
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 22
[(1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, 23
[(5-bromo-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 24
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-fluoro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 25
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-3-yl-vinylcarbamoyl)-
methyl]-phosphonic acid, 26
[benzo[b]thiophen-3-yl-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, 27
{(naphthalen-2-ylcarbamoyl)-[1-(3-phenyl-allyl)-1H-indol-3-yl]-methyl}-
phosphonic acid, 28
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-et-
hyl- phosphinic acid, 29
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-ethyl-phosphinic acid, 30
[(benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-
phosphonic acid, 31
[naphthalen-1-yl-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, 32
methyl-{(naphthalen-2-ylcarbamoyl)-[2-(4-phenyl-piperidine-1-carbonyl)-
benzo[b]thiophen-3-yl]-methyl}-phosphinic acid, 33
methyl-[naphthalen-1-yl-(naphthalen-2-ylcarbamoyl)-methyl]-phosphinic
acid, 34
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-(3-
- methoxy-propyl)-phosphinic acid, 35
[{2-[4-(4-methoxy-phenyl)-piperidine-1-carbonyl]-benzo[b]thiophen-3-yl}-
- (naphthalen-2-ylcarbamoyl)-methyl]-methyl-phosphinic acid, 36
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phenethyl-phosphinic acid, 37
(E)-(naphthalen-1-yl-styrylcarbamoyl-methyl)-phosphonic acid, 38
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 39
(3-benzo[1,3]dioxol-5-yl-propyl)-[(5-chloro-benzo[b]thiophen-3-yl)-
(naphthalen-2-ylcarbamoyl)-methyl]-phosphinic acid, 40
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-(3-
- naphthalen-1-yl-propyl)-phosphinic acid, 41
[{2-[4-(benzyloxycarbonyl)-piperazin-1-ylcarbonyl]-benzothiophen-3-yl}-
(naphthalen-2-ylcarbamoyl)-methyl]-methyl-phosphinic acid, 42
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-p-tolyl-vinylcarbamoyl)-methyl-
]- phosphonic acid, 43
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-[3-
-(4- hydroxy-phenyl)-propyl]-phosphinic acid, 44
({3-[(1-benzoyl-piperidin-4-ylamino)-methyl]-naphthalen-2-ylcarbamoyl}-
naphthalen-1-yl-methyl)-phosphonic acid, 45
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylthiocarbamoyl)-methyl-
]- phosphonic acid, 46
({3-[methyl-(4-phenyl-cyclohex-3-enyl)-carbamoyl]-naphthalen-2-
ylcarbamoyl}-naphthalen-1-yl-methyl)-phosphonic acid, 47
[{2-[4-(4-fluoro-phenyl)-piperidine-1-carbonyl]-benzo[b]thiophen-3-yl}-
(naphthalen-2-ylcarbamoyl)-methyl]-methyl-phosphinic acid, 48
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-(3-
- phenyl-propyl)-phosphinic acid, 49
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 50
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-(4-
-phenyl- butyl)-phosphinic acid, 51
[(6-chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 52
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-[3-
-(4- methoxy-phenyl)-propyl]-phosphinic acid, 53
{naphthalen-1-yl-[3-(3-phenethyl-pyrrolidine-1-carbonyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 54
[(benzo[b]thiophen-5-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-
methyl]-phosphonic acid, 55
[(5-carboxy-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 56
[naphthalen-1-yl-(quinolin-3-ylcarbamoyl)-methyl]-phosphonic acid,
57
[(7-chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 58
[(benzo[b]thiophen-6-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 59
({3-[4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-
carbonyl]-naphthalen-2-ylcarbamoyl}-naphthalen-1-yl-methyl)-phosphonic
acid, 60
[(biphenyl-4-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,
61
[(1-cyclopropylmethyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
- phosphonic acid, 62
[(4-chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 63
[(benzo[b]thiophen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 64
[(5-cyano-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 65
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-hydroxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 66
[(6-bromo-naphthalen-2-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-
methyl]-phosphonic acid, 67
[(1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, 68
[(2-amino-benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-
methyl]-phosphonic acid, 69
[(3-cyclohexylaminomethyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-
methyl]-phosphonic acid, 70
[(5-phenyl-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 71
[(3-benzylcarbamoyloxymethyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-
methyl]-phosphonic acid, 72
{naphthalen-1-yl-[3-(3-pyridin-4-yl-pyrrolidine-1-carbonyl)-naphthalen--
2- ylcarbamoyl]-methyl}-phosphonic acid, 73
[(5-methoxy-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 74
3-(2-naphthalen-1-yl-2-phosphono-acetylamino)-naphthalene-2-carboxylic
acid methyl ester, 75
[(6-bromo-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 76
[(1-isopropyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phospho-
nic acid, 77
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-chloro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 78
[naphthalen-1-yl-(quinolin-6-ylcarbamoyl)-methyl]-phosphonic acid,
79
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-trifluoromethyl-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 80
[(naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyl]-phosphonic
acid, 81
({3-[4-(1H-indol-3-yl)-piperidine-1-carbonyl]-naphthalen-2-ylcarbamoyl}-
- naphthalen-1-yl-methyl)-phosphonic acid, 82
[(indan-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, 83
[(5-chloro-1,1-dioxo-1H-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoy-
l)- methyl]-phosphonic acid, 84
{naphthalen-1-yl-[3-(3-phenyl-pyrrolidine-1-carbonyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 85
[(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phenyl-phosphinic acid, 86
({3-[(3-methyl-cyclohexylamino)-methyl]-naphthalen-2-ylcarbamoyl}-
naphthalen-1-yl-methyl)-phosphonic acid, 87
{[3-(cyclopentyl-methyl-carbamoyl)-naphthalen-2-ylcarbamoyl]-naphthalen-
- 1-yl-methyl}-phosphonic acid, 88
({3-[(5-methoxycarbonyl)-pent-1-ylaminomethyl]-naphthalen-2-
ylcarbamoyl}-naphthalen-1-yl-methyl)-phosphonic acid, 89
(naphthalen-1-yl-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-
e-1- carbonyl]-naphthalen-2-ylcarbamoyl}-methyl)-phosphonic acid,
90
[naphthalen-1-yl-(3-phenylcarbamoyloxymethyl-naphthalen-2-ylcarbamoyl)-
methyl]-phosphonic acid, 91
[naphthalen-1-yl-(3-phenylcarbamoyloxy-naphthalen-2-yl-carbamoyl)-
methyl]-phosphonic acid, 92
[naphthalen-1-yl-(quinolin-2-ylcarbamoyl)-methyl]-phosphonic acid,
93
{naphthalen-1-yl-[3-(4-phenoxy-phenylcarbamoyloxymethyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 94
[[5-(4-fluoro-phenyl)-1-methyl-1H-indol-3-yl]-(naphthalen-2-ylcarbamoyl-
)- methyl]-phosphonic acid, 95
[(4-bromo-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, 96
{[3-(4-benzotriazol-1-yl-piperidine-1-carbonyl)-naphthalen-2-ylcarbamoy-
l]- naphthalen-1-yl-methyl}-phosphonic acid, 97
{naphthalen-1-yl-[3-(4-phenyl-piperidine-1-carbonyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 98
{[3-({methyl-[1-(naphthalene-2-carbonyl)-piperidin-4-yl]-amino}-methyl)-
- naphthalen-2-ylcarbamoyl]-naphthalen-1-yl-methyl}-phosphonic
acid, 99
{[3-(3-benzenesulfonyl-pyrrolidine-1-carbonyl)-naphthalen-2-ylcarbamoyl-
]- naphthalen-1-yl-methyl}-phosphonic acid, 100
{naphthalen-1-yl-[3-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-
carbonyl)-naphthalen-2-ylcarbamoyl]-methyl}-phosphonic acid, 101
{naphthalen-1-yl-[3-(naphthalen-2-ylcarbamoyloxymethyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 102
[(9H-fluoren-3-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 103
{[3-(benzylamino-methyl)-naphthalen-2-ylcarbamoyl]-naphthalen-1-yl-
methyl}-phosphonic acid, 104
[(3-hydroxy-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphon-
ic acid, 105
{[3-(2-benzylcarbamoyl-vinyl)-naphthalen-2-ylcarbamoyl]-naphthalen-1-y-
l- methyl}-phosphonic acid,
106
{naphthalen-1-yl-[3-(5-phenyl-pentylamino)-naphthalen-2-ylcarbamoyl]-
methyl}-phosphonic acid, 107
{[3-(benzyl-methyl-carbamoyl)-naphthalen-2-ylcarbamoyl]-naphthalen-1-y-
l- methyl}-phosphonic acid, 108
{[3-({[3-(5H-dibenzo[a,d]cyclohepten-5-yl)-propyl]-methyl-amino}-methy-
l)- naphthalen-2-ylcarbamoyl]-naphthalen-1-yl-methyl}-phosphonic
acid, 109
{[3-(4-benzothiazol-2-yl-piperidine-1-carbonyl)-naphthalen-2-ylcarbamo-
yl]- naphthalen-1-yl-methyl}-phosphonic acid, 110
(naphthalen-1-yl-{1-[2-oxo-2-(4-phenyl-piperidin-1-yl)-ethoxy]-naphtha-
len- 2-ylcarbamoyl}-methyl)-phosphonic acid, 111
[(3-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-carbamoyl}-naphthalen-2-
ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, 112
[(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-phosphonic acid, 113
({3-[(4-hydroxy-cyclohexylamino)-methyl]-naphthalen-2-ylcarbamoyl}-
naphthalen-1-yl-methyl)-phosphonic acid, 114
[(2-carboxy-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-
methyl-phosphinic acid, 115
[(3-benzylcarbamoyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-
phosphonic acid, 116
{naphthalen-1-yl-[3-(3-phenyl-allyloxy)-naphthalen-2-ylcarbamoyl]-meth-
yl}- phosphonic acid, 117
[(3-benzyloxy-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-
phosphonic acid, 118
[(3-methoxycarbonylmethoxy-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-
methyl]-phosphonic acid, 119
[(3-cyclopentylaminomethyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-
methyl]-phosphonic acid, 120
[1-(5-chloro-benzo[b]thiophen-3-yl)-1-(naphthalen-2-ylcarbamoyl)-ethyl-
]- phosphonic acid, 121
({3-[(methyl-phenethyl-amino)-methyl]-naphthalen-2-ylcarbamoyl}-
naphthalen-1-yl-methyl)-phosphonic acid, 122
[(2-benzylcarbamoyl-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-methyl-phosphinic acid, 123
[(naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyl]-phosphoni-
c acid, 124
[(1H-indol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,
125
(naphthalen-1-yl-{1-[(3-phenyl-propylcarbamoyl)-methoxy]-naphthalen-2-
ylcarbamoyl}-methyl)-phosphonic acid, 126
{naphthalen-1-yl-[3-(2-phenyl-pyrrolidine-1-carbonyl)-naphthalen-2-
ylcarbamoyl]-methyl}-phosphonic acid, 127
[(3-amino-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 128
({3-[(5-hydroxy-pentylamino)-methyl]-naphthalen-2-ylcarbamoyl}-
naphthalen-1-yl-methyl)-phosphonic acid, 129
{[(1-methoxycarbonylmethoxy-naphthalen-2-yl)carbamoyl]-naphthalen-1-yl-
- methyl}-phosphonic acid, 130
[(benzo[1,3]dioxol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 131
[(isoquinolin-3-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, 132
[naphthalen-1-yl-(3-phenoxy-phenylcarbamoyl)-methyl]-phosphonic
acid, 133
{[(3-isopropyloxycarbonyl-naphthalen-2-yl)carbamoyl]-naphthalen-1-yl-
methyl}-phosphonic acid, 134
[(benzo[b]thiophen-2-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, 135
[(3-{[1-(naphthalene-2-carbonyl)-piperidine-4-carbonyl]-amino}-naphtha-
len- 2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, 136
({3-[(benzyl-methyl-amino)-methyl]-naphthalen-2-ylcarbamoyl}-naphthale-
n- 1-yl-methyl)-phosphonic acid, 137
{(naphthalen-2-ylcarbamoyl)-[6-(4-pentyl-phenyl)-benzo[b]thiophen-3-yl-
]- methyl}-phosphonic acid, 138
[(5-chloro-benzo[b]thiophen-3-yl)-(2-phenyl-trans-cyclopropylcarbamoyl-
)- methyl]-methyl-phosphinic acid, 139
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 140
[(benzofuran-2-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-
methyl-phosphinic acid, 141
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 142
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methylcarbonyloxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 143
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-hydroxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 144
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-methyl-phosphinic acid, 145
(E)-[[2-(2-amino-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3--
yl)- methyl]-methyl-phosphinic acid, 146
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethyl-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 147
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 148
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 149
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-o-tolyl-vinylcarbamoyl)-methy-
l]- methyl-phosphinic acid, 150
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 151
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(4-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 152
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-ureido-phenyl)-vinylcarbam-
oyl]- methyl}-methyl-phosphinic acid, 153
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-carbamoylcarbamoylamino-
phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 154
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-methyl-phosphinic acid, 155
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-methyl-phosphinic acid, 156
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 157
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 158
(E)-[[2-(2-bromo-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3--
yl)- methyl]-methyl-phosphinic acid, 159
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 160
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 161
(E)-[[2-(3-bromo-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3--
yl)- methyl]-methyl-phosphinic acid, 162
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 163
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 164
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 165
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 166
(E)-[[2-(3-amino-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3--
yl)- methyl]-methyl-phosphinic acid, 167
(E)-2-(styrylcarbamoyl-naphthalen-1-yl-methyl)-5,5-dimethyl-1,3,2-
dioxaphosphorinane 2-oxide, 168
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid
(3-methoxy- propyl) ester, 169
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid
bis-(3- methoxy-propyl) ester, 170
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid
mono-(2- benzo[1,3]dioxol-2-yl-ethyl) ester, 171
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid (tert-
butylcarbonyloxymethyl) ester, 172
(E)-2-(styrylcarbamoyl-naphthalen-1-yl-methyl)-1,3,2-dioxaphosphorinan-
e 2- oxide, 173
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid
bis-(2- dimethylamino-ethyl) ester, 174
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid bis-
(diethylaminocarbonylmethyl) ester, 175
(E)-(styrylcarbamoyl)-naphthalen-1-yl-methyl-phosphonic acid
bis-(2-tert- butylcarbonylthioethyl) ester, 176
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 177
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid
(2-dimethylaminoethyl) ester, 178
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (2-aminoethyl)
ester, 179
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid
(2-diethylamino-2-oxo- ethyl) ester, 180
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 181
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 182
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(2-diethylamino-2-oxo-ethyl) ester, 183
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 184
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
[(methylcarbonyloxy)-methyl] ester, 185
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
[(isopropoxycarbonyloxy)-methyl] ester, 186
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 187
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-phosphonic acid, 188
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 189
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 190
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 191
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid, 192
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid, 193
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 194
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 195
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 196
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 197
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 198
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 199
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 200
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 201
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 202
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 203
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 204
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 205
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-methyl-phosphinic acid (tert-butylcarbonyloxymethyl) ester,
206
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 207
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 208
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 209
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 210
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 211
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 212
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 213
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 214
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 215
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 216
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 217
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 218
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 219
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 220
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 221
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 222
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 223
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-phosphonic acid bis-(tert-butylcarbonyloxymethyl) ester,
224
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 225
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 226
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 227
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 228
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 229
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 230
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 231
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 232
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 233
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 234
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 235
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 236
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 237
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 238
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 239
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 240
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 241
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-phosphonic acid (tert-butylcarbonyloxymethyl) ester, 242
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 243
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 244
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 245
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
246
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
247 (E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 248
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 249
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
250
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 251
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
252
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
253
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 254
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 255
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 256
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 257
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
258 (E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 259
(E)-2-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-ylvinylcarbamoyl)-
- methyl]-1,3,2-dioxaphosphorinane 2-oxide, 260
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
- vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 261
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 262
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 263
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 264
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 265
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 266
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 267
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 268
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 269
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 270
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 271
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 272
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 273
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 274
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 275
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 276
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 277
(E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-
methyl]-phosphonic acid (isopropyloxycarbonyloxymethyl) ester, 278
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-trifluoromethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 279
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-methoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 280
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,6-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 281
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl)
ester, 282
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-phenyl)-vinylcarbam-
oyl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl)
ester, 283
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 284
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 285
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-bromo-phenyl)-vinylcarbamo-
yl]- methyl} phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
286
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,3-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 287
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
288
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-bromo-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
289
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dimethoxy-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 290
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,5-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 291
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester,
292 (E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 293
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-amino-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
294
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 295
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 296
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 297
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 298
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 299
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 300
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid, 301
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid, 302
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 303
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 304
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 305
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 306
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, 307
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 308
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid, 309
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-phosphonic acid, 310
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 311
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 312
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 313
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 314
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 315
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 316
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)
ester, 317
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-
butylcarbonyloxymethyl) ester, 318
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 319
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 320
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 321
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 322
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
bis-(tert-butylcarbonyloxymethyl) ester, 323
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 324
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid bis-(tert-butylcarbonyloxymethyl)
ester, 325
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-phosphonic acid bis-(tert-
butylcarbonyloxymethyl) ester, 326
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 327
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 328
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 329
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 330
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(tert-butylcarbonyloxymethyl) ester, 331
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
332
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
333
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-phosphonic acid (tert-
butylcarbonyloxymethyl) ester, 334
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 335
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 336
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 337
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 338
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 339
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 340
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-
vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide, 341
(E)-2-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
- phenyl)-vinylcarbamoyl]-methyl}-1,3,2-dioxaphosphorinane 2-oxide,
342
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 343
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-3-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 344
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-chloro-4-fluoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 345
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-fluoro-5-chloro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 346
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dibromo-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester, 347
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
348
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(2-cyano-phenyl)-vinylcarbamo-
yl]- methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl) ester,
and 349
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-vinylcarbamoyl]-methyl}-phosphonic acid
(isopropyloxycarbonyloxymethyl) ester.
[0041] The present invention is further directed to a process for
preparing a compound of Formula (I) selected from the group
consisting of: [0042]
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarba-
moyl]-methyl}-phosphonic acid, [0043]
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarba-
moyl]-methyl}-methyl-phosphinic acid, [0044] 164
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarba-
moyl]-methyl}-methyl-phosphinic acid, [0045] 181
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarba-
moyl]-methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
[0046] 185
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylc-
arbamoyl]-methyl}-phosphonic acid
[(isopropoxycarbonyloxy)-methyl]ester, [0047] 201
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarba-
moyl]-methyl}-phosphonic acid, [0048] 255
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarba-
moyl]-methyl}-phosphonic acid (tert-butylcarbonyloxymethyl) ester,
and [0049] 291
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarba-
moyl]-methyl}-phosphonic acid (isopropyloxycarbonyloxymethyl)
ester.
Discussion of Process Improvements
[0050] Scheme B depicts a reaction system whereby lithium complexes
with the phosphonoyl .alpha.-methylene of a Compound B1, making the
position amenable for reaction with isocyanate, thus enabling
coupling of Compound B2 with a Compound B3 in the solvent THF.
However, the reaction yield for Compound B5 was about 45% due to
the formation of a urea impurity Compound B6 from the precursor
intermediate Compound B4, thus providing an opportunity to develop
a more efficient synthesis amenable to large scale production.
##STR00007##
[0051] As described in the literature, the reaction yield between a
vinyl isocyanate and various Grignard or organolithium species may
be increased by using a less-coordinating, less-polar solvent
system such as a toluene/ether solvent/co-solvent mixture in place
of a toluene/THF system, thus reducing the formation of a urea
byproduct resulting from an excess amount of the isocyanate further
reacting with the desired amide product (Kuramochi K, Watanabe H
and Kitahara T, Synthetic Study on Oximidines: A Concise Synthesis
of (Z)-Enamides, Synlett, 2000, 397-399). However, Kuramochi, et
al. neither suggests using a mono-solvent system nor using a
substoichiometric amount of the isocyanate to increase the yield of
the desired product and provide the potential for an elegant,
direct crystallization.
[0052] In the process of the present invention, we reasoned that
Kuramochi's yield was increased by the use of less-coordinating,
less-polar solvents in a solvent/co-solvent system. Although such a
solvent/co-solvent system is not employed in the present invention,
we replaced the solvent THF used in the method of synthesis
disclosed in U.S. Patent Publication 2005/0176769 with the solvent
toluene and increased the yield of the desired product Compound B5
from about 45% to a higher yield of about 57%.
[0053] Further, to obtain Compound B5 with reduced Compound B6 and
other polymeric urea byproduct impurities resulting from isocyanate
substitution via Compound B7, we also reduced the amount of
isocyanate Compound B3 with respect to Compound B1, using 0.8
equivalents of Compound B3 and 1 equivalent of Compound B1. With
these two improvements, Compound B5 was then able to be isolated as
a solid by subsequent direct crystallization from a solvent mixture
(for example, using a mixture of EtOAc and heptane) in a yield of
from about 60% to about 65% with a purity of greater than about
97%.
[0054] Thus, a discovery of the present invention is that, when the
isocyanate is present in a substoichiometric amount and the
substituted organometallic species is present in the mono-solvent
toluene, the yield of the desired Compound B5 is improved by
minimizing the formation of Compound B6 and other polymeric urea
byproducts. Moreover, direct crystallization of the final product
Compound B5 is thus made possible, enabling an efficient synthesis
amenable to large scale production.
[0055] Scheme C depicts a reaction system wherein TMSBr in pyridine
solution was used to dealkylate the phosphinic acid ethyl ester
Compound B5, making the position amenable for hydrolysis to obtain
the compound of Formula (Ia). However, the reaction yield for the
compound of Formula (Ia) was only about 60%, thus providing another
opportunity to optimize the process.
##STR00008##
[0056] As described in the literature, the use of TMSBr in place of
chlorotrimethylsilane (TMSCl) for dealkylating neat phosphonic acid
dialkyl esters to the corresponding phosphonic acid may provide an
improved reaction yield (McKenna C E, Higa M T, Cheung N H and
McKenna M-C, The Facile Dealkylation of Phosphonic Acid Dialkyl
Esters by Bromotrimethylsilane, Tetrahedron Letters, 1977, 2,
155-158).
[0057] Although McKenna shows an increase in reaction yield as a
result of the use of TMSBr over TMSCl, there is no suggestion that
a solvent used in the reaction system could have an effect on
yield. Moreover, since McKenna's showing is regarding a neat
phosphonic acid dialkyl ester, there is no suggestion that the
reaction system could be operative for a phosphinic acid alkyl
ester or that the use of a solvent and TMSBr for reaction with such
a phosphinic acid could increase the yield.
[0058] In the process of the present invention, TMSBr was reacted
with a phosphinic acid alkyl ester in an ACN solution. As a result,
the yield of the compound of Formula (Ia) was increased to a range
of from about 83% to about 95%; an improvement over previously
described yields. While not wishing to be bound by theory,
Applicants propose that, although the use of TMSBr over another
reagent, such as TMSCl, has been shown to improve phosphonic acid
reaction yield from the dialkyl esters, a discovery of the present
invention is that, additionally, the use of a solvent such as ACN
may act as an accelerant, thus making the TMSBr considerably more
reactive.
[0059] The process of the present invention is also directed to
preparing the compound of Formula (Ia) (Compound 17 hereinabove)
and a salt thereof:
##STR00009##
according to Scheme D, comprising the steps of:
##STR00010## ##STR00011##
[0060] An example of the present invention includes an amount of
Compound B1 in a range of from about 1.2 equivalents to about 1
equivalent and an amount of Compound B3 in a range of from about 1
equivalent to about 0.8 equivalents according to said first
ratio.
[0061] An example of the present invention includes TMSBr in a
range of about 2.5:1 TMSBr:Compound B5 to about 2:1 TMSBr:Compound
B5, according to said second ratio, and pyridine is present in a
range of about 1:1 TMSBr:pyridine to about 1:2 TMSBr:pyridine
according to said third ratio.
[0062] An example of the present invention includes a process
wherein in the third ratio, TMSBr and pyridine are about 1:2
TMSBr:pyridine.
[0063] An example of the present invention includes TMSBr in a
range of about 2.5:1 TMSBr:Compound B5 to about 2:1 TMSBr:Compound
B5, according to said second ratio, wherein pyridine is not
present.
CHEMICAL DEFINITIONS & NOMENCLATURE
[0064] Bond lines drawn into a ring system from a substituent
variable indicate that the substituent may be attached to any of
the substitutable ring atoms.
[0065] As used herein, the following terms are intended to have the
following definitions. The definitions herein may specify that a
chemical term has an indicated formula. The particular formula
provided is not intended to limit the scope of the invention, but
is provided as an illustration of the term. The scope of the per se
definition of the term is intended to include the plurality of
variations expected to be included by one of ordinary skill in the
art. Chemical terms are to be read from right to left, wherein the
right-most group is attached to the core molecule and the left-most
group is the terminal group. The formula (s) illustrating a term
are to be read from left to right, wherein the left-most group is
attached to the core molecule, as indicated by the dash, and the
right-most group is the terminal group.
[0066] The term "C.sub.1-8alkyl" means a saturated aliphatic
branched or straight-chain hydrocarbon radical or linking group
having from 1 up to 8 carbon atoms in a linear or branched
arrangement, wherein the radical is derived by the removal of one
hydrogen atom from a carbon atom and the linking group is derived
by the removal of one hydrogen atom from each of two carbon atoms
in the chain. The term "C.sub.1-8alkyl" also includes a
"C.sub.1-6alkyl" and "C.sub.1-4alkyl" radical or linking group
having from 1 up to 6 carbon atoms and 1 up to 4 carbon atoms
respectively, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,
2-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl,
2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl,
3-octyl and the like. Alkyl radicals may be attached to a core
molecule via a terminal carbon atom or via a carbon atom within the
chain. Similarly, substituent variables may be attached to an alkyl
linking group when allowed by available valences.
[0067] The term "C.sub.2-6alkenyl" means an alkyl radical or
linking group having from 2 up to 6 carbon atoms in a linear or
branched arrangement having at least one carbon-carbon double bond.
The term "C.sub.2-6alkenyl" also includes a "C.sub.2-4alkenyl"
radical or linking group having from 2 up to 4 carbon atoms, such
as ethenyl (also referred to as vinyl), iso-propenyl, allyl (also
referred to as propenyl), propylidene and the like.
[0068] The term "C.sub.2-6alkynyl" means an alkyl radical or
linking group having from 2 up to 6 carbon atoms in a linear or
branched arrangement having at least one carbon-carbon triple bond.
The term "C.sub.2-8alkynyl" also includes a "C.sub.2-4alkynyl"
radical or linking group having from 2 up to 4 carbon atoms, such
as ethynyl, propynyl and the like.
[0069] The term "C.sub.1-6alkoxy" means an alkyl radical or linking
group having from 1 up to 6 carbon atoms in a linear or branched
arrangement, wherein the radical or linking group is attached
through an oxygen linking atom, as in the formula:
--O--C.sub.1-6alkyl. The term "C.sub.1-6alkoxy" also includes a
"C.sub.2-6alkoxy" and "C.sub.1-4alkoxy" radical or linking group
having from 2 up to 6 carbon atoms and from 1 up to 4 carbon atoms
respectively, such as methoxy, ethoxy, propoxy, butoxy and the
like. An alkoxy radical may be attached to a core molecule and
further substituted as a linking group where indicated.
[0070] The term "cycloalkyl" means a saturated or partially
unsaturated cyclic hydrocarbon ring system radical. The term
"cycloalkyl" also includes a C.sub.3-8cycloalkyl,
C.sub.3-10cycloalkyl, C.sub.5-6cycloalkyl, C.sub.5-8cycloalkyl,
C.sub.5-12cycloalkyl, C.sub.9-13cycloalkyl or benzofused cycloalkyl
ring system radical and the like, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl,
indanyl, 9H-fluorenyl, 1,2,3,4-tetrahydro-naphthalenyl,
acenaphthenyl, adamantanyl and the like.
[0071] The term "benzofused cycloalkyl" means a
C.sub.3-12cycloalkyl ring system radical having a benzene ring
fused on the ring system on adjacent carbons. Examples of
benzofused cycloalkyl in compounds representative of the present
invention include a benzofused cycloalkyl ring system radical and
the like, such as 1H-indenyl, indanyl and the like.
[0072] The term "aryl" means an unsaturated aromatic hydrocarbon
ring system radical. Aryl ring systems include phenyl,
naphthalenyl, azulenyl, anthracenyl and the like. Examples of aryl
in compounds representative of the present invention include phenyl
or naphthalenyl.
[0073] The term "hetero", when used as a prefix for a ring system,
refers to the replacement of at least one carbon atom member in the
ring system with a heteroatom selected from N, O, S, S(O), or
SO.sub.2. A hetero ring may have 1, 2, 3 or 4 carbon atom members
replaced by a nitrogen atom. Alternatively, a ring may have 1, 2 or
3 nitrogen atom members and 1 oxygen or sulfur atom member.
Alternatively, a ring may have 1 oxygen or sulfur atom member.
Alternatively, up to two adjacent ring members may be heteroatoms,
wherein one heteroatom is nitrogen and the other heteroatom is
selected from N, S or O.
[0074] The term "heterocyclyl" means a saturated or partially
unsaturated "hetero" ring system radical. Heterocyclyl ring systems
include azetidinyl, 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl,
pyrrolidinyl, 1,3-dioxolanyl, 2-imidazolinyl (also referred to as
4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, tetrazolyl, tetrazolidinyl, piperidinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, azepanyl, hexahydro-1,4-diazepinyl,
hexahydro-1,4-oxazepanyl, tetrahydro-furanyl, tetrahydro-thienyl,
tetrahydro-pyranyl, tetrahydro-pyridazinyl and the like.
[0075] The term "heterocyclyl" also includes a benzofused
heterocyclyl ring system radical and the like, such as indolinyl
(also referred to as 2,3-dihydro-indolyl), benzo[1,3]dioxolyl,
2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-benzofuranyl,
1,2-dihydro-phthalazinyl and the like.
[0076] The term "benzofused heterocyclyl" means a heterocyclyl ring
system radical having a benzene ring fused on the ring system on
adjacent carbons. Examples of benzofused-heterocyclyl in compounds
representative of the present invention include benzo[1,3]dioxolyl
and 2,3-dihydro-indolyl.
[0077] The term "heteroaryl" means a monovalent, unsaturated
aromatic "hetero" ring system radical. Heteroaryl ring systems
include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and
the like.
[0078] The term "heteroaryl" also includes a benzofused heteroaryl
ring system radical and the like, such as indolizinyl, indolyl,
azaindolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl,
azaindazolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl,
benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,
4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl and the like.
[0079] The term "benzofused heteroaryl" means a heteroaryl ring
system radical having a benzene ring fused on the ring system on
adjacent carbons. Examples of benzofused heteroaryl in compounds
representative of the present invention include indazolyl, indolyl,
benzofuranyl and benzoimidazolyl.
[0080] The term "C.sub.1-6alkoxycarbonyloxy" means a radical of the
formula: --O--C(O)--O--C.sub.1-6alkyl.
[0081] The term "(C.sub.1-6)alkylaminocarbonyl" means a radical of
the formula: --C(O)--NH--C.sub.1-6alkyl.
[0082] The term "di(C.sub.1-6)alkylaminocarbonyl" means a radical
of the formula: --C(O)--N(C.sub.1-6alkyl).sub.2.
[0083] The term "C.sub.1-6alkylcarbonyloxy" means a radical of the
formula: --O--C(O)--C.sub.1-6alkyl.
[0084] The term "C.sub.1-6alkylcarbonylthio" means a radical of the
formula: --S--C(O)--C.sub.1-6alkyl.
[0085] The term "C.sub.1-6alkylthio" means a radical of the
formula: --S--C.sub.1-8alkyl.
[0086] The term "aryl(C.sub.1-6)alkyl" means a radical of the
formula: --C.sub.1-6alkyl-aryl.
[0087] The term "aryl(C.sub.2-6)alkenyl" means a radical of the
formula: --C.sub.2-6alkenyl-aryl.
[0088] The term "aryloxy" means a radical of the formula:
--O-aryl.
[0089] The term "halogen" or "halo" means the group chloro, bromo,
fluoro or iodo.
[0090] The term "heteroaryloxy" means a radical of the formula:
--O-heteroaryl.
[0091] The term "nitro" means a radical of the formula:
--NO.sub.2.
[0092] The term "oxo" means a radical of the formula: --C(O).
[0093] The term "ureido" means a linking group of the formula:
--NH--C(O)--NH--.
[0094] The term "substituted" means the independent replacement of
one or more hydrogen atoms within a radical with that amount of
substituents allowed by available valences.
[0095] In general, IUPAC nomenclature rules are used herein.
Compound Forms
[0096] The term "about," whether used explicitly or not in
reference to a quantitative expression given herein, means that
every quantity given herein qualified with the term or otherwise is
meant to refer both to the actual given value and the approximation
to such given value that would reasonably be inferred based on the
ordinary skill in the art, including approximations due to
experimental and/or measurement conditions for such given
value.
[0097] The term "form" means, in reference to compounds of the
present invention, such may exist as, without limitation, a salt,
stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate,
hydrate, ester, prodrug or metabolite form. The present invention
encompasses all such compound forms and mixtures thereof.
[0098] The term "isolated form" means, in reference to compounds of
the present invention, such may exist in an essentially pure state
such as, without limitation, an enantiomer, a racemic mixture, a
geometric isomer (such as a cis or trans stereoisomer), a mixture
of geometric isomers, and the like. The present invention
encompasses all such compound forms and mixtures thereof.
[0099] The compounds of the invention may be present in the form of
pharmaceutically acceptable salts. For use in medicines, the
"pharmaceutically acceptable salts" of the compounds of this
invention refer to non-toxic acidic/anionic or basic/cationic salt
forms.
[0100] Suitable salt forms include acid addition salts which may,
for example, be formed by mixing a solution of the compound
according to the invention with a solution of an acid such as
acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid,
fumaric acid, glycolic acid, hydrochloric acid, maleic acid,
malonic acid, phosphoric acid, saccharinic acid, succinic acid,
sulphuric acid, tartaric acid, trifluoroacetic acid and the
like.
[0101] Furthermore when the compounds of the present invention
carry an acidic moiety, suitable salts thereof may include alkali
metal salts, e.g. sodium or potassium salts; alkaline earth metal
salts, e.g. calcium or magnesium salts; and salts formed with
suitable organic ligands, e.g. quaternary ammonium salts.
[0102] Thus, representative salts include the following: acetate,
adipate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium, camsylate (or
camphorsulphonate), carbonate, chloride, choline (or cholinate),
clavulanate, citrate, dihydrochloride, edetate, fumarate,
gluconate, glutamate, glyconate, hydrabamine, hydrobromine,
hydrochloride, iodide, isothionate, lactate, malate, maleate,
malonate, mandelate, mesylate, nitrate, oleate, pamoate, palmitate,
phosphate/diphosphate, saccharinate, salicylate, stearate, sulfate,
succinate, tartrate, tosylate, trichloroacetate, trifluoroacetate
and the like.
[0103] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
3.sup.rd Edition, John Wiley & Sons, 1999. The protecting
groups may be removed at a convenient subsequent stage using
methods known in the art. The scope of the present invention
encompasses all such protected compound forms and mixtures
thereof.
[0104] The invention includes compounds of various isomers and
mixtures thereof. The term "isomer" refers to compounds that have
the same composition and molecular weight but differ in physical
and/or chemical properties. Such substances have the same number
and kind of atoms but differ in structure. The structural
difference may be in constitution (geometric isomers) or in an
ability to rotate the plane of polarized light (optical
isomers).
[0105] The term "stereoisomer" refers to isomers that have the same
molecular formula and the same sequence of covalently bonded atoms
but a different spatial orientation.
[0106] The term "optical isomer" means isomers of identical
constitution that differ only in the spatial arrangement of their
groups. Optical isomers rotate the plane of polarized light in
different directions. The term "optical activity" means the degree
to which an optical isomer rotates the plane of polarized
light.
[0107] The term "racemate" or "racemic mixture" means an equimolar
mixture of two enantiomeric species, wherein each of the isolated
species rotates the plane of polarized light in the opposite
direction such that the mixture is devoid of optical activity.
[0108] The term "enantiomer" means an isomer having a
nonsuperimposable mirror image. The term "diastereomer" means
stereoisomers that are not enantiomers.
[0109] The term "chiral" means a molecule which, in a given
configuration, cannot be superimposed on its mirror image. This is
in contrast to achiral molecules which can be superimposed on their
mirror images.
[0110] The two distinct mirror image versions of the chiral
molecule are also known as levo (left-handed), abbreviated L, or
dextro (right-handed), abbreviated D, depending on which way they
rotate polarized light. The symbols "R" and "S" represent the
configuration of groups around a stereogenic carbon atom(s).
[0111] The term "geometric isomer" means isomers that differ in the
orientation of substituent atoms in relationship to a carbon-carbon
double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
Substituent atoms (other than hydrogen) on each side of a
carbon-carbon double bond may be in an E or Z configuration
according to priority rules. In the "E" configuration, the
substituents having higher priority are on opposite sides in
relationship to the carbon-carbon double bond. In the "Z"
configuration, the substituents having higher priority are oriented
on the same side in relationship to the carbon-carbon double
bond.
[0112] Substituent atoms (other than hydrogen) attached to a ring
system may be in a cis or trans configuration. In the "cis"
configuration, the substituents are on the same side in
relationship to the plane of the ring; in the "trans"
configuration, the substituents are on opposite sides in
relationship to the plane of the ring. Compounds having a mixture
of "cis" and "trans" species are designated "cis/trans".
[0113] The isomeric descriptors ("R," "S," "E," and "Z") indicate
atom configurations and are intended to be used as defined in the
literature.
[0114] The compounds of the invention may be prepared as individual
isomers by either isomer-specific synthesis or resolved from an
isomeric mixture. Conventional resolution techniques include
combining the free base (or free acid) of each isomer of an
isomeric pair using an optically active acid (or base) to form an
optically active salt (followed by fractional crystallization and
regeneration of the free base), forming an ester or amide of each
of the isomers of an isomeric pair by reaction with an appropriate
chiral auxiliary (followed by fractional crystallization or
chromatographic separation and removal of the chiral auxiliary), or
separating an isomeric mixture of either an intermediate or a final
product using various well known chromatographic methods.
[0115] Furthermore, compounds of the present invention may have one
or more polymorph or amorphous crystalline forms and, as such, are
intended to be included in the scope of the invention. In addition,
some of the compounds may form solvates with water (i.e., hydrates)
or common organic solvents (e.g., organic esters such as ethanolate
and the like) and, as such, are also intended to be encompassed
within the scope of this invention.
SYNTHETIC EXAMPLES
[0116] The terms used in describing the invention are commonly used
and known to those skilled in the art. When used herein, the
following abbreviations have the indicated meanings:
TABLE-US-00002 Abbreviation Meaning Cpd compound h/hr(s)/min(s)
hour(s)/min(s) EtOAc ethyl acetate HPLC High Pressure Liquid
Chromatography MeOH methanol n-BuLi n-butyl lithium RT/rt/r.t. room
temperature THF tetrahydrofuran TMSBr trimethylsilyl bromide
Example 1
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbam-
oyl]-methyl}-methyl-phosphinic acid Formula (Ia)
##STR00012##
[0117] Step 1. 3-(3,4-difluoro-phenyl)-acryloyl azide (Cpd 1b)
[0118] 3,4-difluorocinnamic acid Compound 1a (70.00 g, 380 mmol)
was added to a three-neck 2 L flask equipped with an overhead
mechanical stirrer, an internal temperature probe, and a nitrogen
inlet. After flushing with nitrogen, toluene (700 mL) was added and
the slurry was cooled with stirring to 10.degree. C. Triethylamine
(TEA) (53.0 mL, 380 mmol) was then added and the reaction became
homogeneous. After cooling to 5.degree. C., diphenylphosphoryl
azide (81.9 mL, 380 mmol) was added over 15 minutes. The reaction
was allowed to warm to room temperature and stirred for 15 h. When
the reaction was complete, as shown by HPLC, sodium bicarbonate (3%
aqueous solution, 650 mL) was added and the mixture was stirred
vigorously. After separating the layers, the aqueous layer was
extracted with EtOAc (2.times.700 mL). The first two organic
extracts contained significant amounts of Compound 1b, as shown by
HPLC. The extracts were combined and filtered through a plug of
magnesium sulfate (173 g) on the top of the plug and silica gel
(345 g) at the bottom of the plug. The plug was washed with 2 L of
50% EtOAc/hexanes. The filtrate was concentrated under reduced
pressure at a temperature not exceeding 32.degree. C. Further
removal of residual solvent under high vacuum provided Compound 1b
as a yellow solid (77.7 g, 98% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.58 (d, J=15.9 Hz, 2H), 7.3 (m, 1H), 7.2 (m,
1H), 7.14 (m, 1H), 6.26 (d, J=16.0 Hz, 1H).
Step 2. diethyl methylphosphonite (Cpd 1d)
##STR00013##
[0120] To a 3-neck 2 L round bottom flask equipped with a
thermocouple, mechanical stirrer, addition funnel, and nitrogen
inlet were added pentane (590 mL), ethanol (108.4 mL, 1.860 mol),
and N,N-dimethylaniline (235.8 mL, 1.860 mol). The mixture was
cooled to 0.degree. C. and stirred under a nitrogen atmosphere.
Methylphosphorous dichloride Compound 1c (100 g, 855 mmol) was
added through the addition funnel over a period of about 1.8 h.
After the addition was complete, the mixture was stirred for an
additional 1.5 h at 0.degree. C. The reaction mixture was then
filtered through a 600 mL medium porosity frit. The filter cake was
washed with 1.5 L of pentane. The cloudy filtrate was concentrated
on a rotary evaporator at 0.degree. C. and then distilled. The
product Compound 1d, which was collected between 300 and 400 mTorr
at a distillation head temperature of 20-22.degree. C., was
isolated as a clear oil (70.89 g, 62%) and used directly in the
next step.
Step 3. (5-chloro-benzo[b]thiophen-3-ylmethyl)-methyl-phosphinic
acid ethyl ester (Cpd B1)
##STR00014##
[0121] Into a 3 neck 2 L round bottom flask equipped with a
nitrogen inlet, reflux condenser, heating mantle and thermocouple
probe was added 3-bromomethyl-5-chloro-benzo[b]thiophene Compound
1e (46.45 g, 178 mmol). After flushing with nitrogen, toluene (464
mL) and diethylmethyl phosphonite Compound 1d (41.6 mL, 275 mmol)
were added. The mixture was heated from room temperature to reflux
over 25 minutes and then held at reflux for 1 h. The mixture was
allowed to cool and additional diethylmethyl phosphonite Compound
1d (2.1 mL, 13.8 mmol) was added. The reaction was warmed back to
reflux from 60.degree. C. After 15 minutes at reflux, the mixture
was allowed to cool and stirred at room temperature overnight.
After filtration, the reaction mixture was concentrated under
reduced pressure (60.degree. C. on a rotary evaporator for 2 h and
then over a period of 48 h under high vacuum at room temperature).
The product Compound B1 was obtained as an oil contaminated with
small amounts of residual toluene and a phosphorous containing
impurity (55.0 g, 107%) and was used without additional
purification in the next step. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.79 (d, J=1.9 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.46 (d,
J=3.7 Hz, 1H), 7.33 (dd, J=8.6, 2.0 Hz, 1H), 4.04 (m, 2H), 3.35 (m,
2H), 1.42 (d, J=13.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H).
Step 4. 1,2-difluoro-4-(2-isocyanato-vinyl)-benzene (Cpd B3)
##STR00015##
[0123] To a 3-neck, 1 L round bottom flask equipped with stir bar,
thermometer, heating mantle and condenser was added Compound 1b
(39.84 g, 190.5 mmol). After a nitrogen gas flush, toluene (500 mL)
was added and the reaction flask was warmed to 67.degree. C. over
18 minutes. As off-gassing commenced, the temperature was further
raised to 78.degree. C. over a period of 6 minutes to control the
off-gassing. The mixture was carefully heated to 100.degree. C.
over 17 minutes and then held at that temperature for an additional
45 minutes until off-gassing ceased. The mixture containing
Compound B3 in toluene was cooled to -78.degree. C. for use in the
next step.
Step 5.
{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylca-
rbamoyl]-methyl}-methyl-phosphinic acid ethyl ester (Cpd B5)
##STR00016##
[0125] A 1-neck, 3 L round bottom flask equipped with a stir bar,
nitrogen inlet and thermocouple probe and containing Compound B1
(55.0 g, 190.5 mmol) was flushed with nitrogen. Toluene (500 mL)
was added and the solution was cooled to -70.degree. C. n-BuLi (2.5
M in hexanes, 76.2 mL, 190.5 mmol) was then added over a period of
12 minutes. After stirring for an additional 15 minutes, the
pre-cooled solution of Compound B3 was added over 12 minutes via
cannula. The homogeneous mixture was stirred for 1.25 h and
saturated aqueous ammonium chloride (600 mL) was added to the
mixture. The reaction mixture was allowed to warm to room
temperature. Water (400 mL) was added and the layers were mixed and
separated. The aqueous layer was extracted two additional times
with EtOAc (1.times.1 L and 1.times.500 mL). The combined organic
layers were dried over magnesium sulfate, then filtered and
concentrated. The resulting residue was taken up in 65%
EtOAc/hexanes, loaded onto a plug of silica gel (590 g) and washed
with 65% EtOAc/hexanes (3 L). The eluent was concentrated to a
yellow foam which contained a mixture of the diastereomers of
Compound B5 (65.04 g, crude yield 73%). MS (electrospray): exact
mass calculated for C.sub.21H.sub.19ClF.sub.2NO.sub.3PS, 469.05;
m/z found, 470.2 [MH].sup.+.
[0126] Diastereomer #1: .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
10.33 (d, J=10.2 Hz, 1H), 8.15 (d, J=3.7 Hz, 1H), 7.92 (d, J=1.8
Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), .about.7.35 (dd, J=8.6, 1.8 Hz,
1H), .about.7.2 (dd, J=14.7, 10.4 Hz, 1H), 6.8 to 7.0 (m, 3H), 6.03
(d, J=14.7 Hz, 1H), 5.09 (d, J=22.8 Hz, 1H) 4.2 to 4.4 (m, 2H),
1.82 (d, J=14.4 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H).
[0127] Diastereomer #2: .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
9.97 (d, J=10.3 Hz, 1H), 8.05 (d, J=3.1 Hz, 1H), 7.92 (d, J=1.8 Hz,
1H), 7.84 (d, J=8.6 Hz, 1H), .about.7.35 (dd, J=8.6, 1.8 Hz, 1H),
.about.7.2 (dd, J=14.7, 10.4 Hz, 1H), 6.8 to 7.0 (m, 3H), 6.10 (d,
J=14.7 Hz, 1H), 4.99 (d, J=16.2 Hz, 1H), 4.1 to 4.2 (m, 2H), 1.60
(d, J=14.0 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H).
Step 6.
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vin-
ylcarbamoyl]-methyl}-methyl-phosphinic acid Formula (Ia)
##STR00017##
[0129] Into a 3 L round bottom flask equipped with stir bar,
nitrogen inlet and thermocouple probe was added Compound B5 (60.0
g, 127.7 mmol). After a thorough nitrogen gas flush, pyridine (51.6
mL, 638.5 mmol) and then trimethylsilyl bromide (42.1 mL, 319.2
mmol) were added. The mixture was stirred at room temperature under
nitrogen for a period of about 3.6 h, until HPLC analysis indicated
the reaction was complete. The mixture was concentrated under
reduced pressure at 40.degree. C., then taken up three times in
methanol (900 mL, 900 mL, 650 mL) and concentrated each time at
40.degree. C. on a rotary evaporator. The residue was stirred
mechanically for 2.5 h in 1 N HCl (800 mL) to provide a white
solid. Alternatively, the crude was first taken up in MeOH (180 mL)
and then dripped into mechanically stirred 1 N HCl (1350 mL) to
provide the white solid.
[0130] The slurry was filtered through a medium frit and washed
with 1 N HCl (200 mL) and then water (500 mL). The cake was dried
under high vacuum overnight to provide a solid (114.82 g) that was
taken up in methanol (171 mL) and stirred mechanically for 3 h. The
resulting slurry was cooled to 0.degree. C. and stirred for an
additional hour, then filtered through a medium frit and washed
with 75 mL of methanol. The cake was dried a second time under high
vacuum to provide a solid (42.09 g) that was again taken up in
methanol (200 mL) and stirred mechanically for 2 h. The resulting
slurry was passed through a medium frit and washed with 75 mL of
methanol. The filter cake was dried a third time under high vacuum
to provide the title compound of Formula (Ia) (35.47 g, calculated
yield 59%) as a 1:1 adduct with MeOH (93% product, 7% MeOH by
weight, 32.99 g of product). MS (electrospray): exact mass
calculated for C.sub.19H.sub.15ClF.sub.2NO.sub.3PS, 441.02; m/z
found, 442.1 [MH].sup.+. .sup.1H NMR (400 MHz, DMSO): .delta. 10.53
(d, J=10.1 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.01 (d, J=3.4 Hz, 1H),
7.98 (d, J=2.0 Hz, 1H), 7.52 (ddd, J=12.4, 7.8, 2.0 Hz, 1H), 7.43
(dd, J=8.5, 2.0 Hz, 1H), 7.42 (dd, J=14.5, 10.2 Hz, 1H), 7.32 (m,
1H), 7.23 (m, 1H), 6.19 (d, J=14.7 Hz, 1H), 4.79 (d, J=21.0 Hz,
1H), 1.42 (d, J=14.6 Hz, 3H).
Example 2
(E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbam-
oyl]-methyl}-methyl-phosphinic acid ethyl ester (Cpd B5)
##STR00018##
[0132] Into a 12 L 4-necked round-bottomed flask equipped with a
mechanical stirrer, thermocouple and nitrogen inlet was added
n-BuLi (2.5 M in hexanes, 560 mL, 1.40 mol, 1.28 equivalent) and
toluene (1.5 L). The solution was cooled to -72.degree. C. and
Compound B1 (396.4 g, 93% Wt %, 1.28 mol) in toluene (2.8 L) was
added drop wise over 1.5 hours. After stirring for 1 hour at -60 to
-70.degree. C., a cold solution (-66.degree. C.) of Compound B3
(183.0 g, 95% Wt %, 0.96 mol, 0.75 Eq.) in toluene (1.75 L) was
added slowly over a period of 2.5 hours at a temperature of
-72.degree. C. through a cannula. The reaction mixture was left
overnight to warm to approximately 20.degree. C. At a temperature
of 20.degree. C., the reaction mixture was quenched with 4 L of
saturated NH.sub.4Cl (to convert the bis-amide Compound B6 to the
product Compound B5). The layers were separated and the organic
layer was washed with water (5.0 L), and then exchanged under
reduced pressure with EtOAc (5-7 L). Evaporation of the EtOAc
yielded a yellow solid as a mixture of the desired product Compound
B5, Compound B1 and polymeric impurities. Crystallization of the
crude from ethyl acetate (1.7 L) and heptane (4.0 L) furnished
Compound B5 (282 g. 62% yield based on the presence of Compound B6)
as an off white solid.
[0133] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations and
modifications as come within the scope of the following claims and
their equivalents.
[0134] Throughout this application, various publications are cited.
These publications are hereby incorporated by reference in their
entirety into this application to describe more fully the state of
the art to which this invention pertains.
* * * * *