U.S. patent application number 13/101926 was filed with the patent office on 2012-05-03 for carbamoyl compounds as dgat1 inhibitors 190.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Jonas Gunnar BARLIND, Udo Andreas BAUER, Alan Martin BIRCH, Roger John BUTLIN, Clive GREEN, Ragnar HOVLAND, Petra JOHANNESSON, Jan Magnus JOHANSSON, Andrew LEACH, Alexander Tobias NOESKE, Annika Ulrika PETERSSON.
Application Number | 20120108602 13/101926 |
Document ID | / |
Family ID | 40427160 |
Filed Date | 2012-05-03 |
United States Patent
Application |
20120108602 |
Kind Code |
A1 |
BAUER; Udo Andreas ; et
al. |
May 3, 2012 |
Carbamoyl Compounds as DGAT1 Inhibitors 190
Abstract
DGAT-1 inhibitor compounds of formula (1),
pharmaceutically-acceptable salts and pro-drugs thereof are
described, together with pharmaceutical compositions, processes for
making them and their use in treating, for example, obesity
##STR00001## wherein, for example, Ring A is optionally substituted
2,6-pyrazindiyl; X is .dbd.0; Ring B is optionally substituted
1,4-phenylene; Y.sub.1 is a direct bond or --O--; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane; Ring C is
optionally substituted (4-6C)cycloalkane, (7-10C)bicycloalkane,
(8-12C)tricycloalkane, phenylene or pryidindiyl; L is a direct bond
or --O--; p is 0, 1 or 2 and when p is 1 or 2 R.sup.A1 and R.sup.A2
are each independently hydrogen or (1-4C)alkyl; Z is carboxy or a
mimic or bioisostere thereof.
Inventors: |
BAUER; Udo Andreas;
(Molndal, SE) ; BARLIND; Jonas Gunnar; (Molndal,
SE) ; JOHANNESSON; Petra; (Molndal, SE) ;
JOHANSSON; Jan Magnus; (Molndal, SE) ; NOESKE;
Alexander Tobias; (Molndal, SE) ; PETERSSON; Annika
Ulrika; (Molndal, SE) ; BIRCH; Alan Martin;
(Cheshire, GB) ; BUTLIN; Roger John; (Cheshire,
GB) ; GREEN; Clive; (Cheshire, GB) ; LEACH;
Andrew; (Cheshire, GB) ; HOVLAND; Ragnar;
(Sodertalje, SE) |
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
40427160 |
Appl. No.: |
13/101926 |
Filed: |
May 5, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12339349 |
Dec 19, 2008 |
7994179 |
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13101926 |
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61015397 |
Dec 20, 2007 |
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Current U.S.
Class: |
514/252.11 ;
514/255.05; 514/255.06; 514/354; 514/355; 544/230; 544/357;
544/405; 544/406; 546/316; 546/323 |
Current CPC
Class: |
C07D 213/81 20130101;
A61P 3/00 20180101; C07D 213/82 20130101; A61P 3/10 20180101; C07D
401/10 20130101; C07D 241/24 20130101; A61P 43/00 20180101; C07D
403/10 20130101; C07D 401/04 20130101; A61P 3/04 20180101 |
Class at
Publication: |
514/252.11 ;
544/406; 514/255.06; 544/405; 514/255.05; 546/316; 514/355;
546/323; 514/354; 544/230; 544/357 |
International
Class: |
A61K 31/4965 20060101
A61K031/4965; C07D 401/04 20060101 C07D401/04; A61K 31/497 20060101
A61K031/497; A61P 3/10 20060101 A61P003/10; A61K 31/4425 20060101
A61K031/4425; C07D 213/81 20060101 C07D213/81; A61K 31/4418
20060101 A61K031/4418; C07D 403/10 20060101 C07D403/10; C07D 241/24
20060101 C07D241/24; C07D 213/89 20060101 C07D213/89 |
Claims
1. A compound of formula (I), or a pharmaceutically-acceptable
salt, or pro-drug thereof, ##STR00308## wherein Ring A is
2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each
optionally substituted on an available carbon atom by one or two
substituents independently selected from linear (1-3C)alkyl,
(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino
and cyano; X is .dbd.O or .dbd.S; Ring B is 1,4-phenylene or Ring B
is a di-linked (excluding links via the same or adjacent atoms)
ring selected from pyridindiyl, furandiyl, thiophendiyl,
pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl,
isothiazoldiyl and pyrazoldiyl; each optionally substituted on an
available carbon atom by one or two substituents independently
selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl,
(2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1
is a direct bond between Ring B and Ring C or Y.sub.1 is --O--,
--S-- or --NRa-- wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spino-ring system is formed and Ring C is tri-linked;
Ring C is a di-linked (excluding links via the same or adjacent
atoms) ring or ring system chosen from (4-6C)cycloalkane,
(7-10C)bicycloalkane and (8-12C)tricycloalkane each optionally
substituted on an available carbon atom, including the ring carbon
atom bearing the Z-containing group, by one substituent selected
from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; or Ring C is a di-linked (excluding links
via the same or adjacent atoms) ring selected from phenylene,
pryidindiyl, piperidinediyl N-linked to Y.sub.1, piperazinediyl,
furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl,
imidazoldiyl, isoxazoldiyl, isothiazoldiyl, pyrazoldiyl and
azabicyclo[3.1.0]hexanediyl; each optionally substituted on an
available carbon atom by up to four substituents independently
selected from fluoro, chloro, bromo, cyano, (1-4C)alkyl,
(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; L is a direct bond to
Ring C, --O--, --S-- or --NH--; p is 0 (when L is a direct bond), 1
or 2 and when p is 1 or 2 R.sup.AI and R.sup.A2 are each
independently hydrogen or (1-4C)alkyl or R.sup.A1 and R.sup.A2 are
linked together to form a (3-6C)spiroalkyl ring; Z is carboxy or a
mimic or bioisostere thereof, hydroxy or --CONRbRc wherein Rb and
Rc are independently selected from hydrogen and (1-4C)alkyl, which
(1-4C)alkyl group may be optionally substituted by carboxy or a
mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms; with the proviso that the compound
(4-(4-(6-carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid is
excluded.
2. A compound of formula (I), or a pharmaceutically-acceptable
salt, or pro-drug thereof, as claimed in claim 1, wherein Ring A is
2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each
optionally substituted on an available carbon atom by one or two
substituents independently selected from linear (1-3C)alkyl,
(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino
and cyano; X is .dbd.O or .dbd.S; Ring B is 1,4-phenylene or Ring B
is a di-linked (excluding links via the same or adjacent atoms)
ring selected from pyridindiyl, furandiyl, thiophendiyl,
pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl,
isothiazoldiyl and pyrazoldiyl; each optionally substituted on an
available carbon atom by one or two substituents independently
selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl,
(2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1
is a direct bond between Ring B and Ring C or Y.sub.1 is --O--,
--S-- or --NRa-- wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spiro-ring system is formed; Ring C is a di-linked
(excluding links via the same or adjacent atoms) ring or ring
system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and
(8-12C)tricycloalkane each optionally substituted on an available
carbon atom, including the ring carbon atom bearing the
Z-containing group, by one substituent selected from hydroxy,
(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; or Ring C is
a di-linked (excluding links via the same or adjacent atoms) ring
selected from phenylene, pryidindiyl, piperidinediyl N-linked to
Y.sub.1, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by up to four substituents independently selected from fluoro,
chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; L is a direct bond to Ring C, --O--, --S--
or --NH--; p is 0, 1 or 2 and when p is 1 R.sup.A1 and R.sup.A2 are
each independently hydrogen or (1-4C)alkyl or R.sup.A1 and R.sup.A2
are linked together to form a (3-6C)spiroalkyl ring; Z is carboxy
or a mimic or bioisostere thereof, hydroxy or --CONRbRc wherein Rb
and Rc are independently selected from hydrogen and (1-4C)alkyl,
which (1-4C)alkyl group may be optionally substituted by carboxy or
a mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms.
3. A compound of formula (IA) as claimed in claim 1 or 2, or a
pharmaceutically-acceptable salt, or pro-drug thereof, ##STR00309##
wherein X, Ring A, Ring B, Y.sub.1, p, R.sup.AI, R.sup.A2 and Z are
as defined in claim 1 or 2.
4. A compound of formula (IB) as claimed in claim 1 or 2, or a
pharmaceutically-acceptable salt, or pro-drug thereof, ##STR00310##
wherein X, Ring A, Ring B, Y.sub.1, p, R.sup.A1, R.sup.A2 and Z are
as defined in claim 1 or 2.
5. A compound as claimed in any one of claims 1 to 4, or a
pharmaceutically-acceptable salt, or pro-drug thereof, wherein X is
.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two substituents independently
selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-2C)alkoxy, methoxymethyl, amino and cyano; Ring B is
1,4-phenylene optionally substituted on an available carbon atom by
one or two substituents independently selected from halo, amino,
cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and
(1-4C)alkoxy-(1-4C)alkyl; Ring C is 1,4-cyclohexane; n is 0 and
Y.sub.1 is a direct bond or Y.sub.1 is --O--; L is a direct bond; p
is 1 and R.sup.A1 and R.sup.A2 are each hydrogen; Z is carboxy, a
tetrazole group, --C(O)NHS(O).sub.2Me, hydroxy or --CONRbRc wherein
Rb and Rc are independently selected from hydrogen and (1-4C)alkyl,
which (1-4C)alkyl group may be optionally substituted by carboxy;
and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,
(1-4C)alkyl or (1-4C)alkoxy containing group defined above may be
optionally substituted by up to 3 fluoro atoms.
6. A compound as claimed in any one of claims 1 to 5, or a
pharmaceutically-acceptable salt, or pro-drug thereof, wherein Ring
A is 2,6-pyrazindiyl optionally substituted on an available carbon
atom by one or two linear (1-3C)alkyl substituents.
7. A compound as claimed in claim 1 or 2 selected from
{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceti-
c acid;
3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}c-
yclohexyl)-phenyl]pyrazine-2-carboxamide;
6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-
-2-carboxamide;
N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}ac-
etyl)-2-methylalanine;
6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-c-
arboxamide;
(trans-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}c-
yclohexyl)acetic acid;
{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid;
{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid and
{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid;
2-((1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydros-
piro[cyclohexane-1,1'-indene]-4-yl)acetic acid;
(1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cycl-
ohexane-1,1'-indene]-4-carboxylic acid;
2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)--
2-methylpropanoic acid
2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)acet-
ic acid;
(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-a-
zabicyclo[3.1.0]hexane-6-carboxylic acid;
6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethyl-
pyrazine-2-carboxamide;
4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic
acid; Methyl
trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohe-
xanecarboxylate;
trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecar-
boxylic acid; or a pharmaceutically-acceptable salt of any of
these.
8. A compound as claimed in any one of claims 1 to 6 wherein a
pro-drug thereof is an ester of a carboxy group selected from a
(1-6C)alkyl ester, a (1-6C)alkoxymethyl ester, a
(1-6C)alkanoyloxymethyl ester, a phthalidyl ester, a
(3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl ester, a
1,3-dioxolan-2-ylmethyl ester, a (1-6C)alkoxycarbonyloxyethyl
ester, an aminocarbonylmethyl ester and a mono- or
di-N-((1-6C)alkyl) version of an aminocarbonylmethyl ester.
9. A compound as claimed in any one of claims 1 to 6 wherein a
mimic or bioisostere of a carboxy group is selected from
--SO.sub.3H, --S(O).sub.2NHR.sup.13, S(O).sub.2NHC(O)R.sup.13,
--CH.sub.2S(O).sub.2R.sup.13, --C(O)NHS(O).sub.2R.sup.13,
--C(O)NHOH, --C(O)NHCN, --CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--P(O)(OH).sub.2 and groups of sub-formula (.omega.-(i') below
##STR00311## ##STR00312## ##STR00313## ##STR00314## wherein where p
in sub-formula (k) is 1 or 2, R.sup.27 and R.sup.28 are
independently selected from hydrogen, hydroxy, (1-6C)alkoxy, thiol,
(1-6C)alkylthio, --C(O)R.sup.29, --S(O)R.sup.30,
--SO.sub.2R.sup.31, --NR.sup.32R.sup.33, --NHCN, halogen and
trihalomethyl, where R.sup.29, R.sup.30 and R.sup.31 are
--OR.sup.34, (1-6C)alkyl, --NR.sup.32R.sup.33 or trihalomethyl,
R.sup.32 and R.sup.33 are independently selected from hydrogen,
(1-6C)alkyl, --SO.sub.2R.sup.34 and --COR.sup.35, where R.sup.35 is
(1-6C)alkyl or trihalomethyl, and R.sup.34 is hydrogen, (1-6C)alkyl
or trihalomethyl and R.sup.13 is selected from hydrogen,
(1-6C)alkyl, hydroxy, halo, amino, cyano, ((1-3 C)alkyl)CONH--,
carboxy, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, carbamoyl,
N-((1-6C)alkyl)carbamoyl, halo((1-6C)alkyl) (such as
trifluoromethyl), (1-6C)alkylsulphonyl or (1-6C)alkylsulphinyl.
10. A compound according to any one of claims 1 to 9 or a
pharmaceutically-acceptable salt, or pro-drug thereof for use as a
medicament.
11. A compound, or a pharmaceutically-acceptable salt, or pro-drug
thereof, for use as a medicament as claimed in claim 10 for
treating diabetes mellitus and/or obesity in a warm-blooded animal
such as a human being.
12. The use of a compound according to any one of claims 1 to 9, or
a pharmaceutically-acceptable salt, or pro-drug thereof, in the
manufacture of a medicament for use in the production of an
inhibition of DGAT-1 activity in a warm-blooded animal such as a
human being.
13. The use of a compound of formula (I), or a
pharmaceutically-acceptable salt, or pro-drug thereof, as claimed
in claim 12, in the manufacture of a medicament for use in the
treatment of diabetes mellitus and/or obesity in a warm-blooded
animal such as a human being.
14. A method of treating diabetes mellitus and/or obesity in a
warm-blooded animal, such as a human being, in need of such
treatment which comprises administering to said animal an effective
amount of a compound according to any one of claims 1 to 9, or a
pharmaceutically-acceptable salt, or pro-drug thereof.
15. A pharmaceutical composition which comprises a compound of
formula (I) as claimed in any one of claims 1 to 9, or a
pharmaceutically-acceptable salt, or pro-drug thereof, in
association with a pharmaceutically-acceptable excipient or
carrier.
Description
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of Application No. 61/015,397 US filed on 20 Dec.
2007.
[0002] The present invention relates to compounds which inhibit
acetyl CoA(acetyl coenzyme A): diacylglycerol acyltransferase
(DGAT1) activity, processes for their preparation, pharmaceutical
compositions containing them as the active ingredient, methods for
the treatment of disease states associated with DGAT1 activity, to
their use as medicaments and to their use in the manufacture of
medicaments for use in the inhibition of DGAT1 in warm-blooded
animals such as humans. In particular this invention relates to
compounds useful for the treatment of type II diabetes, insulin
resistance, impaired glucose tolerance and obesity in warm-blooded
animals such as humans, more particularly to the use of these
compounds in the manufacture of medicaments for use in the
treatment of type II diabetes, insulin resistance, impaired glucose
tolerance and obesity in warm-blooded animals such as humans.
[0003] Acyl CoA:diacylglycerol acyltransferase (DGAT) is found in
the microsomal fraction of cells. It catalyzes the final reaction
in the glycerol phosphate pathway, considered to be the main
pathway of triglyceride synthesis in cells by facilitating the
joining of a diacylglycerol with a fatty acyl CoA, resulting in the
formation of triglyceride. Although it is unclear whether DGAT is
rate-limiting for triglyceride synthesis, it catalyzes the only
step in the pathway that is committed to producing this type of
molecule [Lehner & Kuksis (1996) Biosynthesis of
triacylglycerols. Prog. Lipid Res. 35: 169-201].
[0004] Two DGAT genes have been cloned and characterised. Both of
the encoded proteins catalyse the same reaction although they share
no sequence homology. The DGAT1 gene was identified from sequence
database searches because of its similarity to acyl CoA:cholesterol
acyltransferase (ACAT) genes. [Cases et al (1998) Identification of
a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key
enzyme in triacylglycerol synthesis. Proc. Natl. Acad. Sci. USA 95:
13018-13023]. DGAT1 activity has been found in many mammalian
tissues, including adipocytes.
[0005] Because of the previous lack of molecular probes, little is
known about the regulation of DGAT1. DGAT1 is known to be
significantly up-regulated during adipocyte differentiation.
[0006] Studies in gene knockout mice has indicated that modulators
of the activity of DGAT1 would be of value in the treatment of type
II diabetes and obesity. DGAT1 knockout (DgatI.sup.-/-) mice, are
viable and capable of synthesizing triglycerides, as evidenced by
normal fasting serum triglyceride levels and normal adipose tissue
composition. Dgat1.sup.-/- mice have less adipose tissue than
wild-type mice at baseline and are resistant to diet-induced
obesity. Metabolic rate is .about.20% higher in DgatI.sup.-/- mice
than in wild-type mice on both regular and high-fat diets [Smith et
al (2000) Obesity resistance and multiple mechanisms of
triglyceride synthesis in mice lacking DGAT. Nature Genetics 25:
87-90]. Increased physical activity in Dgat1.sup.-/- mice partially
accounts for their increased energy expenditure. The Dgat1.sup.-/-
mice also exhibit increased insulin sensitivity and a 20% increase
in glucose disposal rate. Leptin levels are 50% decreased in the
Dgat1.sup.-/- mice in line with the 50% decrease in fat mass.
[0007] When Dgat1.sup.-/- mice are crossed with ob/ob mice, these
mice exhibit the ob/ob phenotype [Chen et al (2002) Increased
insulin and leptin sensitivity in mice lacking acyl
CoA:diacylglycerol acyltransferase J. Clin. Invest. 109:1049-1055]
indicating that the Dgat1.sup.-/- phenotype requires an intact
leptin pathway. When Dgat1.sup.-/- mice are crossed with Agouti
mice a decrease in body weight is seen with normal glucose levels
and 70% reduced insulin levels compared to wild type, agouti or
ob/ob/Dgat1.sup.-/- mice.
[0008] Transplantation of adipose tissue from Dgat1.sup.-/- mice to
wild type mice confers resistance to diet-induced obesity and
improved glucose metabolism in these mice [Chen et al (2003)
Obesity resistance and enhanced glucose metabolism in mice
transplanted with white adipose tissue lacking acyl
CoA:diacylglycerol acyltransferase J. Clin. Invest. 111:
1715-1722].
[0009] International Application WO 2006/064189 describes certain
oxadiazole compounds which inhibit DGAT-1. However, there remains a
need for further DGAT-1 inhibitors possessing desirable properties,
such as, for example, pharmaco-kinetic/dynamic and/or
physico-chemical and/or toxicological profiles.
[0010] Accordingly, the present invention provides a compound of
formula (I), or a pharmaceutically-acceptable salt, or pro-drug
thereof,
##STR00002##
wherein Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or
2,6-pyridindiyl, each optionally substituted on an available carbon
atom by one or two substituents independently selected from linear
(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy,
methoxymethyl, amino and cyano;
X is .dbd.O or .dbd.S;
[0011] Ring B is 1,4-phenylene or Ring B is a di-linked (excluding
links via the same or adjacent atoms) ring selected from
pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by one or two substituents independently selected from halo,
amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1 is a direct bond
between Ring B and Ring C or Y.sub.1 is --O--, --S-- or --NRa--
wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spino-ring system is formed and Ring C is tri-linked;
Ring C is a di-linked (excluding links via the same or adjacent
atoms) ring or ring system chosen from (4-6C)cycloalkane,
(7-10C)bicycloalkane and (8-12C)tricycloalkane each optionally
substituted on an available carbon atom, including the ring carbon
atom bearing the Z-containing group, by one substituent selected
from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; or Ring C is a di-linked (excluding links
via the same or adjacent atoms) ring selected from phenylene,
pryidindiyl, piperidinediyl N-linked to Y.sub.1, piperazinediyl,
furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl,
imidazoldiyl, isoxazoldiyl, isothiazoldiyl, pyrazoldiyl and
azabicyclo[3.1.0]hexanediyl; each optionally substituted on an
available carbon atom by up to four substituents independently
selected from fluoro, chloro, bromo, cyano, (1-4C)alkyl,
(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; L is a direct bond to
Ring C, --O--, --S-- or --NH--; p is 0 (when L is a direct bond), 1
or 2 and when p is 1 or 2 R.sup.A1 and R.sup.A2 are each
independently hydrogen or (1-4C)alkyl or R.sup.A1 and R.sup.A2 are
linked together to form a (3-6C)spiroalkyl ring; Z is carboxy or a
mimic or bioisostere thereof, hydroxy or --CONRbRc wherein Rb and
Rc are independently selected from hydrogen and (1-4C)alkyl, which
(1-4C)alkyl group may be optionally substituted by carboxy or a
mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms; with the proviso that the compound
(4-(4-(6-Carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid is
excluded.
[0012] In one embodiment there is provided a compound of formula
(I), or a pharmaceutically-acceptable salt, or pro-drug
thereof,
##STR00003##
wherein Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or
2,6-pyridindiyl, each optionally substituted on an available carbon
atom by one or two substituents independently selected from linear
(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy,
methoxymethyl, amino and cyano;
X is .dbd.O or .dbd.S;
[0013] Ring B is 1,4-phenylene or Ring B is a di-linked (excluding
links via the same or adjacent atoms) ring selected from
pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by one or two substituents independently selected from halo,
amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1 is a direct bond
between Ring B and Ring C or Y.sub.1 is --O--, --S-- or --NRa--
wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spiro-ring system is formed; Ring C is a di-linked
(excluding links via the same or adjacent atoms) ring or ring
system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and
(8-12C)tricycloalkane each optionally substituted on an available
carbon atom, including the ring carbon atom bearing the
Z-containing group, by one substituent selected from hydroxy,
(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; or Ring C is
a di-linked (excluding links via the same or adjacent atoms) ring
selected from phenylene, pryidindiyl, piperidinediyl N-linked to
Y.sub.1, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by up to four substituents independently selected from fluoro,
chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; L is a direct bond to Ring C, --O--, --S--
or --NH--; p is 0, 1 or 2 and when p is 1 R.sup.A1 and R.sup.A2 are
each independently hydrogen or (1-4C)alkyl or R.sup.A1 and R.sup.A2
are linked together to form a (3-6C)spiroalkyl ring; Z is carboxy
or a mimic or bioisostere thereof, hydroxy or --CONRbRc wherein Rb
and Rc are independently selected from hydrogen and (1-4C)alkyl,
which (1-4C)alkyl group may be optionally substituted by carboxy or
a mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms.
[0014] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt, or pro-drug
thereof, as in any embodiment hereinbefore or hereinafter, with the
proviso that the compound
(4-(4-(6-carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid is
excluded.
[0015] A further feature is any of the above three embodiments with
the proviso that any of the specific Examples herein are
individually disclaimed. For example, a further feature is any of
the above embodiments with the proviso that any of the compounds
selected from the following are individually disclaimed,
{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceti-
c acid;
3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}c-
yclohexyl)-phenyl]pyrazine-2-carboxamide;
6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-
-2-carboxamide;
N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}ac-
etyl)-2-methylalanine;
6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-c-
arboxamide;
(trans-4-{-4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}-
cyclohexyl)acetic acid;
{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid;
{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid and
{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid; or a pharmaceutically-acceptable salt of any of these.
[0016] It will be understood that Ring B and Ring C as a di-linked
ring or ring system excludes links to Y.sub.1 and L via the same or
adjacent atoms (i.e. -1,1- and -1,2-links are excluded).
[0017] It will be understood that Ring B is numbered clockwise
towards Ring C from the dominant heteroatom in Ring B.
[0018] When p is 0 the group Z is connected directly to direct bond
L (i.e. Z is connected directly to Ring C and L is not --O--, --S--
or --NH--); when p is 2 the group Z is connected as follows to
L;
##STR00004##
[0019] As used herein, the reference to carboxylic acid mimic or
bioisostere includes groups as defined in The Practice of Medicinal
Chemistry, Wermuth C. G. Ed.: Academic Press: New York, 1996, p
203. Particular examples of such groups include --SO.sub.3H,
--S(O).sub.2NHR.sup.13, S(O).sub.2NHC(O)R.sup.13,
--CH.sub.2S(O).sub.2R.sup.13, --C(O)NHS(O).sub.2R.sup.13,
--C(O)NHOH, --C(O)NHCN, --CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--P(O)(OH).sub.2 and groups of sub-formula (a)-(i') below
##STR00005## ##STR00006## ##STR00007## ##STR00008##
where p in sub-formula (k) is 1 or 2, R.sup.27 and R.sup.28 are
independently selected from hydrogen, hydroxy, (1-6C)alkoxy, thiol,
(1-6C)alkylthio, --C(O)R.sup.29, --S(O)R.sup.30,
--SO.sub.2R.sup.31, --NR.sup.32R.sup.33, --NHCN, halogen and
trihalomethyl, where R.sup.29, R.sup.30 and R.sup.31 are
--OR.sup.34, (1-6C)alkyl, --NR.sup.32R.sup.33 or trihalomethyl,
R.sup.32 and R.sup.33 are independently selected from hydrogen,
(1-6C)alkyl, --SO.sub.2R.sup.34 and --COR.sup.35, where R.sup.35 is
(1-6C)alkyl or trihalomethyl, and R.sup.34 is hydrogen, (1-6C)alkyl
or trihalomethyl and R.sup.13 is selected from hydrogen,
(1-6C)alkyl, hydroxy, halo, amino, cyano, ((1-3C)alkyl)CONH--,
carboxy, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, carbamoyl,
N-((1-6C)alkyl)carbamoyl, halo((1-6C)alkyl) (such as
trifluoromethyl), (1-6C)alkylsulphonyl or (1-6C)alkylsulphinyl.
Particular examples of R.sup.27 or R.sup.28 are hydroxy.
[0020] Particular carboxylic acid mimic or bioisosteres are a
tetrazole group of sub-formula (b) --C(O)NHS(O).sub.2Me.
[0021] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups, unless otherwise stated,
and references to individual alkyl groups such as "propyl" are
specific for the straight chain version only. An analogous
convention applies to other generic terms. Unless otherwise stated
the term "alkyl" advantageously refers to chains with 1-10 carbon
atoms, suitably from 1-6 carbon atoms, preferably 1-4 carbon
atoms.
[0022] In this specification the term "alkoxy" means an alkyl group
as defined hereinbefore linked to an oxygen atom.
[0023] Particular values include for linear (1-3C)alkyl, methyl,
ethyl and propyl; for (1-4C)alkyl, methyl, ethyl, propyl and butyl;
for (2-3C)alkenyl, ethenyl; for (2-3C)alkynyl, ethynyl; for
(1-2C)alkoxy, methoxy and ethoxy; for (1-4C)alkoxy, methoxy, ethoxy
and propoxy; for --CONRbRc, --CONH.sub.2 and --CONHMe.
[0024] Particular values include for any carbon atom in a linear
(1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy group that
may be optionally substituted by up to 3 fluoro atoms, a group such
as, for example, trifluoromethyl, difluoromethyl, difluoromethoxy
or trifluoromethoxy.
[0025] When p in formula (I) is 1 and R.sup.A1 and R.sup.A2 are
linked together to form a (3-6C)spiroalkyl ring, such a ring may
be, for example, a spiro-linked cyclopropyl or cyclobutyl.
[0026] When p in formula (I) is 2 and R.sup.A1 and R.sup.A2 are
linked together to form a (3-6C)spiroalkyl ring, such a ring may
be, for example, a spino-linked cyclopropyl or cyclobutyl.
[0027] When Ring C is a di-linked (excluding links via the same or
adjacent atoms) (4-6C)cycloalkane ring this includes
1,4-cyclohexane, 1,3-cyclopentane and 1,3-cyclobutane.
[0028] When Ring C is (7-10C)bicycloalkanediyl this includes
bicyclo[2.2.1]heptanediyl, 1,4-bicyclo[2.2.2]octanediyl,
1,5-bicyclo[3.2.1]octanediyl, 1,5-bicyclo[3.2.2]nonanediyl and
1,5-bicyclo[3.3.2]decanediyl.
[0029] When Ring C is (8-12C)tricycloalkanediyl this includes
adamantanediyl.
[0030] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined` or `defined hereinbefore` the said group encompasses the
first occurring and broadest definition as well as each and all of
the particular definitions for that group.
[0031] If not stated elsewhere, suitable optional substituents for
a particular group are those as stated for similar groups
herein.
[0032] A compound of formula (I) may form stable acid or basic
salts, and in such cases administration of a compound as a salt may
be appropriate, and pharmaceutically acceptable salts may be made
by conventional methods such as those described following.
[0033] Suitable pharmaceutically-acceptable salts include acid
addition salts such as methanesulfonate, tosylate,
.alpha.-glycerophosphate, fumarate, hydrochloride, citrate,
maleate, tartrate and (less preferably) hydrobromide. Also suitable
are salts formed with phosphoric and sulfuric acid. In another
aspect suitable salts are base salts such as Group (I) (alkali
metal) salt, Group (II) (alkaline earth) metal salt, an organic
amine salt for example triethylamine, morpholine,
N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine,
N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl
d-glucamine and amino acids such as lysine. There may be more than
one cation or anion depending on the number of charged functions
and the valency of the cations or anions.
[0034] Other suitable pharmaceutically-acceptable salts are
mentioned in, for example, Berge et al. (J. Pharm. Sci., 1977, 66,
1-19) and/or Handbook of Pharmaceutical Salts: Properties,
Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).
[0035] A feature of the invention relates to a compound of the
invention, such as any one of the Examples, in the free acid or
free base form or as a pharmaceutically acceptable salt thereof.
Such forms may be prepared by standard techniques.
[0036] However, to facilitate isolation of the salt during
preparation, salts which are less soluble in the chosen solvent may
be preferred whether pharmaceutically-acceptable or not.
[0037] Within the present invention it is to be understood that a
compound of the formula (I) or a salt thereof may exhibit the
phenomenon of tautomerism and that the formulae drawings within
this specification can represent only one of the possible
tautomeric forms. It is to be understood that the invention
encompasses any tautomeric form which inhibits DGAT1 activity and
is not to be limited merely to any one tautomeric form utilised
within the formulae drawings.
[0038] Pro-drugs of compounds of formula (I), and salts thereof,
are also within the scope of the invention.
[0039] Various forms of prodrugs are known in the art. For examples
of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et
al. (Academic Press, 1985); b) A Textbook of Drug Design and
Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter
5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191
(1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,
285 (1988); and
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
[0040] Examples of such prodrugs are in vivo cleavable esters of a
compound of the invention. An in vivo cleavable ester of a compound
of the invention containing a carboxy group is, for example, a
pharmaceutically-acceptable ester which is cleaved in the human or
animal body to produce the parent acid. Suitable
pharmaceutically-acceptable esters for carboxy include (1-6C)alkyl
esters, for example methyl or ethyl; (1-6C)alkoxymethyl esters, for
example methoxymethyl; (1-6C)alkanoyloxymethyl esters, for example
pivaloyloxymethyl; phthalidyl esters;
(3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters, for example
1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for
example 5-methyl-1,3-dioxolan-2-ylmethyl;
(1-6C)alkoxycarbonyloxyethyl esters, for example
1-methoxycarbonyloxyethyl; aminocarbonylmethyl esters and mono- or
di-N-((1-6C)alkyl) versions thereof, for example
N,N-dimethylaminocarbonylmethyl esters and
N-ethylaminocarbonylmethyl esters; and may be formed at any carboxy
group in the compounds of this invention. An in vivo cleavable
ester of a compound of the invention containing a hydroxy group is,
for example, a pharmaceutically-acceptable ester which is cleaved
in the human or animal body to produce the parent hydroxy group.
Suitable pharmaceutically acceptable esters for hydroxy include
(1-6C)alkanoyl esters, for example acetyl esters; and benzoyl
esters wherein the phenyl group may be substituted with aminomethyl
or N-- substituted mono- or di-(1-6C)alkyl aminomethyl, for example
4-aminomethylbenzoyl esters and 4-N,N-dimethylaminomethylbenzoyl
esters.
[0041] Particular prodrugs are (1-4C)alkyl esters of the carboxylic
acid in compounds of formula (I), (IA) and/or (IB).
[0042] It will be appreciated by those skilled in the art that
certain compounds of formula (I) contain asymmetrically substituted
carbon and/or sulfur atoms, and accordingly may exist in, and be
isolated in, optically-active and racemic forms. Some compounds of
formula (I) may exhibit polymorphism. It is to be understood that
the present invention encompasses any racemic, optically-active,
polymorphic or stereoisomeric form, or mixtures thereof, which form
possesses properties useful in the inhibition of DGAT1 activity, it
being well known in the art how to prepare optically-active forms
(for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active
starting materials, by chiral synthesis, by enzymatic resolution,
by biotransformation, or by chromatographic separation using a
chiral stationary phase) and how to determine efficacy for the
inhibition of DGAT1 activity by the standard tests described
hereinafter.
[0043] It is also to be understood that certain compounds of the
formula (I) and salts thereof can exist in solvated as well as
unsolvated forms such as, for example, hydrated forms. It is to be
understood that the invention encompasses all such solvated forms
which inhibit DGAT1 activity.
[0044] As stated before, a range of compounds are provided that
have good DGAT1 inhibitory activity. They have good physical and/or
pharmacokinetic properties in general.
[0045] Thus, in one embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof,
##STR00009##
wherein Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or
2,6-pyridindiyl, each optionally substituted on an available carbon
atom by one or two substituents independently selected from linear
(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy,
methoxymethyl, amino and cyano;
X is .dbd.O or .dbd.S;
[0046] Ring B is 1,4-phenylene or Ring B is a di-linked (excluding
links via the same or adjacent atoms) ring selected from
pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by one or two substituents independently selected from halo,
amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1 is a direct bond
between Ring B and Ring C or Y.sub.1 is --O--, --S-- or --NRa--
wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spiro-ring system is formed and Ring C is tri-linked;
Ring C is a di-linked (excluding links via the same or adjacent
atoms) ring or ring system chosen from (4-6C)cycloalkane,
(7-10C)bicycloalkane and (8-12C)tricycloalkane each optionally
substituted on an available carbon atom, including the ring carbon
atom bearing the Z-containing group, by one substituent selected
from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; or Ring C is a di-linked (excluding links
via the same or adjacent atoms) ring selected from phenylene,
pryidindiyl, piperidinediyl N-linked to Y.sub.1, piperazinediyl,
furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl,
imidazoldiyl, isoxazoldiyl, isothiazoldiyl, pyrazoldiyl and
azabicyclo[3.1.0]hexanediyl; each optionally substituted on an
available carbon atom by up to four substituents independently
selected from fluoro, chloro, bromo, cyano, (1-4C)alkyl,
(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; L is a direct bond to
Ring C, --O--, --S-- or --NH--; p is 0, 1 or 2 and when p is 1
R.sup.A1 and R.sup.A2 are each independently hydrogen or
(1-4C)alkyl or R.sup.A1 and R.sup.A2 are linked together to form a
(3-6C)spiroalkyl ring; Z is carboxy or a mimic or bioisostere
thereof, hydroxy or --CONRbRc wherein Rb and Rc are independently
selected from hydrogen and (1-4C)alkyl, which (1-4C)alkyl group may
be optionally substituted by carboxy or a mimic or bioisostere
thereof; and wherein any carbon atom in a linear (1-3C)alkyl,
(1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing group defined
above may be optionally substituted by up to 3 fluoro atoms; with
the proviso that the compound
(4-(4-(6-Carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid is
excluded.
[0047] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt, or pro-drug
thereof wherein
Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each
optionally substituted on an available carbon atom by one or two
substituents independently selected from linear (1-3C)alkyl,
(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino
and cyano;
X is .dbd.O or .dbd.S;
[0048] Ring B is 1,4-phenylene or Ring B is a di-linked (excluding
links via the same or adjacent atoms) ring selected from
pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by one or two substituents independently selected from halo,
amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Y.sub.1 is a direct bond
between Ring B and Ring C or Y.sub.1 is --O--, --S-- or --NRa--
wherein Ra is hydrogen or (1-4C)alkyl; Y.sub.2 is
--(CH.sub.2).sub.r-- wherein r is 2 or 3, and Y.sub.2 is linked at
the same carbon atom as Y.sub.1 in Ring C and Y.sub.2 is linked at
an adjacent carbon atom to Y.sub.1 in Ring B; n is 0 or n is 1 when
Y.sub.1 is a direct bond between Ring B and Ring C and when Ring B
is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or
6-membered spiro-ring system is formed; Ring C is a di-linked
(excluding links via the same or adjacent atoms) ring or ring
system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and
(8-12C)tricycloalkane each optionally substituted on an available
carbon atom, including the ring carbon atom bearing the
Z-containing group, by one substituent selected from hydroxy,
(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; or Ring C is
a di-linked (excluding links via the same or adjacent atoms) ring
selected from phenylene, pryidindiyl, piperidinediyl N-linked to
Y.sub.1, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,
thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and
pyrazoldiyl; each optionally substituted on an available carbon
atom by up to four substituents independently selected from fluoro,
chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; L is a direct bond to Ring C, --O--, --S--
or --NH--; p is 0, 1 or 2 and when p is 1 R.sup.A1 and R.sup.A2 are
each independently hydrogen or (1-4C)alkyl or R.sup.A1 and R.sup.A2
are linked together to form a (3-6C)spiroalkyl ring; Z is carboxy
or a mimic or bioisostere thereof, hydroxy or --CONRbRc wherein Rb
and Rc are independently selected from hydrogen and (1-4C)alkyl,
which (1-4C)alkyl group may be optionally substituted by carboxy or
a mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms.
[0049] In another embodiment there is provided a compound of
formula (IA), or a pharmaceutically-acceptable salt, or pro-drug
thereof,
##STR00010##
wherein X, Ring A, Ring B, Y.sub.1, p, R.sup.A1, R.sup.A2 and Z are
as defined in claim 1 or 2.
[0050] In another embodiment there is provided a compound of
formula (IB), or a pharmaceutically-acceptable salt, or pro-drug
thereof,
##STR00011##
wherein X, Ring A, Ring B, Y.sub.1, p, R.sup.A1, R.sup.A2 and Z are
as defined in claim 1 or 2.
[0051] In another embodiment there is provided a compound as
claimed in any one of claims 1 to 4, or a
pharmaceutically-acceptable salt, or pro-drug thereof, wherein X is
.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two substituents independently
selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-2C)alkoxy, methoxymethyl, amino and cyano;
Ring B is 1,4-phenylene optionally substituted on an available
carbon atom by one or two substituents independently selected from
halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Ring C is
1,4-cyclohexane; n is 0 and Y.sub.1 is a direct bond or Y.sub.1 is
--O--; L is a direct bond; p is 1 and R.sup.A1 and R.sup.A2 are
each hydrogen; Z is carboxy, a tetrazole group,
--C(O)NHS(O).sub.2Me, hydroxy or --CONRbRc wherein Rb and Rc are
independently selected from hydrogen and (1-4C)alkyl, which
(1-4C)alkyl group may be optionally substituted by carboxy; and
wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,
(1-4C)alkyl or (1-4C)alkoxy containing group defined above may be
optionally substituted by up to 3 fluoro atoms.
[0052] In another embodiment there is provided a compound as
claimed in any one of claims 1 to 5, or a
pharmaceutically-acceptable salt, or pro-drug thereof, wherein Ring
A is 2,6-pyrazindiyl optionally substituted on an available carbon
atom by one or two linear (1-3C)alkyl substituents.
[0053] The following compounds possess particular, desirable
pharmaceutical and/or physical and/or pharmacokinetic/dynamic
and/or toxicological properties and/or selective activity for
DGAT1.
[0054] A compound of formula (I), or a pharmaceutically-acceptable
salt, or pro-drug thereof,
##STR00012##
wherein Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or
2,6-pyridindiyl, each optionally substituted on an available carbon
atom by one or two substituents independently selected from linear
(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy,
methoxymethyl, amino and cyano;
X is .dbd.O or .dbd.S;
[0055] Ring B is 1,4-phenylene or Ring B is a di-linked (excluding
links via the same or adjacent atoms) pyridindiyl ring; each
optionally substituted on an available carbon atom by one or two
substituents independently selected from halo, amino, cyano,
(1-4C)alkyl, (2-3 C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and
(1-4C)alkoxy-(1-4C)alkyl; Y.sub.1 is a direct bond between Ring B
and Ring C or Y.sub.1 is --O--, --S-- or --NRa-- wherein Ra is
hydrogen or (1-4C)alkyl; n is 0; Ring C is a di-linked (excluding
links via the same or adjacent atoms) (4-6C)cycloalkane ring,
optionally substituted on an available carbon atom, including the
ring carbon atom bearing the Z-containing group, by one substituent
selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkyl; L is a direct bond to Ring C or --O--; p
is 0, 1 or 2 and when p is 1 R.sup.A1 and R.sup.A2 are each
independently hydrogen or (1-4C)alkyl; Z is carboxy or a mimic or
bioisostere thereof, hydroxy or --CONRbRc wherein Rb and Rc are
independently selected from hydrogen and (1-4C)alkyl, which
(1-4C)alkyl group may be optionally substituted by carboxy or a
mimic or bioisostere thereof; and wherein any carbon atom in a
linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy
containing group defined above may be optionally substituted by up
to 3 fluoro atoms.
[0056] In one aspect, it will be appreciated that in certain
compounds of formula (I) the Ring C substituent bearing the Z group
(or suitable replacement thereof) and the --Y.sub.1-- link are in
either a cis- or a trans-arrangement across the ring, in relation
to each other. Where appropriate the invention encompasses both the
cis- and trans-isomers. Techniques for separation of such isomers
are well known in the art.
[0057] Thus, in one aspect, when Ring C is cyclohexyl the Z
containing group and --Y.sub.1-- link are in a cis-configuration
across the cyclohexyl ring, to give a compound of formula (IA),
wherein the variables are as defined hereinbefore or
hereinafter:
##STR00013##
[0058] Thus, in one aspect, when Ring C is cyclohexyl the Z
containing group and --Y.sub.1-- link are in a trans-configuration
across the cyclohexyl ring, to give a compound of formula (IB),
wherein the variables are as defined hereinbefore or
hereinafter:
##STR00014##
[0059] References hereinbefore or hereinafter to a compound of
formula (I) are taken to apply also to compounds of formulae (IA)
and (IB).
[0060] In one embodiment of the invention there are provided
compounds of formulae (I), (IA) and (IB), in an alternative
embodiment there are provided salts, particularly
pharmaceutically-acceptable salts of compounds of formulae (I),
(IA) and (IB). In a further embodiment, there are provided
pro-drugs, particularly in-vivo cleavable esters, of compounds of
formulae (I), (IA) and (IB). In a further embodiment, there are
provided salts, particularly pharmaceutically-acceptable salts of
pro-drugs of compounds of formulae (I), (IA) and (IB).
[0061] Particular values of substituents in compounds of formulae
(I), (IA) and (IB) are as follows (such values may be used where
appropriate with any of the other values, definitions, claims or
embodiments defined hereinbefore or hereinafter). [0062] 1) X is
.dbd.O; [0063] 2) X is .dbd.S; [0064] 3) Ring A is 2,6-pyrazindiyl;
[0065] 4) Ring A is 2,6-pyrazindiyl substituted with any of the
substituents in the Examples; [0066] 5) Ring A is 2,6-pyrazindiyl
substituted with one or two (1-3C)alkyl; [0067] 6) Ring B is
1,4-phenylene; [0068] 7) Ring B is 2,5-pyridindiyl or
3,6-pyridindiyl; [0069] 8) Ring B is optionally substituted on an
available carbon atom by one or two halo substituents; [0070] 9)
Ring C is 1,4-cyclohexane (i.e. 1,4-cyclohexyl); [0071] 10) n is 0
and Y.sub.1 is a direct bond between Ring B and Ring C or Y.sub.1
is --O--; [0072] 11) Ring B and Ring C are particularly 2,4- or
2,5-furandiyl, 2,4- or 2,5-thiophendiyl, 2,4- or 2,5-pyrroldiyl,
2,4- or 2,5-oxazoldiyl, 2,4- or 2,5-thiazoldiyl, 2,4- or
2,5-imidazoldiyl, 3,4- or 3,5-isoxazoldiyl, 3,4- or
3,5-isothiazoldiyl, 3,4- or 3,5-pyrazoldiyl; [0073] 12) L is a
direct bond; [0074] 13) p is 0; [0075] 14) p is 1 and R.sup.A1 and
R.sup.A2 are each hydrogen; [0076] 15) p is 2 and R.sup.A1 and
R.sup.A2 are each hydrogen; [0077] 16) Z is carboxy, --CONRbRc
(wherein Rb and Rc are independently selected from hydrogen and
(1-4C)alkyl (which (1-4C)alkyl group may be optionally substituted
by carboxy), a tetrazole group or --C(O)NHS(O).sub.2Me; [0078] 17)
Z is carboxy; [0079] 18) a pro-drug for Z as carboxy is a
(1-6C)alkyl ester.
[0080] Thus, for example, in one embodiment there is provided a
compound of formula (I), or a pharmaceutically-acceptable salt
thereof, wherein X.dbd.O; Ring A is 2,6-pyrazindiyl optionally
substituted on an available carbon atom by one or two substituents
independently selected from linear (1-3C)alkyl, (2-3C)alkenyl,
(2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano; Ring B
is 1,4-phenylene (optionally substituted on an available carbon
atom by one or two halo substituents); n is 0 and Y.sub.1 is a
direct bond between Ring B and Ring C; p is 0 or p is 1 and
R.sup.A1 and R.sup.A2 are each hydrogen; L is a direct bond and Z
is carboxy, --CONRbRc (wherein Rb and Rc are independently selected
from hydrogen and (1-4C)alkyl (which (1-4C)alkyl group may be
optionally substituted by carboxy), a tetrazole group or
--C(O)NHS(O).sub.2Me; i.e. a compound of formula (IC), or a
pharmaceutically-acceptable salt thereof, wherein the
2,6-pyrazindiyl ring is optionally substituted on an available
carbon atom by one or two substituents independently selected from
linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy,
methoxymethyl, amino and cyano and other values are as defined
immediately above.
##STR00015##
[0081] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof, wherein
X.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two substituents independently
selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,
(1-2C)alkoxy, methoxymethyl, amino and cyano; Ring B is
1,4-phenylene (optionally substituted on an available carbon atom
by one or two halo substituents); n is 0 and Y.sub.1 is a direct
bond between Ring B and Ring C; p is 1 and R.sup.A1 and R.sup.A2
are each hydrogen; L is a direct bond and Z is carboxy or a
tetrazole group.
[0082] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof, wherein
X.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two substituents independently
selected from linear (1-3C)alkyl; Ring B is 1,4-phenylene
(optionally substituted on an available carbon atom by one or two
fluoro substituents); n is 0 and Y.sub.1 is a direct bond between
Ring B and Ring C; p is 1 and R.sup.A1 and R.sup.A2 are each
hydrogen; L is a direct bond and Z is carboxy or a tetrazole
group.
[0083] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof, wherein
X.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two methyl substituents; Ring B is
1,4-phenylene (optionally substituted on an available carbon atom
by one or two fluoro substituents); n is 0 and Y.sub.1 is a direct
bond between Ring B and Ring C; p is 1 and R.sup.A1 and R.sup.A2
are each hydrogen; L is a direct bond and Z is carboxy or a
tetrazole group.
[0084] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof, wherein
X.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two methyl substituents; Ring B is
1,4-phenylene; n is 0 and Y.sub.1 is a direct bond between Ring B
and Ring C; p is 1 and R.sup.A1 and R.sup.A2 are each hydrogen; L
is a direct bond and Z is carboxy or a tetrazole group.
[0085] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically-acceptable salt thereof, wherein
X.dbd.O; Ring A is 2,6-pyrazindiyl optionally substituted on an
available carbon atom by one or two methyl substituents; Ring B is
1,4-phenylene; n is 0 and Y.sub.1 is a direct bond between Ring B
and Ring C; p is 1 and R.sup.A1 and R.sup.A2 are each hydrogen; L
is a direct bond and Z is carboxy.
[0086] In another embodiment there is provided a compound of
formula (I), wherein X.dbd.O; Ring A is 2,6-pyrazindiyl optionally
substituted on an available carbon atom by one or two methyl
substituents; Ring B is 1,4-phenylene; n is 0 and Y.sub.1 is a
direct bond between Ring B and Ring C; p is 1 and R.sup.A1 and
R.sup.A2 are each hydrogen; L is a direct bond and Z is
carboxy.
[0087] In another embodiment there is provided a compound of
formula (I) as defined in any of the seven embodiments immediately
above, wherein the Z containing group and the --Y.sub.1-- link are
in either a cis- or a trans-arrangement across the ring, in
relation to each other.
[0088] In another embodiment there is provided a compound of
formula (I) as defined in any of the eight embodiments immediately
above wherein a pro-drug for Z as carboxy is a (1-6C)alkyl
ester.
[0089] A further feature is any of the scopes defined herein with
the proviso that specific Examples, such as Example 1, 2, 3, 4 etc.
are individually disclaimed.
[0090] Further particular compounds of the invention are each of
the Examples, each of which provides a further independent aspect
of the invention. In further aspects, the present invention also
comprises any particular compounds of the Examples or a
pharmaceutically-acceptable salt thereof (such as, for example, a
sodium, magnesium, tert-butylammonium,
tris(hydroxymethyl)methylammonium, triethanolammonium,
diethanolammonium, ethanolammonium, methylethanolammonium,
diethylammonium or nicotinamide salt).
[0091] For example, a further feature is any of the particular
compounds of the Examples or a pharmaceutically-acceptable salt
thereof, such as any compound selected from
{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceti-
c acid;
3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}c-
yclohexyl)-phenyl]pyrazine-2-carboxamide;
6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-
-2-carboxamide;
N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}ac-
etyl)-2-methylalanine;
6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-c-
arboxamide;
(trans-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}c-
yclohexyl)acetic acid;
{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid;
{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}a-
cetic acid;
{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid;
2-((1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydros-
piro[cyclohexane-1,1'-indene]-4-yl)acetic acid;
(1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cycl-
ohexane-1,1'-indene]-4-carboxylic acid;
2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)--
2-methylpropanoic acid
2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)acet-
ic acid;
(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-a-
zabicyclo[3.1.0]hexane-6-carboxylic acid;
6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethyl-
pyrazine-2-carboxamide;
4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic
acid; Methyl
trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohe-
xanecarboxylate;
trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecar-
boxylic acid; or a pharmaceutically-acceptable salt of any of
these.
[0092] In a further aspect, the present invention also comprises
any particular isomers of compounds of the Examples, such as the
cis-isomer of compounds such as Examples 1 or 2, i.e.
{cis-4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid or
3,5-dimethyl-6-[4-(cis-4-{2-[(methylsulfonyl)amino]-2-oxoethylcyc-
lohexyl)phenyl]-pyrazine-2-carboxamide or a
pharmaceutically-acceptable salt of either of these; or compounds
such as
6-{4-[cis-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-
-carboxamide;
N-({cis-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl
cyclohexyl}acetyl]-2-methylalanine;
6-{4-[cis-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-car-
boxamide;
(cis-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]p-
henyl}cyclohexyl)acetic acid;
{cis-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}ace-
tic acid;
{cis-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclo-
hexyl}acetic acid;
{cis-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid; or a pharmaceutically-acceptable salt of any of these.
[0093] A compound of formula (I) and its salts may be prepared by
any process known to be applicable to the preparation of chemically
related compounds. Such processes, when used to prepare a compound
of the formula (I), or a pharmaceutically-acceptable salt thereof,
are provided as a further feature of the invention.
[0094] In a further aspect the present invention also provides that
the compounds of the formula (I) and salts thereof, can be prepared
by the following processes, the processes of the Examples and
analogous processes (wherein all variables are as hereinbefore
defined for a compound of formula (I) unless otherwise stated) and
thereafter if necessary any protecting groups can be removed and/or
an appropriate salt formed. Any defined carboxylic acid groups may
be replaced as appropriate by a mimic or bioisostere thereof.
[0095] Variables shown in the schemes are defined or can be
interpreted in the context of the variants described herein for the
compounds of the invention. Analogous chemistry to that shown in
the schemes and Examples may be used to prepare other ring variants
and linking group options within the scope of the invention.
[0096] Also included as an aspect of the invention are the
compounds obtainable by any of the processes or Examples described
herein.
Process a)
[0097] By modifying a substituent in, or introducing a substituent
into, another compound of formula (I). Suitable methods for
converting substituents into other substituents are known in the
art. For example, an acid group may be converted into an amide
group or reduced to an alcohol group.
[0098] An amide in Ring A may be converted into a thioamide by use
of Lawesson's reagent or P.sub.2S.sub.5.
[0099] Compounds of formula (I) where, for example, Z is an
acylsulfonamide group or Z is a tetrazole may be prepared from the
corresponding carboxylic acid. The tetrazole may be introduced
early in the synthetic route via an amide (which, for primary
amides, may be converted to the nitrile by standard methods) which
is then in turn converted into a tetrazole by reaction with azide.
The tetrazole may be carried through the rest of the synthesis in
protected form, e.g. N-benzylated or N-(2-cyanoethyl)ated.
Process b)
[0100] Suzuki coupling of an appropriate iodo-, bromo- or
chloro-substituted Ring A derivative (e.g. pyrazine ester (III))
with a suitably substituted intermediate boronate compound of
formula (II) followed by conversion of the ring A ester group to
the corresponding acid by basic hydrolysis and thence to the
corresponding primary carboxamide by reaction with ammonia in the
presence of a coupling agent, for example PyBOP.
[0101] A protecting group can be removed, for example, by acid
catalysed hydrolysis of a tert-butyl ester to give a compound of
formula (I) where Z.dbd.CO.sub.2H.
##STR00016##
[0102] R and R' may represent any of the variables defined herein
at such positions.
[0103] Analogous chemistry may be used to prepare other Ring A
derivatives (e.g. pyridine compounds).
[0104] Alternatively a Suzuki coupling of an appropriate iodo-,
bromo- or chloro-pyrazine amide (IV), particularly bromo- or
chloro-pyrazine amide (IV), can be used followed by removal of the
protecting group by basic hydrolysis of a methyl or ethyl
ester.
##STR00017##
Preparation of Formula (III) Compound Types (Ring A)
[0105] The following schemes illustrate how certain Ring A variants
may be prepared. Variables shown in the schemes are defined or can
be interpreted in the context of the variants described herein for
the compounds of the invention. Analogous chemistry to that shown
in the schemes and Examples may be used to prepare other Ring
variants and linking group options within the scope of the
invention.
##STR00018##
##STR00019##
##STR00020##
Preparation of Formula (III) and (Iv) Compound Types (Ring A)
##STR00021##
[0106] Analogues of pyrazine can be prepared using the procedure
described by C. Christensen, C. W. Tomoe and M. Meldal, QSAR &
Combinatorial Science, 2004, 23, (2-3), 109-116, for example,
3-methylpyrazine . . .
##STR00022##
Preparation of Formula (II) Compound Types (Ring C and Ring B)
[0107] The following schemes illustrate how certain Ring C and Ring
B variants may be prepared. Variables shown in the schemes are
defined or can be interpreted in the context of the variants
described herein for the compounds of the invention. Analogous
chemistry to that shown in the schemes and Examples may be used to
prepare other ring variants and linking group options within the
scope of the invention. (i) Compounds of formula (II) in which Ring
C is cyclohexane (p is 2 in structure C1) and Ring B is phenyl are
described in the literature or can be made by analogy. These may be
brominated to (C2) and then converted into the boronate esters (C3)
using standard procedures. Alternative leaving groups to bromo in
(C2) are iodo and triflate (see Scheme C1-B).
##STR00023##
##STR00024##
[0108] Scheme C1-B methyl ester has been described in WO
2004/047755.
[0109] Compounds in which a bromo-heteroaryl compound is required
may not be directly obtainable via the unsubstituted heteroaryl
compound. The bromo group, or other suitable alternative, may be
introduced at an earlier stage in the synthetic route.
(ii) For compounds of formula (II) in which Ring C is phenyl and
Ring B is phenyl many appropriate intermediates are in the
literature, or can be made by analogy, and introduction of various
substitution patterns may be achieved through biaryl Suzuki
coupling:
##STR00025##
[0110] In Scheme C2, R and R' are any of the claimed aromatic
substituents which are compatible with the reaction conditions, X
is a suitable leaving group such as bromo, iodo or triflate. The
bromobiaryl is then converted into the corresponding boronate
derivative by standard methods.
[0111] For both Scheme C1 and C2, introduction of .alpha.-alkyl and
dialkyl groups is possible at the intermediate C1 or C2 stage
through standard alkylation methodology, for example by
deprotonation .alpha.-to the ester group using a lithium base such
as LDA followed by quenching with an appropriate alkyl halide.
Preparation of Formula (V) Compound Types (Ring A and Ring B)
[0112] (i) In an alternative sequence of Suzuki couplings a
cyanoheterocyclylphenylboronic ester of type V is generated as a
key intermediate, as illustrated by the scheme below. This
intermediate is then used in further coupling reactions to generate
biaryl compounds of the formula I.
##STR00026##
In Scheme C2, R and R' are any of the claimed aromatic substituents
which are compatible with the reaction conditions. The phenol is
converted into the corresponding triflate with
trifluoromethanesulfonic anhydride and a suitable base, such as
triethylamine, which also results in dehydration of the amide to
the nitrile. The aryltriflate is converted to the corresponding
boronate derivative followed by subsequent Suzuki reaction under
standard methods with a suitable palladium catalyst, such as
1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium(II). Base
hydrolysis, for example with potassium hydroxide in tert-butanol
results in hydrolysis of the ester and nitrile.
##STR00027##
In Scheme C2-B, R and R' are any of the claimed aromatic
substituents which are compatible with the reaction conditions.
(ii) Spirocyclic compounds of formula (II) may be prepared by
analogy with preparations involving the intermediates in Scheme C4
below (see WO 2004/047755--relevant sections of which are hereby
incorporated by reference).
##STR00028##
[0113] The double bond may be reduced at a suitable stage in the
synthesis and the resultant cis- and trans-isomers separated
chromatographically. As above, this route may proceed by conversion
of the bromo into the boronate for coupling to the appropriate Ring
A (e.g. pyrazine) compound.
[0114] The cyclohexanone may be converted to the unsaturated ketone
and the double bond reduced at a suitable stage in the synthesis
and the cis- and trans-isomers separated chromatographically.
Alternatively the cyclohexane may be converted to the aldehyde
which can be oxidised to the acid, for example with oxone and the
acid converted to an ester, for example a tert-butyl and the cis-
and trans-isomers separated chromatographically. As above, this
route may proceed by conversion of the bromo into the boronate for
coupling to the appropriate Ring A (e.g. pyrazine) compound.
[0115] For compounds of the formula (V) in which Ring B is Phenyl
and Ring C is a cyclic amine, introduction of the amine maybe
achieved through transition metal coupling.
##STR00029##
[0116] In Scheme C5 the amines may be introduced using boronic
acids or esters using copper acetate as in the procedure described
by D. M. T. Chan, K. L Monaco, R. Li, D. Bonne, C. G. Clark, P. Y.
S Lam, Tet. Lett., 2003, 44(19), 3863-3865.
(iii) Bicyclooctane derivatives of formula (II) may be prepared by
analogy with preparations involving the phenyl Intermediate C5
below (see WO 2007/071966--relevant sections of which are hereby
incorporated by reference), which is brominated and converted into
the boronate for coupling to the appropriate Ring A (e.g. pyrazine)
compound.
##STR00030##
[0117] Compounds of formula C5 may be made as their ester
derivative according to the process shown below in Scheme C3, or
analogously thereto.
##STR00031##
[0118] Compounds such as C6 may be homologated by standard
procedures such as reduction of the ester to the corresponding
alcohol, conversion of this to a leaving group such as tosylate,
displacing this with cyanide followed by hydrolysis and
esterification, all by standard methods, to compounds such as C5
wherein n=1.
[0119] Compounds in which Ring C is other than
bicyclo[2.2.2]octane-1,4-diyl may be prepared by analogous
processes.
[0120] Adamantyl derivatives of formula (II) may be prepared by
analogy with preparations involving the phenyl Intermediate C7
below (see WO 2007/071966--relevant sections are hereby
incorporated by reference), which is iodinated and converted to the
boronate for coupling to the appropriate Ring A (e.g.
pyrazine).
##STR00032##
[0121] If not commercially available, the necessary starting
materials for the procedures such as those described above may be
made by procedures which are selected from standard organic
chemical techniques, techniques which are analogous to the
synthesis of known, structurally similar compounds, techniques
which are described or illustrated in the references given above,
or techniques which are analogous to the above described procedure
or the procedures described in the examples. The reader is further
referred to Advanced Organic Chemistry, 5.sup.th Edition, by Jerry
March and Michael Smith, published by John Wiley & Sons 2001,
for general guidance on reaction conditions and reagents.
[0122] It will be appreciated that some intermediates to compounds
of the formula (I) are also novel and these are provided as
separate independent aspects of the invention. In particular,
certain compounds of formula (IV) may form a further independent
aspect of the invention. Furthermore, ester derivatives of
compounds of formula (I) form a further aspect of the
invention.
[0123] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in compounds. The instances where protection is
necessary or desirable are known to those skilled in the art, as
are suitable methods for such protection. Conventional protecting
groups may be used in accordance with standard practice (for
illustration see T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley and Sons, 1991).
[0124] Protecting groups may be removed by any convenient method as
described in the literature or known to the skilled chemist as
appropriate for the removal of the protecting group in question,
such methods being chosen so as to effect removal of the protecting
group with minimum disturbance of groups elsewhere in the
molecule.
[0125] Thus, if reactants include, for example, groups such as
amino, carboxy or hydroxy it may be desirable to protect the group
in some of the reactions mentioned herein.
[0126] Examples of a suitable protecting group for a hydroxy group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an aroyl group, for example benzoyl, a silyl group such
as trimethylsilyl or an arylmethyl group, for example benzyl. The
deprotection conditions for the above protecting groups will
necessarily vary with the choice of protecting group. Thus, for
example, an acyl group such as an alkanoyl or an aroyl group may be
removed, for example, by hydrolysis with a suitable base such as an
alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively a silyl group such as trimethylsilyl or SEM may be
removed, for example, by fluoride or by aqueous acid; or an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation in the presence of a catalyst such as
palladium-on-carbon.
[0127] A suitable protecting group for an amino group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulfuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine or 2-hydroxyethylamine, or with
hydrazine.
[0128] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0129] Resins may also be used as a protecting group.
[0130] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art, or they may be removed during a later reaction step
or work-up.
[0131] The skilled organic chemist will be able to use and adapt
the information contained and referenced within the above
references, and accompanying Examples therein and also the examples
herein, to obtain necessary starting materials, and products.
[0132] The removal of any protecting groups and the formation of a
pharmaceutically-acceptable salt are within the skill of an
ordinary organic chemist using standard techniques. Furthermore,
details on the these steps has been provided hereinbefore.
[0133] When an optically active form of a compound of the invention
is required, it may be obtained by carrying out one of the above
procedures using an optically active starting material (formed, for
example, by asymmetric induction of a suitable reaction step), or
by resolution of a racemic form of the compound or intermediate
using a standard procedure, or by chromatographic separation of
diastereoisomers (when produced). Enzymatic techniques may also be
useful for the preparation of optically active compounds and/or
intermediates.
[0134] Similarly, when a pure regioisomer of a compound of the
invention is required, it may be obtained by carrying out one of
the above procedures using a pure regioisomer as a starting
material, or by resolution of a mixture of the regioisomers or
intermediates using a standard procedure.
[0135] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
formula (I), (IA) or (IB) as defined hereinbefore or a
pharmaceutically-acceptable salt thereof, in association with a
pharmaceutically-acceptable excipient or carrier.
[0136] The compositions of the invention may be in a form suitable
for oral use (for example as tablets, lozenges, hard or soft
capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for
example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), for administration by inhalation (for example as a
finely divided powder or a liquid aerosol), for administration by
insufflation (for example as a finely divided powder) or for
parenteral administration (for example as a sterile aqueous or oily
solution for intravenous, subcutaneous, intramuscular or
intramuscular dosing or as a suppository for rectal dosing).
[0137] The compositions of the invention may be obtained by
conventional procedures using conventional pharmaceutical
excipients, well known in the art. Thus, compositions intended for
oral use may contain, for example, one or more colouring,
sweetening, flavouring and/or preservative agents.
[0138] Suitable pharmaceutically acceptable excipients for a tablet
formulation include, for example, inert diluents such as lactose,
sodium carbonate, calcium phosphate or calcium carbonate,
granulating and disintegrating agents such as corn starch or
algenic acid; binding agents such as starch; lubricating agents
such as magnesium stearate, stearic acid or talc; preservative
agents such as ethyl or propyl p-hydroxybenzoate, and
anti-oxidants, such as ascorbic acid. Tablet formulations may be
uncoated or coated either to modify their disintegration and the
subsequent absorption of the active ingredient within the
gastrointestinal tract, or to improve their stability and/or
appearance, in either case, using conventional coating agents and
procedures well known in the art.
[0139] Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules in which the active ingredient
is mixed with water or an oil such as peanut oil, liquid paraffin,
or olive oil.
[0140] Aqueous suspensions generally contain the active ingredient
in finely powdered form together with one or more suspending
agents, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as lecithin or condensation products of an
alkylene oxide with fatty acids (for example polyoxethylene
stearate), or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol,
or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide
with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives (such as ethyl or propyl p-hydroxybenzoate,
anti-oxidants (such as ascorbic acid), colouring agents, flavouring
agents, and/or sweetening agents (such as sucrose, saccharine or
aspartame).
[0141] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil,
sesame oil or coconut oil) or in a mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent
such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set out above, and flavouring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0142] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water generally contain
the active ingredient together with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients such as sweetening,
flavouring and colouring agents, may also be present.
[0143] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, or a mineral oil,
such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example,
naturally-occurring gums such as gum acacia or gum tragacanth,
naturally-occurring phosphatides such as soya bean, lecithin, an
esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation
products of the said partial esters with ethylene oxide such as
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening, flavouring and preservative agents.
[0144] Syrups and elixirs may be formulated with sweetening agents
such as glycerol, propylene glycol, sorbitol, aspartame or sucrose,
and may also contain a demulcent, preservative, flavouring and/or
colouring agent.
[0145] The pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, which may be
formulated according to known procedures using one or more of the
appropriate dispersing or wetting agents and suspending agents,
which have been mentioned above. A sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol.
[0146] Compositions for administration by inhalation may be in the
form of a conventional pressurised aerosol arranged to dispense the
active ingredient either as an aerosol containing finely divided
solid or liquid droplets. Conventional aerosol propellants such as
volatile fluorinated hydrocarbons or hydrocarbons may be used and
the aerosol device is conveniently arranged to dispense a metered
quantity of active ingredient.
[0147] For further information on formulation the reader is
referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal
Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon
Press 1990.
[0148] The amount of active ingredient that is combined with one or
more excipients to produce a single dosage form will necessarily
vary depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from
0.5 mg to 2 g of active agent compounded with an appropriate and
convenient amount of excipients which may vary from about 5 to
about 98 percent by weight of the total composition. Dosage unit
forms will generally contain about 1 mg to about 500 mg of an
active ingredient. For further information on Routes of
Administration and Dosage Regimes the reader is referred to Chapter
25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin
Hansch; Chairman of Editorial Board), Pergamon Press 1990.
[0149] According to a further aspect of the present invention there
is provided a compound of formula (I), (IA) and/or (IB), or a
pharmaceutically acceptable salt, or a pro-drug thereof as defined
hereinbefore for use in a method of treatment of the human or
animal body by therapy.
[0150] We have found that compounds of the present invention
inhibit DGAT1 activity and are therefore of interest for their
blood glucose-lowering effects.
[0151] A further feature of the present invention is a compound of
formula (I), (IA) and/or (IB), or a pharmaceutically-acceptable
salt, or a pro-drug thereof for use as a medicament.
[0152] Conveniently this is a compound of formula (I), (IA) and/or
(IB), or a pharmaceutically-acceptable salt, or a pro-drug thereof,
for (use as a medicament for) producing an inhibition of DGAT1
activity in a warm-blooded animal such as a human being.
[0153] Particularly this is a compound of formula (I), (IA) and/or
(IB), or a pharmaceutically-acceptable salt, or a pro-drug thereof,
for (use as a medicament for) treating diabetes mellitus and/or
obesity in a warm-blooded animal such as a human being.
[0154] Thus according to a further aspect of the invention there is
provided the use of a compound of formula (I), (IA) and/or (IB), or
a pharmaceutically-acceptable salt, or a pro-drug thereof in the
manufacture of a medicament for use in the production of an
inhibition of DGAT1 activity in a warm-blooded animal such as a
human being.
[0155] Thus according to a further aspect of the invention there is
provided the use of a compound of formula (I), (IA) and/or (IB), or
a pharmaceutically-acceptable salt, or a pro-drug thereof in the
manufacture of a medicament for use in the treatment of diabetes
mellitus and/or obesity in a warm-blooded animal such as a human
being.
[0156] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
formula (I), (IA) and/or (IB) as defined hereinbefore, or a
pharmaceutically-acceptable salt, or a pro-drug thereof, in
association with a pharmaceutically-acceptable excipient or carrier
for use in producing an inhibition of DGAT1 activity in an
warm-blooded animal, such as a human being.
[0157] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
formula (I), (IA) and/or (IB) as defined hereinbefore, or a
pharmaceutically-acceptable salt, or a pro-drug thereof, in
association with a pharmaceutically-acceptable excipient or carrier
for use in the treatment of diabetes mellitus and/or obesity in an
warm-blooded animal, such as a human being.
[0158] According to a further feature of the invention there is
provided a method for producing an inhibition of DGAT1 activity in
a warm-blooded animal, such as a human being, in need of such
treatment which comprises administering to said animal an effective
amount of a compound of formula (I), (IA) and/or (IB), or a
pharmaceutically-acceptable salt, or a pro-drug thereof as defined
hereinbefore.
[0159] According to a further feature of the invention there is
provided a method of treating diabetes mellitus and/or obesity in a
warm-blooded animal, such as a human being, in need of such
treatment which comprises administering to said animal an effective
amount of a compound of formula (I), (IA) and/or (IB), or a
pharmaceutically-acceptable salt, or a pro-drug thereof as defined
hereinbefore.
[0160] As stated above the size of the dose required for the
therapeutic or prophylactic treatment of a particular disease state
will necessarily be varied depending on the host treated, the route
of administration and the severity of the illness being treated.
Preferably a daily dose in the range of 1-50 mg/kg is employed. In
another embodiment a daily dose is in the range of 0.01-50 mg/kg,
particularly 0.01-10 mg/kg, 0.01-1 mg/kg or 0.01-0.1 mg/kg. However
the daily dose will necessarily be varied depending upon the host
treated, the particular route of administration, and the severity
of the illness being treated. Accordingly the optimum dosage may be
determined by the practitioner who is treating any particular
patient.
[0161] As stated above compounds defined in the present invention
are of interest for their ability to inhibit the activity of DGAT1.
A compound of the invention may therefore be useful for the
prevention, delay or treatment of a range of disease states
including diabetes mellitus, more specifically type 2 diabetes
mellitus (T2DM) and complications arising there from (for example
retinopathy, neuropathy and nephropathy), impaired glucose
tolerance (IGT), conditions of impaired fasting glucose, metabolic
acidosis, ketosis, dysmetabolic syndrome, arthritis, osteoporosis,
obesity and obesity related disorders, (which include peripheral
vascular disease, (including intermittent claudication), cardiac
failure and certain cardiac myopathies, myocardial ischaemia,
cerebral ischaemia and reperfusion, hyperlipidaemias,
atherosclerosis, infertility and polycystic ovary syndrome); the
compounds of the invention may also be useful for muscle weakness,
diseases of the skin such as acne, various immunomodulatory
diseases (such as psoriasis), HIV infection, inflammatory bowel
syndrome and inflammatory bowel disease such as Crohn's disease and
ulcerative colitis.
[0162] In particular, the compounds of the present invention are of
interest for the prevention, delay or treatment of diabetes
mellitus and/or obesity and/or obesity related disorders. In one
aspect, the compounds of the invention are used for prevention,
delay or treatment of diabetes mellitus. In another aspect, the
compounds of the invention are used for prevention, delay or
treatment of obesity. In a further aspect, the compounds of the
invention are used for prevention, delay or treatment of obesity
related disorders.
[0163] The inhibition of DGAT1 activity described herein may be
applied as a sole therapy or in combination with one or more other
substances and/or treatments for the indication being treated. Such
conjoint treatment may be achieved by way of the simultaneous,
sequential or separate administration of the individual components
of the treatment. Simultaneous treatment may be in a single tablet
or in separate tablets. For example such conjoint treatment may be
beneficial in the treatment of metabolic syndrome [defined as
abdominal obesity (as measured by waist circumference against
ethnic and gender specific cut-points) plus any two of the
following: hypertriglyceridemia (>150 mg/dl; 1.7 mmol/1); low
HDLc (<40 mg/dl or <1.03 mmol/1 for men and <50 mg/dl or
1.29 mmol/l for women) or on treatment for low HDL (high density
lipoprotein); hypertension (SBP.gtoreq.130 mmHg DBP.gtoreq.85 mmHg)
or on treatment for hypertension; and hyperglycemia (fasting plasma
glucose.gtoreq.100 mg/dl or 5.6 mmol/l or impaired glucose
tolerance or pre-existing diabetes mellitus)--International
Diabetes Federation & input from IAS/NCEP].
[0164] Such conjoint treatments may include the following main
categories:
1) Anti-obesity therapies such as those that cause weight loss by
effects on food intake, nutrient absorption or energy expenditure,
such as orlistat, sibutramine and the like. 2) Insulin
secretagogues including sulphonylureas (for example glibenclamide,
glipizide), prandial glucose regulators (for example repaglinide,
nateglinide); 3) Agents that improve incretin action (for example
dipeptidyl peptidase IV inhibitors, and GLP-1 agonists); 4) Insulin
sensitising agents including PPARgamma agonists (for example
pioglitazone and rosiglitazone), and agents with combined PPARalpha
and gamma activity; 5) Agents that modulate hepatic glucose balance
(for example metformin, fructose 1, 6 bisphosphatase inhibitors,
glycogen phopsphorylase inhibitors, glycogen synthase kinase
inhibitors, glucokinase activators); 6) Agents designed to reduce
the absorption of glucose from the intestine (for example
acarbose); 7) Agents that prevent the reabsorption of glucose by
the kidney (SGLT inhibitors); 8) Agents designed to treat the
complications of prolonged hyperglycaemia (for example aldose
reductase inhibitors); 9) Anti-dyslipidaemia agents such as,
HMG-CoA reductase inhibitors (eg statins); PPAR .alpha.-agonists
(fibrates, eg gemfibrozil); bile acid sequestrants
(cholestyramine); cholesterol absorption inhibitors (plant stanols,
synthetic inhibitors); bile acid absorption inhibitors (IBATi) and
nicotinic acid and analogues (niacin and slow release
formulations); 10) Antihypertensive agents such as .beta.-blockers
(eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium
antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg
candesartan), .alpha.-antagonists and diuretic agents (eg.
furosemide, benzthiazide); 11) Haemostasis modulators such as,
antithrombotics, activators of fibrinolysis and antiplatelet
agents; thrombin antagonists; factor Xa inhibitors; factor VIIa
inhibitors); antiplatelet agents (eg. aspirin, clopidogrel);
anticoagulants (heparin and Low molecular weight analogues,
hirudin) and warfarin; 12) Agents which antagonise the actions of
glucagon; and 13) Anti-inflammatory agents, such as non-steroidal
anti-inflammatory drugs (eg. aspirin) and steroidal
anti-inflammatory agents (eg. cortisone).
[0165] In addition to their use in therapeutic medicine, compounds
of formula (I) and their pharmaceutically-acceptable salts are also
useful as pharmacological tools in the development and
standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of DGAT1 activity in
laboratory animals such as cats, dogs, rabbits, monkeys, rats and
mice, as part of the search for new therapeutic agents.
[0166] In the above other pharmaceutical composition, process,
method, use and medicament manufacture features, the alternative,
particular and preferred embodiments of the compounds of the
invention described herein also apply. The alternative, particular
and preferred embodiments of the invention described herein also
apply to a compound of formula (I), or a
pharmaceutically-acceptable salt, or a pro-drug thereof.
[0167] As indicated above, all of the compounds, and their
corresponding pharmaceutically-acceptable salts, are useful in
inhibiting DGAT1. The ability of the compounds of formula (I), and
their corresponding pharmaceutically-acceptable (acid addition)
salts, to inhibit DGAT1 may be demonstrated employing the following
enzyme assay:
Human Enzyme Assay
[0168] See, for example, International Application WO
2005/044250.
[0169] The in vitro assay to identify DGAT1 inhibitors uses human
DGAT1 expressed in insect cell membranes as the enzyme source
(Proc. Natl. Acad. Sci. 1998, 95, 13018-13023). Briefly, sf9 cells
were infected with recombinant baculovirus containing human DGAT1
coding sequences and harvested after 48 h. Cells were lysed by
sonication and membranes isolated by centrifuging at 28000 rpm for
1 h at 4.degree. C. on a 41% sucrose gradient. The membrane
fraction at the interphase was collected, washed, and stored in
liquid nitrogen.
[0170] DGAT1 activity was assayed by a modification of the method
described by Coleman (Methods in Enzymology 1992, 209, 98-102).
Compound at 0.0000256 .mu.M (or 0.003 .mu.M)-33 .mu.M (final cone.)
(typically 10 .mu.M) was incubated with 4 .mu.g/ml (final cone)
membrane protein, 5 mM MgCl.sub.2, and 100 .mu.M 1,2
dioleoyl-sn-glycerol (dissolved in acetone with a final assay conc.
of acetone of 1.8%; other acetone concentrations may be used as
appropriate, for example 10%) in a total assay volume of 200 .mu.l
in a 96 well plate. The reaction was started by adding .sup.14C
oleoyl coenzyme A (30 .mu.M final concentration) and incubated at
room temperature for 30 minutes. The reaction was stopped by adding
200 .mu.l 2-propanol:heptane 7:1. Radioactive triolein product was
separated into the organic phase by adding 300 .mu.l heptane and
100 .mu.l 0.1 M carbonate buffer pH 9.5. DGAT1 activity was
quantified by counting aliquots of the upper heptane layer by
liquid scintillography.
[0171] Using this assay the compounds generally show activity with
an IC.sub.50 around or below 10 .mu.M, preferably below 10 .mu.M
(i.e. IC.sub.50<10 .mu.M), preferably <1 .mu.M, more
preferably <0.1 .mu.M, particularly, <0.05 .mu.M, and more
particularly <0.01 .mu.M. Stated figures are usually a mean of a
number of measurements (usually 2 measurements) according to
standard practice.
[0172] In some cases % inhibition data may have been provided at a
particular concentration (10 .mu.M).
[0173] Example 1 showed an IC.sub.50=0.016 .mu.M (using an assay
acetone concentration of 1.8%) and 0.079 .mu.M (using an assay
acetone concentration of 10%).
[0174] Examples 2 to 20 showed respectively IC.sub.50=0.071 .mu.M;
0.023 .mu.M; 0.042 .mu.M; 0.018 .mu.M; 5.71 .mu.M; 5.09 .mu.M;
0.233 .mu.M; 0.674 .mu.M; 1.34 .mu.M; 0.102 .mu.M; 0.025 .mu.M;
0.428 .mu.M; 0.159 .mu.M; 0.157 .mu.M; 1.23 .mu.M; 0.418 .mu.M;
2.85 .mu.M; 1.55 .mu.M and 6.31 .mu.M.
[0175] Examples 21 to 54 showed respectively IC.sub.50=0.27 .mu.M;
0.067 .mu.M; 0.096 .mu.M; 1 .mu.M; 0.1 .mu.M; 1.5 .mu.M; 0.31
.mu.M; 0.038 .mu.M; 0.1 .mu.M; 0.032 .mu.M; 0.17 .mu.M; 0.27 .mu.M;
1.3 .mu.M; 3 .mu.M; 0.96 .mu.M; Example 36=46-67% inhibition at 10
.mu.M; Example 37=47-50% inhibition at 10 .mu.M; 2.4 .mu.M; 3
.mu.M; 1.4M; 0.95 .mu.M; 0.21 .mu.M; 0.066 .mu.M; 0.093 .mu.M;
0.035 .mu.M; 0.047 .mu.M; 0.056 .mu.M; 4.4 .mu.M; 0.57 .mu.M; 0.6
.mu.M; 3.4 .mu.M; 4.6 .mu.M; 4.6 .mu.M; 1.3 .mu.M.
[0176] Examples 55 to 64 showed respectively IC.sub.50=7 .mu.M;
Example 56=15-31% inhibition at 10 .mu.M; 6.7 .mu.M; (Example
58--no data); 0.12 .mu.M; 0.09 .mu.M; 0.15 .mu.M; 8 .mu.M; 0.18
.mu.M; 0.67 .mu.M.
[0177] Example 65 showed an IC.sub.50=7.8 .mu.M and Example 66 an
IC.sub.50=0.88 .mu.M.
[0178] Example 67 showed IC.sub.50=0.18 .mu.M; Example 68=25%
inhibition at 10 .mu.M.
[0179] Examples 69 and 70 showed respectively IC.sub.50=0.4 .mu.M
and IC.sub.50=4.9 .mu.M.
[0180] The ability of the compounds of formula (I), and their
corresponding pharmaceutically-acceptable (acid) salts, to inhibit
DGAT1 may further be demonstrated employing the following whole
cell assay.
Measurement of Triglyceride Synthesis in HuTu 80 Cells
[0181] HuTu80 cells were cultured to confluency in 6 well plates in
minimum essential media containing foetal calf serum. For the
experiment, the medium was changed to serum-free medium and the
cells pre-incubated with compound solubilised in DMSO (final
concentration 0.1%) for 30 minutes. De novo lipogenesis was
measured by the addition of 0.12 mM sodium oleate plus 1 .mu.Ci/mL
.sup.14C-sodium oleate complexed to 0.03 mM BSA to each well for a
further 2 h. The cells were washed in phosphate buffered saline and
solubilised in 1% sodium dodecyl sulfate. An aliquot was removed
for protein determination using a protein estimation kit (Perbio)
based on the method of Lowry (J. Biol. Chem., 1951, 193, 265-275).
The lipids were extracted into the organic phase using a
heptane:propan-2-ol:water (80:20:2) mixture followed by aliquots of
water and heptane according to the method of Coleman (Methods in
Enzymology, 1992, 209, 98-104). The organic phase was collected and
the solvent evaporated under a stream of nitrogen. The extracts
solubilised in iso-hexane:acetic acid (99:1) and lipids separated
via normal phase high performance liquid chromatography (HPLC)
using a Lichrospher diol-5, 4.times.250 mm column and a gradient
solvent system of iso-hexane:acetic acid (99:1) and
iso-hexane:propan-2-ol:acetic acid (85:15:1), flow rate of 1
mL/minute according to the method of Silversand and Haux (1997).
Incorporation of radiolabel into the triglyceride fraction was
analysed using a Radiomatic Flo-one Detector (Packard) connected to
the HPLC machine
EXAMPLES
[0182] The following examples are for illustration purposes and are
not intended to limit the scope of this application. Each
exemplified compound represents a particular and independent aspect
of the invention. In the following non-limiting Examples, unless
otherwise stated:
(i) evaporations were carried out by rotary evaporation under
reduced pressure and work-up procedures were carried out after
removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at room temperature, that is in
the range 18-25.degree. C. and generally under an atmosphere of an
inert gas such as argon or nitrogen; (iii) yields are given for
illustration only and are not necessarily the maximum attainable;
(iv) the structures of the end-products of the Formula (I) were
confirmed by nuclear (generally proton) magnetic resonance (NMR)
and mass spectral techniques; proton magnetic resonance chemical
shift values were measured on the delta scale and peak
multiplicities are shown as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (v)
intermediates were not generally fully characterised and purity was
assessed by thin layer chromatography (TLC), high-performance
liquid chromatography (HPLC), infra-red (IR) or NMR analysis; (vi)
flash chromatography was carried out on silica unless otherwise
stated with flash chromatography purifications run on Biotage SP1
or SP4 instruments using Biotage Silica columns; (vii) mass spectra
were recorded on a Finnigan LCQ Duo ion trap mass spectrometer
equipped with an electrospray interface (LC-MS) or LC-MS system
consisting of a Waters ZQ using a LC-Agilent 1100 LC system; (viii)
.sup.1H NMR measurements were performed on a Varian Mercury VXR 300
and 400 spectrometer, operating at a 1H frequency of 300 and 400
and Varian UNITY plus 400, 500 and 600 spectrometers, operating at
1H frequencies of 400, 500 and 600 respectively. Chemical shifts
are given in ppm with the solvent as internal standard. Protons on
heteroatoms such as NH and OH protons are only reported when
detected in NMR and can therefore be missing. (ix) HPLC separations
were performed on a Waters YMC-ODS AQS-3 120 Angstrom 3.times.500
mm or on a Waters Delta Prep Systems using Kromasil C8, 10 .mu.m
columns. Acidic HPLC was carried out using gradients of mobilephase
A: 100% ACN and mobilephase B: 5% ACN+95% H.sub.2O+0.2% FA. Neutral
HPLC was carried out using gradients of mobilephase A: 100% ACN and
mobilephase B: 5% ACN+95% 0.1 M NH.sub.4OAc. (x) Reactions
performed in a microwave oven were run in a Biotage Initiator
Instrument. (xi) A number of chemical nomenclature software
packages, such as ACDName; ACDLabs Name: Release 9:00, product
version 9.04 and Struc=Name/CambridgeSoft ELN, have been used in
the naming of compounds.
TABLE-US-00001 List of abbreviations herein: ACN Acetonitrile aq
Aqueous Boc tert-butyloxycarbonyl Brine Saturated solution of
sodium chloride in water BSA Bovine Serum Albumine DCE
1,2-dichloroethane DCM Dichloromethane DEE Diethylether DIPEA
N,N-Diisopropylethylamine DMAP Dimethylaminopyridine DMF
N,N-dimethylformamide DMSO Dimethylsulphoxide Dppf
1,1'-bis(Diphenylphosphino)ferrocene EDCI
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDTA
Ethylenediaminetetraacetic acid EtOAc Ethyl acetate EtOH Ethanol FA
Formic acid HOAc Acetic acid HPLC High-performance liquid
chromatography HWE Horner-Wadsworth-Emmons Hz Hertz IPA
Isopropylalcohol iPr isopropyl LC Liquid chromatography m-CPBA
meta-chloroperoxybenzoicacid MeOH Methanol MHz Megahertz mL
Millilitre MS Mass spectra NMM N-methylmorpholine NMP
N-methylpiperazine NMR Nuclear magnetic resonance OAc acetate Ph
Phenyl PyBOP Benzotriazol-1-yl-oxytri-pyrrolidinophosphonium
hexafluorophosphate PyBROP Bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate RT Room temperature sat saturated TEA
Triethylamine Tf trifluoromethylsulfonyl TFA Trifluoroacetic acid
THF Tetrahydrofurane TLC Thin layer chromatography Ts
p-toluenesulfonyl
Example 1
{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid
##STR00033##
[0184] To a solution of Intermediate 1-1 (363 mg, 0.86 mmol) in DCM
(30 mL) was added TFA (3 mL) dropwise. The colorless solution
gradually turned into pale yellow clear solution. The reaction
mixture was stirred under N.sub.2 at RT overnight. The solvent was
evaporated to give the title compound (100%).
[0185] .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 1.22 (q, 2H), 1.59
(q, 2H), 1.85 (s, 1H), 1.94 (d, 4H), 2.23 (d, 2H), 2.58 (t, 1H),
2.62 (s, 3H), 2.84 (s, 3H), 7.37 (d, 2H), 7.58 (d, 2H); m/z 368
(M+H).sup.+.
Intermediate 1-1
tert-Butyl{trans-4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohe-
xyl}acetate
##STR00034##
[0187] To a solution of PyBOP (717 mg, 1.38 mmol) and NH.sub.4Cl
(196.6 mg, 3.68 mmol) in DMF (50 mL) was added Intermediate 1-2
(390.0 mg, 0.92 mmol) and finally DIPEA (0.80 mL, 4.59 mmol) to
initiate the reaction. The solution was stirred for 5 h at RT. The
reaction was quenched by the addition of sat Na.sub.2CO.sub.3 and
extracted with toluene (3.times.100 mL). The combined organics were
washed with brine and water, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The crude material was
purified by flash chromatography using EtOAc (20-60%) in petroleum
ether. Evaporation of pure product fractions gave title compound
(376 mg, 96%) as white solid.
[0188] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.20 (q, 2H), 1.47
(s, 9H), 1.50-1.64 (m, 2H), 1.80-2.00 (m, 5H), 2.17 (d, 2H), 2.56
(t, 1H), 2.67 (t, 3H), 2.98 (t, 3H), 5.43 (s, 1H), 7.33 (d, 2H),
7.52 (d, 2H), 7.81 (d, 2H); m/z 424 (M+H).sup.+.
Intermediate 1-2
6-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyr-
azine-2-carboxylic acid
##STR00035##
[0190] To a solution of Intermediate 1-3 (0.530 g, 1.17 mmol) in
THF (10 mL) was added LiOH (1M, 15 mL). The reaction was stirred at
room temperature for 5 h. THF was removed under vacuum and the
aqueous residue was acidified with 1M HCl and extracted with EtOAc.
The organic layer was dried through a phase separator and
concentrated to give the title compound (0.5 g, 100%).
[0191] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.12-1.21 (m, 2H),
1.45 (s, 9H), 1.49-1.57 (m, 2H), 1.79-1.96 (m, 5H), 2.15 (d, 2H),
2.51-2.57 (m, 1H), 2.70 (s, 3H), 2.97 (s, 3H), 7.33 (d, 2H), 7.48
(d, 2H); m/z 425 (M+H).sup.+.
Intermediate 1-3
Ethyl
6-{4-[trans-4-(2-tert-butoxy-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimet-
hylpyrazine-2-carboxylate
##STR00036##
[0193] To a solution of Intermediate 1-4 (0.580 g, 2.70 mmol) in
DME (22 mL), EtOH (12 mL) and water (5 mL) was added Intermediate D
(see after Intermediate 1-7; 1.244 g, 3.11 mmol), potassium
phosphate, tribasic (0.688 g, 3.24 mmol) and PdCl.sub.2(dppf)
(0.119 g, 0.16 mmol). The solutions degassed with nitrogen for 10
min and then heated in the microwave oven at 140.degree. C. for 20
min. Additional amounts of Intermediate D and PdCl.sub.2(dppf) was
added to drive the reaction. The microwave heating was continued at
140.degree. C. for an additional 30 min.
[0194] (The ethyl ester can be hydrolyzed here by prolonging the
heating time and adding 3 extra equivalents of potassium phosphate,
to give Intermediate 1-2.)
[0195] The mixtures were combined, filtered through a glass filter
funnel and evaporated. The remaining black residue was dissolved in
EtOAc, washed with 0.5M HCl and extracted with 2.times.EtOAc. The
combined organics were dried through a phase separator and
concentrated. The crude was purified by flash chromatography using
EtOAc (0-50%) in heptane as eluent. Evaporation gave title compound
(1.063 g, 80%) as oil.
[0196] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.13-1.22 (m, 2H),
1.42 (t, 3H), 1.47 (s, 9H), 1.49-1.58 (m, 2H), 1.80-1.95 (m, 5H),
2.16 (d, 2H), 2.49-2.56 (m, 1H), 2.66 (s, 3H), 2.81 (s, 3H), 4.45
(q, 2H), 7.30 (d, 2H), 7.53 (d, 2H); m/z 453 (M+H).sup.+.
Intermediate 1-4
Ethyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate
##STR00037##
[0198] To a suspension of Intermediate 1-5 (0.23 g, 1.17 mmol) in
butyronitrile (4 mL) was added POCl.sub.3 (0.27 mL, 2.93 mmol). The
reaction was heated to 150.degree. C. for 10 min in the microwave
oven and cooled to RT. To the reaction mixture was added water (2
mL) and the phases were separated. The organic layer was
concentrated under reduced pressure. The crude product was purified
by flash chromatography using 0.5% HOAc in DCM as eluent to afford
the title compound (0.18 g, 73%).
[0199] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.43 (t, 3H), 2.68
(s, 3H), 2.78 (s, 3H), 4.46 (q, 2H); m/z 215 (M+H).sup.+.
Intermediate 1-5
Ethyl 3,5-dimethyl-6-oxo-1,6-dihydropyrazine-2-carboxylate
##STR00038##
[0201] To a solution of Intermediate 1-6 (800 mg, 2.53 mmol) in dry
DCE (40 mL) was added TFA (1.95 mL, 25.3 mmol). The reaction
mixture was heated to reflux for 4 h. The solvent was evaporated
and the crude product was purified by flash chromatography using
EtOAc (20-80%) in heptane as eluent. Concentration of pure
fractions gave title compound (160 mg, 32%) as white-yellow powder.
The crude from this reaction can optionally be used directly in the
next step without purification.
[0202] .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 4.42 (q, 2H), 2.61
(s, 3H), 2.52 (s, 3H), 1.41 (t, 3H); m/z 197 (M+H).sup.+.
Intermediate 1-6
Ethyl
2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate
##STR00039##
[0204] Intermediate 1-7 (500 mg, 3.2 mmol) and BOC-Ala-NH.sub.2
(843.8 mg, 4.5 mmol, CAS 85642-13-3) were added to a round bottomed
flask, sealed and backfilled with argon. Dry toluene (30 mL) was
added via syringe and the resulting heterogeneous mixture was
stirred at 90.degree. C. for 10 min to get a homogeneous solution.
Meanwhile, the rhodium (II) octanoate dimer (62.3 mg, 0.080 mmol,
CAS 73482-96-9) was dissolved in toluene (5 mL) and put on an
ultrasound bath for 5 min, to get a fine Rh-dispersion. This
dispersion was then added dropwise to the reaction mixture at
80.degree. C. (a violent N.sub.2 effervescence was observed). After
stirring another 20 min at elevated temperature the reaction
mixture was concentrated under reduced pressure to give a black
pasty solid. The N--H insertion product could here be purified or
taken directly to the next step. The crude was purified by flash
chromatography using EtOAc (20-80%) in heptane to afford the title
compound (850 mg, 84%) (diastercomeric mixture) as a yellow oil.
m/z 317 (M+H).sup.+.
Intermediate 1-7
Ethyl 2-diazo-3-oxobutanoate
##STR00040##
[0206] Polymer-bound tosylazide (11 g, 15.4 mmol) (typical loading
1,4 mmol/g, prepared according to Merz et al J. Org. Chem. 2001,
66, 2509-2511) was swollen in dry DCM (40 mL). Ethyl acetoacetate
(1.0 g, 7.7 mmol, CAS 141-97-9) and TEA (3.2 mL, 23.1 mmol) were
dissolved in DCM (10 mL) and added to the polymer containing
solution. The resulting mixture was then shaken at RT under
nitrogen until the reaction was judged completed by TLC, typically
6 h. The supernatant was filtered off, then the resin was washed
with DCM (3.times.30 mL) to rinse out residual product. The
reaction mixture was then evaporated to dryness to afford the title
compound (1.1 g, 92%) as yellow oil.
[0207] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.28 (q, 2H), 2.45
(s, 3H), 1.33 (t, 3H).
[0208] Typically these intermediates were not characterized due to
their high-energetic properties (Clark et al, Thermochimica Acta,
386, 2002, 73-79), but carried through to the next step as crude
products.
Preparation of Intermediate D
Intermediate A
tert-Butyl[4-(4-hydroxyphenyl)cyclohexylidene]acetate
##STR00041##
[0210] To an ice-cold solution of
4-(4-hydroxy-phenyl)-cyclohexanone (15.22 g, 78.4 mmol, CAS
105640-07-1) in THF (375 mL) under N.sub.2 was added NaH in mineral
oil (3.28 g, 79.3 mmol) to give a thick suspension.
[0211] In a separate flask NaH in mineral oil (4.06 g, 98.0 mmol)
was suspended in dry THF (375 mL) under N.sub.2. The suspension was
cooled to 0.degree. C. and tert-butyl P,P-dimethyl phosphonoacetate
(16.82 mL, 82.32 mmol, CAS 62327-21-3) was added carefully. Both
mixtures were stirred for .about.15 min before the ice-baths were
removed. After 2 h at RT the ketone solution was transferred to the
ylide solution via syringe. The combined mixture was stirred under
N.sub.2 overnight. The reaction was quenched by the addition of
water (.about.100 mL) and THF was then removed under vacuum. More
water was added (150 mL) and the aqueous solution was extracted
with EtOAc (3.times.200 mL). The combined organic layer was washed
with brine (2.times.200 mL) and dried through a phase separator.
Concentration gave product as colorless oil (24.6 g, 99%).
[0212] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.51 (s, 9H),
1.55-1.65 (m, 2H), 1.97-2.07 (m, 3H), 2.29-2.40 (m, 2H), 2.70-2.78
(m, 1H), 3.90-3.96 (m, 1H), 4.60 (s, 1H), 5.62 (s, 1H), 6.77 (d,
2H), 7.09 (d, 2H). m/z 287 (M-H).sup.-.
Intermediate B
tert-Butyl[trans-4-(4-hydroxyphenyl)cyclohexyl]acetate
##STR00042##
[0214] To a solution of Intermediate A (4.2 g, 14.56 mmol) in EtOAc
(120 mL) was added 10% Pd/C (390 mg). The reaction was hydrogenated
for 3 h (5 Bar). The catalyst was filtered off through Celite and
the organic filtrate was washed with water, dried through a phase
separator and concentrated to a colorless oil (4.02 g of cis:trans
mixture). The crude mixture was purified by chiral HPLC (neutral)
using a Chiralpak AD (250.times.50 mm) column and 100% ACN as
mobile phase. Purification gave pure trans phenol (2.88 g, 68%) as
white solid and also pure cis phenol. NMR analysis of both isomers
confirmed that the wanted (major) isomer was trans.
[0215] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.10-1.20 (m, 2H),
1.42-1.52 (m, 2H), 1.48 (s, 9H), 1.77-1.92 (m, 5H), 2.17 (d, 2H),
2.38-2.45 (m, 1H), 4.7-4.9 (m, 1H), 6.78 (d, 2H), 7.09 (d, 2H); m/z
289 (M-H).sup.-.
Intermediate C
tert-Butyl[trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]ac-
etate
##STR00043##
[0217] To a solution of Intermediate B (2.86 g, 9.85 mmol) in DCM
(75 mL) was added pyridine (1.59 mL, 19.7 mmol). The solution was
cooled on an ice-bath and trifluoromethanesulfonic anhydride (1.99
mL, 11.82 mmol, CAS 358-23-6) was added dropwise. The ice-bath was
removed and the reaction was stirred for 10 min. The reaction was
quenched with 1M HCl, diluted with DCM and washed with saturated
NaHCO.sub.3 and brine. The organic layer was dried through a phase
separator and concentrated. The crude product was filtered through
silica using 8% EtOAc in heptane as eluent. Concentration of pure
product fractions gave title compound (4.06 g, 98%) as white
crystalline solid.
[0218] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.12-1.22 (m, 2H),
1.45-1.54 (m, 2H), 1.48 (s, 9H), 1.79-1.88 (m, 1H), 1.89-1.95 (m,
4H), 2.17 (d, 2H), 2.48-2.56 (m, 1H), 7.20 (d, 2H), 7.28 (d, 2H);
m/z 421 (M-H).sup.-.
Intermediate D
tert-Butyl{trans-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
cyclohexyl}acetate
##STR00044##
[0220] To a suspension of PdCl.sub.2(dppf) (0.93 g, 1.27 mmol, CAS
72287-26-4) in dioxane (135 mL) under N.sub.2 was added
Intermediate C (17.9 g, 42.4 mmol), TEA (17.7 mL, 127 mmol) and
finally a 1M solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in
THF (72 mL, 72 mmol, CAS 25015-63-8). The mixture was refluxed for
7 h, cooled to 10.degree. C. and quenched carefully with H.sub.2O.
The aqueous solution was extracted with 2.times.DCM and the
combined organics were dried through a phase separator and
concentrated to a black oil. Flash chromatography using 6% EtOAc in
heptane as eluent gave title compound (12.1 g, 71%) as white
powder.
[0221] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.12-1.22 (m, 2H),
1.36 (s, 12H), 1.49 (s, 9H), 1.48-1.61 (m, 2H), 1.80-1.95 (m, 5H),
2.17 (d, 2H), 2.46-2.54 (m, 1H), 7.25 (d, 2H), 7.78 (d, 2H). m/z no
ionization.
Example 2
3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexy-
l)phenyl]pyrazine-2-carboxamide
##STR00045##
[0223] To a solution of Example 1 (30 mg, 0.082 mmol) in DCM was
added DMAP (2 mg, 0.02 mmol), TEA (16 .mu.L, 0.122 mmol), EDCl (20
mg, 0.11 mmol) and finally methanesulfonamide (11 mg, 0.11 mmol,
CAS 3144-09-0). The solution was stirred at RT overnight. The crude
was concentrated and purified by HPLC (acidic). Evaporation and
co-evaporation with toluene gave title compound (22 mg, 60%).
[0224] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.08-1.18 (m, 2H),
1.45-1.56 (m, 2H), 1.76-1.86 (m, 5H), 2.20 (d, 2H), 2.42-2.52 (m,
1H), 2.57 (s, 3H), 2.72 (s, 3H), 3.22 (s, 3H), 7.35 (d, 2H), 7.59
(s, 1H), 7.64 (d, 2H), 7.99 (s, 1H), 11.67 (s, 1H); m/z 445
(M+H).sup.1.
Example 3
6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine--
2-carboxamide
##STR00046##
[0226] This compound was synthesised from Example 1 using similar
conditions as described in Intermediate 1-1 to afford title
compound (40 mg, 38%) as white solid.
[0227] .sup.1H NMR (500 MHz, DMSO) .delta. 1.05-1.15 (m, 2H),
1.43-1.53 (m, 2H), 1.69-1.86 (m, 5H), 1.97 (d, 2H), 2.47-2.55 (m,
1H), 2.58 (s, 3H), 2.72 (s, 3H), 6.71 (s, 1H), 7.24 (s, 1H), 7.35
(d, 2H), 7.59 (s, 1H), 7.64 (d, 2H), 7.99 (s, 1H); m/z 367
(M+H).sup.+.
Example 4
N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}ace-
tyl)-2-methylalanine
##STR00047##
[0229] This compound was synthesised from Example 1 and
alpha-aminoisobutyric acid methyl ester hydrochloride (CAS
15028-41-8) using similar conditions as in Intermediate 1-1. The
intermediate methyl ester was hydrolysed to the corresponding acid
using similar protocol as described in Intermediate 1-2.
[0230] .sup.1H NMR (500 MHz, DMSO) .delta. 1.04-1.14 (m, 2H), 1.31
(s, 6H), 1.43-1.53 (m, 2H), 1.67-1.75 (m, 1H), 1.77-1.85 (m, 4H),
1.96 (d, 2H), 2.48-2.56 (m, 1H), 2.57 (s, 3H), 2.72 (s, 3H), 7.35
(d, 2H), 7.59 (hr s, 1H), 7.64 (d, 2H), 7.77-7.82 (m, 1H), 8.00 (br
s, 1H); m/z 453 (M+H).sup.+.
Example 5
6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-ca-
rboxamide
##STR00048##
[0232] To a suspension of Example 1 (50 mg, 0.14 mmol) and NMM (71
.mu.L, 0.64 mmol) in THF (1 mL) at 0.degree. C. was added a
solution of ethyl chloroformate (61 .mu.L, 0.64 mmol) in THF (0.5
mL). The reaction was stirred at 0.degree. C. for .about.3 h, but
additional equivalents of NMM and ethyl chloroformate were needed
during this time to drive the reaction. The reaction mixture was
added dropwise to a solution of NaBH.sub.4 in water at 0-5.degree.
C. and the combined mixture was stirred for 30 min. The mixture was
partitioned between EtOAc and 1M HCl and the organic layer was
washed with water, dried through a phase separator and
concentrated. The crude was dissolved in DMSO and purified by HPLC
(neutral). Freeze-drying of pure fractions gave the title compound
(8 mg, 17%) as white powder.
[0233] .sup.1H NMR (500 MHz, DMSO) .delta. 1.02-1.14 (m, 2H),
1.34-1.54 (m, 5H), 1.80-1.87 (m, 4H), 2.47-2.57 (m, 1H), 2.58 (s,
3H), 2.73 (s, 3H), 3.43-3.51 (m, 2H), 4.30-4.35 (m, 1H), 7.35 (d,
2H), 7.60 (br s, 1H), 7.65 (d, 2H), 7.99 (br s, 1H); m/z 354
(M+H).sup.+.
Example 6
cis-4-{[5-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohexa-
necarboxylic acid
##STR00049##
[0235] A solution of Intermediate 6-1 (0.0243 g, 0.06 mmol) in 10
mL of a 4.0 M solution of HCl in 1.4-dioxane and a few drops of
water was stirred at 40.degree. C. for 5 h. The solvent was
evaporated and the remaining solid was purified by HPLC (acidic) to
afford the title compound (8.7 mg, 42%) as a dry film.
[0236] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 1.72-1.83 (m, 4H),
1.90-2.07 (m, 4H), 2.47 (m, 1H), 2.67 (s, 3H), 2.85 (s, 3H), 5.27
(s, 1H), 6.92 (d, 1H), 8.03 (dd, 1H), 8.45 (s, 1H); m/z 371
(M+H).sup.+.
Intermediate 6-1
tert-Butyl
cis-4-{[5-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]ox-
y}cyclohexanecarboxylate
##STR00050##
[0238] This compound was synthesised from Intermediate 6-2 using
similar procedure as described in Intermediate 1-1. Purification
gave title product (24.3 mg, 68%) as white solid.
[0239] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.45 (s, 9H),
1.67-1.79 (m, 4H), 1.85-2.07 (m, 4H), 2.34 (m, 1H), 2.68 (s, 3H),
2.96 (s, 3H), 5.28 (s, 1H), 5.77 (s, 1H), 6.84 (d, 1H), 7.76 (s,
1H), 7.82 (dd, 1H), 8.39 (s, 1H); m/z 427 (M+H).sup.+.
Intermediate 6-2
6-(6-{[cis-4-(tert-Butoxycarbonyl)cyclohexyl]oxy}pyridin-3-yl)-3,5-dimethy-
lpyrazine-2-carboxylic acid
##STR00051##
[0241] This compound was synthesised from Intermediate 6-3 and
Intermediate 1-4 using similar Suzuki conditions as in Intermediate
1-3 to afford the title compound (36 mg, 45%) as white solid.
[0242] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.44 (s, 9H),
1.67-1.79 (m, 4H), 1.84-2.05 (m, 4H), 2.34 (m, 1H), 2.72 (s, 3H),
2.97 (s, 3H), 5.27 (s, 1H), 6.85 (d, 1H), 7.80 (d, 1H), 8.37 (s,
1H); m/z 428 (M+H).sup.+.
Intermediate 6-3
tert-Butyl
cis-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin--
2-yl]oxy}cyclohexanecarboxylate
##STR00052##
[0244] Intermediate 6-4 (0.124 g, 0.35 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.121
g, 0.48 mmol, CAS 73183-34-3) and potassium acetate (0.139 g, 1.41
mmol) in 1,4-dioxane (10 mL) was degassed prior to addition of
PdCl.sub.2(dppf) (0.013 g, 0.02 mmol) under N.sub.2. The reaction
was heated at 85.degree. C. for 16 h. The solvent was evaporated
and the crude was dissolved in EtOAc, washed with water (2.times.25
mL), organics dried over Na.sub.2SO.sub.4, filtered and evaporated.
The brownish oil was purified by flash chromatography using 5-50%
EtOAc in heptane to afford the title compound (74 mg, 52%) as a dry
film.
[0245] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.30 (s, 12H),
1.43 (s, 9H), 1.59-1.77 (m, 4H), 1.80-2.00 (m, 4H), 2.29 (m, 1H),
5.25 (m, 1H), 6.67 (d, 1H), 7.88 (dd, 1H), 8.48 (d, 1H).
Intermediate 6-4
tert-Butyl cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexane
carboxylate
##STR00053##
[0247] A solution of Intermediate 6-5 (0.224 g, 0.75 mmol) in
1,1-di-tert-butoxy-N,N-dimethylmethaneamine (0.893 mL, 3.72 mmol,
CAS 36805-97-7) were heated at 120.degree. C. in a microwave oven
for 45 min. The crude was purified by flash chromatography using
EtOAc (5-70%) in heptane to afford the title compound (124 mg, 46%)
as white solid.
[0248] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.43 (s, 9H),
1.58-1.75 (m, 4H), 1.82-2.00 (m, 4H), 2.3 (m, 1H), 5.13 (m, 1H),
6.61 (d, 1H), 7.59 (dd, 1H), 8.12 (d, 1H); m/z 357 (M+H).sup.+.
Intermediate 6-5
cis-4-[(5-Bromopyridin-2-yl)oxy]cyclohexanecarboxylic acid
##STR00054##
[0250] A solution of (1S,4S)-4-hydroxycyclohexanecarboxylic acid
(2.14 g, 14.9 mmol) in DMA (10 mL) was added to a stirred
suspension of NaH (1.32 g, 30.2 mmol) in DMA (15 mL) at 0.degree.
C. where it was stirred for 10 min. The suspension was taken off
the cooling bath and 5-bromo-2-fluoropyridine (1.53 mL, 14.87 mmol,
CAS 766-11-0) was added followed by DMA (10 mL). The reaction was
heated at 100.degree. C. for 2.5 h. The solvent was evaporated and
DCM and 2M HCl were added, the phases separated and the aqueous
phase was extracted with DCM (2.times.50 mL). The combined organics
were dried over MgSO.sub.4, filtered and evaporated. The remaining
crude was purified by flash chromatography using 5-75% EtOAc (1%
HOAc) in heptane to afford the title compound (1.86 g, 42%) as
solid.
[0251] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.70 (t, 2H),
1.75-1.86 (m, 2H), 1.90-2.06 (m, 4H), 2.49 (m, 1H), 5.18 (m, 1H),
6.64 (d, 1H), 7.62 (dd, 1H), 8.16 (d, 1H); m/z 301 (M+H).sup.+.
Example 7
(cis-4-{[5-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohex-
yl)acetic acid
##STR00055##
[0253] This compound was synthesised from Intermediate 7-1 using
similar conditions as described in Example 1 to give the title
compound (15 mg, 42%) as white solid.
[0254] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 1.51 (t, 2H),
1.61-1.75 (m, 4H), 1.91 (m, 1H), 2.05 (d, 2H), 2.25 (d, 2H), 2.66
(s, 3H), 2.84 (s, 3H), 5.29 (s, 1H), 6.91 (d, 1H), 8.02 (dd, 1H),
8.44 (s, 1H); m/z 385 (M+H).sup.+.
Intermediate 7-1
tert-Butyl(cis-4-{[5-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]ox-
y}cyclohexyl)acetate
##STR00056##
[0256] This compound was synthesised from Intermediate 7-2 using
similar conditions as described in Intermediate 1-1 to afford the
title compound (42 mg, 66%) as white solid.
[0257] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.39-1.50 (m,
11H), 1.55-1.69 (m, 4H), 1.87 (m, 1H), 2.02-2.06 (m, 2H), 2.16 (d,
2H), 2.66 (s, 3H), 2.93 (s, 3H), 5.29 (s, 1H), 6.40 (s, 1H), 6.80
(d, 1H), 7.75-7.82 (m, 2H), 8.37 (d, 1H); m/z 441 (M+H).sup.+.
Intermediate 7-2
6-(6-{[cis-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]oxy}pyridin-3-yl)-3,5-di-
methylpyrazine-2-carboxylic acid
##STR00057##
[0259] This compound was synthesised from Intermediate 7-3 and
Intermediate 1-4 using similar conditions as described in
Intermediate 1-3 to afford the title compound (64 mg, 44%) as white
solid.
[0260] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.38-1.51 (m,
11H), 1.56-1.69 (m, 4H), 1.88 (m, 1H), 2.03 (d, 2H), 2.17 (d, 2H),
2.71 (s, 3H), 2.94 (s, 3H), 5.29 (s, 1H), 6.82 (d, 1H), 7.80 (d,
1H), 8.37 (s, 1H), 9.94 (s, 1H); m/z 442 (M+H).sup.+.
Intermediate 7-3
tert-Butyl(cis-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin--
2-yl]oxy}cyclohexyl)acetate
##STR00058##
[0262] This compound was synthesised from Intermediate 7-4 using
similar conditions as described in Intermediate 6-3 to afford the
title compound (0.149 g, 43%) as white solid.
[0263] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.43 (s, 12H),
1.39-1.50 (m, 11H), 1.53-1.67 (m, 4H), 1.87 (m, 1H), 2.00 (d, 2H),
2.16 (d, 2H), 5.30 (s, 1H), 6.67 (d, 1H), 7.89 (dd, 1H), 8.50 (d,
1H).
Intermediate 7-4
tert-Butyl{cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetate
##STR00059##
[0265] This compound was synthesised from Intermediate 7-5 using
similar conditions as described in Intermediate 6-4 to afford the
title compound (0.303 g, 43%) as white solid.
[0266] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.35-1.46 (m,
11H), 1.52-1.63 (m, 4H), 1.85 (m, 1H), 1.96 (d, 2H), 2.14 (d, 2H),
5.16 (s, 1H), 6.59 (d, 1H), 7.58 (dd, 1H), 8.13 (d, 1H); m/z 372
(M+H).sup.+.
Intermediate 7-5
{cis-4-[(5-Bromopyridin-2-yl)oxy]cyclohexyl}acetic acid
##STR00060##
[0268] This compound was synthesised from Intermediate 7-6 using
similar conditions as described in Intermediate 6-5 to afford the
title compound (1.287 g, 68%) as white solid.
[0269] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.44-1.52 (m, 2H),
1.58-1.68 (m, 4H), 1.93 (m, 1H), 2.00 (d, 2H), 2.31 (d, 2H), 5.19
(s, 1H), 6.63 (d, 1H), 7.62 (dd, 1H), 8.16 (d, 1H); m/z 316
(M+H).sup.+.
Intermediate 7-6
(cis-4-Hydroxycyclohexyl)acetic acid
##STR00061##
[0271] This compound was synthesised from Intermediate 7-7 using
similar conditions as described in Intermediate 1-2 to afford the
title compound (0.943 g, 100%) as white solid.
[0272] .sup.1H NMR (500 MHz, CD3OD) .delta. 1.39-1.60 (m, 6H),
1.65-1.73 (m, 2H), 1.83 (m, 1H), 2.10 (d, 2H), 3.85 (m, 1H).
Intermediate 7-7
Methyl(cis-4-hydroxycyclohexyl)acetate
##STR00062##
[0274] A solution of methyl 4-hydroxyphenylacetate (10.01 g, 60.2
mmol, CAS 14199-15-6), rhodium (5% on Alumina) (0.073 g, 0.71 mmol)
in MeOH (30 mL) was hydrogenated at 8 bar. The crude was filtered
through Celite and concentrated at reduced pressure. The remaining
colorless oil was dissolved in isohexane and EtOAc and purified by
flash chromatography using EtOAc (20-50%) in isohexane to afford
the title cis compound (4.31 g, 42%) as colorless oil. NMR analysis
of both trans and cis isomers were compared to make sure that the
right isomer was used in subsequent steps.
[0275] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.40-1.48 (m, 2H),
1.48-1.62 (m, 4H), 1.66-1.74 (m, 2H), 1.86 (m, 1H), 2.24 (d, 2H),
3.66 (s, 3H), 3.97 (s, 1H).
Example 8
(trans-4-{4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl-
}cyclohexyl)acetic acid
##STR00063##
[0277] This compound was synthesised from Intermediate 8-1 using
similar conditions as described in Example 1 to give the title
compound (3.8 mg, 31%).
[0278] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 1.17-1.30 (m, 2H),
1.54-1.67 (m, 2H), 1.80-2.00 (m, 5H), 2.24 (d, 2H), 2.56-2.65 (m,
1H), 2.74 (s, 3H), 7.42 (m, 2H), 7.67 (m, 2H), 7.79 (t, 1H); m/z
404 (M+H).sup.+.
Intermediate 8-1
tert-Butyl(trans-4-{4-[6-carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl-
]phenyl}cyclohexyl)acetate
##STR00064##
[0280] This compound was synthesised from Intermediate 8-2 using
similar conditions as described in Intermediate 1-1 to give the
title compound (11 mg, 44%).
[0281] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.14-1.24 (m, 2H),
1.47 (s, 9H), 1.51-1.63 (m, 2H), 1.80-2.01 (m, 5H), 2.18 (d, 2H),
2.53-2.62 (m, 1H), 2.81 (s, 3H), 5.72 (s, 1H), 7.37 (m, 2H), 7.56
(m, 2H), 7.84 (s, 1H), 7.97 (t, 1H); m/z 460 (M+H).sup.+.
Intermediate 8-2
6-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3-(difluorometh-
yl)-5-methylpyrazine-2-carboxylic acid
##STR00065##
[0283] This compound was synthesised from Intermediate 8-3 using
similar conditions as described in Intermediate 1-3 to give the
title compound (25 mg, 44%).
[0284] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.14-1.25 (m, 2H),
1.47 (s, 9H), 1.51-1.61 (m, 2H), 1.80-2.01 (m, 5H), 2.14-2.21 (m,
2H), 2.53-2.63 (m, 1H), 2.86 (s, 3H), 7.35-7.60 (m, 4H), 7.83 (t,
1H); m/z 461 (M+H).sup.+.
Intermediate 8-3
Ethyl 6-bromo-3-(difluoromethyl)-5-methylpyrazine-2-carboxylate
##STR00066##
[0286] This compound was synthesised from Intermediate 8-4 using
similar procedure as described in Intermediate 9-3 to afford the
title compound (36 mg, 37%).
[0287] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.45 (t, 3H), 2.83
(s, 3H), 4.50 (q, 2H), 7.24 (t, J=55 Hz, 1H); m/z 295
(M+H).sup.+.
Intermediate 8-4
Ethyl
3-(difluoromethyl)-5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate
##STR00067##
[0289] This compound was synthesised from Intermediate 8-5 using
similar procedure as described in Intermediate 1-5. The cyclized
intermediate product was oxidized by heating at 120.degree. C. for
20 min in a microwave oven with Pd/C in HOAc to afford the title
compound (280 mg, 38.6%).
[0290] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.46 (t, 3H), 2.59
(s, 3H), 4.51 (q, 2H), 7.36 (t, 1H, J=56 Hz); m/z 233
(M+H).sup.+.
Intermediate 8-5
Ethyl
2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-4,4-difluoro-3-oxobutano-
ate
##STR00068##
[0292] This compound was synthesised from Intermediate 8-6 using
similar procedure as described in Intermediate 1-6. The crude was
used directly in next step.
Intermediate 8-6
Ethyl 2-diazo-4,4-difluoro-3-oxobutanoate
##STR00069##
[0294] This compound was synthesised from
4,4-difluoro-3-oxo-butyric acid ethyl ester (CAS 352-24-9) and
polymer-bound tosylazide using similar conditions as described in
Intermediate 1-7. The crude was used directly in next step.
[0295] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.35 (t, 3H), 4.35
(q, 2H), 6.59 (t, J=56 Hz, 1H).
Example 9
{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}ac-
etic acid
##STR00070##
[0297] This compound was synthesised from Intermediate 9-1 using
similar conditions as described in Example 1 to afford the title
compound (5 mg, 29%) as white solid.
[0298] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.17 (q, 2H), 1.21
(t, 3H), 1.52 (q, 2H), 1.75-1.88 (m, 1H), 1.92 (d, 4H), 2.22 (d,
2H), 2.52 (t, 1H), 2.88 (q, 2H), 2.9 (s, 3H), 6.12 (br s, 1H), 7.28
(d, 2H), 7.42 (d, 2H), 7.80 (br s, 1H); m/z 382 (M+H).sup.+.
Intermediate 9-1
tert-Butyl
{trans-4-[4-(6-carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cy-
clohexyl}acetate
##STR00071##
[0300] This compound was synthesised from Intermediate 9-2 using
similar conditions as described in Intermediate 1-1 to afford the
title compound (20 mg, 30%) as white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.18 (q, 2H), 1.26 (t, 3H), 1.46 (s, 9H),
1.48-1.62 (m, 2H), 1.78-1.87 (m, 1H), 1.94 (t, 4H), 2.16 (d, 2H),
2.55 (t, 1H), 2.93 (q, 2H), 2.98 (s, 3H), 5.65 (br s, 1H), 7.31 (d,
2H), 7.46 (d, 2H), 7.80 (s, 1H); m/z 438 (M+H).sup.+.
Intermediate 9-2
6-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-5-ethyl-3-methy-
lpyrazine-2-carboxylic acid
##STR00072##
[0302] This compound was synthesised from Intermediate 9-3 and
Intermediate D using similar Suzuki conditions as described in
Intermediate 1-2 to afford the title compound (65.7 mg, 67% yield)
as white solid.
[0303] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.14-1.23 (m, 2H),
1.28 (t, 3H), 1.47 (s, 9H), 1.55 (q, 2H), 1.78-1.98 (m, 6H), 2.17
(d, 2H), 2.55 (t, 1H), 2.93-3.01 (m, 5H), 7.29-7.36 (m, 2H),
7.40-7.47 (m, 2H); m/z 439 (M+H).sup.+.
Intermediate 9-3
Ethyl 6-bromo-5-ethyl-3-methylpyrazine-2-carboxylate
##STR00073##
[0305] To a solution of POBr.sub.3 (0.307 mL, 3.02 mmol, CAS
7789-59-5) in DCE (10 mL) was added Intermediate 9-4 (0.160 g, 0.76
mmol). The mixture was heated at 100.degree. C. for 19 h. The
reaction was cooled to RT. Saturated NaHCO.sub.3 was added
carefully and the mixture was extracted with DCM. The extracts were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The remaining crude was purified by flash chromatography using
EtOAc (0-25%) in heptane to afford the title compound (60.4 mg,
29%) as pale yellow solid.
[0306] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.30 (t, 3H), 1.41
(t, 3H), 2.74 (s, 3H), 2.98 (q, 2H), 4.43 (q, 2H).
Intermediate 9-4
Ethyl 5-ethyl-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate
##STR00074##
[0308] This compound was synthesised from Intermediate 9-5 using
similar conditions as described in Intermediate 1-5 to afford the
title compound (160 mg, 21%) as white solid.
[0309] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.23 (t, 3H), 1.39
(t, 3H), 2.61 (s, 3H), 2.85 (q, 2H), 4.40 (q, 2H).
Intermediate 9-5
Ethyl
2-({(2S)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-3-oxobutanoat-
e
##STR00075##
[0311] This compound was synthesised from Intermediate 9-6 and
Intermediate 1-7 using similar conditions as in Intermediate 1-6.
Crude residue was taken directly to next step.
Intermediate 9-6
tert-Butyl[(1S)-1-carbamoylpropyl]carbamate
##STR00076##
[0313] To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic
acid (1.01 g, 4.99 mmol) in DMF (5 mL) at -20.degree. C. was added
NMM (1.10 mL, 9.99 mmol) and isobutyl chloroformate (1.30 mL, 9.99
mmol). The reaction was stirred for 10 min at -20.degree. C. The
precipitate was removed by filtration. 26% NH.sub.4OH (aq) solution
(0.39 mL, 9.99 mmol) was added and the reaction was stirred at
-20.degree. C. for 3 h. The volume was reduced under vacuum and
hexane was added. A white precipitate was formed after a few
minutes. The precipitate was collected in a filter and washed with
additional hexane. The precipitate was recrystallised from EtOAc
and hexane to give the title compound (0.811 g, 80%) as white
solid.
[0314] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.96 (t, 3H), 1.45
(s, 9H), 1.61 (m, 1H), 1.78 (m, 1H), 3.93 (t, 1H), 6.63 (s, 1H),
6.96 (s, 1H), 7.51 (s, 1H).
Example 10
{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}ac-
etic acid
##STR00077##
[0316] This compound was synthesised from Intermediate 10-1 using
similar conditions as described in Example 1 to give title compound
(13 mg, 95%).
[0317] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.19-1.30 (2H, m),
1.36 (3H, t), 1.52-1.65 (2H, m), 1.84-2.04 (5H, m), 2.35 (2H, d),
2.54-2.64 (1H, m), 2.73 (3H, s), 3.39 (2H, q), 7.29 (1H, s), 7.36
(2H, m), 7.52 (2H, m), 8.10 (1H, s), 8.50 (1H, br s); m/z 382
(M+H).sup.+.
Intermediate 10-1
tert-Butyl
{trans-4-[4-(6-carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cy-
clohexyl}acetate
##STR00078##
[0319] This compound was synthesised from Intermediate 10-2 using
similar procedure as described in Intermediate 1-1 to give title
compound (15 mg, 50%).
[0320] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.13-1.25 (m, 2H),
1.36 (t, 3H), 1.47 (s, 9H), 1.52-1.62 (m, 2H), 1.80-2.00 (m, 5H),
2.18 (d, 2H), 2.52-2.60 (m, 1H), 2.68 (s, 3H), 3.39 (q, 2H), 5.48
(br s, 1H), 7.33 (d, 2H), 7.52 (d, 2H), 7.81 (br s, 1H); m/z 438
(M+H).sup.+.
Intermediate 10-2
6-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3-ethyl-5-methy-
lpyrazine-2-carboxylic acid
##STR00079##
[0322] This compound was synthesised from Intermediate 10-3 and
Intermediate D using similar Suzuki conditions as described in
Intermediate 1-3. Purification gave title product (30 mg, 62%).
[0323] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.13-1.25 (m, 2H),
1.37 (t, 3H), 1.47 (s, 9H), 1.52-1.62 (m, 2H), 1.80-2.00 (m, 5H),
2.18 (d, 2H), 2.53-2.61 (m, 1H), 2.74 (s, 3H), 3.42 (q, 2H), 7.36
(d, 2H), 7.51 (d, 2H), 11.21 (br s, 1H); m/z 439 (M+H).sup.+.
Intermediate 10-3
Ethyl 6-bromo-3-ethyl-5-methylpyrazine-2-carboxylate
##STR00080##
[0325] This compound was synthesised from Intermediate 10-4 using
similar protocol as described in Intermediate 9-3 to give title
compound (30 mg, 8%).
[0326] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.30 (t, 3H), 1.42
(t, 3H), 2.71 (s, 3H), 3.06 (q, 2H), 4.45 (q, 2H); m/z 275
(M+H).sup.+.
Intermediate 10-4
Ethyl 3-ethyl-5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate
##STR00081##
[0328] This compound was synthesised from Intermediate 10-5 using
similar protocol as described in Intermediate 1-5. Purification
gave title compound (0.340 g, 67%) as bright yellow oil.
[0329] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.23 (t, 3H), 1.43
(t, 3H), 2.54 (s, 3H), 3.02 (q, 2H), 4.44 (q, 2H), 9.20 (br s, 1H);
m/z 211 (M+H).sup.+.
Intermediate 10-5
ethyl N-(tert-butoxycarbonyl)-L-alanyl-3-oxonorvalinate
##STR00082##
[0331] This compound was synthesised from Intermediate 10-6 using
similar conditions as described in Intermediate 1-6. Crude product
(1 g, 46%) was taken directly to next step. m/z 331
(M+H).sup.+.
Intermediate 10-6
Ethyl 2-diazo-3-oxopentanoate
##STR00083##
[0333] This compound was synthesised from ethyl propionylacetate
(CAS 4949-44-4) and polymer-bound tosylazide using similar protocol
as described in Intermediate 1-7. Crude material (0.9 g, 95%) was
taken directly to next step.
Example 11
{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid
##STR00084##
[0335] This compound was synthesised from Intermediate 11-1 using
similar conditions as described in Example 1 to give title compound
(16 mg, 53%).
[0336] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.15-1.25 (m, 2H),
1.51-1.61 (m, 2H), 1.83-2.00 (m, 5H), 2.26 (d, 2H), 2.53-2.61 (m,
1H), 2.71 (s, 3H), 7.34 (d, 2H), 7.51 (d, 2H), 9.18 (s, 1H); m/z
354 (M+H).sup.+.
Intermediate 11-1
tert-Butyl
{trans-4-[4-(6-carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl-
}acetate
##STR00085##
[0338] This compound was synthesised from Intermediate 11-2 using
similar conditions as described in Intermediate 1-1. The crude was
taken directly to next step. m/z 410 (M+H).sup.+.
Intermediate 11-2
6-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-5-methylpyrazin-
e-2-carboxylic acid
##STR00086##
[0340] This compound was synthesised from Intermediate 11-3 and
Intermediate D using similar Suzuki conditions as described in
Intermediate 1-3. Purification gave title compound (410 mg,
66%).
[0341] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.15-1.26 (m, 2H),
1.48 (s, 9H), 1.52-1.62 (m, 2H), 1.81-2.00 (m, 5H), 2.19 (d, 2H),
2.54-2.61 (m, 1H), 2.78 (s, 3H), 7.37 (d, 2H), 7.53 (d, 2H), 9.26
(s, 1H); m/z 411 (M+H).sup.+.
Intermediate 11-3
Methyl 6-bromo-5-methylpyrazine-2-carboxylate
##STR00087##
[0343] This compound was synthesised from Intermediate 11-4 using
similar conditions as described in Intermediate 9-3 to give the
title compound (0.493 mg, 54%).
[0344] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 2.78 (s, 3H), 4.02
(s, 3H), 9.10 (s, 1H); m/z 233 (M+H).sup.+.
Intermediate 11-4
Methyl 5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate
##STR00088##
[0346] To a solution of intermediate 11-5 (0.98 g, 5.76 mmol) in
DCM (180 mL) was added polymer-bound sulfurtrioxide (7.3 g, 3 eq,
CAS 26412-87-3). The mixture was stirred at RT for 4 days. The
polymer was filtered off and washed with portions of DCM.
Concentration of filtrate gave title compound (0.8 g, 80%) as
yellow solid.
[0347] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 2.56 (s, 3H), 4.00
(s, 3H), 7.94 (s, 1H); m/z 169 (M+H).sup.+.
Intermediate 11-5
Methyl 5-methyl-6-oxo-1,4,5,6-tetrahydropyrazine-2-carboxylate
##STR00089##
[0349] To a solution of Intermediate 11-6 (3.0 g, 8.56 mmol) in
EtOH (250 mL) under N.sub.2 was added 10% Pd/C (1.35 g) and
ammonium formate (2.43 g, 38.5 mmol). The solution was stirred at
RT for 90 min. The alcohol was removed under vacuum and the black
residue was dissolved in EtOAc and filtered through Celite.
Concentration of filtrate gave the title compound (1.2 g, 80%). m/z
171 (M+H).sup.+.
Intermediate 11-6
Ethyl
N-[(1Z)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxoprop-1-en-1-yl-
]-L-alaninate
##STR00090##
[0351] A solution of Intermediate 11-7 (0.450 g, 0.78 mmol),
L-alanine ethyl ester hydrochloride (0.179, 1.17 mmol, CAS
1115-59-9) and TEA (0.33 mL, 2.33 mmol) in MeOH (10 mL) was stirred
at RT overnight. The residue was concentrated, dissolved in EtOAc
(50 mL) and washed with brine (2.times.25 mL). The organic layer
was dried through a phase separator and concentrated. The crude
residue was purified by flash chromatography using a gradient of
EtOAc (30-50%) in heptane as eluent. Pure product fractions were
concentrated to give the title compound (230 mg, 85%) as colorless
oil.
[0352] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.24-1.33 (m, 6H),
3.70 (s, 3H), 3.94-4.02 (m, 1H), 4.22 (q, 2H), 5.16 (s, 2H), 5.75
(br s, 1H), 6.13 (br s, 1H), 7.25 (d, 1H), 7.30-7.45 (m, 5H); m/z
351 (M+H).sup.+.
Intermediate 11-7
Methyl
(2Z)-2-{[(benzyloxy)carbonyl]amino}-3-{[(4-methylphenyl)sulfonyl]ox-
y}acrylate
##STR00091##
[0354] To a pre-cooled (-30.degree. C.) solution of DMF:DMSO (1:1,
200 mL) under nitrogen was added TsCl (76.3 g, 0.4 mol) in small
portions over 30 min. NOTE: This reaction is highly exotermic and
careful temperature control is essential! The solution was stirred
at -10.degree. C. for 10 min, then again taken to -30.degree. C. A
solution of cbz-L-serine methyl ester (20.3 g, 0.08 mol, CAS
1676-81-9) in DMF was added dropwise, again with careful
temperature control. After stirring for 10 min at -30.degree. C.
triethylamine (110 mL, 0.79 mol) was added and the reaction was
slowly taken to 0.degree. C. and kept at this temperature for 2 h.
The reaction was quenched by addition of ice-cold water. The
solution was extracted with 3.times.EtOAc, then the combined
organic layer was washed extensively with brine and water. Drying
and evaporation gave product as yellow oil (30 g, 94%).
[0355] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 2.47 (s, 3H), 3.77
(s, 3H), 5.11 (s, 2H), 6.01 (br s, 1H), 7.32-7.41 (m, 7H), 7.48 (s,
1H), 7.84 (d, 2H); m/z 406 (M+H).sup.+.
Example 12
(trans-4-{4-[6-(Aminocarbonothioyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl-
)acetic acid
##STR00092##
[0357] This compound was synthesised from Intermediate 12-1 using
similar procedure as in Example 1 to afford the title compound (46
mg, 100%).
[0358] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.20-1.34 (m, 2H),
1.50-1.67 (m, 2H), 1.92 (s, 1H), 2.0 (d, 4H), 2.37 (d, 2H), 2.60
(t, 1H), 2.78 (s, 3H), 7.38 (d, 2H), 7.53 (d, 2H), 7.83 (s, 1H),
9.18 (s, 1H), 9.67 (s, 1H); m/z 370 (M+H).sup.+.
Intermediate 12-1
tert-Butyl(trans-4-{4-[6-(aminocarbonothioyl)-3-methylpyrazin-2-yl]phenyl}-
cyclohexyl)acetate
##STR00093##
[0360] A solution of Example 11 (40 mg, 0.10 mmol) and Lawesson's
reagent (39.5 mg, 0.10 mmol) in toluene:THF (3:1 mL) was heated at
80.degree. C. overnight. An additional amount (0.5 eq) of
Lawesson's reagent was added followed by continued heating for
another 1 h. The reaction mixture was concentrated and purified by
flash chromatography using EtOAc (10-30%) in petroleum ether as
eluent to give the title compound (37 mg, 89%) as slightly
yellowish powder.
[0361] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.12-1.25 (m, 3H),
1.45 (s, 9H), 1.50-1.60 (m, 1H), 1.83 (s, 1H), 1.93 (t, 4H), 2.15
(d, 2H), 2.54 (t, 1H), 2.70 (s, 3H), 7.33 (d, 2H), 7.50 (d, 2H),
7.54 (s, 1H), 9.21 (s, 1H), 9.64 (s, 1H); m/z 426 (M+H).sup.+.
Example 13
{trans-4-[4-(6-Carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetic
acid
##STR00094##
[0363] This compound was synthesised from Intermediate 13-1 using
similar procedure as described in Example 1 to afford the title
compound (0.5 g, 95%).
[0364] .sup.1H NMR (500 MHz, DMSO) .delta. 1.08-1.19 (m, 2H),
1.47-1.57 (m, 2H), 1.71-1.87 (m, 5H), 2.15 (d, 2H), 2.52-2.58 (m,
1H), 7.40 (d, 2H), 8.27 (d, 2H), 9.06 (s, 1H), 9.40 (s, 1H); m/z
340 (M+H).sup.+.
Intermediate 13-1
tert-Butyl
{trans-4-[4-(6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetate
##STR00095##
[0366] This compound was synthesised from Intermediate 13-2 and
Intermediate D using similar Suzuki conditions as described in
Intermediate 1-3. This gave the title compound (570 mg, 45%) as
light-yellow solid.
[0367] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.14-1.24 (m, 2H),
1.47 (s, 9H), 1.51-1.61 (m, 2H), 1.81-1.98 (m, 5H), 2.18 (d, 2H),
2.53-2.61 (m, 1H), 5.67 (br s, 1H), 7.39 (d, 2H), 7.77 (br s, 1H),
7.96 (d, 2H), 9.18 (s, 1H), 9.32 (s, 1H); m/z 396 (M+H).sup.+.
Intermediate 13-2
6-chloropyrazine-2-carboxamide
##STR00096##
[0369] A solution of 6-chloro-pyrazine carboxylic acid (2.00 g,
12.62 mmol) in DMF (7 mL) was cooled to -40.degree. C. NMP (2.77
mL, 25.23 mmol) and isobutyl chloroformate 3.27 mL, 25.23 mmol)
were added. The temperature was allowed to increase to -20.degree.
C. during 20 min and then NH.sub.4OH was added. A precipitate was
rapidly formed and after 15 min it was filtered off and washed with
water. Crystallization from EtOH gave the title compound (670 mg,
34%) as light-brown needles.
[0370] .sup.1H NMR (500 MHz, DMSO) .delta. 7.93 (br s, 1H), 8.24
(br s, 1H), 8.99 (s, 1H), 9.12 (s, 1H).
Example 14
6-{4-[(trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}pyrazine-2-carboxamid-
e
##STR00097##
[0372] This compound was synthesised from Example 13 using similar
conditions as described in Intermediate 1-1. Aqueous work-up gave
low yield and is not recommended here (4 mg, 10%).
[0373] .sup.1H NMR (500 MHz, DMSO) .delta. 1.05-1.17 (m, 2H),
1.45-1.56 (m, 2H), 1.71-1.87 (m, 5H), 1.99 (d, 2H), 2.50-2.59 (m,
1H), 6.71 (s, 1H), 7.25 (s, 1H), 7.39 (d, 2H), 7.88 (s, 1H), 8.26
(d, 2H), 8.40 (s, 1H), 9.07 (s, 1H), 9.39 (s, 1H); m/z 339
(M+H).sup.+.
Example 15
6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}pyrazine-2-carboxamide
##STR00098##
[0375] This compound was synthesised from Example 13 using similar
conditions as in Example 5 to afford the title compound (3 mg, 11%)
as white solid.
[0376] .sup.1H NMR (500 MHz, THF) .delta. 1.11-1.21 (m, 2H), 1.47
(q, 2H), 1.52-1.63 (m, 3H), 1.90-1.98 (m, 4H), 2.55-2.64 (m, 1H),
3.33 (br s, 1H), 3.56-3.63 (m, 2H), 7.09 (br s, 1H), 7.40 (d, 2H),
7.95 (br s, 1H), 8.15 (d, 2H), 9.18 (s, 1H), 9.26 (s, 1H); m/z 326
(M+H).sup.+.
Example 16
Methyl
N-({trans-4-[4-(6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-
-methylalaninate
##STR00099##
[0378] This compound was synthesised from Example 13 and
alpha-aminoisobutyric acid methyl ester hydrochloride using similar
conditions as in Intermediate 1-1. Purification gave title compound
(40 mg, 76%).
[0379] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.13-1.23 (m, 2H),
1.52-1.62 (m, 2H), 1.58 (s, 6H), 1.86-1.98 (m, 5H), 2.11 (d, 2H),
2.52-2.61 (m, 2H), 3.76 (s, 3H), 5.71 (br s, 1H), 6.02 (br s, 1H),
7.38 (d, 2H), 7.77 (br s, 1H), 7.96 (d, 2H), 9.18 (s, 1H), 9.32 (s,
1H); m/z 439 (M+H).sup.+.
Example 17
N-({trans-4-[4-(6-Carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methyl-
alanine
##STR00100##
[0381] The methyl ester from Example 16 was hydrolysed to the
corresponding acid using similar protocol as described in
Intermediate 1-2 to afford the title compound (21 mg, 72%) as white
solid.
[0382] .sup.1H NMR (500 MHz, DMSO) .delta. 1.04-1.14 (m, 2H), 1.31
(s, 6H), 1.43-1.53 (m, 2H), 1.69-1.85 (m, 5H), 1.99 (d, 2H),
2.48-2.57 (m, 2H), 7.39 (d, 2H), 7.87 (br s, 1H), 7.98 (s, 1H),
8.26 (d, 2H), 8.42 (br s, 1H), 9.06 (s, 1H), 9.39 (s, 1H), 12.0 (s,
1H); m/z 425 (M+H).sup.+.
Example 18
3-Carbamoyl-5-{4-[(trans-4-(carboxymethyl)cyclohexyl]phenyl}pyrazin-2-amin-
ium chloride
##STR00101##
[0384] To a solution of Intermediate 18-1 (26 mg, 0.06 mmol) in
dioxane (5 mL) was added a solution of 4M HCl in dioxane (0.316 mL)
in one portion. A precipitate formed. Water (1 mL) was added to
dissolve the precipitate. The reaction mixture was heated in a
microwave oven at 120.degree. C. Evaporation gave title compound
(25.8 mg, 100%) as yellow solid.
[0385] .sup.1H NMR (400 MHz, DMSO) .delta. 1.05-1.20 (m, 2H), 1.48
(q, 2H), 1.66-1.87 (m, 5H), 2.14 (d, 2H), 2.50 (1H, covered by
DMSO), 7.29 (d, 2H), 7.64 (s, 1H), 8.01 (d, 2H), 8.23 (s, 1H), 8.77
(s, 1H); m/z 355 (M+H--HCl).sup.+.
Intermediate 18-1
tert-Butyl
{trans-4-[4-(5-amino-6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}-
acetate
##STR00102##
[0387] This compound was synthesised from Intermediate 18-2 using
similar procedure as described in Intermediate 1-1 to afford the
title compound (26 mg, 24%) as white-yellow powder.
[0388] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.08-1.32 (m, 4H),
1.46 (s, 9H), 1.84 (m, 1H), 2.16 (d, 2H), 2.52 (t, 1H), 5.46 (s,
1H), 7.31 (d, 2H), 7.78 (d, 2H), 7.83 (s, 1H), 8.63 (s, 1H); m/z
411 (M+H).sup.+.
Intermediate 18-2
3-amino-6-{4-[trans-4-(2-tert-butoxy-2-oxoethyl)cyclohexyl]phenyl}pyrazine-
-2-carboxylic acid
##STR00103##
[0390] This compound was synthesised from
3-Amino-6-bromo-pyrazine-2-carboxylic acid methyl ester (CAS
6966-01-4) and Intermediate D using similar Suzuki protocol as
described in Intermediate 1-3. Crude was not isolated. m/z 412
(M+H).sup.+.
Example 19
3-Carbamoyl-5-{4-[trans-4-(carboxymethyl)cyclohexyl]phenyl}pyridinium
trifluoroacetate
##STR00104##
[0392] This compound was synthesised from Intermediate 19-1 using
similar procedure as described in Example 1. Evaporation yielded
the title compound (22 mg, 69%) as white powder.
[0393] .sup.1H NMR (600 MHz, DMSO) .delta. 1.12 (2H, q), 1.50 (2H,
q), 1.74 (1H, s), 1.82 (4H, d), 2.13 (2H, d), 2.51 (1H, t); m/z 339
(M+H-TFA).sup.+.
Intermediate 19-1
tert-Butyl
{trans-4-[4-(5-carbamoylpyridin-3-yl)phenyl]cyclohexyl}acetate
##STR00105##
[0395] This compound was synthesised from Intermediate 19-2 using
similar reaction conditions as described in Intermediate 1-1.
Purification gave title compound (40 mg, 37%) as white powder.
[0396] .sup.1H NMR (400 MHz, CDCl.sub.1) .delta. 0.78-1.70 (13H,
m), 1.83 (1H, s), 1.91 (4H, t), 2.15 (2H, d), 2.52 (1H, t), 5.68
(1H, s), 6.28 (1H, s), 7.33 (2H, d), 7.54 (2H, d), 8.39 (1H, t),
8.95 (1H, s), 8.99 (1H, s); m/z 395 (M+H).sup.1.
Intermediate 19-2
5-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}nicotinic
acid
##STR00106##
[0398] This compound was synthesised from 5-bromonicotinic acid
(CAS 20826-04-4) and Intermediate D using similar Suzuki protocol
as described in Intermediate 1-3. Purification gave title compound
(230 mg, 74%) as white solid.
[0399] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.18 (2H, q), 1.44
(9H, s), 1.55 (2H, q), 1.81 (1H, s), 1.89 (4H, t), 2, 14 (2H, d),
2.53 (1H, t), 7.34 (2H, d), 7.59 (2H, d), 8.50 (1H, t), 8.76 (1H,
d), 8.97 (1H, d); m/z 396 (M+H).sup.+.
Example 20
{trans-4-[4-(6-Carbamoyl-3-methylpyridin-2-yl)phenyl]cyclohexyl}acetic
acid
##STR00107##
[0401] This compound was synthesised from Intermediate 20-1 using
similar conditions as described in Example 1 to afford title
compound (11 mg, 85%).
[0402] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.02-1.18 (m, 2H),
1.37-1.51 (m, 2H), 1.62-1.82 (m, 5H), 2.08 (d, 2H), 2.32 (s, 3H),
2.40-2.51 (m, 1H), 7.27 (d, 2H), 7.49 (d, 3H), 7.81 (d, 2H), 7.86
(s, 1H); m/z 353 (M+H).sup.+.
Intermediate 20-1
tert-Butyl
{trans-4-[4-(6-carbamoyl-3-methylpyridin-2-yl)phenyl]cyclohexyl-
}acetate
##STR00108##
[0404] This compound was synthesised from Intermediate 20-2 and
Intermediate D using similar Suzuki protocol as in Intermediate
1-3. Purification gave title product (15 mg, 21%).
[0405] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.09-1.30 (m, 2H),
1.45 (s, 9H), 1.48-1.61 (m, 2H), 1.76-1.98 (m, 5H), 2.15 (d, 2H),
2.41 (s, 3H), 2.48-2.57 (m, 1H), 5.60 (s, 1H), 7.29 (d, 2H), 7.45
(d, 2H), 7.71 (d, 1H), 7.87 (s, 1H), 8.04 (d, 1H).
Intermediate 20-2
6-chloro-5-methylpyridine-2-carboxamide
##STR00109##
[0407] To a solution of Intermediate 20-3 (112 mg, 0.65 mmol) in
DCM (5 mL) was added PyBROP (457 mg, 0.98 mmol), NH.sub.4Cl (70 mg,
1.30 mmol) and DIPEA (0.43 mL, 2.61 mmol). The reaction mixture was
stirred at RT for 2 h. After dilution with DCM (15 mL) the solution
was washed with sat NaHCO.sub.3 (2.times.15 mL) and water (15 mL),
dried through a phase separator and evaporated. The crude product
was purified by flash chromatography using EtOAc in heptane as
eluent. Pure fractions were evaporated to dryness to afford the
title compound (83 mg, 74%).
[0408] .sup.1H NMR (400 MHz, DMSO) .delta. 2.35 (s, 3H), 7.63 (s,
1H), 7.85-7.90 (m, 3H); m/z 171 (M+H).sup.+.
Intermediate 20-3
6-Chloro-5-methylpyridine-2-carboxylic acid
##STR00110##
[0410] This compound was synthesised from the corresponding
Me-ester using similar protocol as described in Intermediate 1-2 to
give title compound (0.11 g, 80%); m/z 172 (M+H).sup.+.
Intermediate 20-4
Methyl 6-chloro-5-methylpyridine-2-carboxylate
##STR00111##
[0412] A solution of Intermediate 20-5 (1.67 g, 9.99 mmol) in
POCl.sub.3 (15 mL) was heated to reflux for 3 h. After cooling to
RT the reaction mixture was added to an ice-water solution,
basified with 1M NaOH (aq) and extracted with DCM (3.times.30 mL).
Organic layers were combined, passed through a phase separator and
evaporated. The crude product was purified by flash chromatography
using EtOAc (15%) in heptane as eluent. Pure fractions were
evaporated to dryness to afford the title compound (0.73 g,
39%).
[0413] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.44 (s, 3H), 3.97
(s, 3H), 7.67 (d, 1H), 7.96 (d, 1H); m/z 186 (M+H).sup.+.
Intermediate 20-5
Methyl 5-methylpyridine-2-carboxylate 1-oxide
##STR00112##
[0415] To a solution of Intermediate 20-6 (2.11 g, 14.0 mmol) in
DCM (40 mL) was added m-CPBA (4.70 g, 21.0 mmol) and the reaction
was stirred at RT for 5 h. Sat Na.sub.2SO.sub.2 (15 mL) was added
and the reaction was stirred for 5 min. The two phases were
separated and the organic phase was washed with 1M NaHCO.sub.3,
passed through a phase separator and evaporated. The crude product
was taken to the next step without further purification. m/z 168
(M+H).sup.+.
Intermediate 20-6
Methyl 5-methylpyridine-2-carboxylate
##STR00113##
[0417] To a solution of 2,5-dimethylpyridine (3.00 g, 28.0 mmol,
CAS 589-93-5) in pyridine (15 mL) was added selenium dioxide (4.66
g, 42.0 mmol, CAS 7446-08-4). The reaction mixture was heated at
reflux overnight. After cooling to RT a solid was filtered off and
washed with water and pyridine (2.times.5 mL/wash). The filtrate
was evaporated and the crude retaken in methanol (100 mL).
Sulphuric acid (1.34 mL, 25.0 mmol) was added and the reaction
mixture was heated at reflux for 5 h. After cooling to RT the
reaction mixture was basified with 20% NaOH (aq). The methanol was
evaporated off and water was added (50 mL). This mixture was
extracted with DEE (3.times.100 mL). The combined organics were
dried (Na.sub.2SO.sub.4) and evaporated to afford the title
compound (2.11 g, 50%) as light-brown oil.
[0418] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.40 (s, 3H), 3.97
(s, 3H), 7.61 (d, 1H), 8.01 (d, 1H), 8.54 (s, 1H).
Example 21
4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]octane-1-c-
arboxylic acid
##STR00114##
[0420] Powdered potassium hydroxide (204 mg, 3.63 mmol) was added
in one portion to Intermediate 21-1 (493 mg, 1.21 mmol) in
tert-butanol (10 mL) at 40.degree. C. under nitrogen. The resulting
suspension was stirred at 45.degree. C. for 5 h, a thick white
precipitate suspension slowly formed. Acetic acid (0.346 mL, 6.05
mmol) was added and the resulting solution stirred for a several
minutes before being partitioned between EtOAc (100 mL) and IN
citric acid (50 mL). The suspension was filtered and dried to
afford of desired product as a white solid (300 mg), the organic
phase was separated, dried over MgSO.sub.4, filtered and evaporated
to afford crude product as a colourless oil which solidified on
standing. The filtrate was purified by preparative HPLC (Waters
XBridge Prep C18 OBD column, 5.mu., silica, 50 mm diameter, 150 mm
length), using decreasingly polar mixtures of water (containing
0.1% formic acid) and MeCN as eluents. Fractions containing the
desired compound were evaporated to dryness and combined with the
solid to afford the title compound (376 mg, 82%) as a white
solid.
[0421] .sup.1H NMR (400 MHz, DMSO) .delta. 1.84 (12H, s), 2.58 (3H,
s), 2.73 (3H, s), 7.46 (2H, d), 7.57 (1H, s), 7.66 (2H, d), 7.98
(1H, s), 12.08 (1H, s); m/z 380 (M+H).sup.+.
Intermediate 21-1
Ethyl
4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]octa-
ne-1-carboxylate
##STR00115##
[0423] A solution of Intermediate 21-2 (525 mg, 1.37 mmol),
Intermediate 21-4 (254 mg, 1.37 mmol), and tripotassium phosphate
(348 mg, 1.64 mmol) in DME (15 mL), EtOH (5 mL) and water (2 mL)
were degassed before addition of
(1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM
adduct) (56.2 mg, 0.07 mmol). The reaction mixture was heated to
80.degree. C., under nitrogen, and left to stir at 80.degree. C.
for 2 h. The reaction mixture was allowed to cool to room
temperature and then evaporated. The crude product was partitioned
between EtOAc (100 mL) and water (50 mL), filtered through celite
and the organic phase was separated, washed with saturated brine
(50 mL). The organic layer was dried over MgSO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by flash silica chromatography, elution gradient 20 to 50% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (493 mg, 89%) as a white solid.
[0424] .sup.1H NMR (400 MHz, DMSO) .delta. 1.18 (3H, t), 1.85 (12H,
s), 2.58 (3H, s), 2.73 (3H, s), 4.05 (2H, q), 7.46 (2H, d), 7.57
(1H, s), 7.66 (2H, d), 7.97 (1H, s); m/z 408 (M+H).sup.+.
Intermediate 21-2
Ethyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[2.2-
.2]octane-1-carboxylate
##STR00116##
[0426] To a degassed solution of Intermediate 21-3 (1.66 g, 4.32
mmol) in DMSO (30 mL) was added potassium acetate (1.272 g, 12.96
mmol) and bis(pinacolato)diboron (1.207 g, 4.75 mmol), the reaction
mixture was degassed for a further 20 minutes.
(1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM
adduct) (0.212 g, 0.26 mmol) was added and the suspension was
degassed and then heated, under nitrogen at 80.degree. C. for 3 h.
The reaction mixture was allowed to cool, poured onto water (125
mL), the suspension was filtered and the solid was purified by
flash silica chromatography, elution gradient 0 to 20% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (1.080 g, 65.0%) as a white solid.
[0427] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.25 (3H, t), 1.33
(12H, s), 1.84-1.93 (12H, m), 4.12 (2H, q), 7.33 (2H, d), 7.75 (2H,
d); m/z (EI+) 384 M.sup.+.
Intermediate 21-3
Ethyl 4-(4-iodophenyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00117##
[0429] [Bis(trifluoroacetoxy)iodo]benzene (3.78 g, 8.78 mmol) and
iodine (1.061 g, 4.18 mmol) were added to a stirred solution of
ethyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (prepared
according to the procedure described in WO 2007/071966) (2.16 g,
8.36 mmol, CAS 10207-26-8) in CHCl.sub.3 (50 mL). The resulting
solution was stirred at ambient temperature for 90 minutes. The
reaction mixture was poured into sodium thiosulfate (100 mL),
extracted with DCM (2.times.100 mL), the organic layer was washed
with aqueous sodium thiosulfate (2.times.80 mL), separated, dried
over MgSO.sub.4, filtered and evaporated to afford a yellow oil
which solidified on standing. The crude product was purified by
flash silica chromatography, elution gradient 0 to 20% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (2.78 g, 87%) as a white solid.
[0430] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24 (3H, t),
1.79-1.84 (6H, m), 1.88-1.93 (6H, m), 4.11 (2H, q), 7.05 (2H, d),
7.61 (2H, d); m/z 385 (M+H).sup.+.
Intermediate 21-4
6-Chloro-3,5-dimethylpyrazine-2-carboxamide
##STR00118##
[0432] Intermediate 1-4 (227 g, 1057.54 mmol) was stirred in
ammonia (7N in MeOH) (1957 mL, 89633.59 mmol) at ambient
temperature overnight. The mixture was evaporated to dryness and
the residue was triturated with ether and the suspension was
filtered and at 40.degree. C. under vacuum to afford the title
compound (181 g, 92%) as a light brown solid.
[0433] .sup.1H NMR (400 MHz, DMSO) .delta. 2.59 (3H, s), 2.67 (3H,
s), 7.70 (1H, s), 7.99 (1H, s) m/z 186 (M+H).sup.+.
Example 22
2-(4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo-[2.2.2]octan--
1-yl)acetic acid
##STR00119##
[0435] This compound was synthesised from Intermediate 22-1 using
similar conditions as described in Example 21 to give the title
compound (292 mg, 77%) as a white solid.
[0436] .sup.1H NMR (400 MHz, DMSO) .delta. 1.60-1.65 (6H, m),
1.80-1.84 (6H, m), 2.05 (2H, s), 2.58 (3H, s), 2.72 (3H, s), 7.45
(2H, d), 7.56 (1H, s), 7.64 (2H, d), 7.97 (1H, s), 11.91 (1H, s);
m/z 394 (M+H).sup.+.
Intermediate 22-1
Methyl
2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]-
octan-1-yl)acetate
##STR00120##
[0438] This compound was synthesised from Intermediate 21-4 and
Intermediate 22-2 using similar conditions as described in
Intermediate 21-1 to give the title compound (392 mg, 96%) as a
white solid.
[0439] .sup.1H NMR (400 MHz, DMSO) .delta. 1.57-1.63 (6H, m),
1.80-1.86 (6H, m), 2.15 (2H, s), 2.58 (3H, s), 2.73 (3H, s), 3.58
(3H, s), 7.44 (2H, d), 7.57 (1H, s), 7.64 (2H, d), 7.97 (1H, s);
m/z 408 (M+H).sup.+.
Intermediate 22-2
Methyl
2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo-
[2.2.2]octan-1-yl)acetate
##STR00121##
[0441] This compound was synthesised from Intermediate 22-3 using
similar conditions as described in Intermediate 21-2 to give the
title compound (0.701 g, 55.6%) as a white solid.
[0442] .sup.1H NMR (400, CDCl.sub.3) .delta. 1.33 (12H, s),
1.62-1.66 (6H, m), 1.82-1.87 (6H, m), 2.16 (2H, s), 3.65 (3H, s),
7.32 (2H, d), 7.74 (2H, d); m/z (EI+) 384 M.sup.+.
Intermediate 22-3
Methyl 2-(4-(4-iodophenyl)bicyclo[2.2.2]octan-1-yl)acetate
##STR00122##
[0444] This compound was synthesised from methyl
2-(4-phenylbicyclo[2.2.2]octan-1-yl)acetate (prepared according to
the procedure described in WO 2007/071966, CAS 70631-58-2) using
similar conditions as described in Intermediate 21-3 to give the
title compound (1.320 g, 80%) as a white solid.
[0445] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.62-1.66 (6H, m),
1.77-1.82 (6H, m), 2.16 (2H, s), 3.66 (3H, s), 7.05 (2H, d), 7.59
(2H, d); m/z (EI+) 384 M.sup.+.
Example 23
3-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]adamantane-1-carboxylic
acid
##STR00123##
[0447] This compound was synthesised from Intermediate 23-1 using
similar conditions as described in Example 21. Except after 70
minutes the reaction mixture was allowed to cool and 1N citric acid
(15 mL) was added, the precipitate was collected by filtration,
washed with 1N citric acid (10 mL), water (10 mL) and dried under
vacuum to afford the title compound (360 mg, 90%) as a white
solid.
[0448] .sup.1H NMR (400 MHz, DMSO) .delta. 1.69-1.73 (2H, m),
1.84-1.89 (8H, m), 1.96 (2H, s), 2.17-2.19 (2H, m), 2.59 (3H, s),
2.74 (3H, s), 7.50 (2H, d), 7.59 (1H, s), 7.68 (2H, d), 7.98 (1H,
s), 12.07 (1H, s); m/z 406 (M+H).sup.+.
Intermediate 23-1
Methyl
3-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]adamantane-1-carb-
oxylate
##STR00124##
[0450] This compound was synthesised from Intermediate 21-4 and
Intermediate 23-2 using similar conditions as described in
Intermediate 21-1 to give the title compound (412 mg, 74.3%) as a
white solid.
[0451] .sup.1H NMR (400 MHz, DMSO) .delta. 1.70-1.73 (2H, m),
1.85-1.91 (8H, m), 1.98 (2H, s), 2.18-2.20 (2H, m), 2.58 (3H, s),
2.73 (3H, s), 3.60 (3H, s), 7.49 (2H, d), 7.58 (1H, s), 7.68 (2H,
d), 7.97 (1H, s); m/z 420 (M+H).sup.+.
Intermediate 23-2
Methyl
3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]adamantane-
-1-carboxylate
##STR00125##
[0453] This compound was synthesised from Intermediate 23-3 using
similar conditions as described in Intermediate 21-2 to give the
title compound (1.758 g, 63.9%) as a white solid.
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.33 (12H, s),
1.73-1.75 (2H, m), 1.88-1.95 (8H, m), 2.05 (2H, s), 2.21-2.25 (2H,
m), 3.67 (3H, s), 7.37 (2H, d), 7.77 (2H, d); m/z 396 (EI+)
M.sup.+.
Intermediate 23-3
Methyl 3-(4-iodophenyl)adamantane-1-carboxylate
##STR00126##
[0456] This compound was synthesised from Intermediate 23-4 using
similar conditions as described in Intermediate 21-3 to give the
title compound (2.75 g, 88%) as a colourless oil.
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.72-1.74 (2H, m),
1.89-1.95 (8H, m), 1.99 (2H, s), 2.22-2.24 (2H, m), 3.67 (3H, s),
7.11 (2H, d), 7.63 (2H, d); m/z 396 (EI+) M.sup.+.
Intermediate 23-4
Methyl 3-phenyladamantane-1-carboxylate
##STR00127##
[0459] Trimethylsilyldiazomethane 2M solution in hexane (8.15 mL,
16.31 mmol) was added dropwise to a stirred solution of
3-phenyl-1-adamantanecarboxylic acid (2.09 g, 8.15 mmol, CAS
37589-22-3) in toluene (20 mL) and methanol (10 mL) over a period
of 2 minutes. The resulting solution was stirred at ambient
temperature for 60 minutes. The reaction mixture was evaporated to
afford crude product. The crude product was purified by flash
silica chromatography, elution gradient 0 to 20% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (2.140 g, 97%) as a colourless oil.
[0460] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.73-1.75 (2H, m),
1.90-1.93 (8H, m), 2.04 (2H, s), 2.22-2.25 (2H, m), 3.67 (3H, s),
7.17-7.21 (1H, m), 7.30-7.38 (4H, m); m/z 270 (EI+) M.
Example 24
2-[3-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]-1-adamantyl]acetic
acid
##STR00128##
[0462] This compound was synthesised from Intermediate 24-1 using
similar conditions as described in Example 21 to give the title
compound (126 mg, 62.0%) as a white solid.
[0463] .sup.1H NMR (400 MHz, DMSO) .delta. 1.62-1.71 (6H, m), 1.75
(2H, s), 1.81-1.88 (4H, m), 2.07 (2H, s), 2.15 (2H, s), 2.59 (3H,
s), 2.73 (3H, s), 7.47 (2H, d), 7.58 (1H, s), 7.67 (2H, d), 7.97
(1H, s), 11.89 (1H, s); m/z 420 (M+H).sup.+.
Intermediate 24-1
Methyl
2-[3-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]-1-adamantyl]a-
cetate
##STR00129##
[0465] This compound was synthesised from Intermediate 21-4 and
Intermediate 24-2 using similar conditions as described in
Intermediate 21-1 to give the title compound (210 mg, 48.4%) as a
colourless oil which solidified on standing.
[0466] .sup.1H NMR (400 MHz, DMSO) .delta. 1.60-1.70 (6H, m), 1.73
(2H, s), 1.81-1.89 (4H, m), 2.14-2.16 (2H, m), 2.16 (2H, s), 2.59
(3H, s), 2.74 (3H, s), 3.57 (3H, s), 7.47 (2H, d), 7.58 (1H, s),
7.68 (2H, d), 7.97 (1H, s); m/z 434 (M+H).sup.+.
Intermediate 24-2
Methyl
2-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-adam-
antyl]acetate
##STR00130##
[0468] This compound was synthesised from Intermediate 24-3 using
similar conditions as described in Intermediate 21-2 to give the
title compound (1.240 g, 76%) as a white solid.
[0469] .sup.1H NMR (400 MHz, CDCl.sub.1) .delta. 1.33 (12H, s),
1.61-1.72 (6H, m), 1.75 (2H, s), 1.82-1.90 (2H, m), 2.17 (2H, s),
2.17-2.20 (4H, m), 3.64 (3H, s), 7.36 (2H, d), 7.77 (2H, d); m/z
410 (EI+) M.sup.+.
Intermediate 24-3
Methyl 2-[3-(4-iodophenyl)-1-adamantyl]acetate
##STR00131##
[0471] This compound was synthesised from methyl
2-(3-phenyl-1-adamantyl)acetate (CAS 175721-57-0, prepared
according to the procedure described in WO 2007/071966 using
similar conditions as described in Intermediate 21-3 to give the
title compound (1.680 g, 81%) as a yellow oil which solidified on
standing.
[0472] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.62-1.71 (8H, m),
1.78-1.84 (4H, m), 2.16 (2H, s), 2.17-2.20 (2H, m), 3.65 (3H, s),
7.09 (2H, d), 7.62 (2H, d); m/z 410 (EI+) M.
Example 25
3-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)pr-
opanoic acid
##STR00132##
[0474] This compound was synthesised from Intermediate 25-1 using
similar conditions as described in Example 21. Except the crude
product was purified by crystallisation from boiling EtOH
(.about.10 mL) to afford the title compound (180 mg, 65.3%) as a
pale red solid.
[0475] .sup.1H NMR (400 MHz, DMSO) .delta. 1.02-1.11 (2H, m),
1.27-1.36 (1H, m), 1.43-1.53 (4H, m), 1.81-1.87 (4H, m), 2.25 (2H,
t), 2.51-2.55 (1H, m), 2.58 (3H, s), 2.73 (3H, s), 7.35 (2H, d),
7.57 (1H, s), 7.64 (2H, d), 7.97 (1H, s), 11.97 (1H, s); m/z 382
(M+H).sup.+.
Intermediate 25-1
Methyl
3-(1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohe-
xyl)propanoate
##STR00133##
[0477] Acetonitrile (4.345 mL) added to 1,1
bis(di-tert-butylphosphino)ferrocene palladium dichloride (57.7 mg,
0.10 mmol) and stirred at room temperature for 5 min before
addition of potassium carbonate (540 mg, 3.91 mmol), water (4.35
mL) and Intermediate 25-2 (728 mg, 1.96 mmol). After a further 5
minutes Intermediate 21-4 (364 mg, 1.96 mmol) was added and the
reaction mixture heated to 80.degree. C. for 5 hours. The reaction
mixture was partitioned between EtOAc (100 mL) and water (50 mL)
and the mixture was filtered through celite, washing through with
EtOAc (50 mL). The organic layer was dried over MgSO.sub.4,
filtered and evaporated to afford crude product. The crude product
was purified by flash silica chromatography, elution gradient 0 to
50% EtOAc in isohexane. Pure fractions were evaporated to dryness
to afford the title compound (286 mg, 37.0%) as a red brown
solid.
[0478] .sup.1H NMR (400 MHz, DMSO) .delta. 1.02-1.13 (3H, m),
1.26-1.37 (1H, m), 1.42-1.53 (4H, m), 1.80-1.88 (4H, m), 2.35 (2H,
t), 2.58 (3H, s), 2.74 (3H, s), 3.59 (3H, s), 7.34 (2H, d), 7.57
(1H, s), 7.64 (2H, d), 7.96 (1H, s); m/z 396 (M+H).sup.+.
Intermediate 25-2
Methyl
3-(1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
cyclohexyl)propanoate
##STR00134##
[0480] A solution of Intermediate 25-3 (4.40 g, 11.16 mmol) in
dioxane (85 mL) was degassed with nitrogen for a period of 5
minutes. Potassium acetate (3.28 g, 33.47 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.12
g, 12.27 mmol),
(1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM
adduct) (0.551 g, 0.67 mmol) and
1,1'-Bis(diphenylphosphino)ferrocene (0.375 g, 0.67 mmol) were
added. The resulting mixture was stirred at 85.degree. C. under
nitrogen for 17 hours. The reaction mixture was concentrated and
diluted with EtOAc (200 mL), and then mixture was filtered through
celite. The filtrate was washed with saturated brine, the organic
layer was dried over MgSO.sub.4, filtered and evaporated to afford
crude product. The crude product was purified by flash silica
chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure
fractions were evaporated to dryness to afford the title compound
(2.68 g, 64.5%) as a white solid.
[0481] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.02-1.13 (2H, m),
1.31-1.33 (1H, m), 1.33 (12H, s), 1.40-1.52 (2H, m), 1.59 (2H, q),
1.84-1.92 (4H, m), 2.36 (2H, t), 2.43-2.52 (1H, m), 3.68 (3H, s),
7.21 (2H, d), 7.73 (2H, d); m/z 372 (EI+) M.sup.+.
Intermediate 25-3
Methyl
3-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)-cyclohexyl)prop-
anoate
##STR00135##
[0483] Triethylamine (2.59 mL, 18.57 mmol) was added to a stirred
solution of Intermediate 25-4 (3.27 g, 12.46 mmol) and
trifluoromethanesulphonic anhydride (2.56 mL, 15.58 mmol) in DCM
(120 mL) cooled to 0.degree. C., over a period of 5 minutes under
nitrogen. The resulting red solution was stirred at 0.degree. C.
for 2 hours and then allowed to warm to ambient temperature
overnight. The reaction mixture was diluted with DCM (100 mL), and
washed sequentially with water (100 mL), saturated NaHCO.sub.3 (100
mL), and saturated brine (100 mL). The organic layer was dried over
MgSO.sub.4, filtered and evaporated to afford crude product. The
crude product was purified by flash silica chromatography, elution
gradient 0 to 20% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (4.42 g, 90%) as
a yellow oil.
[0484] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.07-1.11 (2H, m),
1.29-1.35 (1H, m), 1.37-1.47 (2H, m), 1.58 (2H, q), 1.88-1.91 (4H,
m), 2.36 (2H, t), 2.46-2.53 (1H, m), 3.68 (3H, s), 7.15-7.19 (2H,
m), 7.23-7.27 (2H, m); m/z 394 (EI+) M.sup.+.
Intermediate 25-4
Methyl 3-(1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)propanoate
##STR00136##
[0486] A solution of Intermediate 25-5 (3.82 g, 15.38 mmol) in MeOH
(100 mL) and concentrated H.sub.2SO.sub.4 (1.0 mL) was stirred at
70.degree. C. for 3 hours and allowed to cool to ambient
temperature overnight. The reaction mixture was evaporated to
dryness and redissolved in EtOAc (200 mL) and washed with saturated
brine (2.times.150 mL). The organic layer was dried over
MgSO.sub.4, filtered and evaporated to afford crude product. The
crude product was purified by flash silica chromatography, elution
gradient 0 to 20% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (3.27 g, 81%) as
a white solid.
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.01-1.12 (2H, m),
1.26-1.33 (1H, m), 1.35-1.45 (2H, m), 1.58 (2H, q), 1.83-1.89 (4H,
m), 2.36 (2H, t), 2.35-2.44 (1H, m), 3.68 (3H, s), 4.62 (1H, s),
6.73-6.77 (2H, m), 7.04-7.08 (2H, m); m/z 262 (EI+) M.sup.+.
Intermediate 25-5
3-(1r,4r)-4-(4-Hydroxyphenyl)cyclohexyl)propanoic acid
##STR00137##
[0489] A solution of Intermediate 25-6 (5.49 g, 17.86 mmol) and
sodium hydroxide (10.71 g, 267.88 mmol) in 1,2-propanediol (65 mL)
and water (16 mL) was heated to 140.degree. C. for 1 hour. The
reaction mixture was allowed to cool to ambient temperature,
adjusted to pH 2 with 2M HCl and the suspension was extracted into
EtOAc (2.times.200 mL). The organic extracts were combined, washed
with saturated brine (200 mL), dried over MgSO.sub.4, filtered and
evaporated to afford crude product. This was slurried in isohexane
(120 mL), filtered and air dried to afford the title compound (3.87
g, 86%) as a white solid, which was used without further
purification.
[0490] .sup.1H NMR (400 MHz, DMSO) .delta. 0.95-1.05 (2H, m),
1.16-1.39 (3H, m), 1.44 (2H, q), 1.73-1.79 (4H, m), 2.23 (2H, t),
2.29-2.38 (1H, m), 6.62-6.66 (2H, m), 6.98 (2H, d), 9.03 (1H, s),
11.92 (1H, s); m/z 247 (M-H).sup.-.
Intermediate 25-6
4-((1r,4r)-4-(2-Cyanoethyl)cyclohexyl)phenyl methanesulfonate
##STR00138##
[0492] Sodium cyanide (1.669 g, 34.06 mmol) was added to a stirred
solution of Intermediate 25-7 (8.55 g, 22.71 mmol) in DMF (153 mL).
The resulting mixture was stirred at 80.degree. C. for 3 h and then
allowed to cool to ambient temperature. The reaction mixture was
diluted with EtOAc (150 mL), and washed with saturated brine
(2.times.250 mL). The organic layer was dried over MgSO.sub.4,
filtered and evaporated to afford desired product. This still
contained DMF so it was re dissolved in EtOAc (150 mL), and washed
with saturated brine (2.times.200 mL), the organic layer was dried
over MgSO.sub.4, filtered and evaporated to afford crude product.
The crude product was purified by flash silica chromatography,
elution gradient 30 to 60% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (4.08 g, 58.4%)
as a white solid.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.06-1.16 (2H, m),
1.41-1.52 (3H, m), 1.54 (3H, s), 1.64 (2H, q), 1.89-1.95 (4H, m),
2.40 (2H, t), 2.47-2.53 (1H, m), 3.13 (3H, s), 7.18-7.24 (4H, m);
m/z 307 (EI+) M.sup.+.
Intermediate 25-7
4-(1r,4r)-4-(2-(Methylsulfonyloxy)ethyl)cyclohexyl)phenyl
methanesulfonate
##STR00139##
[0495] Methanesulphonyl chloride (6.56 mL, 84.58 mmol) was added to
a stirred suspension of Intermediate 25-8 (8.47 g, 38.45 mmol) and
triethylamine (11.79 mL, 84.58 mmol) in DCM (300 mL). The resulting
solution was stirred at ambient temperature for 16 h. The reaction
mixture was washed with saturated brine (100 mL), the organic layer
was dried over MgSO.sub.4, filtered and evaporated to afford crude
product. The crude product was purified by flash silica
chromatography, elution gradient 20 to 70% EtOAc in isohexane. Pure
fractions were evaporated to dryness to afford the title compound
(13.84 g, 96%) as a white solid.
[0496] .sup.1H NMR (400 MHz, DMSO) .delta. 0.99-1.15 (2H, m),
1.32-1.51 (3H, m), 1.62 (2H, q), 1.75-1.87 (4H, m), 2.52-2.56 (1H,
m), 3.16 (3H, s), 3.27 (3H, 3), 4.26 (1H, t), 7.22-7.26 (2H, m),
7.31-7.35 (2H, m); m/z 399 (M+Na).sup.+.
Intermediate 25-8
4-((1r,4r)-4-(2-Hydroxyethyl)cyclohexyl)phenol
##STR00140##
[0498] A 1M solution of lithium aluminum hydride in THF (80 mL,
79.75 mmol) was added dropwise to a stirred solution of methyl
2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate (prepared
according to WO 2004/047755) (12.3 g, 49.53 mmol, CAS 701232-67-9)
in THF (280 mL) at 0.degree. C. under nitrogen. A thick suspension
formed so the mixture was removed from the cooling bath and stirred
at ambient temperature for 1 h. The reaction mixture was cooled in
0.degree. C. and carefully quenched with saturated NH.sub.4Cl (75
mL), water (50 mL) and 2N HCl (50 mL). The mixture was filtered
through celite, washing through with MeOH (150 mL) and EtOAc
(2.times.250 mL). The filtrate was concentrated, the residue was
diluted with EtOAc (300 mL), washed sequentially with 2N HCl (100
mL) and saturated brine (200 mL). The organic layer was dried over
MgSO.sub.4, filtered and evaporated to afford the title compound
(10.37 g, 95%) as a white solid.
[0499] .sup.1H NMR (400 MHz, DMSO) .delta. 0.97-1.06 (2H, m),
1.29-1.42 (5H, m), 1.71-1.79 (4H, m), 2.29-2.36 (1H, m), 3.42-3.47
(2H, m), 4.27 (1H, t), 6.64 (2H, d), 6.98 (2H, d), 9.03 (1H, s);
m/z 220 (EI+) M.sup.+.
Example 26
(1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cycloh-
exanecarboxylic acid
##STR00141##
[0501] A solution of Intermediate 26-1 (561 mg, 1.22 mmol) in TFA
(6.098 mL) allowed to stand at ambient temperature for 30 minutes.
The reaction mixture was evaporated and ether was added to the
residue to give a solid which was purified by recrystallisation
from boiling absolute EtOH (.about.10 mL) to afford the title
compound (293 mg, 59.5%) as a yellow solid.
[0502] .sup.1H NMR (400 MHz, DMSO) .delta. 1.45-1.59 (4H, m),
1.93-2.00 (2H, m) 2.08-2.10 (2H, m), 2.28-2.34 (1H, m), 2.59 (3H,
s), 2.73 (3H, s), 4.48-4.52 (1H, m), 7.32 (1H, d), 7.59 (1H, s),
7.63-7.66 (1H, m), 7.86 (1H, d), 8.05 (1H, s), 12.10 (1H, s); m/z
404 (M+H).sup.+.
Intermediate 26-1
(1r,4r)-tert-Butyl
4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexaneca-
rboxylate
##STR00142##
[0504] This compound was synthesised from Intermediate 26-2 using
similar conditions as described in Intermediate 25-1 to give the
title compound (561 mg, 71.5%) as a yellow solid.
[0505] .sup.1H NMR (400 MHz, DMSO) .delta. 1.47 (9H, s), 1.54-1.65
(4H, m), 1.96-2.04 (2H, m), 2.12-2.17 (2H, m), 2.32-2.39 (1H, m),
2.66 (3H, s), 2.80 (3H, s), 4.53-4.60 (1H, m), 7.39 (1H, d), 7.66
(1H, s), 7.71 (1H, d), 7.92 (1H, s), 8.12 (1H, s); m/z 460
(M+H).sup.+.
Intermediate 26-2
(1r,4r)-tert-Butyl
4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cycloh-
exanecarboxylate
##STR00143##
[0507] This compound was synthesised from Intermediate 26-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (4.23 g, 88%) as a colourless oil which solidified
on standing.
[0508] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.33 (12H, s),
1.45 (9H, s), 1.55-1.62 (4H, m), 2.03-2.08 (2H, m), 2.13-2.19 (2H,
m), 2.24-2.31 (1H, m), 4.25-4.31 (1H, m), 6.92 (1H, d), 7.61 (1H,
d), 7.79 (1H, s); m/z 436 (EI+) M.sup.+.
Intermediate 26-3
(1r,4r)-tert-Butyl
4-(4-bromo-2-chlorophenoxy)cyclohexane-carboxylate
##STR00144##
[0510] To a solution of Intermediate 26-4 (5.3 g, 26.46 mmol, CAS
931110-79-1), 4-bromo-2-chlorophenol (6.59 g, 31.76 mmol) and
triphenylphosphine (8.33 g, 31.76 mmol) in THF (200 mL) was added
diisopropyl azodicarboxylate (5.73 mL, 29.11 mmol). The solution
was stirred at room temperature for 4 h. The reaction mixture was
evaporated. The crude product was purified by flash silica
chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure
fractions were evaporated to dryness to afford the title compound
(4.27 g, 41.4%) as a colourless oil.
[0511] .sup.1H NMR (400 MHz, DMSO) .delta. 1.37-1.53 (13H, m),
1.88-2.03 (4H, m), 2.23-2.28 (1H, m), 4.35-4.39 (1H, m), 7.19 (1H,
d), 7.42-7.44 (1H, m), 7.63 (1H, d); HPLC tR=3.65 min.
Intermediate 26-4
(1s,4s)-tert-Butyl 4-hydroxycyclohexanecarboxylate
##STR00145##
[0513] To a suspension of (1s,4s)-4-hydroxycyclohexanecarboxylic
acid (5 g, 34.68 mmol, CAS 3685-22-1) in toluene (160 mL) at
90.degree. C. was added N,N-Dimethylformamide di-tert-butyl acetal
(16.63 mL, 69.36 mmol) in one portion. The resultant solution was
stirred at 90.degree. C. for 1 h. A further portion of
N,N-Dimethylformamide di-tert-butyl acetal (16.63 mL, 69.36 mmol)
was then added and the reaction mixture stirred for 30 min at
90.degree. C. and then room temperature overnight. Further
N,N-Dimethylformamide di-tert-butyl acetal (10 mL) added dropwise
over 10 minutes, the reaction mixture was stirred at 70.degree. C.
for 1 h and then allowed to cool. The reaction mixture was washed
with 2M NaOH (100 mL), brine (100 mL) and then evaporated to give
the title compound (5.30 g, 76%) as an oil.
[0514] .sup.1H NMR (400 MHz, DMSO) .delta. 1.36-1.39 (1H, m), 1.39
(9H, s), 1.41-1.51 (6H, m), 1.70-1.81 (2H, m), 2.19-2.25 (1H, m),
3.62 (1H, m), 4.32 (1H, d).
Example 27
(1
s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclo-
hexanecarboxylic acid
##STR00146##
[0516] This compound was synthesised from Intermediate 27-1 using
similar conditions as described in Example 21 to give the title
compound (182 mg, 50.8%) as a white solid, which was crystallised
from boiling absolute EtOH (.about.2 mL).
[0517] .sup.1H NMR (400 MHz, DMSO) .delta. 1.67-1.74 (4H, m),
1.76-1.93 (4H, m), 2.35-2.41 (1H, m), 2.60 (3H, s), 2.73 (3H, s),
4.77 (1H, brs), 7.28 (1H, d), 7.59 (1H, s), 7.65 (1H, dd), 7.87
(1H, d), 8.05 (1H, s), 12.07 (1H, s); m/z 404 (M+H).sup.+.
Intermediate 27-1
(1s,4s)-Methyl
4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexaneca-
rboxylate
##STR00147##
[0519] This compound was synthesised from Intermediate 27-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 25-1 to give the title compound (371 mg, 48.1%) as a
white solid.
[0520] .sup.1H NMR (400 MHz, DMSO) .delta. 1.68-1.75 (4H, m),
1.78-1.93 (4H, m), 2.52-2.54 (1H, m) 2.60 (3H, s), 2.73 (3H, s),
3.61 (3H, s), 4.76-4.79 (1H, m), 7.29 (1H, d), 7.59 (1H, s), 7.65
(1H, dd), 7.87 (1H, d), 8.05 (1H, s); m/z 418 (M+H).sup.+.
Intermediate 27-2
(1s,4s)-Methyl
4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cycloh-
exanecarboxylate
##STR00148##
[0522] This compound was synthesised from Intermediate 27-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (4.73 g, 85%) as a pale yellow oil which solidified
on standing.
[0523] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.33 (12H, s),
1.60-1.68 (2H, m), 1.74-1.81 (2H, m), 1.98-2.09 (4H, m), 2.37-2.44
(1H, m), 3.69 (3H, s), 4.57-4.60 (1H, m), 6.90 (1H, d), 7.60-7.62
(1H, m), 7.80 (1H, d); m/z 394 (EI+) M.sup.+.
Intermediate 27-3
(1s,4s)-methyl
4-(4-bromo-2-chlorophenoxy)cyclohexane-carboxylate
##STR00149##
[0525] This compound was synthesised from (1r,4r)-methyl
4-hydroxycyclohexanecarboxylate (CAS 6125-57-1) and
4-bromo-2-chlorophenol using similar conditions as described in
Intermediate 26-3 to give the title compound (4.88 g, 55.5%) as a
colourless oil.
[0526] .sup.1H NMR (400 MHz, DMSO) .delta. 1.62-1.86 (8H, m), 3.60
(3H, s), 4.66 (1H, m), 7.15 (1H, d), 7.42-7.45 (1H, m), 7.64 (1H,
d) one CH obscured; HPLC tR=2.99 min.
Example 28
6-((1r,4s)-4-((2H-Tetrazol-5-yl)methyl)-2',3'-dihydrospiro[cyclohexane-1,1-
'-indene]-5'-yl)-3,5-dimethylpyrazine-2-carboxamide
##STR00150##
[0528] A solution of Intermediate 21-4 (197 mg, 1.06 mmol),
Intermediate 28-1 (473 mg, 1.06 mmol) and tripotassium phosphate
(449 mg, 2.11 mmol) in DME (10 mL), EtOH (6.25 mL) and water (2.5
mL) was degassed before addition of
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (43.5
mg, 0.05 mmol). The reaction mixture was heated to 80.degree. C.,
under nitrogen, and left to stir overnight for 5 hrs. The reaction
mixture was allowed to cool to room temperature and then
evaporated. The residue was acidfied with 2N HCl (3 mL), diluted
with water (20 mL) and extracted into EtOAc (4.times.50 mL). The
organic extracts were combined, dried over MgSO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by preparative HPLC (Waters XBridge Prep C18 OBD column, 5.mu.
silica, 50 mm diameter, 150 mm length), using decreasingly polar
mixtures of water (containing 0.1% formic acid) and MeCN as
eluents. Fractions containing the desired compound were evaporated
to dryness to afford the title compound (51.9 mg, 11.76%) as a
white solid.
[0529] .sup.1H NMR (400 MHz, DMSO) .delta. 1.23-1.38 (2H, m),
1.58-1.73 (6H, m), 1.86-1.96 (1H, m), 2.04 (2H, t), 2.63 (3H, s),
2.79 (3H, s), 2.91 (2H, d), 2.97 (2H, t), 7.33 (1H, d), 7.55 (1H,
d), 7.60 (1H, s), 7.62 (1H, s), 8.02 (1H, s); NH not seen; m/z 418
(M+H).sup.+.
Intermediate 28-1
3-(5-(((1r,4s)-5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihy-
drospiro[cyclohexane-1,1'-indene]-4-yl)methyl)-2H-tetrazol-2-yl)propanenit-
rile
##STR00151##
[0531] To a solution of triphenylphosphine (1.453 g, 5.54 mmol) and
Intermediate 28-2 (900 mg, 2.13 mmol) in THF (25.400 mL) in an ice
bath was added diisopropyl azodicarboxylate (1.133 mL, 5.75 mmol).
The resulting yellow solution was allowed to stir at 0.degree. C.,
after 2 minutes azidotrimethylsilane (0.820 mL, 6.18 mmol) was
added dropwise. After 17 hours at ambient temperature further
triphenylphosphine (1.453 g, 5.54 mmol), diisopropyl
azodicarboxylate (1.133 mL, 5.75 mmol) and azidotrimethylsilane
(0.820 mL, 6.18 mmol) were added and the suspension was stirred at
ambient temperature for a further 24 hours. The reaction mixture
was cooled in an ice bath and a solution of Sodium nitrite (162 mg,
2.34 mmol) in water (3 mL) was added and after 30 minutes a
solution of ammonium cerium(IV) nitrate (1285 mg, 2.34 mmol) in
water (10 mL) was added (CAUTION: Gas evolution). The reaction
mixture was stirred for a further 45 minutes. The reaction mixture
was poured into water (50 mL) and extracted with DCM (200 mL and
100 mL). The organic extracts were combined, dried over MgSO.sub.4,
filtered and evaporated to afford crude product.
[0532] The crude product was purified by flash silica
chromatography, elution gradient 0 to 80% EtOAc in isohexane. Mixed
fractions were evaporated to dryness to afford the title compound
(487 mg, 51.1%) as a cream solid.
[0533] .sup.1H NMR (400 MHz, DMSO) .delta. 1.20-1.38 (14H, m),
1.40-1.50 (2H, m), 1.53-1.70 (4H, m), 1.83-1.97 (3H, m), 2.82 (2H,
t), 2.89 (2H, d), 3.18 (2H, t), 4.69 (2H, t), 7.16 (1H, d), 7.48
(1H, d), 7.49 (1H, s); m/z 448 (M+H).sup.+.
Intermediate 28-2
N-(2-Cyanoethyl)-2-((1r,4s)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-yl)acetamide
##STR00152##
[0535] 3-Aminopropionitrile (0.215 mL, 2.94 mmol) was added to a
stirred solution of Intermediate 28-3 (725 mg, 1.96 mmol),
N-ethyldiisopropylamine (1.023 mL, 5.87 mmol) and PyBROP (1.369 g,
2.94 mmol) in DCM (50 mL). The resulting solution was stirred at
ambient temperature for 4 hours. The reaction mixture was
evaporated to dryness and redissolved in EtOAc (125 mL), and washed
sequentially with 2M HCl (75 mL) and saturated brine (75 mL). The
organic layer was dried over MgSO.sub.4, filtered and evaporated to
afford crude product. The crude product was purified by flash
silica chromatography, elution gradient 0 to 100% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (900 mg, 109%) as a white foam.
[0536] .sup.1H NMR (400 MHz, DMSO) .delta. 1.09-1.20 (2H, m), 1.27
(12H, s), 1.42-1.46 (2H, m), 1.53-1.67 (4H, m), 1.72-1.79 (1H, m),
1.90 (2H, t), 2.03 (2H, d), 2.63 (2H, t), 2.81 (2H, t), 3.26-3.29
(2H, m), 7.17 (1H, d), 7.46 (1H, d), 7.48 (1H, s), 8.16 (1H, t);
m/z 423 (M+H).sup.+.
Intermediate 28-3
2-((1r,4s)-5'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydros-
piro(cyclohexane-1,1'-indene]-4-yl)acetic acid
##STR00153##
[0538] TFA (15.90 mL) was added to a stirred solution of
Intermediate 29-3 (802 mg, 1.88 mmol) in DCM (15.90 mL) at
0.degree. C. The resulting solution was stirred at 0.degree. C. for
30 minutes, the reaction mixture was evaporated and the residue was
azeotroped with toluene to afford the title compound (676 mg, 97%)
as a white solid.
[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21-1.28 (2H, m),
1.33 (12H, s), 1.56-1.70 (4H, m), 1.76-1.82 (2H, m), 1.85-1.93 (1H,
m), 1.97 (2H, t), 2.31 (2H, d), 2.87 (2H, t), 7.15 (1H, d),
7.64-7.67 (2H, m); COOH not seen; m/z 370 (EI+) M.
Example 29
N:
2-((1s,4r)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro-
(cyclohexane-1,1'-indene]-4-yl)acetic acid
##STR00154##
[0541] A solution of Intermediate 29-1 (0.748 g, 1.66 mmol) in TFA
(8 mL) allowed to stand at room temperature for 0.5 h. The reaction
mixture was evaporated to a solid. The crude product was purified
by recrystallisation twice from MeOH to afford the title compound
(0.201 g, 30.7%) as an off-white crystalline solid.
[0542] .sup.1H NMR (400 MHz, DMSO) .delta. 1.40-1.56 (4H, m),
1.66-1.80 (4H, m), 1.96 (2H, t), 2.03 (1H, br s), 2.39 (2H, d),
2.58 (3H, s), 2.73 (3H, s), 2.89 (2H, t), 7.46-7.50 (2H, m), 7.54
(1H, s), 7.57 (1H, s), 7.97 (1H, s), 11.99 (1H, s); m/z 394
(M+H).sup.+.
Intermediate 29-1
N: tent-Butyl 2-((1s,
4r)-5'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cyclohex-
ane-1,1'-indene]-4-yl)acetate
##STR00155##
[0544] This compound was synthesised from Intermediate 29-2 using
similar conditions as described in Intermediate 25-1 to give the
title compound (0.748 g, 50.3%) as a solid which was a 2:1 mixture
with the other diastereoisomer. m/z 450 (M+H).sup.+.
Intermediate 29-2
N: tert-Butyl
2-((1s,4r)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydro-
spiro[cyclohexane-1,1'-indene]-4-yl)acetate and
Intermediate 29-3
tert-Butyl
2-((1r,4s)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',-
3'-dihydrospiro[cyclohexane-1,1'-indene]-4-yl)acetate
##STR00156##
[0546] To a solution of Intermediate 29-4 (5.42 g, 12.77 mmol) in
THF (125 mL), under nitrogen, was added 10% (w/w) palladium on
carbon (1.4 g). The atmosphere was replaced with hydrogen and the
reaction stirred at room temperature overnight. The reaction
mixture was filtered and evaporated to a colourless oil. This was
dissolved in methanol (ca. 20 mL) and cooled in a dry ice/acetone
bath to produce a white solid. The suspension was allowed to warm
and then evaporated to give the crude product as a white solid.
This was recrystallised by dissolving in DCM (ca. 20 mL) adding
methanol (ca. 20 mL) and cooling in a dry ice/acetone bath. The
resultant suspension was filtered and the collected solid dried to
give Intermediate 29-3 (2.290 g, 42.1%) as a white solid. .sup.1H
NMR (400 MHz, DMSO) .delta. 1.17-1.21 (2H, m), 1.26 (12H, s), 1.40
(9H, s), 1.44-1.67 (7H, m), 1.90 (2H, t), 2.13 (2H, d), 2.81 (2H,
t), 7.18 (1H, d), 7.46-7.48 (2H, m).
[0547] The mother liquors were evaporated to give Intermediate 29-2
(1.610 g, 29.6%) as a solid as a 2:1 mixture with the other
diastereoisomer.
Intermediate 29-4
N: tert-Butyl
2-(5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydrospiro[cy-
clohexane-1,1'-indene]-4-ylidene)acetate
##STR00157##
[0549] This compound was synthesised from Intermediate 29-5 using
similar conditions as described in Intermediate 25-2 to give the
title compound (5.42 g, 66.4%) as a solid.
[0550] .sup.1H NMR (400 MHz, DMSO) .delta. 1.28 (12H, t), 1.42 (8H,
s), 1.60-1.73 (4H, m), 2.04-2.13 (3H, m), 2.26 (1H, d), 2.31-2.36
(1H, m), 2.87 (2H, t), 3.66 (1H, d), 5.60 (1H, s), 7.17 (1H, d),
7.45-7.47 (1H, m), 7.50 (1H, s) one proton obscured; m/z 423
(M-H).sup.-.
Intermediate 29-5
N: tert-Butyl
2-(5'-bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-ylidene)acetate
##STR00158##
[0552] To a solution of tert-butyldiethylphosphonoacetate (8.80 mL,
37.47 mmol) in THF (100 mL) was added 60% w/w sodium hydride (1.498
g, 37.47 mmol). The reaction mixture was stirred at room
temperature for 30 min. A solution of
5'-bromo-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-4-one (prepared
according to the procedure described in WO 2004/047755, CAS
701232-89-5) (8.716 g, 31.22 mmol) in THF (50 mL) was added and
stirring continued at room temp for 1 hour. The reaction mixture
was quenched with saturated brine (150 mL), extracted with EtOAc
(2.times.200 mL), the organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to afford the crude
product as a brown oil (13.66 g). The crude oil was triturated with
isohexane to give a solid which was collected by filtration and
dried under vacuum to give the title compound (4.84 g, 41%) as a
beige solid. A second crop of the title compound (2.42 g, 21%) was
obtained from the filtrate.
[0553] .sup.1H NMR (400 MHz, DMSO) .delta. 1.42 (9H, s), 1.59-1.69
(4H, m), 2.05-2.12 (3H, m), 2.24-2.35 (2H, m), 2.88 (2H, t), 3.66
(1H, d), 5.60 (1H, s), 7.14 (1H, d), 7.27-7.30 (1H, m), 7.38 (1H,
t).
Example 30
2-((1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cy-
clohexane-1,1'-indene]-4-yl)acetic acid
##STR00159##
[0555] A solution of Intermediate 30-1 (1.16 g, 2.58 mmol) in TFA
(12 mL) was allowed to stand at RT for 0.5 h. The reaction mixture
was evaporated to a solid. The crude product was purified by
recrystallisation from MeOH to afford the title compound (0.648 g,
63.8%) as a white crystalline solid.
[0556] .sup.1H NMR (300 MHz, DMSO) .delta. 1.14-1.27 (2H, m),
1.51-1.80 (7H, m), 1.98 (2H, t), 2.17 (2H, d), 2.58 (3H, s), 2.73
(3H, s), 2.90 (2H, t), 7.30 (1H, d), 7.50 (1H, d), 7.54 (1H, s),
7.62 (1H, s), 8.01 (1H, s), 12.05 (1H, s); m/z 394 (M+H).sup.+.
Intermediate 30-1
tert-Butyl
2-((1r,4s)-5'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihy-
drospiro[cyclohexane-1,1'-indene]-4-yl)acetate
##STR00160##
[0558] This compound was synthesised from Intermediate 29-3 using
similar conditions as described in Intermediate 25-1 to give the
title compound (1.260 g, 89%) as a solid.
[0559] .sup.1H NMR (400 MHz, DMSO) .delta. 1.20-1.23 (2H, m), 1.41
(9H, s), 1.51-1.69 (7H, m), 1.97 (2H, t), 2.14 (2H, d), 2.57 (3H,
s), 2.73 (3H, s), 2.90 (2H, t), 7.29 (1H, d), 7.47-7.57 (2H, m),
7.53 (1H, s), 7.96 (1H, s); m/z 450 (M+H).sup.+.
Example 31
(1r,4s)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cyclo-
hexane-1,1'-indene]-4-carboxylic acid
##STR00161##
[0561] 4M HCl in dioxane (10 mL, 0.43 mmol) was added to
Intermediate 31-1 (188 mg, 0.43 mmol) in DCM (5 mL). The resulting
solution was stirred for 16 hours. The resulting mixture was
evaporated to dryness and the residue was slurried with ether then
filtered to afford the title compound (158 mg, 96%) as a pale
yellow solid.
[0562] .sup.1H NMR (400 MHz, DMSO) .delta. 1.48-1.73 (6H, m),
1.85-1.93 (2H, m), 2.00 (2H, t), 2.28-2.36 (1H, m), 2.58 (3H, s),
2.73 (3H, s), 2.91 (2H, t), 7.29 (1H, d), 7.50 (1H, d), 7.56 (3H,
d), 7.98 (1H, s); m/z 380 (M+H).sup.+.
Intermediate 31-1
(1r 4s)-tert-Butyl
5'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2'3'-dihydrospiro[cyclohexane-1-
,1'-indene]-4-carboxylate
##STR00162##
[0564] This compound was synthesised from Intermediate 31-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 25-1 to give the title compound (188 mg, 32.0%) as a
solid.
[0565] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40 (9H, s),
1.54-1.68 (6H, m), 1.86-1.96 (2H, m), 2.02 (2H, t), 2.16-2.28 (1H,
m), 2.60 (3H, s), 2.82-2.95 (5H, m), 5.40 (1H, s), 7.15 (1H, d),
7.30 (1H, d), 7.33 (1H, dd), 7.72 (1H, s); m/z 436 (M+H).sup.+.
Intermediate 31-2
(1r,4s)-tert-Butyl
5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydrospiro[cyclo-
hexane-1,1'-indene]-4-carboxylate
##STR00163##
[0567] This compound was synthesised from Intermediate 31-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (3.13 g, 73.7%) as a white solid.
[0568] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.26 (12H, s),
1.39 (19H, s), 1.50 (2H, d), 1.50-1.60 (6H, m), 1.80-1.90 (2H, m),
1.93 (2H, t), 2.15-2.25 (1H, m), 2.81 (2H, t), 7.07 (1H, d), 7.59
(1H, dd), 7.59 (1H, s).
Intermediate 31-3
(1r,4s)-tert-Butyl
5'-bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate
##STR00164##
[0570] To a solution of Intermediate 31-4 (3.47 g, 11.22 mmol) in
tert-butanol (100 mL) was added DMAP (0.411 g, 3.37 mmol) and
di-tort-butyl dicarbonate (14.70 g, 67.34 mmol) (effervescence).
The resulting solution was stirred at ambient temperature for 16
hours. Saturated NaHCO.sub.3 (100 mL) was added and the reaction
stirred for 30 minutes before adding EtOAc (400 mL). The organic
layer was separated and washed with water (200 mL) then saturated
brine (200 mL) and evaporated to afford crude product. The crude
product was purified by flash silica chromatography, elution
gradient 0 to 10% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (3.76 g, 92%) as
a colourless oil.
[0571] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (9H, s),
1.52-1.67 (6H, m), 1.90-1.97 (2H, m), 1.98-2.03 (2H, m), 2.20-2.30
(1H, m), 2.86 (2H, t), 6.96 (1H, d), 7.28 (1H, dt), 7.32 (1H,
d).
Intermediate 31-4
(1r,4s)-5'-Bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic
acid
##STR00165##
[0573] Oxone (6.98 g, 11.36 mmol) was added to Intermediate 31-5
(3.33 g, 11.36 mmol), in DMF (70 mL). The resulting suspension was
stirred for 16 hours. The reaction mixture was diluted with EtOAc
(300 mL), and washed sequentially with water (3.times.150 mL) and
saturated brine (150 mL). The organic layer was evaporated to
afford the title compound (3.51 g, 100%).
[0574] .sup.1H NMR (400 MHz, DMSO) .delta. 1.30-1.73 (6H, m),
1.80-2.00 (4H, m), 2.20-2.32 (1H, m), 2.83 (2H, t), 7.12 (1H, d),
7.31 (1H, dt), 7.36 (1H, t), 12.03 (1H, s); m/z 309 M-H.sup.-.
Intermediate 31-5
(1r,4s)-5'-Bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carbaldehyd-
e and
Intermediate 31-6
(1s,4r)-5'-Bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carbaldehyd-
e
##STR00166##
[0576] (Methoxymethyl)triphenylphosphonium chloride (20.76 g, 60.55
mmol) was added to a stirred suspension of potassium tert-butoxide
(6.79 g, 60.55 mmol) in 1,4-dioxane (113 mL) at ambient
temperature, over a period of 10 minutes under nitrogen. The
resulting red solution was stirred at ambient temperature for 2
hours and then a solution of
5'-bromo-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-4-one (prepared
according to the procedure described in WO 2004/047755, CAS
701232-89-5) (7.35 g, 26.33 mmol) in 1,4-dioxane (63.4 mL) was
added over a period of 10 minutes under nitrogen. The resulting
solution was stirred at ambient temperature for 1 hour and then
heated at 70.degree. C. for 16 hours. The reaction mixture was
poured into water (200 mL), extracted with EtOAc (2.times.200 mL),
the organic layer was washed with saturated brine (200 mL) and
evaporated to afford a black oil. To the crude oil was added EtOAc
and isohexane (1:3, 200 mL) to give a solid which was collected by
filtration, washed with EtOAc and isohexane (75 mL). The filtrate
was evaporated to afford a solid residue, which was added to 90%
acetic acid in water (200 mL, 3493.64 mmol). The resulting solution
was stirred at 70.degree. C. for 16 hours, the mixture was allowed
to cool, evaporated to dryness and the crude product was purified
by flash silica chromatography, elution gradient 0 to 15% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford
Intermediate 31-5 (3.33 g, 43.1%) and Intermediate 31-6 (1.17 g,
15%) as colourless gums.
Intermediate 31-5
[0577] .sup.1H NMR (400 MHz, CDCl.sub.1) .delta. 1.36-1.67 (6H, m),
1.84-2.00 (4H, m), 2.19-2.29 (1H, m), 2.80 (2H, t), 6.92 (1H, m),
7.22 (1H, m), 7.23 (1H, dd), 9.61 (1H, d); m/z (EI+) 292
M.sup.+.
Intermediate 31-6
[0578] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.35-1.60 (4H, m),
1.68-1.80 (2H, m), 1.93 (2H, t), 2.09 (2H, dt), 2.37-2.44 (1H, m),
2.75-2.85 (2H, m), 6.90 (1H, d), 7.19 (1H, d), 7.24 (1H, d), 9.72
(1H, s); m/z 292 (EI+) M.sup.+.
Example 32
(1s,4r)-5'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2'3'-dihydrospiro[cycloh-
exane-1,1'-indene]-4-carboxylic acid
##STR00167##
[0580] This compound was synthesised from Intermediate 32-1 using
similar conditions as described in Example 31 to give the title
compound (176 mg, 59.9%) as a pale yellow solid.
[0581] .sup.1H NMR (400 MHz, DMSO) .delta. 1.45 (2H, dd), 1.72 (3H,
dd), 1.77 (1H, m), 1.96 (1H, s), 1.99 (3H, t), 2.58 (4H, s), 2.73
(3H, s), 2.90 (2H, t), 7.25 (1H, d), 7.49 (1H, dd), 7.55 (1H, d),
7.57 (1H, s), 7.97 (1H, s); m/z 380 (M+H).sup.+.
Intermediate 32-1
(1s,4r)-tert-Butyl
5'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2',3'-dihydrospiro[cyclohexane--
1,1'-indene]-4-carboxylate
##STR00168##
[0583] This compound was synthesised from Intermediate 32-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 25-1 to give the title compound (342 mg, 58.2%) as a
solid.
[0584] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40-1.50 (2H, m),
1.44 (9H, s), 1.65-1.75 (2H, m), 1.75-1.85 (2H, m), 1.95-2.08 (4H,
m), 2.45-2.51 (1H, m), 2.60 (3H, s), 2.85-2.93 (5H, m), 5.39 (1H,
s), 7.26-7.35 (3H, m), 7.73 (1H, s); m/z 436 (M+H).sup.+.
Intermediate 32-2
(1s,4r)-tert-Butyl
5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydrospiro[cyclo-
hexane-1,1'-indene]-4-carboxylate
##STR00169##
[0586] This compound was synthesised from Intermediate 32-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (0.935 g, 62.3%) as a colourless oil which
solidified on standing.
[0587] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.32 (12H, s),
1.44-1.47 (2H, m), 1.50 (9H, s), 1.67-1.86 (4H, m), 1.96 (2H, t),
2.01-2.09 (2H, m), 2.48-2.53 (1H, m), 2.83-2.90 (2H, m), 7.25 (1H,
d), 7.63 (1H, d), 7.67 (1H, s); m/z 412 (EI+) M.sup.+.
Intermediate 32-3
(1s,4r)-tert-Butyl
5'-bromo-2'3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate
##STR00170##
[0589] This compound was synthesised from Intermediate 32-4 using
similar conditions as described in Intermediate 31-3 to give the
title compound (1.330 g, 89%) as a colourless oil.
[0590] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.42-1.46 (2H, m),
1.49 (9H, s), 1.67-1.81 (4H, m), 1.96 (2H, t), 2.00-2.06 (2H, m),
2.48-2.53 (1H, m), 2.85 (2H, t), 7.08 (1H, d), 7.26-7.28 (1H, m),
7.32 (1H, s); m/z 364 (EI+) M.sup.+.
Intermediate 32-4
(1s,4r)-5'-Bromo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic
acid
##STR00171##
[0592] This compound was synthesised from Intermediate 31-6 using
similar conditions as described in Intermediate 31-4 to give the
title compound (1.27 g, 100%) as a solid.
[0593] .sup.1H NMR (400 MHz, DMSO) .delta. 1.35-1.44 (2H, m),
1.60-1.73 (4H, m), 1.85-2.00 (4H, m), 2.53 (1H, q), 2.82 (2H, t),
7.08 (1H, d), 7.30 (1H, dt), 7.37 (1H, t), 12.12 (1H, s); m/z 309
(M-H).sup.-.
Example 33
2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)piperidin-4-yl)acetic
acid
##STR00172##
[0595] Powdered potassium hydroxide (44.5 mg, 0.79 mmol) was added
in one portion to Intermediate 33-1 (60 mg, 0.16 mmol) in
tert-butanol (5 mL). The resulting pale yellow suspension was
stirred at 40.degree. C. for 30 minutes. The reaction mixture was
quenched with acetic acid (0.073 mL, 1.27 mmol) in EtOH (10.0 mL)
and the resulting solution stirred for a further 10 minutes before
being evaporated to dryness. The resulting solid was partitioned
between water (20 mL) and EtOAc (20 mL). The aqueous layer showed a
pH=6. The organic layer was separated and the aqueous re-extracted
with EtOAc (2.times.25 mL). The combined organics were washed with
brine (15 mL), dried over MgSO.sub.4 and evaporated in vacuo to
give crude product. This was recrystallised from hot EtOH (6 mL) to
give a yellow solid which was washed with ethylacetate (5 mL) and
dried under vacuum at room temperature to give the title compound
(41.0 mg, 70.2%) as a yellow solid.
[0596] .sup.1H NMR (400 MHz, DMSO) .delta. 1.28 (2H, m), 1.76 (2H,
m), 1.86 (1H, m), 2.15 (2H, d), 2.60 (3H, s), 2.71 (3H, s), 2.76
(2H, d), 3.79 (2H, d), 7.00 (2H, d), 7.55 (1H, s), 7.60 (2H, d),
7.96 (1H, s); m/z 369 (M+H).sup.+.
Intermediate 33-1
ethyl
2-(1-(4-(6-cyano-3,5-dimethylpyrazin-2-yl)phenyl)piperidin-4-ylaceta-
te
##STR00173##
[0598] Pyridine (0.050 mL, 0.62 mmol) was added dropwise to
Intermediate 33-2 (78 mg, 0.31 mmol), ethyl
2-(piperidin-4-yl)acetate (79 mg, 0.46 mmol) and Copper(II) acetate
(56.0 mg, 0.31 mmol) in anhydrous DCM (10 mL) The resulting blue
solution was stirred at 25.degree. C. for 16 hours. The reaction
mixture was diluted with DCM (25 mL), and washed with a 20% aqueous
EDTA solution (25 mL). The organic layer was evaporated to afford
crude product. The crude product was purified by flash silica
chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure
fractions were evaporated to dryness to afford the title compound
(53.0 mg, 45.4%) as a pale yellow solid.
[0599] .sup.1H NMR (400 MHz, DMSO) .delta. 1.20 (5H, m), 1.69 (2H,
d), 1.84 (1H, m), 2.22 (2H, m), 2.61 (6H, s), 2.71 (2H, m), 3.77
(2H, d), 4.02 (2H, m), 6.97 (2H, m), 7.47 (2H, m); m/z 379
(M+H).sup.+.
Intermediate 33-2
4-(6-Cyano-3,5-dimethylpyrazin-2-yl)phenylboronic acid
##STR00174##
[0601] Sodium periodate (5.02 g, 23.45 mmol) was added in one
portion to Intermediate 33-3 (2.62 g, 7.82 mmol) in THF (80 mL) and
water (20 mL) and the cloudy suspension was stirred at room
temperature for 30 minutes. 1M HCl (5.47 mL, 5.47 mmol) was added
and the reaction mixture was stirred at room temperature for 2
hours. The THF was evaporated under reduced pressure, the reaction
mixture was diluted with water (100 mL) and extracted with ethyl
acetate (2.times.100 mL). The combined extracts were washed with
water (2.times.30 mL) and brine (30 mL), dried over sodium sulfate,
concentrated to dryness by rotary evaporation to give the title
compound (1.980 g, 100%).
[0602] .sup.1H NMR (400 MHz, DMSO) .delta. 2.62 (3H, s), 2.70 (3H,
s), 7.60 (2H, d), 7.92 (2H, d), 8.16 (2H, s); m/z 254
(M+H).sup.+.
Intermediate 33-3
3,5-Dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyra-
zine-2-carbonitrile
##STR00175##
[0604] This compound was synthesised from Intermediate 33-4 using
similar conditions as described in Intermediate 25-2 to give the
title compound (70.0 mg, 50.4%) as a white crystalline solid.
[0605] .sup.1H NMR (400 MHz, DMSO) .delta. 1.39 (12H, s), 2.68 (3H,
s), 2.77 (3H, s), 7.73 (2H, d), 7.88 (2H, d); HPLC tR=2.85 min.
Intermediate 33-4
4-(6-Cyano-3,5-dimethylpyrazin-2-yl)phenyl
trifluoromethanesulfonate
##STR00176##
[0607] Trifluoromethanesulphonic anhydride (27.3 mL, 166.57 mmol)
was added to a stirred solution of Intermediate 33-5 (10.13 g,
41.64 mmol) in DCM (400 mL) cooled to 0.degree. C., over a period
of 20 minutes under nitrogen. The resulting slurry was then allowed
to warm to ambient temperature overnight under a nitrogen
atmosphere. Triethylamine (46.4 mL, 333.14 mmol) was added dropwise
over 10 minutes (under ice bath cooling, keeping temperature
between 5-10.degree. C.) and the resulting solution stirred at
30.degree. C. for 3 hours under nitrogen. The reaction mixture was
diluted with DCM (200 mL), and washed sequentially with water (200
mL), saturated NaHCO.sub.3 (200 mL), and saturated brine (100 mL).
The organic layer was dried over MgSO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by flash silica chromatography, elution gradient 0 to 40% EtOAc in
isohexane. Pure fractions were evaporated to dryness to the title
compound (9.87 g, 66.3%) as a yellow oil.
[0608] .sup.1H NMR (400 MHz, DMSO) .delta. 2.68 (3H, s), 2.78 (3H,
s), 7.74 (2H, d), 7.93 (2H, d); m/z=mass ion not seen; HPLC tR=2.84
min.
Intermediate 33-5
6-(4-Hydroxyphenyl)-3,5-dimethylpyrazine-2-carboxamide
##STR00177##
[0610] This compound was synthesised from Intermediate 21-4 and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (CAS
269409-70-3) using similar conditions as described in Intermediate
25-1 to give the title compound (10.13 g, 97%) as an orange
solid.
[0611] .sup.1H NMR (400 MHz, DMSO) .delta. 2.58 (3H, s), 2.71 (3H,
s), 6.87 (2H, d), 7.56-7.60 (3H, m), 7.95 (1H, s), 9.73 (1H, s);
m/z 244 (M+H).sup.+.
[0612] The following examples were synthesised using similar
conditions as described in Example 33 to give the desired compounds
34-39.
TABLE-US-00002 .sup.1H NMR (400 MHz, m/z Example Structure DMSO)
.delta. (M + H).sup.+ 34 ##STR00178## 1.58 (2H, m), 1.72 (1H, m),
1.92 (1H, m), 2.53 (1H, m), 2.60 (3H, s), 2.72 (3H, s), 2.90 (1H,
m), 3.04 (1H, m), 3.58 (1H, m), 3.76 (1H, m), 7.02 (2H, d), 7.56
(1H, s), 7.62 (2H, d), 7.96 (1H, s) 355 35 ##STR00179## 1.66 (2H,
m), 1.80 (1H, m), 2.00 (1H, m), 2.61 (1H, m), 2.67 (3H, s), 2.78
(3H, s), 2.98 (1H, t), 3.14 (1H, t), 3.65 (1H, d), 3.83 (1H, d),
7.10 (2H, d), 7.63 (1H, s), 7.69 (2H, d), 8.02 (1H, s) 355 36
##STR00180## 2.60 (3H, s), 2.71 (7H, m), 3.20 (2H, s), 3.27 (4H,
m), 7.03 (2H, d), 7.56 (1H, s), 7.63 (2H, d), 7.96 (1H, s) 370 37
##STR00181## 1.20 (1H, m), 1.55 (1H, m), 1.69 (1H, m), 1.81 (1H,
m), 1.98 (1H, m), 2.17 (1H, m), 2.28 (1H, m), 2.60 (4H, m), 2.71
(3H, s), 2.81 (1H, t), 3.73 (2H, t), 7.00 (2H, d), 7.56 (1H, s),
7.61 (2H, d), 7.96 (1H, s), 12.11 (1H, s) 369 38 ##STR00182## 1.64
(2H, m), 1.90 (2H, m), 2.45 (1H, m), 2.60 (3H, s), 2.71 (3H, s),
2.87 (2H, t), 3.76 (2H, d), 7.03 (2H, d), 7.56 (1H, s), 7.61 (2H,
d), 7.96 (1H, s), 12.19 (1H, s) 355 39 ##STR00183## 1.12 (3H, d),
1.39 (2H, m), 1.75 (3H, m), 2.27 (1H, m), 2.66 (3H, s), 2.77 (5H,
m), 3.91 (2H, m), 7.08 (2H, d), 7.62 (1H, s), 7.67 (2H, d), 8.02
(1H, s), 12.14 (1H, s) 383
Example 40
2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)aceti-
c acid
##STR00184##
[0614] Powdered potassium hydroxide (122 mg, 2.17 mmol) was added
in one portion to Intermediate 40-1 (170 mg, 0.43 mmol) in
tert-butanol (5 mL). The resulting yellow suspension was stirred at
40.degree. C. for 90 minutes. The reaction mixture was quenched
with acetic acid (0.198 mL, 3.47 mmol) in EtOH (10.0 mL) and the
resulting solution stirred for a further 10 minutes before being
evaporated to dryness. The resulting solid was partitioned between
water (20 mL) and EtOAc (20 mL). The aqueous layer showed a pH=6.
The organic layer was separated and evaporated to dryness to afford
crude product (185 mg). The crude product was dissolved in DCM
(5.00 mL) and TFA (1.0 mL, 12.99 mmol) was added. The brown
solution was stirred at room temperature for 2 hours. The reaction
mixture was purified by ion exchange chromatography, using an SCX
column. The column was eluted with DCM (100 mL) followed by MeOH
(100 mL) and then the desired product was eluted from the column
using 0.35M NH.sub.3/MeOH (100 mL) and fractions containing the
product were evaporated to dryness to afford crude product as a
yellow solid (110 mg). This product was purified by preparative
HPLC (Waters XBridge Prep C18 OBD column, 5.mu. silica, 50 mm
diameter, 150 mm length), using decreasingly polar mixtures of
water (containing 0.1% formic acid) and MeOH as eluents. Fractions
containing the desired compound were evaporated to dryness to
afford the title compound (76 mg, 49.5%) as a yellow solid.
[0615] .sup.1H NMR (400 MHz, DMSO) .delta. 1.65 (1H, m), 2.13 (1H,
m), 2.38 (2H, m), 2.55 (4H, m), 2.65 (3H, s), 2.93 (1H, t), 3.26
(1H, m), 3.33 (1H, m), 3.47 (1H, m), 6.55 (2H, d), 7.50 (1H, s),
7.56 (2H, d), 7.89 (1H, s), 12.13 (1H, s); m/z 355 (M+H).sup.+.
Example 41
(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-azabicyclo-
[3.1.0]hexane-6-carboxylic acid
##STR00185##
[0617] Powdered potassium hydroxide (101 mg, 1.79 mmol) was added
in one portion to Intermediate 41-1 (175 mg, 0.45 mmol) in
tert-butanol (4 mL) at 40.degree. C. under nitrogen. The resulting
suspension was stirred at 40.degree. C. for 6 hours. A thick
precipitate formed so the reaction was quenched with acetic acid
(0.205 mL, 3.59 mmol) in EtOH (10 mL) and the resulting solution
stirred for a further 10 minutes before being evaporated to
dryness. The crude material was treated with a 5% HCl in methanol
solution (10 mL), and stirred overnight. The mixture was then
treated with powdered potassium hydroxide (101 mg, 1.79 mmol) in
tert-butanol. The resulting mixture was stirred at 40.degree. C.
for 2 hours, before being quenched with acetic acid (0.205 mL, 3.59
mmol) in EtOH (5 mL) and evaporated to a gum. The crude product was
purified by preparative HPLC (Waters XBridge Prep C18 OBD column,
5.mu. silica, 50 mm diameter, 150 mm length), using decreasingly
polar mixtures of water (containing 0.1% formic acid) and MeCN as
eluents. Fractions containing the desired compound were evaporated
to dryness to afford the title compound (66.5 mg, 42.1%) as a
yellow solid.
[0618] .sup.1H NMR (400 MHz, DMSO) .delta. 1.51 (1H, t), 2.23-2.26
(2H, m), 2.66 (3H, s), 2.77 (3H, s), 3.39 (2H, d), 3.72 (2H, d),
6.71 (2H, d), 7.62 (1H, s), 7.66 (2H, d), 8.01 (1H, s,) COOH not
seen; m/z 353 (M+H).sup.+.
[0619] The following compounds were synthesised from Intermediate
33-2 and the appropriate amine using similar conditions as
described in Intermediate 33-1 to give the desired Intermediates
34-1 to 40-1.
TABLE-US-00003 .sup.1H NMR (400 MHz, m/z Intermediate Structure
DMSO) .delta. (M + H).sup.+ 34-1 ##STR00186## 1.27 (3H, t), 1.71
(3H, m), 1.99 (1H, m), 2.70 (7H, m), 3.04 (1H, m), 3.23 (1H, m),
3.64 (1H, d), 3.83 (1H, d), 4.16 (2H, q), 7.10 (2H, d), 7.61 (2H,
d). 365 35-1 ##STR00187## 1.14 (3H, t), 1.59 (3H, m), 1.87 (1H, m),
2.58 (7H, m), 2.92 (1H, t), 3.10 (1H, t), 3.52 (1H, d), 3.71 (1H,
d), 4.04 (2H, q), 6.98 (2H, d), 7.49 (2H, d). 365 36-1 ##STR00188##
2.60 (3H, s), 2.71 (7H, m), 3.20 (2H, s), 3.27 (4H, m), 7.03 (2H,
d), 7.56 (1H, s), 7.63 (2H, d), 7.96 (1H, s). 370 37-1 ##STR00189##
1.23 (1H, m), 1.55 (1H, m), 1.69 (1H, m), 1.79 (1H, m), 2.00 (1H,
m), 2.28 (1H, m), 2.38 (1H, m), 2.63 (7H, m), 2.83 (1H, m), 3.62
(3H, s), 3.74 (2H, m), 7.01 (2H, d), 7.53 (2H, d). 365 38-1
##STR00190## 1.13 (3H, t), 1.60 (2H, m), 1.86 (2H, m), 2.51 (1H,
m), 2.59 (3H, s), 2.61 (3H, s), 2.84 (2H, t), 3.72 (2H, d), 4.03
(2H, q), 6.98 (2H, d), 7.48 (2H, d). 365 39-1.sup.a ##STR00191##
1.07 (3H, d), 1.18 (3H, t), 1.31 (2H, m), 1.68 (3H, m), 2.30 (1H,
m), 2.65 (3H, s), 2.66 (3H, s), 2.73 (2H, m), 3.87 (2H, t), 4.07
(2H, m), 7.02 (2H, d), 7.52 (2H, d). 393 40-1 ##STR00192## 1.39
(1H, m), 1.42 (9H, s), 1.69 (1H, m), 2.16 (1H, m), 2.40 (2H, m),
2.59 (1H, m), 2.65 (6H, s), 2.96 (1H, t), 3.37 (1H, m), 3.50 (1H,
m), 6.61 (2H, d), 7.53 (2H, d). 393 41-1.sup.a ##STR00193## 1.41
(9H, s), 1.42-1.45 (1H, m), 2.17-2.19 (2H, m), 2.64 (3H, s), 2.65
(3H, s), 3.27 (2H, d), 3.66 (2H, d), 6.64 (2H, d), 7.51 (2H, d).
391 Note: 39-1.sup.a ethyl 2-(piperidin-4-yl)propanoate, CAS
141060-27-7 was prepared according to the procedure described in WO
2008042925. 41-1.sup.a (1R,5S,6r)-tert-butyl
3-azabicyclo[3.1.0]hexane-6-carboxylate, CAS 681424-89-5 (prepared
according to the procedure described in WO 2004033451).
Example 42
2-((1r,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-
-methylpropanoic acid
##STR00194##
[0621] Powdered potassium hydroxide (193 mg, 3.44 mmol) was added
in one portion to Intermediate 42-1 (470 mg, 1.15 mmol) in
tert-butanol (20 mL) at 40.degree. C. under nitrogen. The resulting
suspension was stirred at 40.degree. C. for 2 hours. The reaction
was incomplete so the temperature was increased to 100.degree. C.
and the reaction mixture was stirred for a further 16 hours. The
reaction was quenched with acetic acid (0.329 mL, 5.74 mmol) in
EtOH (10 mL) and the resulting solution stirred for a further 20
minutes before being evaporated to dryness. The resulting solid was
partitioned between water (50 mL) and EtOAc (50 mL). The aqueous
layer was acidified with 2M HCl (5 mL) was added and the organic
layer was separated and the aqueous re-extracted with EtOAc (50
mL). The combined organics were washed with saturated brine (50 mL)
and evaporated in vacuo to give crude solid product. This was
recrystallised from hot EtOH (15 mL) and washed with ether (10 mL)
and dried under vacuum at room temperature to give the title
compound (90 mg, 19.83%) as a pink solid.
[0622] .sup.1H NMR (400.13 MHz, DMSO) .delta. 1.06 (6H, s),
1.15-1.30 (2H, m), 1.43-1.56 (2H, m), 1.60-1.80 (3H, m), 1.80-1.95
(2H, m), 2.40-2.60 (1H, m), 2.58 (3H, s), 2.73 (3H, s), 3.29 (3H,
s), 7.36 (2H, d), 7.57 (1H, s), 7.64 (2H, d), 7.97 (1H, s), 12.03
(1H, s); m/z 396 (M+H).sup.+.
Intermediate 42-1
Methyl
2-((1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cycloh-
exyl)-2-methylpropanoate
##STR00195##
[0624] This compound was synthesised from Intermediate 42-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 25-1 to give the title compound (494 mg, 44.8%).
[0625] .sup.1H NMR (400 MHz, CDCl.sub.1) .delta. 1.10 (6H, s),
1.12-1.28 (2H, m), 1.40-1.53 (2H, m), 1.60-1.73 (3H, m), 1.90-2.00
(2H, m), 2.43-2.52 (1H, m), 2.60 (3H, s), 2.91 (3H, s), 3.62 (3H,
s), 5.42 (1H, s), 7.25 (2H, d), 7.44 (2H, dt), 7.72 (1H, s); m/z
410 (M+H).sup.+.
Intermediate 42-2
Methyl
2-methyl-2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)cyclohexyl)propanoate
##STR00196##
[0627] To a solution of diisopropylamine (4.83 mL, 34.17 mmol) in
THF (50 mL) under nitrogen, cooled to -70.degree. C. was added
butyllithium (21.35 mL, 34.17 mmol) dropwise while maintaining the
temperature between -70 and -60.degree. C. After 30 minutes
Intermediate 42-3 (3.18 g, 8.54 mmol) in THF (20 mL) was added and
the mixture was allowed to warm to .about.20.degree. C. over 90
minutes. The solution was cooled to -65.degree. C., methyl iodide
(2.129 mL, 34.17 mmol) was added and the reaction allowed to stir
for 1 hour and then allowed to warm to -30.degree. C. The reaction
was quenched with saturated ammonium chloride (100 mL), extracted
with EtOAc (200 mL), the organic phase separated, washed with water
(100 mL) and saturated brine (100 mL). The organic layer was dried
over MgSO.sub.4, filtered and evaporated to afford crude product
(2.99 g). The crude product was purified by flash silica
chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure
fractions were evaporated to dryness to afford the title compound
(1.830 g, 55.5%) as a white solid.
[0628] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.15 (6H, s),
1.15-1.28 (2H, m), 1.33 (12H, s), 1.49 (2H, dd), 1.65-1.75 (3H, m),
1.90-1.98 (2H, m), 2.42-2.51 (1H, m), 3.68 (3H, d), 7.21 (2H, d),
7.74 (2H, dd); m/z (EI+) 386 M.sup.+.
Intermediate 42-3
Methyl
2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)cyclohexyl)propanoate
##STR00197##
[0630] Lithium bis(trimethylsilyl)amide (16.75 mL, 16.75 mmol) was
added to methyl
2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl)cyclohexyl)acetate (CAS 701232-69-1) (prepared according to
the procedure described in WO 2004047755) (5 g, 13.96 mmol) in THF
(50 mL) at 0.degree. C. under nitrogen. The resulting solution was
stirred at 0.degree. C. for 30 minutes and then methyl iodide
(1.304 mL, 20.93 mmol) was added and the reaction stirred for 30
minutes. The reaction was quenched with saturated ammonium chloride
(50 mL), extracted with EtOAc (100 mL), the organic phase
separated, washed with water (50 mL) and saturated brine (50 mL).
The organic layer was dried over MgSO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by flash silica chromatography, elution gradient 0 to 10% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (3.38 g, 65.1%) as a white solid.
[0631] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.08-1.30 (5H, m),
1.33 (12H, s), 1.40-1.70 (3H, m), 1.70-1.97 (4H, m), 2.31 (1H, t),
2.43-2.53 (1H, m), 3.68 (3H, m), 7.21 (2H, d), 7.74 (2H, d); m/z
395 (M+Na).sup.+.
Example 43
2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cycl-
ohexyl)acetic acid
##STR00198##
[0633] This compound was synthesised from Intermediate 43-1 using
similar conditions as described in Example 21. Except the crude
product was purified by crystallisation from boiling EtOH (6 mL) to
afford the title compound (89 mg, 43.6%).
[0634] .sup.1H NMR (400 MHz, DMSO) .delta. 1.09-1.22 (3H, m),
1.53-1.61 (2H, m), 1.72-1.89 (4H, m), 2.14-2.16 (2H, m), 2.60 (3H,
s), 2.73 (3H, s), 2.79-2.87 (1H, m), 7.43-7.48 (1H, m), 7.53 (1H,
d), 7.56-7.60 (2H, m), 8.04 (1H, s), 12.11 (1H, s); m/z 386
(M+H).sup.+.
Intermediate 43-1
Ethyl
2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluoropheny-
l)cyclohexyl)acetate
##STR00199##
[0636] This compound was synthesised from Intermediate 43-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 21-1 to give the title compound (0.219 g, 23.90%) as a
colourless oil.
[0637] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21 (3H, t),
1.54-1.64 (2H, m), 1.87-1.98 (7H, m), 2.26 (2H, d), 2.67 (3H, s),
2.86-2.94 (1H, m), 2.98 (3H, s), 4.13-4.18 (2H, m), 5.91 (1H, s),
7.24-7.36 (3H, m), 7.78 (1H, s); m/z 414 (M+H).sup.+.
Intermediate 43-2
Ethyl
2-((1r,4r)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)cyclohexyl)acetate
##STR00200##
[0639] This compound was synthesised from Intermediate 43-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (0.865 g, 43.8%) as a white crystalline solid.
[0640] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.09-1.17 (2H, m),
1.21 (3H, t), 1.26 (2H, s), 1.46 (12H, s), 1.48-1.54 (2H, m),
1.78-1.87 (4H, m), 2.73-2.81 (1H, m), 3.42 (1H, d), 4.05-4.11 (2H,
m), 7.11 (1H, d), 7.14 (1H, d), 7.19-7.21 (1H, m).
Intermediate 43-3
Ethyl
2-((1r,4r)-4-(2-fluoro-4-(trifluoromethylsulfonyloxy)-phenyl)cyclohe-
xyl)acetate
##STR00201##
[0642] This compound was synthesised from Intermediate 43-4 using
similar conditions as described in Intermediate 25-4 to give the
title compound (2.087 g, 62.2%) as a yellow oil.
[0643] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.14-1.25 (2H, m),
1.27 (3H, t), 1.46-1.56 (3H, m), 1.83-1.94 (4H, m), 2.24 (2H, d),
2.79-2.87 (1H, m), 4.12-4.17 (2H, m), 6.96-6.99 (1H, m), 7.01-7.05
(1H, m), 7.27-7.31 (1H, m); m/z 411 (M-H).sup.-.
Intermediate 43-4
Ethyl 2-((1r,4r)-4-(2-fluoro-4-hydroxyphenyl)-cyclohexyl)acetate
and
Intermediate 43-5
Ethyl 2-(1s,4s)-4-(2-fluoro-4-hydroxyphenyl)-cyclohexyl)acetate
##STR00202##
[0645] Intermediate 43-6 (6.29 g, 22.60 mmol) and palladium on
carbon (10%) (0.6 g, 0.56 mmol) in EtOH (200 mL) was evacuated with
hydrogen (4 cycles) and then stirred under a balloon of hydrogen at
ambient temperature for 2 hours. The reaction mixture was filtered
and evaporated to give a colourless oil. The crude product was
purified by flash silica chromatography, elution gradient 10 to 20%
EtOAc in isohexane. Pure fractions were evaporated to dryness to
afford the desired product as a mixture of cis and trans isomers as
a colourless oil which was further purified by preparative
chiral-HPLC on a Chiralcel OJ column, eluting isocratically with
10% IPA in isohexane as eluent. The fractions containing the
desired compounds were evaporated to dryness to afford Intermediate
43-4 (2.28 g, 36%) as a white solid and Intermediate 43-5 (3.08 g,
48.6%) as a pale yellow gum.
Intermediate 43-4
[0646] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.11-1.24 (2H, m),
1.26 (3H, t), 1.42-1.53 (2H, m), 1.80-1.89 (5H, m), 2.23 (2H, d),
2.69-2.76 (1H, m), 4.14 (2H, q), 4.82 (1H, s), 6.50-6.57 (2H, m),
7.04 (1H, t); m/z (EI+) 280 M.
Intermediate 43-5
[0647] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (3H, t),
1.59-1.76 (8H, m), 2.29-2.36 (1H, m), 2.45 (2H, d), 2.75-2.83 (1H,
m), 4.15 (2H, q), 4.94 (1H, s), 6.51-6.57 (2H, m), 7.08 (1H, t);
m/z (EI+) 280 M.sup.+.
Intermediate 43-6
Ethyl 2-(4-(2-fluoro-4-hydroxyphenyl)cyclohex-3-enyl)acetate
##STR00203##
[0649] A solution of Intermediate 43-7 (18.48 g, 62.82 mmol) in DMF
(100 mL) was added to a stirred suspension of
4-bromo-3-fluorophenol (10 g, 52.36 mmol), potassium carbonate
(21.71 g, 157.07 mmol) and
[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.163
g, 1.41 mmol) in DMF (100 mL) at ambient temperature. The resulting
suspension was stirred at 80.degree. C. under nitrogen for 2 hours.
The reaction was incomplete so the temperature was increased to
100.degree. C. and the reaction mixture was stirred for a further
30 minutes and then further
[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.163
g, 1.41 mmol) was added and the suspension was stirred at
100.degree. C. for a further 45 minutes and then further
[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg,
0.487 mmol) was added and the suspension was stirred at 100.degree.
C. for a further 45 minutes. The reaction mixture was evaporated to
dryness and redissolved in EtOAc (200 mL) and 2M HCl (250 mL) was
cautiously added. The aqueous layer was further extracted with
EtOAc (3.times.200 mL) and the organic extracts were combined,
washed saturated brine (300 mL), dried over MgSO.sub.4, filtered
and evaporated to afford crude product. The crude product was
purified by flash silica chromatography, elution gradient 0 to 20%
EtOAc in isohexane. Pure fractions were evaporated to dryness to
afford the title compound (6.34 g, 43.5%) as a pale yellow oil.
[0650] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (3H, t),
1.41-1.50 (1H, m), 1.85-1.95 (2H, m), 2.14-2.21 (1H, m), 2.32 (2H,
d), 2.32-2.48 (3H, m), 4.16 (2H, q), 4.98 (1H, s), 5.81 (1H, s),
6.51-6.56 (2H, m), 7.05-7.09 (1H, m); m/z 277 (M-H).sup.-.
Intermediate 43-7
Ethyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)ac-
etate
##STR00204##
[0652] This compound was synthesised from Intermediate 43-8 using
similar conditions as described in Intermediate 25-2 to give the
title compound (10.4 g, 71%) as a colourless oil.
[0653] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.24-1.28 (18H, m),
1.77-1.80 (2H, m), 2.18-2.27 (2H, m), 2.20-2.24 (2H, m), 4.09-4.16
(2H, m), 6.51 (1H, d)
Intermediate 43-8
Ethyl 2-(4-(trifluoromethylsulfonyloxy)cyclohex-3-enyl)acetate
##STR00205##
[0655] Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was
added portionwise to a solution of
2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in DCM
(250 mL). A solution of ethyl 2-(4-oxocyclohexyl)acetate (10.88 g,
59.05 mmol, CAS 58012-34-3) in DCM (100 mL) was then added dropwise
and the reaction mixture was allowed to stir open to air and at
room temperature overnight. The reaction mixture was washed with
water, saturated Na.sub.2CO.sub.3, saturated brine, dried over
MgSO.sub.4 and evaporated to afford crude product. The crude
product was purified by flash silica chromatography, elution
gradient 0 to 10% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (16.05 g, 86%)
as a yellow oil.
[0656] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.22-1.29 (3H, m),
1.39-1.51 (1H, m), 1.76-1.85 (2H, m), 2.07-2.23 (4H, m), 2.29 (2H,
d), 4.09-4.18 (2H, m), 4.96 (1H, s).
Example 44
2-((1s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cycl-
ohexyl)acetic acid
##STR00206##
[0658] This compound was synthesized from Intermediate 44-1 using
similar conditions as described in Example 21 to give the title
compound (252 mg, 71%) as a white solid.
[0659] .sup.1H NMR (400 MHz, DMSO) .delta. 1.65 (8H, m), 2.22 (1H,
m), 2.41 (2H, d), 2.60 (3H, s), 2.74 (3H, s), 2.88 (1H, m), 7.53
(4H, m), 8.05 (1H, s), 12.03 (1H, s); m/z 386 (M+H).sup.+.
Intermediate 44-1
Ethyl
2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluoropheny-
l)cyclohexyl)acetate
##STR00207##
[0661] This compound was synthesized from Intermediate 44-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 21-1 to give the title compound (453 mg, 68%) as a
pale yellow solid.
[0662] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (3H, t), 1.74
(8H, m), 2.39 (1H, m), 2.48 (2H, d), 2.68 (3H, s), 2.97 (4H, m),
4.16 (2H, q), 5.51 (1H, s), 7.26 (1H, m), 7.32 (1H, m), 7.38 (1H,
t), 7.75 (1H, s); m/z 414 (M+H).sup.1.
Intermediate 44-2
Ethyl
2-((1s,4s)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)cyclohexyl)acetate
##STR00208##
[0664] This compound was synthesized from Intermediate 44-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (1.45 g, 61%) as a white solid.
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (3H, t), 1.32
(12H, s), 1.67 (8H, m), 2.35 (1H, m), 2.46 (2H, d), 2.89 (1H, m),
4.14 (2H, q), 7.25 (1H, t), 7.42 (1H, d), 7.52 (1H, d); m/z (ES+)
(M+H)+=No mass ion; HPLC tR=3.62 min.
Intermediate 44-3
Ethyl
2-((1s,4s)-4-(2-fluoro-4-(trifluoromethylsulfonyloxy)-phenyl)cyclohe-
xyl)acetate
##STR00209##
[0667] This compound was synthesized from Intermediate 43-5 using
similar conditions as described in Intermediate 25-4 to give the
title compound (2.53 g, 86%) as a yellow oil.
[0668] .sup.1H NMR (400 MHz, DMSO) .delta. 1.12 (3H, t), 1.55 (8H,
m), 2.15 (1H, m), 2.41 (2H, d), 2.77 (1H, m), 4.00 (3H, q), 7.24
(1H, m), 7.43 (1H, m), 7.56 (1H, t); m/z (ES-) 411 (M-H).sup.-.
Example 45
((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cycloh-
exyl)acetic acid
##STR00210##
[0670] This compound was synthesised from Intermediate 45-1 using
similar conditions as described in Example 21. Except the crude
product was recrystallised from hot EtOH (15 mL) to give a solid
which was washed with Ether (10 mL) and dried under vacuum at room
temperature to give the title compound (313 mg, 80%).
[0671] .sup.1H NMR (400 MHz, DMSO) .delta. 1.12-1.23 (2H, m),
1.49-1.60 (2H, m), 1.76-1.90 (5H, m), 2.18 (2H, d), 2.60 (3H, s),
2.75 (3H, s), 2.91-3.00 (1H, m), 7.52 (1H, d), 7.65 (1H, s),
7.67-7.70 (1H, m), 7.84 (1H, d), 8.10 (1H, s), 12.09 (1H, s); m/z
402 (M+H).sup.+.
Intermediate 45-1
Ethyl
2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloropheny-
l)cyclohexyl)acetate
##STR00211##
[0673] This compound was synthesized from Intermediate 45-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 21-1 to give the title compound (482 mg, 91%) as a
yellow solid.
[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21 (3H, t),
1.40-1.47 (1H, m), 1.84-1.94 (4H, m), 2.20 (2H, d), 2.60 (3H, s),
2.91 (3H, s), 2.94-3.02 (1H, m), 3.42 (4H, d), 4.06-4.11 (2H, m),
5.40 (1H, s), 7.29-7.32 (1H, m), 7.36-7.38 (1H, m), 7.51 (1H, d),
7.67 (1H, s); m/z 430 (M+H).sup.+.
Intermediate 45-2
Ethyl
2-((1r,4r)-4-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)cyclohexyl)acetate
##STR00212##
[0676] This compound was synthesized from Intermediate 45-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (1.046 g, 70.7%) as a colourless oil which
crystallised on standing.
[0677] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76-0.87 (4H, m),
1.20 (3H, t), 1.35-1.44 (1H, m), 1.48 (12H, s), 1.80-1.86 (4H, m),
2.18 (2H, d), 2.89-2.97 (1H, m), 4.05-4.10 (2H, m), 7.18 (1H, d),
7.56 (1H, d), 7.70 (1H, d); m/z 430 (M+Na).sup.+.
Intermediate 45-3
Ethyl
2-((1r,4r)-4-(2-Chloro-4-(trifluoromethyl-sulfonyloxy)phenyl)cyclohe-
xyl)acetate
##STR00213##
[0679] This compound was synthesized from Intermediate 45-4 using
similar conditions as described in Intermediate 25-4 to give the
title compound (1.560 g, 85%) as a yellow oil.
[0680] .sup.1H NMR (400 MHz, CDCl.sub.1) .delta. 1.18-1.29 (4H, m),
1.39-1.49 (2H, m), 1.88-1.95 (4H, m), 2.25 (2H, d), 2.93-3.01 (1H,
m), 3.49 (2H, d), 4.12-4.18 (2H, m), 7.14-7.17 (1H, m), 7.29 (1H,
d), 7.32 (1H, d); m/z 427 (M-H).sup.-.
Intermediate 45-4
Ethyl 2-((1r,4r)-4-(2-chloro-4-hydroxyphenyl)-cyclohexyl)acetate
and
Intermediate 45-5
Ethyl 2-((1s,4s)-4-(2-chloro-4-hydroxyphenyl)cyclohexyl)acetate
##STR00214##
[0682] These compounds were synthesized from Intermediate 45-6
using similar conditions as described in Intermediate 43-4 and
43-5, except after silica chromatography the crude product was
purified by preparative HPLC (Phenomenex Gemini C18 110A (axia)
column, 5.mu., silica, 21 mm diameter, 150 mm length), using
decreasingly polar mixtures of water (containing 0.1% formic acid)
and MeCN as eluents. Fractions containing the desired compound were
evaporated to dryness to afford crude product as a mixture of
isomers (5.78 g, 49.9%) as a colourless oil. The oil was purified
by preparative chiral-HPLC on a Merck 50 mm 20 .mu.m Chiralcel OJ
column, eluting isocratically with 70% isohexane in IPA (modified
with AcOH/Et.sub.3N) as eluent. The fractions containing the
desired compound were evaporated to dryness to afford Intermediate
45-4 (1.264 g, 21.87%) as a white solid and Intermediate 45-5 (3.52
g, 60.9%) as white solid.
Intermediate 45-4
[0683] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.13-1.24 (2H, m),
1.27 (3H, t), 1.34-1.45 (2H, m), 1.80-1.91 (5H, m), 2.24 (2H, d),
2.84-2.92 (1H, m), 4.12-4.18 (2H, m), 6.70-6.73 (1H, m), 6.86 (1H,
d), 7.08 (1H, d) phenol OH not seen; m/z (ES-) (M-H)-=295, 297
Intermediate 45-5
[0684] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (3H, t),
1.46-1.58 (3H, m), 1.65-1.78 (5H, m), 2.33-2.40 (1H, m), 2.47 (2H,
d), 2.89-2.96 (1H, m), 4.13-4.18 (2H, m), 6.70-6.73 (1H, m), 6.86
(1H, d), 7.12 (1H, d) phenol OH not seen; m/z (ES-) (M-H)-=295,
297
Intermediate 45-6
Ethyl 2-(4-(2-chloro-4-hydroxyphenyl)cyclohex-3-enyl)acetate
##STR00215##
[0686] This compound was synthesized from Intermediate 43-7 and
4-bromo-3-chlorophenol using similar conditions as described in
Intermediate 43-6 to give the title compound (5.30 g, 74.7%) as a
colourless oil.
[0687] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21 (3H, t),
1.36-1.45 (1H, m), 1.58 (1H, s), 1.76-1.87 (2H, m), 2.07-2.17 (1H,
m), 2.22-2.29 (4H, m), 4.07-4.12 (2H, m), 5.16 (1H, s), 5.50-5.52
(1H, m), 6.59-6.62 (1H, m), 6.78 (1H, d), 6.93 (1H, d); m/z 293
(M-H).sup.-.
Example 46
2-((1s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cycl-
ohexyl)acetic acid
##STR00216##
[0689] This compound was synthesized from Intermediate 46-1 using
similar conditions as described in Example 21 to give the title
compound (184 mg, 44%) as a white solid.
[0690] .sup.1H NMR (400 MHz, DMSO) .delta. 1.65 (8H, m), 2.24 (1H,
m), 2.44 (2H, d), 2.59 (3H, s), 2.73 (3H, s), 2.99 (1H, m), 7.58
(2H, m), 7.67 (1H, d), 7.81 (1H, s), 8.05 (1H, s), 12.01 (1H, s);
m/z 402 (M+H).sup.+.
Intermediate 46-1
Ethyl
2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloropheny-
l)cyclohexyl)acetate
##STR00217##
[0692] This compound was synthesized from Intermediate 46-2 and
Intermediate 21-4 using similar conditions as described in
Intermediate 21-1 to give the title compound (365 mg, 78%) as a
colourless gum.
[0693] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (3H, t), 1.67
(2H, m), 1.78 (6H, m), 2.42 (1H, m), 2.50 (2H, d), 2.67 (3H, s),
2.98 (3H, s), 3.10 (1H, m), 4.16 (2H, m), 5.53 (1H, s), 7.43 (2H,
m), 7.59 (1H, d), 7.75 (1H, s); m/z 430 (M+H).sup.+.
Intermediate 46-2
Ethyl
2-((1s,4s)-4-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl)cyclohexyl)acetate
##STR00218##
[0695] This compound was synthesized from Intermediate 46-3 using
similar conditions as described in Intermediate 25-2 to give the
title compound (1.19 g, 62%) as a colourless oil.
[0696] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (3H, t), 1.33
(12H, s), 1.59 (2H, m), 1.72 (6H, m), 2.39 (1H, m), 2.47 (2H, d),
3.05 (1H, m), 4.15 (2H, q), 7.28 (1H, t), 7.64 (1H, d), 7.77 (1H,
s); m/z 430 (M+Na).sup.+.
Intermediate 46-3
Ethyl
2-((1s,4s)-4-(2-chloro-4-(trifluoromethyl-sulfonyloxy)phenyl)cyclohe-
xyl)acetate
##STR00219##
[0698] This compound was synthesized from Intermediate 45-5 using
similar conditions as described in Intermediate 25-4 to give the
title compound (2.051 g, 71.0%) as a colourless oil.
[0699] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.26 (3H, t), 1.56
(2H, m), 1.73 (6H, m), 2.40 (1H, m), 2.46 (2H, d), 3.02 (1H, t),
4.16 (1H, q), 7.16 (1H, m), 7.30 (1H, d), 7.37 (1H, d); m/z 427
(M-H).sup.-.
Example 47
6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethylp-
yrazine-2-carboxamide
##STR00220##
[0701] This compound was synthesised from Intermediate 47-1 using
similar conditions as described in Example 28 to give the title
compound (220 mg, 41.7%) as a white solid. The material was
recrystallised from hot Methanol, filtered off and washed with
ether before drying under vacuum to give the title compound (223
mg, 42.3%).
[0702] .sup.1H NMR (300 MHz, DMSO) .delta. 1.13-1.27 (2H, m),
1.43-1.56 (2H, m), 1.74-1.88 (5H, m), 2.53-2.57 (1H, m), 2.58 (3H,
s), 2.74 (3H, s), 2.84 (2H, d), 7.35 (2H, d), 7.58 (1H, s), 7.65
(2H, d), 7.97 (1H, s), 16.00 (1H, s); m/z 392 (M+H).sup.+.
Intermediate 47-1
3-(5-(((1r,4r)-4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cy-
clohexyl)methyl)-1H-tetrazol-1-yl)propanenitrile
##STR00221##
[0704] This compound was synthesised from Intermediate 47-2 using
similar conditions as described in Intermediate 28-1 to give the
title compound (1.960 g, 59.9%) contaminated with triphenyphosphine
oxide (3 mol %).
[0705] .sup.1H NMR (400 MHz, DMSO) .delta. 0.96-1.05 (2H, m), 1.06
(12H, s), 1.19-1.30 (2H, m), 1.54-1.64 (5H, m), 2.67 (2H, d), 2.97
(2H, t), 3.07 (1H, s), 4.47 (2H, t), 7.02 (2H, d), 7.37 (2H, d);
HPLC tR=2.81.
Intermediate 47-2
N-(2-Cyanoethyl)-2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)cyclohexyl)acetamide
##STR00222##
[0707] This compound was synthesised from Intermediate 47-3 using
similar conditions as described in Intermediate 28-2 to give the
title compound (3.08 g, 77%).
[0708] .sup.1H NMR (400 MHz, DMSO) .delta. 1.03-1.13 (2H, m), 1.27
(12H, s), 1.37-1.47 (2H, m), 1.71-1.80 (5H, m), 2.02 (2H, d), 2.63
(2H, t), 7.22 (2H, d), 7.58 (2H, d), 8.16 (1H, t), 3.times.CH
obscured by solvent.
Intermediate 47-3
2-((1r,4r)-4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cycloh-
exyl)acetic acid
##STR00223##
[0710] Methyl
2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclo-
hexyl)acetate (CAS 701232-69-1, prepared according to the procedure
described in WO 2004/047755) (3.6 g, 10.05 mmol) was dissolved in a
solution of sodium hydroxide (1.326 g, 33.16 mmol) in methanol (36
mL) and water (4.00 mL). The reaction mixture was split in two and
heated to 120.degree. C. for 30 min in a microwave. The reaction
mixtures were combined, acidified with 2M HCl and evaporated. The
crude product was taken onto the next step without
purification.
[0711] .sup.1H NMR (400 MHz, DMSO) .delta. 1.08-1.12 (2H, m), 1.27
(12H, s), 1.42-1.46 (2H, m), 1.74-1.82 (5H, m), 2.13 (2H, d), 7.22
(2H, d), 7.58 (2H, d) one CH and COOH not seen.
Example 48
4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic
acid
##STR00224##
[0713] This compound was synthesised from Intermediate 48-1 using
similar conditions as described in Example 21 to give the title
compound (42.2 mg, 74.5%) as an off white solid.
[0714] .sup.1H NMR (400 MHz, DMSO) .delta. 2.58 (3H, s), 2.70 (3H,
s), 3.57 (2H, s), 7.32 (2H, d), 7.55 (1H, s), 7.64 (2H, d), 7.73
(2H, d), 7.78 (2H, d), 7.96 (1H, s), 12.29 (1H, s); m/z 362
(M+H).sup.+.
Intermediate 48-1
Methyl
4'-(6-cyano-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylate
##STR00225##
[0716] This compound was synthesised from Intermediate 33-3 and
methyl 4-bromobenzoate using similar conditions as described in
Intermediate 21-1 to give the title compound (124 mg, 72.1%) as a
white solid.
[0717] .sup.1H NMR (400 MHz, DMSO) .delta. 2.68 (3H, s), 2.72 (3H,
s), 3.89 (3H, s), 7.80 (2H, d), 7.89-7.93 (4H, m), 8.07 (2H, d);
HPLC tR=2.92 min.
[0718] The following examples were synthesised from Intermediates
49-1- to 53-1 using similar conditions as described in Example 21
to give the desired compounds.
TABLE-US-00004 .sup.1H NMR (400 MHz, m/z Example Structure DMSO)
.delta. (M + H).sup.+ 49 ##STR00226## 2.64 (3H, s), 2.76 (3H, s),
3.63 (2H, s), 7.38 (2H, d), 7.61 (1H, s), 7.70 (2H, d), 7.79 (2H,
d), 7.84 (2H, d), 8.02 (1H, s), 12.33 (1H, s). 362 50 ##STR00227##
2.55 (2H, t), 2.64 (3H, s), 2.75 (3H, s), 2.87 (2H, t), 7.35 (2H,
d), 7.61 (1H, s), 7.65 (2H, d), 7.77 (2H, d), 7.83 (2H, d), 8.02
(1H, s). COOH not seen. 376 51 ##STR00228## 2.65 (3H, s), 2.76 (3H,
s), 7.35 (1H, t), 7.61 (2H, d), 7.77 (2H, d), 7.82-7.86 (3H, m),
8.05 (1H, s), 8.19 (1H, s), COOH not seen. 348 52 ##STR00229## 2.71
(3H, s), 2.82 (3H, s), 3.74 (2H, s), 7.36 (1H, d), 7.51 (1H, t),
7.69 (3H, d), 7.85 (2H, d), 7.92 (2H, d), 8.09 (1H, s), 12.43 (1H,
s). 362 53 ##STR00230## 2.61 (2H, t), 2.64 (3H, s), 2.76 (3H, s),
2.92 (2H, t), 7.26 (1H, d), 7.40 (1H, t), 7.56 (1H, d), 7.60-7.63
(2H, m), 7.79 (2H, d), 7.84 (2H, d), 8.02 (1H, s), 12.12 (1H, s).
376
[0719] The following Intermediates were synthesised from
Intermediate 33-3 and the appropriate aryl bromide or triflate
using similar conditions as described in Intermediate 21-1 to give
the desired compounds.
TABLE-US-00005 .sup.1H NMR (400 MHz, m/z Intermediate Structure
DMSO) .delta. (M + H).sup.+ 49-1.sup.a ##STR00231## 2.75 (3H, s),
2.79 (3H, s), 3.70 (3H, s), 3.81 (2H, s), 7.46 (2H, d), 7.78 (2H,
d), 7.82 (2H, d), 7.89 (2H, d) HPLC tR = 2.83 min 50-1.sup.b
##STR00232## 2.73-2.77 (5H, m), 2.78 (3H, s), 2.98 (2H, t), 3.35
(3H, s), 7.42 (2H, d), 7.74 (2H, d), 7.81 (2H, d), 7.87 (2H, d)
HPLC tR = 2.97 min. 51-1.sup.c ##STR00233## 2.75 (3H, s), 2.79 (3H,
s), 3.97 (3H, s), 7.74 (1H, t), 7.86 (2H, d), 7.95 (2H, d),
8.05-8.08 (1H, m), 8.10- 8.13 (1H, m), 8.34 (1H, t). HPLC tR = 2.93
min. 52-1.sup.d ##STR00234## 2.75 (3H, s), 2.79 (3H, s), 3.70 (3H,
s), 3.85 (2H, s), 7.38 (1H, d), 7.52 (1H, t), 7.70-7.73 (2H, m),
7.83 (2H, d), 7.88 (2H, d). 358 53-1.sup.e ##STR00235## 2.74 (3H,
s), 2.76-2.80 (5H, m), 3.02 (2H, t), 3.66 (3H, s), 7.34 (1H, d),
7.48 (1H, t), 7.64 (1H, d), 7.68- 7.69 (1H, m), 7.82 (2H, d), 7.89
(2H, d). 372 Note: 49-1.sup.a methyl 2-(4-bromophenyl)acctatc, CAS
41841-16-1 was made according to the procedure described by E. E.
Knaus at al, Bioorg. Med. Chem., 2005, 13, 4694-4703. 50-1.sup.b
methyl 3-(4-(trifluoromethylsulfonyloxy)phenyl)propanoate, CAS
475272-11-8. was made according to the procedure described in WO
2002089738. 51-1.sup.c methyl 3-bromobenzoate, CAS 618-89-3.
52-1.sup.d methyl 2-(3-bromophenyl)acetate, CAS 150529-73-0.
53-1.sup.e methyl 3-(3-bromophenyl)propanoate, CAS 151583-29-8 was
made according to the procedure described in WO 2007089667.
[0720] The following Examples 54-56 were synthesised from
Intermediates 54-1 to 56-1 using similar conditions as described in
Example 26 and Examples 57 to 63 were synthesised from
Intermediates 57-1 to 63-1 using similar conditions as described in
Example 21. All crude products were purified by preparative HPLC
(Waters XBridge Prep C18 OBD column, 5.mu. silica, 50 mm diameter,
150 mm length), using decreasingly polar mixtures of water
(containing 0.1% formic acid) and MeCN as eluents. Fractions
containing the desired compound were evaporated to dryness to
afford the desired products.
TABLE-US-00006 .sup.1H NMR m/z Example Structure DMSO) .delta. (M +
H).sup.+ 54 ##STR00236## 2.45 (3H, s), 2.75 (3H, s), 3.62 (2H, s),
7.38 (2H, d), 7.60 (1H, s), 7.66-7.68 (3H, m), 7.73 (2H, d), 7.96
(1H, s), 12.33 (1H, s) 380 55 ##STR00237## 2.40 (3H, s), 2.78 (3H,
s), 3.64 (2H, s), 7.39 (2H, d), 7.60-7.62 (2H, m), 7.73 (2H, d),
7.78-7.81 (1H, m), 7.90 (1H, d), 7.92 (1H, s), 12.35 (1H, s) 396 56
##STR00238## 2.41 (3H, s), 2.87 (3H, s), 3.72 (2H, s), 7.49 (2H,
d), 7.65 (1H, s), 7.75 (1H, d), 7.84 (3H, d), 8.17 (2H, t), COOH
not seen. 430 57 ##STR00239## 2.65 (3H, s), 2.76 (3H, s), 3.60 (2H,
s), 3.83 (3H, s), 7.31 (2H, d), 7.34-7.43 (3H, m), 7.47 (2H, d),
7.60 (1H, s), 8.05 (1H, s). COOH not seen. 392 58 ##STR00240## 2.37
(3H, s), 2.75 (3H, s), 3.63 (2H, s), 3.87 (3H, s), 7.35-7.40 (4H,
m), 7.45 (1H, d), 7.55 (1H, s), 7.72 (2H, d), 7.91 (1H, s), 12.34
(1H, s). 392 59 ##STR00241## 2.75 (3H, s), 2.84 (3H, s), 3.72 (2H,
s), 7.48 (2H, d), 7.53 (2H, d), 7.70 (1H, s), 7.74-7.80 (2H, m),
8.20 (1H, s), 12.47 (1H, s) 398 60 ##STR00242## 2.59 (3H, s), 2.71
(3H, s), 3.59 (2H, s), 7.32-7.34 (2H, m), 7.39-7.41 (2H, m), 7.48
(1H, d), 7.57 (1H, s), 7.73-7.75 (1H, m), 7.92 (1H, d), 8.04 (1H,
s), 12.31 (1H, s). 396 61 ##STR00243## 2.68 (3H, s), 2.78 (3H, s),
3.66 (2H, s), 7.42 (2H, d), 7.59 (2H, dd), 7.64 (1H, m), 7.69 (2H,
dd), 7.80 (1H, dd), 8.10 (1H, s), 12.40 (1H, s). 380 62
##STR00244## 2.15 (3H, s), 2.37 (3H, s), 2.77 (3H, s), 3.62 (2H,
s), 7.37 (3H, m), 7.54 (1H, s), 7.58 (1H, d), 7.67 (3H, m), 7.90
(1H, s), 12.34 (1H, s). 376 63 ##STR00245## 2.04 (6H, s), 2.63 (3H,
s), 2.75 (3H, s), 3.63 (2H, s), 7.14 (2H, d), 7.37 (2H, d), 7.47
(2H, s), 7.60 (1H, s), 8.00 (1H, s), 12.33 (1H, s). 390
[0721] The following Intermediates 54-1 to 63-1 were synthesised
from Intermediates 54-2 to 63-2 and Intermediate 21-4 using similar
conditions as described in Intermediate 21-1 to afford the desired
compounds.
TABLE-US-00007 .sup.1H NMR (400 MHz, m/z Intermediate Structure
DMSO) .delta. (M + H).sup.+ 54-1 ##STR00246## 1.48 (9H, s), 2.53
(3H, s), 2.83 (3H, s), 3.69 (2H, s), 7.45 (2H, d), 7.69 (1H, s),
7.74-7.78 (3H, m), 7.82 (2H, d), 8.05 (1H, s) 436 55-1 ##STR00247##
1.42 (9H, s), 2.40 (3H, s), 2.78 (3H, s), 3.63 (2H, s), 7.38 (2H,
d), 7.59-7.62 (2H, m), 7.74 (2H, d), 7.78- 7.81 (1H, m), 7.90-7.91
(2H, m) 452 56-1 ##STR00248## 1.42 (9H, s), 2.34 (3H, s), 2.80 (3H,
s), 3.64 (2H, s), 7.41 (2H, d), 7.59 (1H, s), 7.68 (1H, d), 7.75
(1H, s), 7.79 (2H, d), 8.09-8.11 (2H, m) 486 57-1 ##STR00249## 2.65
(3H, s), 2.77 (3H, s), 3.64 (3H, s), 3.72 (2H, s), 3.84 (3H, s),
7.31 (2H, d), 7.36-7.42 (3H, m), 7.49 (2H, d), 7.61 (1H, s), 8.05
(1H, s) 406 58-1 ##STR00250## 2.37 (3H, s), 2.75 (3H, s), 3.64 (3H,
s), 3.75 (2H, s), 3.87 (3H, s), 7.36-7.40 (4H, m), 7.45 (1H, d),
7.55 (1H, s), 7.73 (2H, d), 7.90 (1H, s) 406 59-1 ##STR00251## 2.75
(3H, s), 2.84 (3H, s), 3.72 (3H, s), 3.84 (2H, s), 7.49 (2H, d),
7.55 (2H, d), 7.71 (1H, s), 7.75-7.80 (2H, m), 8.20 (1H, s). 412
60-1 ##STR00252## 2.71 (3H, s), 2.83 (3H, s), 3.72 (3H, s), 3.95
(2H, s), 7.46 (2H, d), 7.52-7.54 (2H, m), 7.60 (1H, d), 7.69 (1H,
s), 7.85-7.87 (1H, m), 8.05 (1H, d), 8.16 (1H, s). 410 61-1
##STR00253## (CDCl.sub.3) .delta. 2.65 (3H, s), 2.93 (3H, s), 3.63
(2H, s), 3.66 (3H, s), 5.58 (1H, s), 7.31-7.39 (4H, m), 7.46- 7.53
(3H, m), 7.69 (1H, s). 394 62-1 ##STR00254## 2.16 (3H, s), 2.36
(3H, s), 2.78 (3H, s), 3.64 (3H, s), 3.74 (2H, s), 7.38 (3H, d),
7.55 (1H, s), 7.59 (1H, d), 7.67 (3H, m), 7.90 (1H, s). 390 63-1
##STR00255## 2.05 (6H, s), 2.63 (3H, s), 2.75 (3H, s), 3.66 (3H,
s), 3.76 (2H, s), 7.15 (2H, d), 7.38 (2H, d), 7.47 (2H, s), 7.60
(1H, s), 8.00 (1H, s). 404
[0722] The following Intermediates 54-2 to 63-2 were synthesised
from Intermediates 54-3 to 63-3 using similar conditions as
described in Intermediate 25-2 to afford the desired compounds.
TABLE-US-00008 Intermediate Structure .sup.1H NMR (400 MHz) m/z
54-2 ##STR00256## (CDCl.sub.3) .delta. 1.38 (12H, s), 1.45 (9H, s),
3.56 (2H, s), 7.24-7.27 (1H, m), 7.33- 7.38 (3H, m), 7.55 (2H, d),
7.77-7.80 (1H, m) 412 M.sup.+. (EI+) 55-2 ##STR00257## (CDCl.sub.3)
.delta. 1.39 (12H, s), 1.45 (9H, s), 3.56 (2H, s), 7.34 (2H, d),
7.43-7.45 (1H, m), 7.53 (2H, d), 7.58 (1H, s), 7.75 (1H, d) 428
M.sup.+. (EI+) 56-2 ##STR00258## (CDCl.sub.3) .delta. 1.38 (12H,
s), 1.46 (9H, s), 3.57 (2H, s), 7.37 (2H, d), 7.56 (2H, d), 7.72
(1H, d), 7.80 (1H, d), 7.87 (1H, s) 462 M.sup.+. (EI+) 57-2
##STR00259## (CDCl.sub.3) .delta. 1.36 (12H, s), 3.65 (2H, s), 3.71
(3H, s), 3.85 (3H, s), 7.31-7.33 (3H, m), 7.39 (1H, s), 7.47- 7.51
(3H, m) 382 M.sup.+. (EI+) 58-2 ##STR00260## (DMSO) .delta. 1.34
(12H, s), 3.35 (3H, s), 3.80 (2H, s), 3.89 (3H, s), 7.24 (1H, d),
7.26-7.28 (1H, m), 7.43 (2H, d), 7.67 (1H, d), 7.72 (2H, d) mass
ion not seen; HPLC tR = 3.01 min. 59-2 ##STR00261## (DMSO) .delta.
1.38 (12H, s), 3.70 (3H, s), 3.82 (2H, s), 7.40 (2H, d), 7.46 (4H,
s) mass ion not seen; HPLC tR = 3.30 min. 60-2 ##STR00262## (DMSO)
.delta. 1.31 (12H, s), 3.64 (3H, s), 3.75 (2H, s), 7.35-7.41 (4H,
m), 7.42 (1H, d), 7.65-7.67 (1H, m), 7.72 (1H, d). mass ion not
seen; HPLC tR = 3.42 min. 61-2 ##STR00263## (DMSO) .delta. 1.31
(12H, s), 3.63 (3H, s), 3.74 (2H, s), 7.36-7.46 (3H, m), 7.52 (2H,
dd), 7.55 (2H, d). 388 M + Na.sup.+ 62-2 ##STR00264## (DMSO)
.delta. 1.30 (12H, s), 2.52 (3H, s), 3.62 (3H, s), 3.72 (2H, s),
7.26 (1H, m), 7.40 (3H, m), 7.62 (2H, d), 7.70 (1H, d). no mass ion
seen HPLC tR = 3.44 min 63-2 ##STR00265## (DMSO) .delta. 1.28 (12H,
s), 1.94 (6H, s), 3.64 (3H, s), 3.74 (2H, s), 7.06 (2H, d), 7.34
(2H, d), 7.41 (2H, s). no mass ion seen HPLC tR = 3.39 min.
[0723] The following Intermediates 54-3 to 63-3 were synthesised
from Intermediates 54-4 to 63-4 either using similar conditions as
described in Intermediate 25-4 (Method A) or by Method B (the
procedure described by A. Bengtson, A. Hallberg and M. Larhed, Org.
Lett., 2002, 4, 1231-1233) to afford the desired compounds.
Representative Example of Method B
Intermediate 54-3
tert-Butyl
2-(3'-fluoro-4'-(trifluoromethylsulfonyl-oxy)biphenyl-4-yl)acet-
ate
[0724] Intermediate 54-4 (637 mg, 2.11 mmol),
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(753 mg, 2.11 mmol) and potassium carbonate (874 mg, 6.32 mmol)
were suspended in THF (11 mL) and sealed into a microwave tube. The
reaction was heated to 120.degree. C. for 6 minutes in the
microwave reactor and cooled to RT. The suspension was filtered,
the solid was washed with EtOAc (20 mL) and the filtrate was
evaporated to afford crude product. The crude product was purified
by flash silica chromatography, elution gradient 0 to 10% EtOAc in
isohexane. Pure fractions were evaporated to dryness to afford the
title compound (690 mg, 75%) as a colourless oil.
TABLE-US-00009 m/z Intermediate Structure .sup.1H NMR (400 MHz) (M
- H).sup.- 54-3 ##STR00266## (CDCl.sub.3) .delta. 1.46 (9H, s),
3.58 (2H, s), 7.35-7.39 (4H, m), 7.43-7.51 (3H, m) 433 55-3
##STR00267## (CDCl.sub.3) .delta. 1.46 (9H, s), 3.57 (2H, s),
7.36-7.41 (3H, m), 7.48-7.53 (3H, m), 7.71 (1H, s) 449 56-3
##STR00268## (CDCl.sub.3) .delta. 1.46 (9H, s), 3.59 (2H, s), 7.40
(2H, d), 7.52 (2H, d), 7.56 (1H, d), 7.80-7.83 (1H, m), 7.92 (1H,
d) 483 57-3 ##STR00269## (CDCl.sub.3) .delta. 3.67 (2H, s), 3.72
(3H, s), 3.83 (3H, s), 6.85 (1H, d), 6.92-6.95 (1H, m), 7.33-7.35
(3H, m), 7.44 (2H, d) 404 58-3 ##STR00270## (DMSO) .delta. 3.63
(3H, s), 3.74 (2H, s), 3.99 (3H, s), 7.30-7.33 (1H, m), 7.38 (2H,
d), 7.48 (1H, d), 7.52 (1H, d), 7.69 (2H, d) 403 59-3 ##STR00271##
(DMSO) .delta. 3.70 (3H, s), 3.83 (2H, s), 7.46-7.52 (4H, m), 7.74
(2H, d). 409 60-3 ##STR00272## (DMSO) .delta. 3.71 (3H, s), 3.82
(2H, s), 7.43-7.50 (4H, m), 7.64-7.69 (2H, m), 7.95 (1H, d). mass
ion not seen; HPLC tR = 3.14 min. 61-3 ##STR00273## (DMSO) .delta.
3.63 (3H, s), 3.75 (2H, s), 7.41 (2H, dd), 7.53 (2H, dt), 7.72 (1H,
d), 7.73 (1H, t). 391 62-3 ##STR00274## (DMSO) .delta. 2.40 (3H,
s), 3.63 (3H, s), 3.73 (2H, s), 7.27 (1H, m), 7.40 (3H, m), 7.65
(2H, m), 7.77 (1H, s). 387 63-3 ##STR00275## (DMSO) .delta. 2.01
(6H, s), 3.64 (3H, s), 3.73 (2H, s), 7.12 (2H, d), 7.26 (2H, s),
7.37 (2H, d). 401 Notes: Method A 58-3, 59-3, 60-3; Method B 54-3,
55-3, 56-3, 57-3, 61-3, 62-3, 63-3
[0725] The following Intermediates 54-4 to 63-4 were synthesised
from either Intermediate 54-5 or 54-7 and the appropriate
bromophenol using similar conditions as described in Intermediate
21-1 to afford the desired compounds.
TABLE-US-00010 m/z Intermediate Structure .sup.1H NMR (400 MHz) (M
- H).sup.- 54-4.sup.a ##STR00276## (CDCl.sub.3) .delta. 1.45 (9H,
s), 3.55 (2H, s), 5.11 (1H, d), 7.04 (1H, t), 7.24-7.27 (1H, m),
7.28-7.33 (3H, m), 7.46 (2H, d). 301 55-4.sup.b ##STR00277##
(CDCl.sub.3) .delta. 1.45 (9H, s), 3.55 (2H, s), 5.54 (1H, s), 7.07
(1H, d), 7.31-7.33 (2H, m), 7.38-7.41 (1H, m), 7.45-7.47 (2H, m),
7.54 (1H, d). 317 56-4.sup.c ##STR00278## (CDCl.sub.3) .delta. 1.45
(9H, s), 3.55 (2H, s), 5.11 (1H, d), 7.04 (1H, t), 7.24-7.27 (1H,
m), 7.28-7.33 (3H, m), 7.46 (2H, d) 351 57-4.sup.d ##STR00279##
(CDCl.sub.3) .delta. 3.65 (2H, s), 3.71 (3H, s), 3.78 (3H, s), 4.88
(1H, s), 6.45-6.47 (1H, m), 6.51 (1H, s), 7.15 (1H, d), 7.29 (2H,
d), 7.44 (2H, d) 271 58-4.sup.e ##STR00280## (DMSO) .delta. 3.69
(3H, s), 3.75 (2H, s), 3.91 (3H, s), 6.90 (1H, d), 7.11-7.13 (1H,
m), 7.23 (1H, d), 7.35 (2H, d), 7.61 (2H, d), 9.10 (1H, s). mass
ion not seen; HPLC tR = 2.20 min. 59-4.sup.f ##STR00281## (DMSO)
.delta. 3.38 (3H, s), 3.47 (2H, s), 6.28-6.34 (2H, m), 7.05-7.10
(4H, m), 10.18 (1H, s). 277 60-4.sup.g ##STR00282## (DMSO) .delta.
3.63 (3H, s), 3.71 (2H, s), 6.80-6.83 (1H, m), 6.92 (1H, d), 7.20
(1H, d), 7.28-7.33 (4H, m), 9.93 (1H, s). 275 61-4.sup.h
##STR00283## (DMSO) .delta. 3.62 (3H, s), 3.70 (2H, s), 6.65 (1H,
dd), 6.70 (1H, dd), 7.30 (1H, d), 7.32 (2H, dd), 7.41 (2H, dd),
9.96 (1H, s). 259 62-4.sup.i ##STR00284## (DMSO) .delta. 2.18 (3H,
s), 3.62 (3H, s), 3.67 (2H, s), 6.83 (1H, d), 7.27 (3H, d), 7.36
(1H, s), 7.50 (2H, d), 9.35 (1H, s). no mass ion seen HPLC tR =
2.28 min. 63-4.sup.j ##STR00285## (DMSO) .delta. 1.87 (6H, s), 3.64
(3H, s), 3.71 (2H, s), 6.50 (2H, s), 7.03 (2H, d), 7.29 (2H, d),
9.12 (1H, s). no mass ion seen HPLC tR = 2.31 min. Notes:
54-4.sup.a 4-Bromo-2-fluorophenol and Intermediate 54-5 55-4.sup.b
4-Bromo-2-chlorophenol and Intermediate 54-5. 56-4.sup.c
4-Bromo-2-(trifluoromethyl)benzenol and Intermediate 54-5.
57-4.sup.d 4-Bromo-3-methoxyphenol and Intermediate 54-5.
58-4.sup.e 4-Bromo-2-methoxyphenol and Intermediate 54-7.
59-4.sup.f 4-Bromo-3,5-Difluorophenol and Intermediate 54-7.
60-4.sup.g 4-Bromo-3-chlorophenol and Intermediate 54-7. 61-4.sup.h
4-Bromo-3-fluorophenol and Intermediate 54-7. 62-4.sup.i
4-Bromo-2-methylphenol and Intermediate 54-7. 63-4.sup.j
4-Bromo-3,5-dimethylphenol and Intermediate 54-7.
Intermediate 54-5
tert-Butyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetat-
e
##STR00286##
[0727] This compound was synthesised from Intermediate 54-6 using
similar conditions as described in Intermediate 25-2 to give the
title compound (8.37 g, 69.3%) as a pale yellow oil.
[0728] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.34 (12H, s),
1.42 (9H, s), 3.53 (2H, s), 7.27 (2H, d), 7.75 (2H, d); m/z (EI+)
318 M.
Intermediate 54-6
tert-Butyl 2-(4-bromophenyl)acetate CAS 33155-58-7
##STR00287##
[0730] N,N-Dimethylformamide di-tert-butyl acetal (29.8 mL, 124.44
mmol) was added portionwise over 10 minutes to a stirred solution
of 4-bromophenylacetic acid (13.38 g, 62.22 mmol) in toluene (400
mL) at 85.degree. C. The resulting solution was stirred at
85.degree. C. for 4 hours and allowed to cool to ambient
temperature. The reaction mixture was evaporated afford crude
product which was purified by flash silica chromatography, elution
gradient 0 to 20% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (10.29 g, 61.0%)
as a colourless oil.
[0731] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.43 (9H, s), 3.46
(2H, s), 7.14 (2H, d), 7.44 (2H, d); m/z (EI+) 270 M.
Intermediate 54-7
Methyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate
(CAS 454185-98-9)
##STR00288##
[0733] This compound was synthesised from methyl
2-(4-bromophenyl)acetate (CAS 41841-16-1 made according to the
procedure described by E. E. Knaus at al, Bioorg. Med. Chem., 2005,
13, 4694-4703) using similar conditions as described in
Intermediate 25-2 to afford the title compound (2.140 g, 100%) as a
white solid.
[0734] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.34 (12H, s),
3.64 (2H, s), 3.68 (3H, s), 7.28 (2H, d), 7.77 (2H, d); m/z (EI+)
276 M.
Example 64
2-((1r,4r)-4-(4-(6-Carbamoyl-5-methylpyrazin-2-yl)phenyl)cyclohexyl)acetic
acid
##STR00289##
[0736] This compound was synthesised from Intermediate 64-1 using
similar conditions as described in Example 21 to afford the title
compound (120 mg, 64.3%) as a white solid.
[0737] .sup.1H NMR (400 MHz, DMSO) .delta. 1.10-1.18 (2H, m),
1.49-1.53 (2H, m), 1.84 (4H, d), 2.15 (2H, d), 2.31-2.33 (1H, m),
2.65-2.67 (1H, m), 2.75 (3H, s), 7.38 (2H, d), 7.70 (1H, s), 8.14
(2H, d), 8.22 (1H, s), 9.18 (1H, s), 11.97 (1H, s); m/z 395
(M+H).sup.+.
Intermediate 64-1
Methyl
2-((1r,4r)-4-(4-(6-Carbamoyl-5-methylpyrazin-2-yl)phenyl)cyclohexyl-
)acetate
##STR00290##
[0739] This compound was synthesised from Intermediate 64-2 and
methyl
2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclo-
hexyl)acetate (CAS 701232-69-1: see also Intermediate 64-8) using
similar conditions as described in Intermediate 21-1 to afford the
title compound (194 mg, 83%) as a white solid.
[0740] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.15 (3H, m), 1.60
(2H, m) 1.87 (4H, s), 2.20-2.22 (2H, m), 2.40-2.50 (1H, m) 2.94
(3H, s), 3.63 (3H, s), 5.5 (1H, s), 7.29 (2H, d), 7.80 (1H, s),
7.85 (2H, d), 8.95 (1H, s); m/z 368 (M+H).sup.+.
Intermediate 64-2
6-Chloro-3-methylpyrazine-2-carboxamide
##STR00291##
[0742] This compound was synthesised from Intermediate 64-3 using
similar conditions as described in Intermediate 21-4 to afford the
title compound (109 mg, 83%) as a white solid.
[0743] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.89 (3H, s),
5.45-5.55 (1H, s), 7.45-7.55 (1H, s), 8.56 (1H, s).
Intermediate 64-3
Methyl 6-chloro-3-methylpyrazine-2-carboxylate
##STR00292##
[0745] A suspension of Intermediate 64-4 (314 mg, 1.87 mmol) and
Phosphorus oxychloride (2.088 mL, 22.40 mmol) stirred at 90.degree.
C. for 70 minutes. The reaction mixture was added dropwise to water
(20 mL) over 2-3 hours while maintaining the temperature below
40.degree. C. (external cooling required). The mixture was
extracted with DCM (5.times.50 mL), the organic layer was dried
over MgSO.sub.4, filtered and evaporated to afford a yellow oil.
This was then purified by flash silica chromatography, elution
gradient 0 to 20% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (142 mg, 40.8%)
as a white solid.
[0746] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.76 (3H, s), 3.94
(3H, s), 8.56 (1H, s); m/z 187 (M+H).sup.+.
Intermediate 64-4
Methyl 6-hydroxy-3-methylpyrazine-2-carboxylate
##STR00293##
[0748] A solution of Intermediate 64-5 (1.3 g, 5.79 mmol) in
pyridine (58.5 mL) was stirred at 60.degree. C. for 90 minutes. The
reaction mixture was evaporated to afford crude product. The crude
product was purified by flash silica chromatography, elution
gradient 50 to 80% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford the title compound (0.340 g, 34.9%)
as a yellow solid.
[0749] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.59 (3H, s), 3.94
(3H, s), 8.27 (1H, s); m/z 169 (M+H).sup.+.
Intermediate 64-5
(S)-Methyl 2-(2-aminoacetamido)-3-oxobutanoate hydrochloric acid
salt
##STR00294##
[0751] A 4M solution of Hydrogen chloride (7.98 mL, 31.91 mmol) in
dioxane was added to Intermediate 64-6 (2.3 g, 7.98 mmol). The
resulting solution was stirred at ambient temperature for 4 hours.
The reaction mixture was evaporated to afford the title compound
(1.790 g, 119%) as a cream solid, which was used without further
purification. m/z 189 (M+H).sup.+.
Intermediate 64-6
(S)-Methyl
2-(2-(tert-butoxycarbonylamino)acetamido)-3-oxobutanoate
##STR00295##
[0753] A solution of Intermediate 64-7 (12.9 g, 44.43 mmol) in DCM
(72 mL) was added to a stirred suspension of pyridinium
chlorochromate (22.99 g, 106.64 mmol) in DCM (43 mL) at 0.degree.
C., over a period of 15 minutes under air. The resulting mixture
was stirred at ambient temperature for 24 hours. The reaction
mixture was evaporated to dryness and ether (400 mL) and water (300
mL) were added. The suspension was filtered through celite and the
flask was rinsed with ether (4.times.300 mL) and water (3.times.200
mL). The washings were filtered through celite and the organic
layers were combined, washed with saturated brine (200 mL), The
aqueous phase was re extracted with EtOAc (2.times.500 mL), the
organic layers were combined dried over MgSO.sub.4, filtered and
evaporated to afford 5.5 g of crude product. The crude product was
purified by flash silica chromatography, elution gradient 50 to 80%
EtOAc in isohexane. Pure fractions were evaporated to dryness to
afford the title compound (18.29%) as a yellow oil.
[0754] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.39 (9H, d),
1.97-2.01 (3H, m), 2.31 (2H, s), 3.68 (1H, t), 3.75 (3H, s),
3.76-3.82 (3H, m), 4.05 (2H, q), 5.19 (1H, d).
Intermediate 64-7
Methyl
2-(2-(tert-butoxycarbonylamino)acetamido)-3-hydroxybutanoate
##STR00296##
[0756] HATU (46.9 g, 123.30 mmol) was added to a stirred solution
of 2-(tert-butoxycarbonylamino)acetic acid (18 g, 102.75 mmol) DMA
(230 mL) at ambient temperature. After 5 minutes a solution of
(2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (17.43 g,
102.75 mmol) and DIPEA (71.8 mL, 411.00 mmol) in DMA (230 mL) was
added and the resulting solution was stirred at ambient temperature
for 20 hours, The reaction mixture was diluted with EtOAc (300 mL),
and washed with 1N citric acid (300 mL), salt was added to the
aqueous layer which was re extracted with EtOAc (4.times.400 mL).
The organic extracts were combined, washed with saturated
NaHCO.sub.3 (200 mL), dried over MgSO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by flash silica chromatography, elution gradient 50 to 100% EtOAc
in isohexane. Pure fractions were evaporated to dryness to afford
the title compound (12.97 g, 43.5%) as a yellow glass which formed
a solid on standing.
[0757] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.16 (3H, t), 1.38
(9H, d), 3.70 (3H, s), 3.80-3.81 (2H, m), 4.25-4.28 (1H, m),
4.51-4.54 (1H, m), 5.36 (1H, s), 6.96 (1H, d); m/z 291
(M+H).sup.+.
Intermediate 64-8
Methyl
2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)cyclohexyl)acetate
##STR00297##
[0759] Trimethylphosphonoacetate (1.05X-1.06X) was added dropwise
to a suspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol)
at 5-10.degree. C. The resulting solution was stirred at
15-20.degree. C. for 3.5-4.0 hours. The reaction mixture was cooled
to 5-10.degree. C. and DIPEA (0.81-0.82X) was added to the reaction
at 10-15.degree. C. 4-(4-Hydroxyphenyl)cyclohexanone (1.0X) was
added in portions to the above reaction mixture at 10-15.degree. C.
and the resulting solution was stirred at 15-20.degree. C. for 3-6
hours and then sampled for HPLC analysis. NH4Cl-sol (5.0X-6.0X) was
added to the reaction mixture at 0-15.degree. C., and the reaction
was quenched. The organic layer was separated and the aqueous layer
was extracted with 2-MeTHF (2.5X-3.0X). The two organic extracts
were combined and washed with NaHSO.sub.3 aq. and then
NaCl-solution (2.5X-3.0X) twice. The organic layer was concentrated
to 2-3 vol and n-heptane was added to give a suspended solution,
and the above mixture was concentrated to below 3% of 2-MeTHF
residue to give a suspended solution. The mixture was cooled to
0-5.degree. C., stirred for 1.0-2.0 h, filtered and the cake washed
with n-heptane (2 vol X2). Dry in vacuum at below 45.degree. C. to
give the desired phenoxyacrylate product.
[0760] AcOH (0.05X) and Toluene (20 vol) were added to a pressure
reactor, then the above phenoxyacrylate (1.0X) was added to the
mixture. The reactor was carefully inertised, then 10% Pd/C (0.15X)
was added to the reaction mixture under nitrogen protection. The
agitation was slowed down and the nitrogen-atmosphere was exchanged
by hydrogen three times, and hydrogenation was performed at 1200
mbar at 25-28.degree. C. The resulting solution was stirred at
25-28.degree. C. for 14-18 h. HPLC showed conversion of >98%.
The reaction mixture was filtered, and the cake was washed with
EtOH (1.5X.times.2), then the filtrate was concentrated in vacuo to
2-3 vol, n-heptane(10 vol) was added to precipitate, then
concentrated until toluene residue <1.0%, cooled to 0-5.degree.
C., filtered, the cake was dried in vacuo to dryness. The crude
product was dissolved in EtOH:H.sub.2O=2:1 (1.09X of crude product)
by heating to reflux and stirred at this temperature for .about.5
min, then cooled slowly to 20.degree. C. over 3 h and stirred at
20.degree. C. for 1 h, followed by cooling slowly to
0.about.5.degree. C. over 90 min and stirred at 0.about.5.degree.
C. for 1 h. After filtering the filter cake was washed with cold
EtOH:H.sub.2O=2:1 (0.18X.times.2 of crude product,
0.about.5.degree. C.). The filter cake was dried in vacuo at
45-50.degree. C. for 24 h to give the pure trans-ester product.
[0761] The above trans ester (1.0X) was dissolved in anhydrous
CH.sub.2Cl.sub.2 (12 vol), NMM (0.57X, 1.4 eq) was added dropwise
to the mixture under N.sub.2. The resulting solution was cooled to
-10.about.0.degree. C. and stirred for 10 min, then Tf.sub.2O
(1.36X, 1.2 eq) was added dropwise at -10.about.0.degree. C. (N.B.
CF.sub.3SO.sub.2Cl can be appropriately used in place of triflic
anhydride Tf.sub.2O). The resulting solution was stirred at
-10.about.0.degree. C. for 30 min, warmed to 0.about.10.degree. C.
and stirred for 30 min. (sampled for HPLC analysis, conversion was
>98%). 10% citric acid solution (10.0X) was added dropwise to
the mixture. The mixture was stirred for 10 min, the organic layer
was separated, washed with 10% citric acid (10.0X) and brine
(10.0X), dried with anhydrous MgSO.sub.4 (0.5X) for 2 hrs, filtered
and concentrated to remove CH.sub.2Cl.sub.2. Heptane (10X) was
added and concentrated to remove the residual CH.sub.2Cl.sub.2
(expectation<1.0%), then the suspension in heptane was
concentrated to 1.5.about.2.0 vol, the mixture was cooled to
0.about.5.degree. C. and stirred for 30.about.60 min at
0.about.5.degree. C. After filtering the cake was dried under
vacuum at 30.about.40.degree. C. to give the desired triflate as a
white solid. Pinacoldiboron ester (0.8X, 1.2 eq), TBAF (0.13X, 0.2
eq) and KOAc (0.38X, 1.5 eq) were dissolved in CH.sub.3CN (5 vol),
then PCy.sub.3 (1.5% X, 0.02 eq) and PdCl.sub.2 (0.47% X, 0.01 eq)
were added. The mixture was degassed with nitrogen. A solution of
the triflate (1.0X, 1.0 eq) in CH.sub.3CN (7 vol) was added to the
mixture at 20-25.degree. C. Then the resulting solution was heated
to reflux and stirred for 16 hrs (overnight--sampled for HPLC
analysis, conversion was >98%). The mixture was filtered via a
pad of 20 um cellulose, activated carbon (0.2X) was added to the
filtrate and the resulting solution was heated to reflux for
2.about.3 hrs. The mixture was cooled to 40.about.50.degree. C. and
then filtered and the filtrate was concentrated to dryness. The
residue solid was dissolved in EtOAc, and the EtOAc solution was
washed with water (10 vol), 1N HCl (10 vol) and brine (10 vol). The
organic layer was separated and concentrated to 1.about.2 vol, then
heptane (5.about.6 vol) was added to the solution and concentrated
until EtOAc was removed (EtOAc/Heptane=0-1%), heptane (5.about.6
vol) was added to the resulting solution and heated to
50.about.60.degree. C. for 30 min. There were two layers (a clear
upper heptane layer and a yellowish bottom layer). The heptane
layer was separated, heptane (5.about.6 vol) was added to the
yellowish bottom layer and heated to 50.about.60.degree. C. for 30
min, and the heptane layer was separated again. The heptane layers
were combined and filtered via silica gel. The filtrate was
concentrated to 1.about.1.5 vol and the precipitate was filtered
and dried in vacuo to give the desired boronate ester as a white
solid.
Example 65
Methyl
trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohex-
anecarboxylate
##STR00298##
[0763] Ethyl chloroformate (245 .mu.l, 2.54 mmol) was added
dropwise to a stirred solution of
6-{4-[trans-4-(methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carb-
oxylic acid (Intermediate 65-1, 751 mg, 2.12 mmol) and
N-methylmorpholine (350 .mu.l 3.18 mmol) in DCM (20 mL) at
0.degree. C. Ammonia (5 mL of a 7M solution in MeOH) was added. The
reaction mixture was allowed to warm up over 1 h then was
concentrated and the residue was purified by chromatography eluting
with 0-10% MeOH/DCM to give the title compound (226 mg, 30%) as a
solid; .sup.1H NMR .delta. 9.00 (1H, s), 8.08 (1H, s), 7.74 (1H,
s), 7.70 (2H, d), 7.40 (2H, d), 3.63 (3H, s), 2.70-2.55 (1H, m),
2.67 (3H, s), 2.50-2.35 (1H, m), 2.10-1.98 (2H, m), 1.96-1.83 (2H,
m), 1.65-1.43 (4H, m); MS 354.
Intermediate 65-1
6-{4-[trans-4-(Methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carbo-
xylic acid
##STR00299##
[0765] Diaminopropionic acid hydrochloride (496 mg, 3.52 mmol) was
added to a stirred solution of methyl
trans-4-(4-pyruvoylphenyl)cyclohexanecarboxylate (Intermediate
65-2, 844 mg, 2.93 mmol) and triethylamine (1.6 mL, 11.72 mmol) in
MeOH (6 mL). After 48 h the reaction mixture was concentrated and
the residue was triturated with ether to give the title compound
(751 mg, 72%) as a solid that was used without further
purification; .sup.1H NMR .delta. 9.04 (1H, s), 7.62 (2H, d), 7.40
(2H, d), 3.64 (3H, obs. s), 2.70-2.55 (1H, m), 2.66 (3H, s),
2.50-2.36 (1H, m), 2.08-1.96 (2H, m), 1.95-1.85 (2H, m), 1.65-1.45
(4H, m); MS 355.
Intermediate 65-2
Methyl trans-4-(4-pyruvoylphenyl)cyclohexanecarboxylate
##STR00300##
[0767] 1,1,1-tris(Acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
(5.14 g, 12.12 mmol) was added to a stirred solution of methyl
trans-4-(4-lactoylphenyl)cyclohexanecarboxylate (Intermediate 65-3,
1.758 g, 6.06 mmol) in DCM (25 mL). The mixture was stirred for 1
h, hexanes (50 mL) was added and the mixture was filtered through a
pad of diatomaceous earth. Volatile material was removed by
evaporation to give the title compound (1.55 g, 88%) as a solid
that was used without further purification; .sup.1H NMR .delta.
7.88 (2H, d), 7.45 (2H, d), 3.63 (3H, s), 2.70-2.57 (1H, m), 2.50
(3H, s), 2.48-2.36 (1H, m), 2.08-1.94 (2H, m), 1.90-1.80 (2H, m),
1.60-1.40 (4H, m); MS 311 (M+Na).sup.+.
Intermediate 65-3
Methyl trans-4-(4-lactoylphenyl)cyclohexanecarboxylate
##STR00301##
[0769] Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was
added to a stirred solution of methyl
trans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate
(prepared as described in Patent Application WO2004/047755) (3.264
g, 9.25 mmol) in DMF (10 mL). The mixture was stirred for 40
minutes then extracted with ether (5.times.20 mL). The extracts
were combined, dried and concentrated. The crude product was
purified by flash column chromatography eluting with 20-40%
EtOAc/hexanes to give the title compound (1.76 g, 66%) as a solid;
.sup.1H NMR .delta. 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d),
5.08-4.98 (1H, m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H,
m), 2.08-1.94 (2H, m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28
(3H, s); MS 313 (M+Na).sup.+.
Example 66
trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecarb-
oxylic acid
##STR00302##
[0771] Lithium hydroxide monohydrate (42 mg, 1.00 mmol) was added
to a stirred solution of methyl
trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecar-
boxylate (Example 65, 71 mg, 0.20 mmol) in MeOH (2 mL), THF (1 mL)
and water (0.5 mL). After 16 h the reaction mixture was
concentrated in vacuo and purified by reverse phase HPLC (150
mm.times.21 mm Phenomenex Column packed with Luna 10u C18 silica,
eluting with 5-95% acetonitrile/water) to give the title compound
as a yellow solid (6 mg, 9%); .sup.1H NMR .delta. 9.01 (1H, s),
8.08 (1H, s), 7.73 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 2.70-2.50
(1H, m), 2.65 (3H, s), 2.37-2.25 (1H, m), 2.10-2.00 (2H, m),
1.95-1.85 (2H, m), 1.65-1.40 (4H, m); MS 340.
Examples 67 to 70
[0772] Other compounds which have been made by processes analogous
to those described herein are
2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2'-methylbiphenyl-4-yl)aceti-
c acid;
2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)naphthalen-1-yl)phen-
yl)acetic acid;
2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2'-cyanobiphenyl-4-yl)acetic
acid and
2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-3',5'-difluorobiphe-
nyl-4-yl)acetic acid.
Alternative Preparations
Intermediate 1-4
Ethyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate
##STR00303##
[0774] A suspension of Intermediate 1-5 (268 g, 1365.93 mmol) in
phosphorus oxychloride (1273 mL, 13659.31 mmol) was heated at
90.degree. C. under nitrogen for 1 hour then cooled to ambient
temperature. The reaction was cautiously added to water (6 L) with
vigorous stirring keeping the temperature between 17.degree. C. and
20.degree. C. The mixture was then extracted with DCM (5.times.2.5
L), washed with water, saturated brine and dried over MgSO.sub.4
and evaporated to afford crude product. The crude product was
purified by flash silica chromatography, elution gradient 0 to 25%
EtOAc in isohexane. Pure fractions were evaporated to dryness to
afford the title compound (227 g, 77%) as a yellow oil which
solidified on standing.
[0775] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.43 (3H, t), 2.68
(3H, s), 2.77 (3H, s), 4.46 (2H, q); m/z 215 (M+H).sup.+.
Intermediate 1-5
Ethyl 6-hydroxy-3,5-dimethylpyrazine-2-carboxylate
##STR00304##
[0777] A solution of 2M Hydrochloric acid in 1,4-dioxane (1177 mL,
4709.97 mmol) was added to Intermediate 1-6 (745 g, 2354.99 mmol)
and stirred at room temperature for 15 minutes then warmed to
40.degree. C. for a further 40 minutes. Pyridine (6500 mL) was then
slowly added and then the reaction was heated to 80.degree. C. for
2 hours in the presence of air. The reaction was then allowed to
cool to ambient temperature and evaporated to dryness to afford a
viscous oil. This was suspended in DCM (2.5 L) and washed water
(1.5 L). The DCM was then dried over MgSO.sub.4, filtered and
concentrated to afford an orange semi-solid, which was triturated
with 1:1 EtOAc/iso-hexane (250 mL) to afford ethyl
6-hydroxy-3,5-dimethyl-1,4-dihydropyrazine-2-carboxylate (127 g,
27.1%) as a cream solid. The mother liqours were then purified by
flash silica chromatography (gradient from 20% ethyl
acetate/iso-hexane to 80% ethyl acetate/iso-hexane). Fractions
containing the desired product were concentrated and the residue
was triturated with a small volume of 1:1 EtOAc/iso-hexane to
afford the title compound (9.00 g, 1.948%).
[0778] Manganese dioxide (150 g) was added to a suspension of ethyl
6-hydroxy-3,5-dimethyl-4,5-dihydropyrazine-2-carboxylate (121 g,
610.44 mmol) in DCM (1.8 L) at ambient temperature giving rise to a
2.degree. C. exotherm. The reaction was stirred for 10 minutes then
warmed to 35.degree. C. for 1 hour. The reaction was incomplete so
an additional 115 g of Manganese dioxide was added and the reaction
stirred for 1 hour at 35.degree. C. then stirred to cool to ambient
temperature. The reaction was filtered through a short bed of
silica and washed through with 2 L of 1:1 EtOAc/iso-hexane and
finally 2.times.2 L EtOAc. The fractions were then combined and
reduce in-vacuo to give an orange solid, which was slurried in 300
mL of 1:1 EtOAc/iso-hexane, filtered and washed with iso-hexane to
afford the title compound (87 g, 72.6%) as an orange solid.
[0779] .sup.1H NMR (400 MHz, DMSO) .delta. 1.31 (3H, t), 2.35 (3H,
s), 2.50 (3H, s), 4.31 (2H, q), 11.93 (1H, s); m/z 197
(M+H).sup.+
Intermediate 1-6 can Also be Prepared by the Following
Procedure
Intermediate 1-6
Ethyl
2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate
##STR00305##
[0781] A solution of 4-methylmorpholine (900 g) in THF (15 L) was
added to 2-(tert-butoxycarbonylamino)propanoic acid (1690 g,
8933.17 mmol). The mixture was cooled to -25.degree. C. and
isobutyl chloroformate (1.164 L, 8933.17 mmol) was added. After 20
minutes the second equivalent of 4-methylmorpholine (900 g) was
added followed by ethyl 2-amino-3-oxobutanoate Tosylate salt (see
J-P. Genet et al, Eur. J. Org. Chem., 2004, 3017-3026) (2700 g,
8507.78 mmol) suspended in THF (2.5 L). The mixture was stirred at
-25.degree. C. for 30 minutes and then left to warm to ambient
temperature overnight. The reaction was quenched with water (15 L),
extracted with EtOAc (3.times.5 L) and the combined extracts washed
with 50% saturated brine (5 L). The organic layer was dried over
MgSO.sub.4, filtered and evaporated to afford crude product. The
crude product was purified by flash silica chromatography, elution
gradient 50 to 80% EtOAc in isohexane. Pure fractions were
evaporated to dryness to afford ethyl
2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate (1850 g,
68.7%).
Example 1
2-((1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)ac-
etic acid
##STR00306##
[0783] Powdered potassium hydroxide (2.81 g, 50.10 mmol) was added
in one portion to Intermediate 1-8 (6.37 g, 16.70 mmol) in
tert-butanol (150 mL) at 40.degree. C. under nitrogen. The
resulting suspension was stirred at 40.degree. C. for 20 minutes. A
thick precipitate formed so the reaction was quenched with acetic
acid (4.78 mL, 83.49 mmol) in ethanol (100.0 mL) and the resulting
solution stirred for a further 20 minutes before being evaporated
to dryness. The resulting solid was partitioned between water (500
mL) and EtOAc (500 mL). The aqueous layer showed a pH=4.about.5.
The organic layer was separated and the aqueous re-extracted with
EtOAc (2.times.250 mL). The combined organics were washed with
brine (100 mL), dried over MgSO.sub.4 and evaporated in vacuo to
give crude product. This was recrystallised from hot ethanol (250
mL) to give a yellow solid which was washed with ether (100 mL) and
dried under vacuum at room temperature to give the title compound
(4.82 g, 79%).
[0784] [.sup.1H NMR (400.132 MHz, DMSO) .delta. 1.09-1.19 (2H, m),
1.46-1.57 (2H, m), 1.70-1.78 (1H, m), 1.81-1.87 (4H, m), 2.15 (2H,
d), 2.58 (3H, s), 2.73 (3H, s), 3.29 (1H, s), 7.36 (2H, d), 7.57
(1H, s), 7.64 (2H, d), 7.98 (1H, s), 11.98 (1H, s)].
[0785] A melting point with an onset value of approximately
225.degree. C. has been determined for
{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceti-
c acid.
Intermediate 1-8
methyl
2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cycloh-
exyl)acetate
##STR00307##
[0787] A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide
(see Intermediate 21-4) (3.15 g, 16.97 mmol), methyl
2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclo-
hexyl)acetate (see Intermediate 64-8) (6.08 g, 16.97 mmol) and
tripotassium phosphate (4.32 g, 20.37 mmol) in DME (120 mL),
ethanol (75 mL) and water (30.0 mL) were degassed before addition
of (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
(0.698 g, 0.85 mmol). The reaction mixture was heated to 80.degree.
C., under nitrogen, and left to stir overnight for 16 hrs. The
reaction mixture was allowed to cool to room temperature and then
evaporated. The crude product was partitioned between water (250
mL) and EtOAc (250 mL). The catalyst was filtered off from the
biphasic mixture. The organic phase was separated and washed with
brine (100 mL), dried (Na.sub.2SO.sub.4) and evaporated. The crude
product was purified by flash silica chromatography, elution
gradient 5 to 90% EtOAc in isohexane on 330 g silicyle column. Pure
fractions were evaporated to dryness to afford the title compound
(6.47 g, 100%) as a yellow solid.
[0788] [.sup.1H NMR (400.132 MHz, DMSO) .delta. 1.10-1.21 (2H, m),
1.46-1.56 (2H, m), 1.73-1.86 (5H, m), 2.25 (2H, d), 2.58 (3H, s),
2.73 (3H, s), 3.28 (1H, s), 3.60 (3H, s), 7.35 (2H, d), 7.58 (1H,
s), 7.64 (2H, d), 7.97 (1H, s); HPLC tR=2.53 min.]
* * * * *