Field of the Invention
The present invention relates to compounds of formula (I) that are antagonists or
inverse agonists of the glucagon receptor, and to pharmaceutical compositions thereof,
and the uses of same in the treatment of the human or animal body. The present
compounds show a high affinity and selective binding for the glucagon receptor.
Background of the invention
Glucagon is a key hormonal agent that, in cooperation with insulin, mediates
homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by
stimulating certain cells (important among these are liver cells) to release glucose when
blood glucose levels fall. The action of glucagon is opposite to that of insulin, which
stimulates cells to take up and store glucose whenever blood glucose levels rise. Both
glucagon and insulin are peptide hormones. Glucagon is produced in the alpha islet cells
of the pancreas and insulin is produced in the beta islet cells. Glucagon exerts its action
by binding to and activating its receptor, which is a member of the Glucagon-Secretin
branch of the 7-transmembrane G-protein coupled receptor family. The receptor
functions by activating the adenylyl cyclase second messenger system resulting in an
increase in cAMP levels. The glucagon receptor, or naturally occurring variants of the
receptor, may possess intrinsic constitutive activity, invitro, as well as in vivo (i.e.
activity in the absence of an agonist). Compounds acting as inverse agonists can inhibit
this activity. Diabetes mellitus is a common disorder of glucose metabolism. The disease
is characterized by hyperglycemia and may be classified as type 1 diabetes, the insulin-
dependent form, or type 2 diabetes, which is non-insulin-dependent in character. Subjects
with type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional
treatment for this form of the disease is to provide insulin. However, in some patients
with type 1 or type 2 diabetes, absolute or relative elevated glucagon levels have been
shown to contribute to the hyperglycemic state. Both in healthy control animals as well as
in animal models of type 1 and type 2 diabetes, removal of circulating glucagon with
selective and specific antibodies has resulted in reduction of the glycemic level. Mice
with a homozygous deletion of the glucagon receptor exhibit increased glucose tolerance.
Also, inhibition of glucagon receptor expression using antisense oligonucleotides
This patent application claims the benefit of United States Provisional Patent
Application No. 60/579,362 filed June 14, 2004.
This invention relates to compounds that are antagonists or inverse agonists of the
glucagon receptor, and to pharmaceutical compositions thereof, and the uses of these
compounds and compositions in the treatment of the human or animal body. The present
compounds show a high affinity and selective binding for the glucagon receptor, and as
such are useful in the treatment of disorders responsive to the modulation of glucagon
receptors, such as diabetic and other glucagon related metabolic disorders, and the like.
Glucagon is a key hormonal agent that, in cooperation with insulin, mediates
homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by
stimulating certain cells (important among these are liver cells) to release glucose when
blood glucose levels fall. The action of glucagon is opposite to that of insulin, which
stimulates cells to take up and store glucose whenever blood glucose levels rise. Both
glucagon and insulin are peptide hormones. Glucagon is produced in the alpha islet cells
of the pancreas and insulin is produced in the beta islet cells. Glucagon exerts its action
by binding to and activating its receptor, which is a member of the Glucagon-Secretin
branch of the 7-transmembrane G-protein coupled receptor family. The receptor functions
by activating the adenylyl cyclase second messenger system resulting in an increase in
cAMP levels. The glucagon receptor, or naturally occurring variants of the receptor, may
possess intrinsic constitutive activity, invitro, as well as in vivo (i.e. activity in the
absence of an agonist). Compounds acting as inverse agonists can inhibit this activity.
Diabetes mellitus is a common disorder of glucose metabolism. The disease is
characterized by hyperglycemia and may be classified as type 1 diabetes, the insulin-
dependent form, or type 2 diabetes, which is non-insulin-dependent in character. Subjects
with type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional
treatment for this form of the disease is to provide insulin. However, in some patients
with type 1 or type 2 diabetes, absolute or relative elevated glucagon levels have been
shown to contribute to the hyperglycemic state. Both in healthy control animals as well as
in animal models of type 1 and type 2 diabetes, removal of circulating glucagon with
selective and specific antibodies has resulted in reduction of the glycemic level. Mice
with a homozygous deletion of the glucagon receptor exhibit increased glucose tolerance.
Also, inhibition of glucagon receptor expression using antisense oligonucleotides
' ameliorates diabetic syndrome in db/db mice. These studies suggest that glucagon
suppression or an action that antagonizes glucagon could be a useful adjunct to
conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can
be suppressed by providing an antagonist or an inverse agonist, i.e. substances that inhibit
or prevent constituitive, or glucagon-induced, glucagon receptor mediated responses.
Several publications disclose peptides that are stated to act as glucagon
antagonists. Peptide antagonists of peptide hormones are often potent; however they are
generally known not to be orally available because of degradation by physiological
enzymes and poor distribution in vivo. Therefore, orally available non-peptide antagonists
of peptide hormones are generally preferred.
A number of publications have appeared in recent years reporting non-peptide
agents that act at the glucagon receptor. In spite of the number of treatments for diseases
that involve glucagon, the current therapies suffer from one or more inadequacies,
including poor or incomplete efficacy, unacceptable side effects, and contraindications for
certain patient populations. Thus, there remains a need for an improved treatment using
alternative or improved pharmaceutical agents that modulate glucagon receptor activity
and treat the diseases that could benefit from glucagon receptor modulation. The present
invention provides such a contribution to the art based on the finding that a novel class of
compounds has a high affinity, selective, and potent inhibitory activity at the glucagon
receptor. The present invention is distinct in the particular structures and their activities.
SUMMARY OF THE INVENTION
The present invention provides a compound structurally represented by Formula I:

or a pharmaceutically acceptable salt thereof wherein:
Yis-O-or-S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the optional
substituents as indicated herein), or nitrogen (optionally substituted with oxygen),
provided that no more than two of Q, D, X, and T are nitrogen;
Rl is-H,-OH, or-halogen;
R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);
R3 and R4 are independently
- H, -halogen, -CN, -OH, -(C1-C7) alkoxy, -(C1-C7) alkyl(optionally substituted
with I to 3 halogens), or -(C2-C7) alkenyl;
R5 is selected from the group consisting of
-H, -(C1-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C]2)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-C|2)alkyl,
-aryl, -aryl-(C|-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl, -(C2-Ci2)alkenyl,
-(C3-C|2)cycloalkenyl, -heterocycloalkyl, -aryl-(C2-C|0)alkenyl,
-heteroaryl-(C2-C,0)alkeny 1, -(C2-C12)alkynyl, -(C3-C12)cycloalkynyl,
-aryl-( C2-C|2)alkynyl, and -heteroaryl-(C2-C|2)alkynyl, and wherein -(C,-
C]2)alkyl, -(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl,
-aryl-(Ci-Ci2)aIkyl, -heteroaryl, -heteroaryl-(Ci-C|2)alkyl, -heterocycloalkyl, -(C2-
C]2)alkenyl, -(C3-C|2)cycloalkenyl, -aryI-(C2-C10)alkenyl,
-heteroaryl-(C2-C|0)alkenyl, -(C2-C]2)alkynyl, -(C3-C12) cycloalkynyl,
-aryl-(C2-Ci2)alkynyl, -heteroaryl-(C2-C]2)alkynyl, are each optionally substituted
with from one to three substituents each independently selected from the group
consisting of-hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, -(C1-C7)alkyl
(optionally substituted with 1 to 3 halogens), -(C1-C7)alkyl-COOR12,
-(Ct-C7)alkoxy, -(C3-C7)cycloalkyl, -C(0)R12, -C00R12, -OC(O)R12,
-OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12,
-S(O)2R12, and -S(O)2N(R12)2;
R6 and R7 are independently at each occurrence selected from the group consisting of
-H, -halogen, -hydroxy, -CN, -(CrC7) alkoxy, -(C2-C7)alkenyl, -(Ci-C,0)alkyl
(optionally substituted with 1 to 3 halogens), -(C3-C12)cycloalkyl,
tert-butoxyiminomethyl, l,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morphylino-4-yI-methyl, 4-methyIpentyloxy, and
pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not attached to D,
and provided that wherein T is nitrogen, then R6 or R7 are not attached to T, and
provided that wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the atoms to
which they are attached, and the ring so formed may optionally contain up to two
oxygens, and further the ring so formed may optionally be substituted with up to
four halogens;
R8 and R9 are independently at each occurrence selected from the group consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C]-C7)alkyl(optionally substituted with
1 to 3 halogens), -(C)-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(CrC7)alkyl,
-heteroaryl, -heteroaryl-(CrC7)alkyI, -aryloxy, -C(O)R12, -C(O)OR12,
-0C(0)R12, -OS(O)2R12, -N(R12)2, -NR12C(O) R12, -NR12SO2 R12, -SRI2,
-S(O)R12, -S(O)2R12, -O(C2-C7)alkenyl, and -S(O)2N(R12)2; and wherein
-(CrC7)alkyl, -(C1-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(CrC7)alkyl,
-heteroaryl, -heteroaryl-(C|-C7)alkyl, -aryloxy, and -O(C2-C7)aIkenyl are each
optionally substituted with from one to three substituents independently selected
from the group consisting of-hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo,
-(C1-C7)alkyl, -(C1-C7)alkyl-C(O)OR12, -(C1-C7)alkoxyl, -(C3-C7)cycloalkyl,
-heterocycloalkyl, -C(0)R12, -C(O)OR12, -OC(O)R12, -OS(O)2Rl2, -N(R12)2,
-NR12C(O)R12, -NR12SO2 R12, -SR12, -S(O)R12, -S(O)2R12, and
-S(O)2N(R12)2;
RIO is selected from the group consisting of
-H, halogen, -(Ci-Ci2)alkyl(optionally substituted with 1 to 3 halogens),
-cycloalkyl, -aryl, -aryI-(C1-C7)alkyl, -heteroaryl, -heteroaryl -(C1-C7)alkyl,
-(C2-C|2)alkenyl, -(C3-C12)cycloalkenyl, -aryl-(C2-Cio)alkenyl,
-heteroaryl-(C2-Cio)alkenyI,-(C2-C,2)alkynyl,-(C3-C12)cycloalkynyl,
-aryl-(C2-C|2)alkynyl, and -heteroaryl-(C2-C]2)alkynyl;
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen,
wherein the zig-zag mark shows the point of attachment to the
parent molecule, wherein A, G, and E independently represent carbon (substituted
with hydrogen or the optional substituents as indicated herein) or nitrogen,
provided that no more than two of A, G, and E are nitrogen;
provided however that wherein A is nitrogen, then R8, R9, and R14 are not
attached to A, and provided that wherein G is nitrogen, then R8, R9, and R14 are
not attached to G, and provided that wherein E is nitrogen, then R8, R9, and R14
are not attached to E,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3, and
when m is 0, then (CH2)m is a bond, and
/herein the zig-zag mark shows the point of attachment to the
parent molecule,
provided however that wherein D is nitrogen, then Rl 1 is not attached to D, and
provided that wherein T is nitrogen, then Rl 1 is not attached to T, and provided
that wherein Q is nitrogen, then Rl 1 is not attached to Q, and provided that
wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), and -aryl;
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
phenyl, and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C|-C7) alkyl (optionally substituted with 1 to 3 halogens).
The present invention provides compounds that are useful as glucagon receptor
antagonists or inverse agonists. The present invention further provides compounds that
are selective antagonists or inverse agonists of the glucagon receptor over the GLP-1
receptor. The present invention further provides a pharmaceutical composition which
comprises a compound of Formula I, or a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient.
Due to their interaction with the glucagon receptor, the present compounds are
useful in the treatment of a wide range of conditions and disorders in which an interaction
with the glucagon receptor is beneficial. These disorders and conditions are defined
herein as "diabetic and other glucagon related metabolic disorders". One of skill in the art
is able to identify "diabetic and other glucagon related metabolic disorders" by the
involvement of glucagon receptor mediated signaling either in the pathophysiology of the
disorder, or in the homeostatic response to the disorder. Thus, the compounds may find
use for example to prevent, treat, or alleviate, diseases or conditions or associated
symptoms or sequelae, of the endocrinological system, the central nervous system, the
peripheral nervous system, the cardiovascular system, the pulmonary system, and the
gastrointestinal system, while reducing and or eliminating one or more of the unwanted
side effects associated with the current treatments. "Diabetic and other glucagon related
metabolic disorders" include, but are not limited to, diabetes, type 1 diabetes, type 2
diabetes, hyperglycemia, hyper insulinemia, beta-cell rest, improved beta-cell function by
restoring first phase response, prandial hyperglycemia, preventing apoptosis, impaired
fasting glucose (IFG), metabolic syndrome, hypoglycemia, hyper-/hypokalemia,
normalizing glucagon levels, improved LDL/HDL ratio, reducing snacking, eating
disorders, weight loss, polycystic ovarian syndrome (PCOS), obesity as a consequence of
diabetes, latent autoimmune diabetes in adults (LADA), insulitis, islet transplantation,
pediatric diabetes, gestational diabetes, diabetic late complications, micro-
/macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic foot ulcers, reduced
intestinal motility due to glucagon administration, short bowel syndrome, antidiarrheic,
increasing gastric secretion, decreased blood flow, erectile dysfunction, glaucoma, post
surgical stress, ameliorating organ tissue injury caused by reperfusion of blood flow after
ischemia, ischemic heart damage, heart insufficiency, congestive heart failure, stroke,
myocardial infarction, arrythmia, premature death, anti-apoptosis, wound healing,
impaired glucose tolerance (1GT), insulin resistance syndromes, syndrome X,
hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipoproteinemia,
hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute
pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal
disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.
In addition, the present invention provides a compound of Formula I, or a
pharmaceutical salt thereof, or a pharmaceutical composition which comprises a
compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient: for use in inhibiting the glucagon receptor; for
use in inhibiting a glucagon receptor mediated cellular response in a mammal; for use in
reducing the glycemic level in a mammal; for use in treating a disease arising from
excessive glucagon; for use in treating diabetic and other glucagon related metabolic
disorders in a mammal; and for use in treating diabetes, obesity, hyperglycemia,
atheroscelerosis, ischemic heart disease, stroke, neuropathy, and wound healing. Thus, the
methods of this invention encompass a prophylactic and therapeutic administration of a
compound of Formula I.
The present invention further provides the use of a compound of Formula I, or a
pharmaceutical salt thereof for the manufacture of a medicament for inhibiting the
glucagon receptor; for the manufacture of a medicament for inhibiting a glucagon
receptor mediated cellular response in a mammal; for the manufacture of a medicament
for reducing the glycemic level in a mammal; for the manufacture of a medicament for
treating a disease arising from excessive glucagon; for the manufacture of a medicament
for treating diabetic and other glucagon related metabolic disorders in a mammal; and for
the manufacture of a medicament for preventing or treating diabetes, obesity,
hyperglycemia, atheroscelerosis, ischemic heart disease, stroke, neuropathy, and improper
wound healing.
The present invention further provides a method of treating conditions resulting
from excessive glucagon in a mammal; a method of inhibiting the glucagon receptor in a
mammal; a method of inhibiting a glucagon receptor mediated cellular response in a
mammal; a method of reducing the glycemic level in a mammal; a method of treating
diabetic and other glucagon related metabolic disorders in a mammal; a method of
preventing or treating diabetes, obesity, hyperglycemia, atheroscelerosis, ischemic heart
disease, stroke, neuropathy, and improper wound healing; said methods comprising
administering to a mammal in need of such treatment a glucagon receptor-inhibiting
amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or
excipient.
In addition, the present invention provides a pharmaceutical composition which
comprises a compound of Formula I, or a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient: adapted for use in inhibiting the
glucagon receptor; adapted for use in inhibiting glucagon receptor mediated cellular
responses; adapted for use in reducing the glycemic level in a mammal; adapted for use in
treating diabetic and other glucagon related metabolic disorders in a mammal; and
adapted for use in preventing or treating diabetes, obesity, hyperglycemia, atherosclerosis,
ischemic heart disease, stroke, neuropathy, and wound healing.
The compound or salt of the present invention further provides a diagnostic agent
for identifying patients having a defect in the glucagon receptor, as a therapy to increase
gastric acid secretions, and to reverse intestinal hypomobility due to glucagon
administration. The invention also provides a method for the treatment of disorders or
diseases, wherein a glucagon antagonistic action is beneficial, the method comprising
administering to a subject in need thereof an effective amount of a compound according
to the invention. In another embodiment of the invention, the present compounds are used
for the preparation of a medicament for the treatment of any glucagon-mediated
conditions and diseases. In another embodiment of the invention, the present compounds
are used for the preparation of a medicament for the treatment of hyperglycemia. In yet
another embodiment of the invention, the present compounds are used for the preparation
of a medicament for lowering blood glucose in a mammal. The present compounds are
effective in lowering the blood glucose, both in the fasting and the postprandial stage.
In still another embodiment of the invention, the present compounds are used for the
preparation of a pharmaceutical composition for the treatment of IGT. In a further
embodiment of the invention, the present compounds are used for the preparation of a
pharmaceutical composition for the treatment of type 2 diabetes. In yet a further
embodiment of the invention the present compounds are used for the preparation of a
pharmaceutical composition for the delaying or prevention of the progression from IGT to
type 2 diabetes. In yet another embodiment of the invention the present compounds are
used for the preparation of a pharmaceutical composition for the delaying or prevention
of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2
diabetes. In a further embodiment of the invention the present compounds are used for the
preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such
treatment is normally accompanied by insufin therapy. In yet a further embodiment of the
invention the present compounds are used for the preparation of a pharmaceutical
composition for the treatment of obesity. In still a further embodiment of the invention
the present compounds are used for the preparation of a pharmaceutical composition for
the treatment of disorders of the lipid metabolism. In still another embodiment of the
invention the present compounds are used for the preparation of a pharmaceutical
composition for the treatment of an appetite regulation or energy expenditure disorder. In
•a further embodiment of the invention, treatment of a patient with the present compounds
is combined with diet and/or exercise.
Statement of the Invention
The present invention relates to a compound structurally represented by Formula 1

or a pharmaceutically acceptable salt thereof wherein:
Y is -O- or -S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the
optional substituents as indicated herein), or nitrogen (optionally substituted with
oxygen), provided that no more than two of Q, D, X, and T are nitrogen;
Rl is -H, -OH, or -halogen;
R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);
R3 and R4 are independently
- H, -halogen, -CN, -OH, -(C1-C7) alkoxy, -(C1-C7) alkyl(optionally
substituted with 1 to 3 halogens), or -(C2-C7)*alkenyl;
R5 is selected from the group consisting of
-H, -(C1-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl,
-aryl, -aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl,
-(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl, -heterocycloalkyl,
-aryl-(C2-C10)alkenyl,-heteroaryl-(C2-C10)alkenyl,-(C2-Ci2)alkynyl,
-(C3-C12)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, and
-heteroaryl-(C2-Ci2)alkynyl, and wherein -(Ci-Ci2)alkyl,
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl,
-aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl,
-heterocycloalkyl, -(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl,
-aryl-(C2-C[0)alkenyl,-heteroaryl-(C2-C10)alkenyl,-(C2-Ci2)alkynyl,
-(C3-C12) cycloalkynyl, -aryl-(C2-Ci2)alkynyl, -heteroaryl-(C2-Ci2)alkynyl,
are each optionally substituted with from one to three substituents each
independently selected from the group consisting of-hydrogen, -hydroxy,
-cyano, -nitro, -halo, -0x07 -(C1-C7)alkyl (optionally substituted with 1 to 3
halogens), -(C1-C7)alkyl-C(O)OR12, -(d-C7)alkoxy, -(C3-C7)cycloalkyl,
-C(O)R12, -C(O)OR12, -OC(O)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12, -S(O)2R12, and
-S(O)2N(R12)2;
R6 and R7 are independently at each occurrence selected from the group
consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl,
-(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, tert-butoxyiminomethyl, 1,3-dioxan-2-yl,
hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl,
4-methylpentyloxy, and pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not
attached to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6 or R7
are not attached to Q, and provided that wherein X is nitrogen, then R6 or
R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the
atoms to which they are attached, and the ring so formed may optionally
contain up to two oxygens, and further the ring so formed may optionally
be substituted with up to four halogens;
R8 and R9 are independently at each occurrence selected from the group
consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C1-C7)alkyl(optionally
substituted with 1 to 3 halogens), -(C1-C7)alkoxy, -(C3-C7)cycloalkyl,
-aryl, -aryl-(C1-C7)alkyl, -heteroaryl, -heteroaryl-(C1-C7)alkyl, -aryloxy,
-C(0)R12, -COOR12, -OC(O)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O)R12, -NR12SO2R12, -SRI2, -S(O)R12, -S(O)2R12,
-O(C2-C7)alkenyl, and -S(O)2N(R12)2; and wherein -(C1-C7)alkyl,
-(C1-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl,
-heteroaryl-(C1-C7)alkyl, -aryloxy, and -O(C2-C7)alkenyl are each
optionally substituted with from one to three substituents independently
selected from the group consisting of-hydrogen, -hydroxy, -cyano, -nitro,
-halo, -oxo, -(C1-C7)alkyl, -(C1-C7)alkyl-C(O)OR12, -(CrC7)alkoxyl,
-(C3-C7)cycloalkyl, -heterocycloalkyl, -C(O)R12, -COOR12, -OC(O)R12,
-OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12,
-S(0)R12, -S(O)2R12, and -S(O)2N(R12)2;
RIO is selected from the group consisting of
-H, halogen, -(Ci-Ci2)alkyl(optionally substituted with 1 to 3 halogens),
-cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl, -heteroaryl-(C1-C7)alkyl,
-(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl, -aryl-(C2-Ci0)alkenyl,
-heteroaryl-(C2-Cio)alkenyl, -(C2-Ci2)alkynyl, -(C3-C12)cycloalkynyl,
-aryl-(C2-Ci2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl;
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen,
f"
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A, G, and
E are nitrogen;
provided however that wherein A is nitrogen, then R8, R9, and R14 are
not attached to A, and provided that wherein G is nitrogen, then R8, R9,
and R14 are not attached to G, and provided that wherein E is nitrogen,
then R8, R9, and R14 are not attached to E,
, wherein the zig-zag mark shows the point of
, attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3,
and when m is 0 then (CH2)m is a bond, and
wherein the zig-zag mark shows the point of attachment
to the parent molecule,
provided however that wherein D is nitrogen, then Rl 1 is not attached to
D, and provided that wherein T is nitrogen, then Rl 1 is not attached to T,
and provided that wherein Q is nitrogen, then Rl 1 is not attached to Q,
and provided that wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of '
-hydrogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), and
-aryl;
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), phenyl, and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3
halogens).
The present invention also relates to the pharmaceutical composition comprising a
compound of formula (I), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
General terms used in the description of compounds, compositions, and methods
herein described, bear their usual meanings. Throughout the instant application, the
following terms have the indicated meanings:
"GLP-1" means gluc'agon-like peptide 1. The term "glucagon receptor" means one
or more receptors that interact specifically with glucagon to result in a biological signal.
The term "GLP-1 receptor" means one or more (eceptors that interact specifically with
glucagon-like peptide 1 to result in a biological signal.
The term "glucagon receptor antagonist" means a compound of the present
invention with the ability to block cAMP production in response glucagon.
The term "glucagon receptor inverse agonist" means a compound of the present invention
with the ability to inhibit the constitutive activity of glucagon receptor.
The term "selective" antagonist or inverse agonist means a compound having greater
affinity for the glucagon receptor as compared to the affinity for the GLP-1 receptor.
In the general formulae of the present document, the general chemical terms have
their usual meanings. For example;
"Halogen" or "halo" means fluoro, chloro, bromo and iodo.
The term "alkyI," unless otherwise indicated, refers to those alkyl groups of a
designated number of carbon atoms of either a straight or branched saturated
configuration. "(C1-C3) alkyl" are one to three carbon atoms, such as methyl, ethyl,
propyl, n-propyl, isopropyl, and the like and branched or isomeric forms thereof, and
optionally may be substituted with one to three halogens or a designated number of
substituents as set forth in the embodiments recited herein, "(C1-C7) alkyl" are one to
seven carbon atoms such as methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl, pentyl, isopentyl, hexyl, heptyl, and the like, and branched or
isomeric forms thereof, and optionally may be substituted with one to three halogens or a
designated number of substituents as set forth in the embodiments recited herein, and
"(C1-C10) alkyl" are one to ten carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, nonyl, decyl, and the like, and branched or isomeric forms thereof, and
optionally may be substituted with one to three halogens or a designated number of
substituents as set forth in the embodiments recited herein. "(C1-C12) alkyl" are one to
twelve carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, nonyl,
decyl, and the like, and branched or isomeric forms thereof, and optionally may be
substituted with one to three halogens or a designated number of substituents as set forth
in the embodiments recited herein.
The term "(C3-C12) cycloalkyl" refers to a saturated or partially saturated
carbocycle containing one or more rings of from 3 to 12 carbon atoms, typically 3 to 7
carbon atoms optionally substituted with up to three halogens. Examples of (C3-C12)
cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl, and the like. "(C3-C7) cycloalkyl" means a ring with three to seven
carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl,
and the like, optionally substituted with up to three halogens.
The term "(C|-C7) alkoxy" represents an alkyl group of one to seven carbon atoms
attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy,
butoxy, tert-butoxy, pentoxy, and the like, and may be optionally substituted with three
halogens or a designated number of substituents as set forth in the embodiments recited
herein.
The terms "(C2-C7) alkenyl", "(C2-C,0) alkenyl", "(C2-C,o) alkylenyl", "(C2-C,2)
alkenyl", or "(C2-C|2) alkylenyl" means hydrocarbon chains of the indiacted number of
carbon atoms of either a straight or branched configuration having at least one carbon-
carbon double bond which may occur at any point along the chain, such as ethenyl,
propenyl, butenyl, pentenyl, vinyl, alkyl, 2-butenyl and the like, and may be optionally
substituted with one to three halogens or a designated number of substituents as set forth
in the embodiments recited herein.
The term "(C3-C|2) cycloalkenyl " refers to a partially saturated carbocycle
containing one or more rings of from 3 to 12 carbon atoms, typically 3 to 7 carbon atoms
optionally substituted with up to three halogens.
The term "(C2-C12) alkynyl" means a hydrocarbon chain of two to twelve carbon
atoms of either a straight or branched configuration and having at least one carbon-carbon
triple bond, which may occur at any point along the chain. Example of alkynyl is
acetylene. Alkynyl as defined above may be optionally substituted with up to three
halogens or the designated number of substituents as set forth in the embodiments recited
herein.
The term "(C3-C12) cycloalkynyl" refers to a carbocycle containing one or more
rings of from 3 to 12 carbon atoms, typically 3 to 7 carbon atoms, having at least one
carbon-carbon triple bond which may occur at any point along the chain or ring,
optionally substituted with up to three halogens. Cycloalkynyl as defined above may be
optionally substituted with the designated number of substituents as set forth in the
embodiments recited herein.
The term "aryl" includes carbocyclic aromatic ring systems (e.g. phenyl), fused
polycyclic aromatic ring systems (e.g. naphthyl and anthracenyl), and aromatic ring
systems fused to carbocyclic non-aromatic ring systems (e.g., 1,2,3,4-
tetrahydronaphthyl). "Aryl" as defined above may be optionally substituted with a
designated number of substituents as set forth in the embodiments recited herein.
The term "aryloxy" refers to an aryl group which is linked to the parent molecule
through an oxygen bridge.
The term "heteroaryl" group, as used herein, is an aryl ring system having at least
one heteroatom such as nitrogen, sulfur, or oxygen, and includes monocyclic, bicyclic, or
tricyclic aromatic rings of 5 to 14 carbon atoms containing one or more heteroatoms
selected from the group consisting of O, N, and S. The "heteroaryl" as defined above
may be optionally substituted with a designated number of substituents as set forth in the
embodiments recited herein. Examples of heteroaryl are, but are not limited to, furanyl,
indolyl, thienyl (also referred to herein as "thiophenyl") thiazolyl, imidazolyl, isoxazoyl,
oxazoyl, pyrazoyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl,
cinnolinyl, benzofuranyl, benzothienyl, benzotriazolyl, benzoxazolyl, quinoline,
isoxazolyl, isoquinoline, and the like.
The term "arylalkyl" refers to an aryl group which is linked to the parent molecule
through an alkyl moiety, and "arylalkyl" may be further optionally substituted with a
designated number of substituents as set forth in the embodiments recited herein.
The term "heterocycloalkyl" refers to a non-aromatic ring which contains one or
more oxygen, nitrogen or sulfur and includes a monocyclic, bicyclic or tricyclic non-
aromatic ring of 5 to 14 carbon atoms containing one or more heteroatoms selected from
O, N, or S.
The term "optionally substituted," or "optional substituents," as used herein,
means that the groups in question are either unsubstituted or substituted with one or more
of the substituents specified. When the groups in question are substituted with more than
one substituent, the substituents may be the same or different. Furthermore, when using
the terms "independently," "independently are," and "independently selected from" mean
that the groups in question may be the same or different. Certain of the herein defined
terms may occur more than once in the structural formulae, and upon such occurrence
each term shall be defined independently of the other.
The term "patient" includes human and non-human animals such as companion
animals (dogs and cats and the like) and livestock animals. Livestock animals are
animals raised for food production. Ruminants or "cud-chewing" animals such as cows,
bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock.
Other examples of livestock include pigs and avians (poultry) such as chickens, ducks,
turkeys and geese. Yet other examples of livestock include fish, shellfish and crustaceans
raised in aquaculture. Also included are exotic animals used in food production such as
alligators, water buffalo and ratites (e.g., emu, rheas or ostriches). The patient to be
treated is preferably a mammal, in particular a human being.
The term "a glucagon receptor mediated cellular response" includes various
responses by mammalian cells to glucagon stimulation or glucagon receptor activity. For
example "glucagon receptor mediated cellular responses," include but are not limited to,
release of glucose from liver, or other cells, in response to glucagon stimulation or
glucagon receptor activity. One of ordinary skill in the art can readily identify other
cellular responses mediated by glucagon receptor activity, for example by observing a
change in the responsive cellular endpoint after contacting the cell with an effective dose
of glucagon.
The terms "treatment", "treating" and "treat", as used herein, include their
generally accepted meanings, i.e., the management and care of a patient for the purpose of
preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, delaying,
or reversing the progression or severity of a disease, disorder, or pathological condition,
described herein, including the alleviation or relief of symptoms or complications, or the
cure or elimination of the disease, disorder, or condition.
"Composition" means a pharmaceutical composition and is intended to encompass
a pharmaceutical product comprising the active ingredient(s) including compound(s) of
Formula I, and the inert ingredient(s) that make up the carrier. Accordingly, the
pharmaceutical compositions of the present invention encompass any composition made
by admixing a compound of the present invention and a pharmaceutically acceptable
carrier.
The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to
the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
The term "unit dosage form" means physically discrete units suitable as unitary
dosages for human subjects and other non-human animals, each unit containing a
predetermined quantity of active material calculated to produce the desired therapeutic
effect, in association with a suitable pharmaceutical carrier.
In one embodiment, the present invention provides compounds of Formula I as
described in detail herein. While all of the compounds of the present invention are useful,
certain of the compounds are particularly interesting and are preferred. The following
listing sets out several groups of preferred compounds. It will be understood that each of
die listings may be combined with other listings to create additional groups of preferred
embodiments.
1. wherein Y is -O-,
2. wherein Y is -S-,
3. wherein D, Q, X, and T are carbon(substituted with hydrogen or the optional
substituents as indicated herein),
4. wherein Rl, R2, R3, R4 and RIO are hydrogen,
5. wherein X is carbon and Rl 1 is attached to X,
6. wherein D is carbon and Rl 1 is attached to D,
7. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E independently represent carbon (substituted with
hydrogen or the optional substituents as indicated herein) or nitrogen, provided
that no more than two of A, G, and E are nitrogen;
8. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E independently represent carbon (substituted with
hydrogen or the optional substituents as indicated herein) or nitrogen, provided
that no more than two of A, G, and E are nitrogen, and R8 and R9 are
independently at each occurrence selected from the group consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C1-C7)alkyl(optionally substituted with
1 to 3 halogens), -(C1-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(Ci-Cy)alkyl,
-heteroaryl, -heteroaryI-(C1-C7)alkyl, -aryloxy, -C(0)R12, -C(O)OR12,
-OC(O)R12, -OS(O)2R12, -N(R12)2, -NR12C(O)R12, -N R12SO2 R12, -SR12,
-S(O)R12, -S(O)2 R12, and -S(O)2N(R12)2,
9. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E independently represent carbon (substituted with
hydrogen or the optional substituents as indicated herein) or nitrogen, provided
that no more than two of A, G, and E are nitrogen, and R8 and R9 are
independently at each occurrence selected from the group consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C|-C7)alkyl(optionally substituted with
1 to 3 halogens), -(C i-C7)alkoxy, and -(C3-C7)cycloalkyl,
10. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E are carbon (substituted with hydrogen or the optional
substituents as indicated herein),
11. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E are carbon(substituted with hydrogen or the optional
substituents as indicated herein), and R8 and R9 are independently at each
occurrence selected from the group consisting of-hydrogen, -hydroxy, -CN,
-nitro, -halo, -(C|-C7)alkyl(optionally substituted with 1 to 3 halogens),
-(C1-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl,
-heteroaryl-(C1-C7)alkyl, -aryloxy, -C(O)R12, -C(O)OR12, -OC(O)R12,
-OS(O)2R12, -N(R12)2, -NR12C(O)R12, -N R12SO2 R12, -SR12, -S(O)R12,
-S(O)2 R12, and -S(O)2N(R12)2,
12. wherein X is carbon and Rl 1 is attached to X and Rl 1 is
wherein the zig-zag mark shows the point of attachment to the parent molecule,
and wherein A, G, and E are carbon(substituted with hydrogen or the optional
substituents as indicated herein), and R8 and R9 are independently at each
occurrence selected from the group consisting of-hydrogen, -hydroxy, -CN,
-nitro, -halo, -(C1-C7)alkyl(optionally substituted with 1 to 3 halogens),
-(C|-C7)alkoxy, and -(C3-C7)cycloalkyl,
13. wherein one of D, X, Q or T is nitrogen,
14. wherein D is nitrogen,
15. wherein X is nitrogen,
16. wherein Q is nitrogen,
17. wherein T is nitrogen,
18. wherein two of D, X, Q and T are nitrogen,
19. wherein D and T are nitrogen,
20. wherein Q and X are nitrogen,
21. wherein Rl is hydrogen,
22. wherein Rl is-OH,
23. wherein Rl is halogen,
24. wherein R2 is hydrogen,
25. wherein R2 is -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens),
26. wherein R3 is hydrogen,
27. wherein R3 is halogen,
28. wherein R4 is hydrogen,
29. wherein R4 is halogen,
30. wherein R3 is selected from the group consisting of -(C1-C7) alkoxy, -(C1-C7)
alkyl(optionally substituted with 1 to 3 halogens), and -(C2-C7) alkenyl,
31. wherein R4 is selected from the group consisting of -(C1-C7) alkoxy, -(C1-C7)
alkyl(optionally substituted with 1 to 3 halogens), and -(C2-C7) alkenyl,
32. R5 is selected from the group consisting of
-H, -(Ci-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C|2)cycloalkyl, -phenyl, -phenyl-phenyl-(C|-C)2)alkyl, -aryl,
-aryl-(C|-C|2)alkyl, -heteroaryl, -heteroaryl-(C]-C]2)alkyl, -(C2-C|2)alkenyl,
-(C3-C12)cycloalkenyI, -heterocycloalkyl, -ary 1-(C2-C]0)alkenyI,
-heteroaryl-(C2-C,0)alkenyl, -(C2-C|2)alkynyl, -(C3-C12)cycloalkynyl,
-aryl-(C2-C|2)alkynyl, and -heteroaryl-( C2-Ci2)alkynyl,
33. R5 is selected from the group consisting of
-H, -(C1 -C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C|2)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -(C2-C)2)alkenyl,
-(C3-C|2)cycloalkenyl, -heterocycloalkyl, -(C2-Ci2)alkynyl, and
-(C3-C12)cycloalkyny 1,
34. R5 is selected from the group consisting of -(C1-C12) alkyl(optionally substituted
with 1 to 3 halogens), and -(C3-C|2)cycloalkyl,
35. wherein R6 and R7 are methyl,
36. wherein R6 and R7 form a six membered ring with the atoms to which they are
attached, and the ring so formed may optionally contain up to two oxygens, and
further the ring so formed may optionally be substituted with up to four
halogens,
37. wherein R8 is attached in the para postion and is tertbutyl or trifloromethyl,
38. RIO is selected from the group consisting of-H, halogen,
-(Ci-Ci2)alkyl(optionally substituted with 1 to 3 halogens), -(C3-C]2)cycloalkyl,
-(C2-C,2)alkenyl, -(C3-C12)cycloalkenyl, -(C2-Ci2)alkynyl,
-(C3-C12)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, and -heteroaryl-(C2-C|2)alkynyl,
39. RIO is selected from the group consisting of-H, halogen, or
-(C]-Ci2)alkyl(optionally substituted with 1 to 3 halogens,
Another embodiment is a compound of Formula I or a pharmaceutically
acceptable salt thereof wherein:
Y is -O- or -S-;
Q, D, X, and T independently represent carbon or nitrogen, provided that no more than
two of Q, D, X, and T are nitrogen;
Rl is -H, -OH, or -halogen;
R2is-Hor-(C,-C3)alkyl;
R3 and R4 are independently at each occurrence selected from the group consisting of
- H, -halogen, -CN, -OH, -(C1-C7) alkoxy, -(C1-C7) alky!, -(C2-C7) alkenyl;
R5 is selected from the group consisting of
-H, -(C1-C12) alkyl, -(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(C,-C,2)alkyl,
-aryl, -aryl-(C|-Ci2)alkyl, -heteroaryl, -heteroaryl-(C]-Ci2)alkyl, -(C2-Ci2)alkenyl,
-(C3-C12)cycloalkenyl, -heterocycloalkyl, -aryl-(C2-C10)alkenyl,
-heteroary 1-(C2-C}0)alkenyl, -(C2-C12)alkynyl, -(C3-C12)cycloalkynyl,
-aryI-( C2-Ci2)alkynyl, and -heteroaryl-( C2-Ci2)alkynyl, and wherein -(C|-
Ci2)alkyl, -(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl, -aryl-
(Ci-C|2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl, -heterocycloalkyl, -(C2-
C|2)alkenyl, -(C3-C12)cycloalkenyl, -aryl-(C2-C]0)alkenyl, -heteroaryl-(C2-
C|0)alkenyl, -(C2-Ci2)alkynyl, -(C3-C12) cycloalkynyl, -aryl-(C2-C,2)alkynyl, and
-heteroaryl-(C2-C|2)alkynyl, are each optionally substituted with from one to three
substituents each independently selected from the group consisting of-hydrogen,
-hydroxy, -cyano, -nitro, -halo, -oxo, -(CrC7)alkyl, -(C1-C7)alkyl-COOR12, -(Cr
C7)alkoxy, -(C3-C7)cycloalkyl, -aryloxy, -aryl, -aryl-(C|-C7)alkyl, -
heteroaryl,-heterocycloalkyl, -C(O)R12, -C00R12, -OC(O)R12, -OS(O)2R12,
-N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12, -S(O)2R12, and
-S(O)2N(R12)2;
R6 and R7 are independently at each occurrence selected from the group consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl, and -(C1-C7)alkyl,
provided however that wherein D is nitrogen, then R6 or R7 are not attached to D,
and provided that wherein T is nitrogen, then R6 or R7 are not attached to T, and
provided that wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the atoms to
which they are attached, and the ring so formed may optionally contain up to two
oxygens, and further the ring so formed may optionally be substituted with up to
four halogens;
R8 and R9 are independently at each occurrence selected from the group consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C1-C7)alkyl, -(Cj-C7)alkoxy,
-(C3-C7)cycloalkyl, -aryl, -aryl-(C|-C7)alkyl, -heteroaryl, -heteroaryl-(C1-C7)alkyl,
-aryloxy, -C(0)R12, -COOR12, -OC(O)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O) R12, -NR12SO2 R12, -SRI2, -S(O)R12, -S(O)2 R12, and
-S(O)2N(R12)2; and wherein -(CrC7)alkyl, -(C1-C7)alkoxy, -(C3-C7)cycloalkyl,
-aryl, -aryl-(C|-C7)alkyl, -heteroaryl, -heteroaryl-(d-C7)alkyl, -aryloxy, are each
optionally substituted with from one to three substituents independently selected
from the group consisting of-hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo,
-(C1-C7)alkyl, -(C1-C7)alkyl-COOR12, -(C1-C7)alkoxyl, -(C3-C7)cycloalkyl,
-aryloxy, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl, -heterocycloalkyl, -C(O)R12,
-COOR12, -0C(0)R12, -OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2 R12,
-SR12, -S(O)R12, -S(O)2R12, and -S(O)2N(R12)2;
RIO is selected from the group consisting of
-H, -(Ci-C]2)alkyl, -cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl, -heteroaryl-
(C.-C7)alkyl, -(C2-C12)alkenyL -(C3-C,2)cycloalkenyl., -aryl-(C2-C10)alkenyl,
-heteroaryl-(C2-C 1 o)alkeny 1, -(C2-C12)alkyny 1, -(C3-C12)cycloalkynyl,
-aryl-(C2-C]2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl, and wherein -(Cr
Ci2)alkyl, -cycloalkyl, -aryl, -aryl-(C|-Cr)alkyi. -heteroaryl, -heteroaryl -(C'i-
C7)alkyl, -(C2-C]2)alkenyl, -(C3-C,2)cycloalkenyl, -aryl-(C2-Ci0)alkenyl,
-heteroaryl-(C2-C)0)alkenyl, -(C2-C]2)alkynyl, -(C3-C12)cycloalkynyl, -aryl-(C2-
Ci2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl, are each optionally substituted with
from one to three substituents each independently selected from the group
consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, -(C1-C7)alkyl, -(Ci-
C7)alkyl-COOR12, -(C|-C7)alkoxyl, -(C3-C7)cycloalkyl, -aryloxy, -aryl, -aryl-Cr
C7 alkyl, -heteroaryl, -heterocycloalkyl, -C(0)R12, -COOR12, -OC(O)R12,
-OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2 R12, -SRI2, -S(O)R12,
-S(O)2R12, and -S(O)2N(R12)2;
Rl 1 is idependently at each occurrence selected from the group consisting of
-H,
wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein A, G, and E independently represent carbon or
nitrogen, provided that no more than two of A, G, and E are nitrogen;
provided however that wherein A is nitrogen, then R8 or R9 are not attached to A,
and provided that wherein G is nitrogen, then R8 or R9 are not attached to G, and
provided that wherein E is nitrogen, then R8 or R9 are not attached to E;
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3, and
when m is 0 m is a bond,
provided however that wherein D is nitrogen, then Rl 1 is not attached to D, and
provided that wherein T is nitrogen, then Rl 1 is not attached to T, and provided
that wherein Q is nitrogen, then Rl 1 is not attached to Q, and provided that
wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, -(C1-C7) alkyl, and -aryl,
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl, and -(C2-C7)alkenyl.
Another preferred embodiment is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein:
Y is -O- or -S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the
optional substituents as indicated herein) or nitrogen, provided that no more than
two of Q, D, X, and T are nitrogen;
Rl is-H,-OH, or-halogen;
R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);
R3 and R4 are independently
- H, -halogen, -CN, -(C1-C7) alkoxy, -(Q-C7) alkyl(optionally substituted
with 1 to 3 halogens), or -(C2-C7) alkenyl;
R5 is selected from the group consisting of
-(C1-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(C|-Ci2)alkyl,
-(C2-C,2)alkenyl,
-(C3-C12)cycloalkenyl, -heterocycloalkyl, -(C2-Ci2)alkynyl, and
-(C3-C12)cycloalkynyl, and wherein -(C|-Ci2)alkyl, -(C3-C12)cycloalkyl,
-phenyl, -phenyl-phenyl-(C]-Ci2)alkyl, -heterocycloalkyl,
-(C2-C,2)alkenyl, -(C3-C,2)cycloalkenyl, -(C2-C,2)alkynyl, and
-(C3-C12)cycloalkynyl, are each optionally substituted with from one to
three substituents each independently selected from the group consisting of
-hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, -(C)-C7)alkyl (optionally
substituted with 1 to 3 halogens);
R6 and R7 are independently at each occurrence selected from the group
consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl,
-(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, tert-butoxyiminomethyl, l,3-dioxan-2-yl,
hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl,
4-methylpentyloxy, and pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not
attached to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6 or R7
are not attached to Q, and provided that wherein X is nitrogen, then R6 or
R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the
atoms to which they are attached, and the ring so formed may optionally
contain up to two oxygens, and further the ring so formed may optionally
be substituted with up to four halogens;
R8 and R9 are independently at each occurrence selected from the group
consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C|-C7)alkyl(optionally
substituted with 1 to 3 halogens), -(C]-C7)alkoxy, -(C3-C7)cycloalkyl,
-C(O)R12, -C(O)OR12, -OC(O)R12, -OS(O)2R12, -N(R12)2, -NR12C(0)
R12, -NR12SO2 R12, -SR12, -S(O)R12, -S(O)2R12, -O(C2-C7)alkenyl,
and -S(O)2N(R12)2; and wherein -(C1-C7)alkyl, -(C1-C7)alkoxy,
-(C3-C7)cycloalkyl, and -O(C2-C7)alkenyl are each optionally substituted
with from one to three substituents independently selected from the group
consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, and
-(C1-C7)alkyl;
RIO is selected from the group consisting of
-H, halogen, and -(Ci-Ci2)alkyl(optionally substituted with 1 to 3
halogens);
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A, G, and
E are nitrogen;
provided however that wherein A is nitrogen, then R8, R9, and R14 are not
attached to A, and provided that wherein G is nitrogen, then R8, R9, and
R14 are not attached to G, and provided that wherein E is nitrogen, then
R8, R9, and R14 are not attached to E,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3,
and when m is 0 then (CH2)m is a bond, and
vherein the zig-zag mark shows the point of attachment to
the parent molecule,
provided however that wherein D is nitrogen, then Rl 1 is not attached to
D, and provided that wherein T is nitrogen, then Rl 1 is not attached to T,
and provided that wherein Q is nitrogen, then Rl 1 is not attached to Q, and
provided that wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, and -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens);
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), phenyl, and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3 halogens).
Another preferred embodiment is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein:
Yis-O-or-S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the optional
substituents as indicated herein);
Rl is -H, -OH, or -halogen;
R2 is -H;
R3 and R4 are independently -H, -halogen, or -(C1-C7) alkyl(optionally substituted with 1
to 3 halogens);
* '15 is selected from the group consisting of
-(C1-C12) alkyl(optionally substituted with 1 to 3 halogens), and
-(C3-C12)cycloalkyl(optionally substituted with 1 to 3 halogens);
R6 and R7 are independently at each occurrence selected from the group consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl, -(C1-C10)alkyl
(optionally substituted with 1 to 3 halogens), -(C3-C12)cycloalkyl,
tert-butoxyiminomethyl, l,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morphylino-4-yl-methyl, 4-methylpentyloxy, and
pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not attached to D,
and provided that wherein T is nitrogen, then R6 or R7 are not attached to T, and
provided that wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached to X;
R8 and R9 are independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7)alkyl(optionally substituted with 1 to 3 halogens),
-(CrC7)alkoxy, -(C3-C7)cycloalkyl, -C(O)R12, -COOR12, -OC(O)R12,
-OS(O)2R12, -SR12, -S(O)R12, -S(O)2R12, and -O(C2-C7)alkenyl;
RIO is-H,
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen, and
, wherein the zig-zag mark shows the point of attachment to the
parent molecule, wherein A, G, and E independently represent carbon (substituted
with hydrogen or the optional substituents as indicated herein),
provided however that wherein A is nitrogen, then R8, R9, and R14 are not
attached to A, and provided that wherein G is nitrogen, then R8, R9, and R14 are
not attached to G, and provided that wherein E is nitrogen, then R8, R9, and R14
are not attached to E;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, and -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens);
r R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3 halogens).
As used herein, the term "stereoisomer" refers to a compound made up of the
same atoms bonded by the same bonds but having different three-dimensional structures
called configurations. As used herein, the term "enantiomer" refers to two stereoisomers
whose molecules are nonsuperimposable mirror images of one another. The term "chiral
center" refers to a carbon atom to which four different groups are attached. As used
herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In
addition, two diastereomers which have a different configuration at only one chiral center
are referred to herein as "epimers." The terms "racemate," "racemic mixture" or "racemic
modification" refer to a mixture of equal parts of enantiomers.
The compounds of the present invention may be chiral, and it is intended that any
enantiomers, whether pure, partially purified, or racemic mixtures, are included within the
scope of the invention. Furthermore, when a double bond or a fully or partially saturated
ring system or more than one center of asymmetry or a bond with restricted rotatability is
present in the molecule diastereomers may be formed. It is intended that any
diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof
are included within the scope of the invention. Furthermore, some of the compounds of
the present invention may exist in different tautomeric forms and it is intended that any
tautomeric forms, which the compounds are able to form, are included within the scope of
the present invention. Thus, as one skilled in the art knows, certain aryls may exist in
tautomeric forms. The invention also includes tautomers, enantiomers and other
stereoisomers of the compounds of Formula I. Such variations are contemplated to be
within the scope of the invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to
denote specific configuration of a chiral center. The term "R" (rectus) refers to that
configuration of a chiral center with a clockwise relationship of group priorities (highest
to second lowest) when viewed along the bond toward the lowest priority group. The
term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise
? relationship of group priorities (highest to second lowest) when viewed along the bond
toward the lowest priority group. The priority of groups is based upon their atomic
number (in order of decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in "Nomenclature of Organic Compounds:
Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
The designation " ~~mm " refers to a bond that protrudes forward out of the plane
of the page. The designation " ....." " refers to a bond that protrudes backward out of the
plane of the page. The designation " ~~*AA/ " refers to a bond wherein the stereochemistry
is not defined.
The compounds of Formula I, when existing as a diastereomeric mixture, may be
separated into diastereomeric pairs of enantiomers by, for example, fractional
crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture
thereof. The pair of enantiomers thus obtained may be separated into individual
stereoisomers by conventional means, for example by the use of an optically active acid
as a resolving agent. Alternatively, any enantiomer of a compound of Formula I may be
obtained by stereospecific synthesis using optically pure starting materials or reagents of
known configuration or through enantioselective synthesis.
The term "enantiomeric enrichment" as used herein refers to the increase in the
amount of one enantiomer as compared to the other. A convenient method of expressing
the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee,"
which is found using the following equation:

wherein E1 is the amount of the first enantiomer and E2 is the amount of the
second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is
present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final
ratio of 70:30 is achieved, the ee with respect to the first enantiomer is 40%. However, if
the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of
greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of
greater than 99% is most especially preferred. Enantiomeric enrichment is readily
determined by one of ordinary skill in the art using standard techniques and procedures,
such as gas or high performance liquid chromatography with a chiral column. Choice of
the appropriate chiral column, eluent and conditions necessary to effect separation of the
enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In
addition, the specific stereoisomers and enantiomers of compounds of Formula I, can be
prepared by one of ordinary skill in the art utilizing well known techniques and processes,
such as those disclosed by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions,"
John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of
Organic Compounds," (Wiley-Interscience 1994), and European Patent Application No.
EP-A-838448, published April 29, 1998. Examples of resolutions include
recrystallization techniques or chiral chromatography. Unless otherwise indicated, a
compound indicated to be "isomer 1" will be the first isomer eluted from the chiral
separation column and "isomer 2" will be the second.
In general, the term "pharmaceutical" when used as an adjective means
substantially non-toxic to living organisms. For example, the term "pharmaceutical salt"
as used herein, refers to salts of the compounds of Formula I, which are substantially
non-toxic to living organisms. See, e.g., Berge, S.M, Bighley, L.D., and Monkhouse,
D.C., "Pharmaceutical Salts,"/ Pharm Sci., 66:1, 1977. The present invention also
encompasses pharmaceutically acceptable salts of the present compounds. Such salts
include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable
metal salts, ammonium and alkylated ammonium salts. Also intended as pharmaceutically
acceptable acid addition salts are any hydrates that the present compounds are able to
form. Furthermore, the pharmaceutically acceptable salts comprise basic amino acid salts
such as lysine, arginine and ornithine. Typical pharmaceutical salts include those salts
prepared by reaction of the compounds of Formula I, with an inorganic or organic acid or
base. Such salts are known as acid addition or base addition salts respectively. These
pharmaceutical salts frequently have enhanced solubility characteristics compared to the
compound from which they are derived, and thus are often more amenable to formulation
as liquids or emulsions.
The term "acid addition salt" refers to a salt of a compound of Formula I, prepared
by reaction of a compound of Formula I, with a mineral or organic acid. For
exemplification of pharmaceutical acid addition salts see, e.g., Berge, S.M, Bighley, L.D.,
and Monkhouse, D.C., J. Pharm. Sci., 66:1, 1977. Since compounds of this invention can
>e basic in nature, they accordingly react with any of a number of inorganic and organic
icids to form pharmaceutical acid addition salts.
The acid addition salts may be obtained as the direct products of compound
synthesis. In the alternative, the free base may be dissolved in a suitable solvent
containing the appropriate acid, and the salt isolated by evaporating the solvent or
otherwise separating the salt and solvent.
Acids commonly employed to form acid addition salts are inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and
the like, and organic acids, such as/?-toluenesulfonic acid, ethanesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic
acid, citric acid, tartaric acid, benzoic acid, acetic acid and the like. Preferred
pharmaceutical acid addition salts are those formed with mineral acids such as
hydrochloric acid, hydrobromic acid, and sulfuric acid, and those formed with organic
acids such as maleic acid, tartaric acid, and methanesulfonic acid. Examples of such
pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caproate, heptanoate. propiolate, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycollate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like.
The skilled artisan would appreciate that some compounds of Formula I, may be
acidic in nature and accordingly react with any of a number of inorganic and organic
bases to form pharmaceutical base addition salts. The term "base addition salt" refers to a
salt of a compound of Formula I, prepared by reaction of a compound of Formula I, with
a mineral or organic base. For exemplification of pharmaceutical base addition salts see,
e.g., Berge, S.M, Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci., 66:1, 1977. Bases
commonly employed to form pharmaceutical base addition salts are inorganic bases, such
as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and
he like. Such bases useful in preparing the salts of this invention thus include sodium
hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium
carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium
carbonate, and the like. Examples of pharmaceutical base addition salts are the
ammonium, lithium, potassium, sodium, calcium, magnesium, methylamino,
diethylamino, ethylene diamino, cyclohexylamino, and ethanolamino salts, and the like of
a compound of Formula I. The potassium and sodium salt forms are particularly
preferred. The present invention also contemplates pharmaceutical base addition salts of
compounds of Formula I.
The pharmaceutical salts of the invention are typically formed by reacting a
compound of Formula I, with an equimolar or excess amount of acid or base. The
reactants are generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like for acid addition
salts, or water, an alcohol or a chlorinated solvent such as dichloromethane for base
addition salts. The salts normally precipitate out of solution within about one hour to
about ten days and can be isolated by filtration or other conventional methods. All
pharmaceutically acceptable salts are contemplated in the present invention. The
compound or salt of the present invention may form a solvate with low molecular weight
solvents. Such solvates are also contemplated as being within the scope of the present
invention.
The invention also encompasses prodrugs of the present compounds, which on
administration undergo chemical conversion by metabolic processes before becoming
pharmacologically active substances. In general, such prodrugs will be functional
derivatives of present compounds, which are readily convertible in vivo into a compound
of the present invention. Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
In a further aspect of the invention the present compounds are administered in
combination with one or more further active substances in any suitable ratios. Such
further active substances may for example be selected from antidiabetics, antiobesity
agents, antihypertensive agents, agents for the treatment of complications resulting from
or associated with diabetes and agents for the treatment of complications and disorders
resulting from or associated with obesity. The following listing sets out several groups of
combinations. It will be understood that each of the agents named may be combined with
other agents named to create additional combinations.
Thus, in a further embodiment of the invention the present compounds may be
administered in combination with one or more antidiabetics.
Suitable antidiabetic agents include insulin, insulin analogues and derivatives such
as those disclosed in EP 792 290 (Novo Nordisk A/S), for example N£B29-tetradecanoyl
des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), for example
Asp828 human insulin, US 5,504,188 (Eli Lilly), for example LysB28 Pro829 human insulin,
EP 368 187 (Aventis), for example Lantus®, which are all incorporated herein by
reference, GLP-1 and GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo
Nordisk A/S), which is incorporated herein by reference, as well as orally active
hypoglycemic agents.
The orally active hypoglycemic agents preferably comprise imidazolines,
sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones,
insulin sensitizers, insulin secretagogues, such as glimepiride, a-glucosidase inhibitors,
agents acting on the ATP-dependent potassium channel of the p-cells for example
potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and
WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or
mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon
antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk
A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference,
GLP-1 antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine
phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of
gluconeogenesis and/or glycogenolysis, glucose uptake modulators, activators of
glucokinase (GK) such as those disclosed in WO 00/58293, WO 01/44216, WO
01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and WO 02/08209 (Hoffman-La
Roche) or those disclosed in WO 03/00262, WO 03/00267 and WO 03/15774
(AstraZeneca), which are incorporated herein by reference, GSK-3 (glycogen synthase
kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic
agents such as HMG CoA inhibitors (statins), compounds lowering food intake, PPAR
(Peroxisome proliferator-activated receptor) ligands including the PPAR-alpha, PPAR-
h gamma and PPAR-delta substypes, and RXR (retinoid X receptor) agonists, such as
ALRT-268, LG-1268 or LG-1069
In another embodiment, the present compounds are administered in combination
with insulin or an insulin analogue or derivative, such as NEB29-tetradecanoyl des (B30)
human insulin, Asp628 human insulin, LysB28 Pro829 human insulin, Lantus®, or a mix-
preparation comprising one or more of these.
In a further embodiment of the invention the present compounds are administered
in combination with a sulphonylurea such as glibenclamide, glipizide, tolbautamide,
chloropamidem, tolazamide, glimepride, glicazide and glyburide.
In another embodiment of the invention the present compounds are administered
in combination with a biguanide for example metormin.
In yet another embodiment of the invention the present compounds are
administered in combination with a meglitinide for example repaglinide or nateglinide.
In still another embodiment of the invention the present compounds are
administered in combination with a thiazolidinedione insulin sensitizer for example
troglitazone, ciglitazone, piolitazone, rosiglitazone, isaglitazone, darglitazone,
englitazone, CS-01 l/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO
97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research
Foundation), which are incorporated herein by reference.
In still another embodiment of the invention the present compounds may be
administered in combination with an insulin sensitizer for example such as GI 262570,
YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-
H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in
WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such as
ragaglitazar (NN 622 or (-)DRF 2725) (Dr. Reddy's Research Foundation) and WO
00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416,
WO 00/63153, WO 63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo
Nordisk A/S), which are incorporated herein by reference.
In a further embodiment of the invention the present compounds are administered
in combination with an a-glucosidase inhibitor for example voglibose, emiglitate, miglitol
or acarbose.
In another embodiment of the invention the present compounds are administered
in combination with an agent acting on the ATP-dependent potassium channel of the p1-
cells for example tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or
repaglinide.
In yet another embodiment of the invention the present compounds may be
administered in combination with nateglinide.
In still another embodiment of the invention the present compounds are
administered in combination with an antilipidemic agent or antihyperlipidemic agent for
example cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin,
simvastatin, pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate or
atorvastin.
In still another embodiment of the invention the present compounds are
administered in combination with compounds lowering food intake.
In another embodiment of the invention, the present compounds are administered
in combination with more than one of the above-mentioned compounds for example in
combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and
acarbose; nateglinide and metformin; repaglinide and metformin, acarbose and
metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin
and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin
and lovastatin; etc.
In a further embodiment of the invention the present compounds may be
administered in combination with one or more antiobesity agents or appetite regulating
agents.
Such agents may be selected from the group consisting of CART (cocaine
amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4
(melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF
(tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP
(corticotropin releasing factor binding protein) antagonists, urocortin agonists, P3
idrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or
^Z-40140 MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-
;oncentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake
inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-uptake
inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,
bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin
or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing
hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists,
DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome
proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR p
agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid
antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor (such
as axokine), cannaboid receptor antagonist for example CB-1 (such as rimonabant).
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is leptin. In another embodiment the
antiobesity agent is fenfluramine or exfenfluramine. In still another embodiment the
antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine. In still another
embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine.
bupropion, topiramate or ecopipam.
Furthermore, the present compounds may be administered in combination with
one or more antihypertensive agents. Examples of antihypertensive agents are P-blockers
such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, SCE
(angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril,
fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine,
felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ot-blockers
such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to
Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, PA, 1995.
The compounds of the present invention may be administered in combination with
FAS inhibitors.
The compounds of the present invention may also be administered in combination
with chemical uncouplers, hormone sensitive lipase inhibitor, imidazolines, 11-|3-
hydroxysteroid dehydrogenase inhibitors, lipoprotein lipase activator, AMPK activators,
immunosuppresive drugs, nicotinamide, ASIS, anti-androgens or carboxypeptidase
inhibitors.
It should be understood that any suitable combination of the compounds according
to the invention with diet and/or exercise, one or more of the above-mentioned
compounds and optionally one or more other active substances are considered to be
within the scope of the present invention.
The compounds of Formula I, can be prepared by one of ordinary skill in the art
following a variety of procedures, some of which are illustrated in the procedures and
schemes set forth below. The particular order of steps required to produce the compounds
of Formula I is dependent upon the particular compound to being synthesized, the starting
compound, and the relative liability of the substituted moieties. The reagents or starting
materials are readily available to one of skill in the art, and to the extent not commercially
available, are readily synthesized by one of ordinary skill in the art following standard
procedures commonly employed in the art, along with the various procedures and
schemes set forth below.
The following Schemes, Preparations, Examples and Procedures are provided to
better elucidate the practice of the present invention and should not be interpreted in any
way as to limit the scope of the same. Those skilled in the art will recognize that various
modifications may be made while not departing from the spirit and scope of the
invention. All publications mentioned in the specification are indicative of the level of
those skilled in the art to which this invention pertains.
The optimal time for performing the reactions of the Schemes, Preparations,
Examples and Procedures can be determined by monitoring the progress of the reaction
via conventional chromatographic techniques. Furthermore, it is preferred to conduct the
reactions of the invention under an inert atmosphere, such as, for example, argon, or,
particularly, nitrogen. Choice of solvent is generally not critical so long as the solvent
employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to
effect the desired reaction. The compounds are preferably isolated and purified before
their use in subsequent reactions. Some compounds may crystallize out of the reaction
solution during their formation and then collected by filtration, or the reaction solvent
may be removed by extraction, evaporation, or decantation. The intermediates and final
products of Formula I may be further purified, if desired by common techniques such as
recrystallization or chromatography over solid supports such as silica gel or alumina.
The skilled artisan will appreciate that not all substituents are compatible with all
reaction conditions. These compounds may be protected or modified at a convenient point
in the synthesis by methods well known in the art.
The terms and abbreviations used in the instant Schemes, Preparations, Examples
and Procedures have their normal meanings unless otherwise designated. For example, as
used herein, the following terms have the meanings indicated: "eq" refers to equivalents;
"N" refers to normal or normality, "M" refers to molar or molarity, "g" refers to gram or
grams, "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "\xL"
refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to
pounds per square inch; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers
to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high
performance liquid chromatography; "Rf" refers to retention factor; "Rt" refers to
retention time; "8"refers to part per million down-field from tetramethylsilane; "MS"
refers to mass spectrometry, Observed Mass indicates [M+H] unless indicated otherwise.
"MS(FD)" refers to field desorption mass spectrometry, "MS(IS)" refers to ion spray
mass spectrometry, "MS(FIA)" refers to flow injection analysis mass spectrometry,
"MS(FAB)" refers to fast atom bombardment mass spectrometry, "MS(EI)" refers to
electron impact mass spectrometry, "MS(ES)" refers to electron spray mass spectrometry,
"UV" refers to ultraviolet spectrometry, 'llH NMR" refers to proton nuclear magnetic
resonance spectrometry. In addition, "IR" refers to infra red spectrometry, and the
absorption maxima listed for the IR spectra are only those of interest and not all of the
maxima observed. "RT" refers to room temperature. "DEAD" refers to
diethylazodicrboxylate. "PPI13" refers to triphenylphosphine. "ADDP" refers to 1,1'-
(azodicarbonyl)dipiperidine. "PPBU3" refers to tributylphosphine. "OTF" refers to
triflate. "LAH" refers to lithium aluminum hydride. "DIBAL-H" refers to
diisobutylaluminum hydride. "KOtBu" refers to potassoium t-butoxide. "THF" refers to
tetrahydrofuran. "TBP" refers to tributylphosphine. "EDCI" refers to
l-(3-dimethylaminopropyl)-3-ethylcarbodiamide hydrochloride. "DMAP" refers to
dimethylaminopyridine. "HNMe(OMe)" refers to N,N,dimethylhydroxyamine.
"CDMT" refers to 2-chloro-4,6-dimethoxy-[ 1,3,5] triazine. "NMM" refers to N-methyl
morpholine. "DCM" refers to dichloromethane. "DMSO" refers to dimethylsulfoxide.
"ET3N" refers to triethylamine. "DMF" refers to dimethylformamide. "Et" in a formula
refers to ethyl, for example Et20 refers to diethylether, and EtOAc refers to ethylacetate.
"PyBOP" refers to bromo-tris-pyrrolidino-phosphonium hexafluorophosphate. "Me"
refers to methyl as in MeOH which is methanol. "Pd/C" refers to 10% palladium on
carbon. Unless otherwise indicated, isomer 1 refers to the first isomer to be eluted in a
chiral separation and isomer 2 refers to the second isomer to be eluted in a chiral
separation.
Infrared spectra are recorded on a Perkin Elmer 781 spectrometer. !H NMR
spectra are recorded on a Varian 400 MHz spectrometer at ambient temperature. Data are
reported as follows: chemical shift in ppm from internal standard tetramethylsilane on the
5 scale, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn =
quintet and m = multiplet), integration, coupling constant (Hz) and assignment. I3C NMR
are recorded on a Varian 400 MHz spectrometer at ambient temperature. Chemical shifts
are reported in ppm from tetramethylsilane on the 5 scale, with the solvent resonance
employed as the internal standard (CDCb at 77.0 ppm and DMSO-d6 at 39.5 ppm).
Combustion analyses are performed by Eli Lilly & Company Microanalytical Laboratory.
High resolution mass spectra are obtained on VG ZAB 3F or VG 70 SE spectrometers.
Analytical thin layer chromatography is performed on EM Reagent 0.25 mm silica gel 60-
F plates. Visualization is accomplished with UV light.
GENERAL SCHEMES
Compounds of the present invention have been formed as specifically described in the
examples. Further, many compounds are prepared as more generally using a) alkylation
of a alcohol, phenol or thiophenol with a halide, b) a Mitsunobu protocol (O. Mitsunobu,
1981 Synthesis, pi); c) and other methods known to the skilled artisan. Alternative
synthesis methods may also be effective and known to the skilled artisan. Unless
otherwise indicated, all variables, such as Y', Rl' to R15', etc., are as defined for
analogous variables (Rl to R15, etc.) in the summary of the invention, and otherwise as
defined herein.
For example, an intermediate like A is alkylated with an alkylating agent B in the
presence of a base (e.g. NaH, K2CO3, CS2CO3 etc.). Hydrolysis in the presence of aqueous
NaOH or LiOH gave the acid product.

Alternatively, an intermediate like A is coupled with an alcohol C under
Mitsunobu reaction condition (DEAD/PPh3, ADDP/PBu3 etc.). Hydrolysis in the presence
of aqueous NaOH or LiOH gave the acid product:

Under certain circumstances, the synthetic sequence can be altered, where an
intermediate like D is coupled with an aryl boronic acid or ester under Suzuki reaction
conditions (Pd catalyst, base). Hydrolysis in the presence of aqueous NaOH or LiOH
gave the acid product:
Scheme 3
The alcohol intermediates A and C can be made by A) reduction of the ketone with or
without chiral auxiliary or B) alkylation of aldehyde with an organometallic reagent, e.g.
Grignard reagent.
The biaryl phenol analogs can be made by a palladium catalyzed cross coupling reaction:

The enantiomeric purifiedproducts are prepared either through A) chiral
chromatography or B) Mitsunobu coupling between a phenol or thiophenol and a chiral
alcohol that can be prepared using the methods known to the art.
PREPARATIONS AND EXAMPLES
The Examples provided herein are illustrative of the invention claimed herein and
are not intended to limit the scope of the claimed invention in any way. Names of the
preparations and examples are derived using ChemDraw.
Infrared spectra are recorded on a Perkin Elmer 781 spectrometer. 1H NMR
spectra are recorded on a Varian 400 MHz spectrometer at ambient temperature. Data are
reported as follows: chemical shift in ppm from internal standard tetramethylsilane on the
(scale, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet
and m = multiplet), integration, coupling constant (Hz) and assignment. 13C NMR are
recorded on a Varian 400 MHz spectrometer at ambient temperature. Chemical shifts are
reported in ppm from tetramethylsilane on the (scale, with the solvent resonance
employed as the internal standard (CDC13 at 77.0 ppm and DMSO-d6 at 39.5 ppm).
Combustion analyses are performed by Eli Lilly & Company Microanalytical Laboratory.
High resolution mass spectra are obtained on VG ZAB 3F or VG 70 SE spectrometers.
Analytical thin layer chromatography is performed on EM Reagent 0.25 mm silica gel 60-
F plates. Visualization is accomplished with UV light.
Preparation 1
Racemic 4-(l-Hydroxy-propyl)-benzoic acid methyl ester

To a solution of 4-formyl-benzoic acid methyl ester (3.0 g, 18.3 mmol) in THF
(10 mL) at 0 °C is added ethylmagnesium bromide (2M, 10 mL). After stirring at room
temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with
EtOAc. The organic is concentrated to give the titled compound as colorless oil: 2.2 g
(62 %).
The following compounds are made in a similar manner:
Preparation 2
Racemic 4-(l-Hydroxy-butyI)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and
n-propylmagnesium chloride following the general method exemplified in Preparation 1.
Preparation 3
Racemic 4-(l-Hydroxy-2-methyl-propyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and
isopropylmagnesium chloride following the general method exemplified in Preparation 1.
Preparation 4
Racemic 4-(l-Hydroxy-pentyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and n-butyl
magnesium chloride following the general method exemplified in Preparation 1.
Preparation 5
Racemic 4-(l-Hydroxy-3-methyl-butyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and
isobutylmagnesium chloride following the general method exemplified in Preparation 1.
Preparation 6
Racemic 4-(l-Hydroxy-hexyI)-benzoic acid methyl ester
This compound is made from 4-formyI-benzoic acid methyl ester and n-
pentylmagnesium chloride following the general method exemplified in Preparation 1.
Preparation 7
Racemic 4-(l-Hydroxy-heptyl)-benzoic acid methyl ester
This compound is made from 4-formyl-benzoic acid methyl ester and
n-hexylmagnesium chloride following the general method of Preparation 1.
Preparation 8
Racemic 4-(l-Hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and 4,4-
dimethylpentylmagnesium bromide following the general method of Preparation 1.
Preparation 9
Racemic 4-(l-Hydroxy-butyl)-benzoic acid methyl ester
Step A. N-Methoxy-N-methyl-terephthalamic acid methyl ester
To a solution of Terephthalic acid monomethyl ester (5.4 g, 30 mmol) and 2-
chloro-4,6-dimethoxy-[l,3,5]triazine (7.9 g, 45 mmol) in THF (300 mL) is added N-
methyl morpholine (4.95 mL, 45 mmol), the mixture is stirred at room temperature
overnight. Additional N-methyl morpholine (4.95 mL, 45 mmol) is added, followed by
the addition of O, N-dimethyl-hydroxylamine HCI salt (3.51 g, 45 mmol). The reaction
mixture is stirred overnight, and filtered through celite. The filtrate was concentrated and
purified by column chromatography on silica gel (hexane/ethyl acetate) giving the title
compound (6.8 g).
Step B. 4-Butyryl-benzoic acid methyl ester
To a solution of N-methoxy-N-methyl-terephthalamic acid methyl ester (4.56 g,
20.4 mmol) in THF (100 mL) is added PrMgCI (2.0M, 30.6 mmol) at 0 °C, the reaction is
warmed to room temperature, stirred overnight, quenched by NH4CI aqueous solution,
extracted with ethyl acetate. The combined organic layers are washed with brine, dried
over sodium sulfate, concentrate. Column chromatography on silica gel gives the title
compound (1 g, 23.7 %).
Step C. Racemic 4-(l-Hydroxy-butyl)-benzoic acid methyl ester
To a solution of 4-butyryl-benzoic acid methyl ester (400 mg, 1.94 mmol) in
ethanol (5 mL) and THF (4 mL) is added sodium borohydride (110 mg, 2.9 mmol), the
mixture is stirred at room temperature for 2 h. The reaction mixture is quenched by acetic
acid (0.5 mL) and water (10 mL), extracted with ethyl acetate. Combined organic layers
are washed with brine and dried over sodium sulfate. Concentration and column
chromatography on silica gel gives the title compound (370 mg).
Preparation 10
Racemic 3-[4-(l-Hydroxy-nonyl)-benzoyIamino]-propionic acid methyl ester

Step A. 3-(4-FormyI-benzoylamino)-propionic acid methyl ester
4-Formyl-benzoic acid, CDMT, and 4-methylmorpholine are combined in
anhydrous DCM under nitrogen. The reaction is allowed to stir under nitrogen at room
temperature overnight. The amine is then added to the reaction mixture, and allowed to
stir at room temperature. Some water (<10% volume) is added to help solubility. The
reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction
is diluted with DCM. The reaction is diluted with water and rinsed with IN HC1. Upon
acidification, a white solid precipitated from the biphasic mixture. The solid was isolated
by filtration and dried under vacuum to afford the titled compound.
Step B. Racemic 3-[4-(l-Hydroxy-nonyl)-benzoylamino]-propionic acid methyl ester
To a solution of 3-(4-formyl-benzoylamino)-propionic acid methyl ester (1.2 g, 5
mmol) in THF (10 mL) at 0 °C is added ethylmagnesium bromide (2M, 1.1 mL). After
stirring at room temperature for 2 hours, it is quenched with saturated ammonium
chloride, extracted with EtOAc. The organic is concentrated to give the titled compound
as colorless oil: 270 mg (15 %).
The following compound is made in a substantially similar manner:
Preparation 11
Racemic 3-[4-(4,4,4-Trifluoro-l-hydroxy-butyI)-benzoylamino]-propionic acid
methyl ester

This compound is made by the general method exemplified in Preparation 10
using 3,3,3-trifluoropropylmagnesium bromide.
Preparation 12
Racemic 3-[4-(l-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid
methyl ester

This compound is made by the general method exemplified in Preparation 10
using 2,2-dimethylbutylmagnesium bromide.
Preparation 13
Racemic 3-[4-(l-Hydroxy-butyI)-benzoylamino]-propionic acid methyl ester

This compound is made by the general method exemplified in Preparation 10
using n-propylmagnesium bromide.
Preparation 14
Racemic 3-[4-(l-Hydroxy-3-methyl-butyl)-benzoylamino]-propionic acid methyl
ester

This compound is made by the general methods as exemplified in Preparation 10
using isobutyl magnesium bromide as reagent.
Preparation 15
Racemic 3-[4-(l-Hydroxy-heptyl)-benzoylamino]-propionic acid methyl ester

This compound is made by the general methods as exemplified in Preparation 10
using hexyl magnesium bromide as reagent.
Preparation 16
4'-TrifluoromethyI-biphenyl-4-ol

4-Bromophenol (5 g, 28.9 mmol), 4-trifluoromethyl phenyl boronic acid (6.59 g,
34.7 mmol), potassium carbonate (12 g, 86.7 mmol) and palladium acetate (0.324 g,
1.445 mmol) are placed in water (50 mL), and the resulting mixture is stirred at room
temperature over night under open air. The mixture is filtered through celite and extracted
with ethyl acetate (3 x 200 ml). The combined organic layers are washed with water, IN
HC1, water, brine, dried (MgSO4), concentrated and chromatographed to yield the title
compound as a white solid (6.0 g, 87%).
The following compound is made in a substantially similar manner:
Preparation 17
4'-tert-Butyl-biphenyl-4-ol

This compound is made by the general method exemplified in Preparation 16
using 4-tert-butyl phenyl boronic acid as reagent.
Preparation 18
4-(5-Trifluoromethyl-pyridin-2-yl)-phenoI

Step A. 2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine
A mixture of 2-chloro-5-trifluoromethylpyridine (1.81 g, 10 mmol), 4-
benzyloxyphenyl boronic acid (2.74 g, 12 mmol) and CsF (5.32 g, 35 mmol) in dioxane
(40 mL) is degaseed and filled with nitrogen. PdCl2(dppf) (200 mg) is added under
nitrogen, the reaction mixture is heated at 105 °C overnight. The mixture is cooled to
room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of Celite.
The filtrate is concentrated and the residue is purified by column chromatography on
silica gel giving the title compound (2.55g, 77.4 %).
Step B. 4-(5-Trifluoromethyl-pyridin-2-yl)-phenol
To a solution of 2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine (2.55g) in
ethanol (100 mL) and THF (25 mL) is added Pd/C (5%, 0.253 g), the mixture is stirred
under 60 psi of hydrogen overnight. The catalyst is filtered off, concentration of the
filtrate gave the title compound (1.25 g, 67.5%).
Preparation 19
Racemic 4-(l-Hydroxy-3,3-dimethyI-butyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and 3,3-
dimethyl-butanemagnesium bromide following the general method exemplified in
Preparation 1.
Preparation 20
Racemic 4-(Cyclopropyl-hydroxy-methyl)-benzoic acid methyl ester

This compound is made from 4-formyl-benzoic acid methyl ester and Cycloprop
magnesium bromide following the general method exemplified in Preparation 1.
Preparation 21
Racemic 3-Fluoro-4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester
This compound is made from 3-Fluoro-4-formyl-benzoic acid methyl ester and
isobutylmagnesium bromide following the general method exemplified in Preparation 1.
Preparation 22
Racemic 3-Fluoro-4-(l-hydroxy-heptyl)-benzoic acid methyl ester
This compound is made from 3-Fluoro-4-formyl-benzoic acid methyl ester and
hexylmagnesium bromide following the general method exemplified in Preparation 1.
Preparation 23
4-Bromo-3-[l,3]dioxan-2-yl-phenol
To the solution of 2-bromo-5-methoxy-benzaldehyde (lOg, 46.5 mmol) at -78°C
is added BBr3 (25g, 93.75 mmol) and allowed to warm to room temperature. After 2h, the
reaction is quenched with water and extracted with ethyl acetate. The combined organic
layers are washed with water, brine, dried over MgSC>4, concentrated and purified by
column chromatography to afford 3.6g of 2-bromo-5-hydroxy-benzaldehyde. To the
solution of 2-bromo-5-hydroxy-benzaldehyde (1.45 g, 7.2mmol in benzene (30ml) and
THF (6ml) is added 1,3-propanediol (2.74g, 36mmol) and TsOH (37mg, 0.22mmol). The
mixture is refluxed for 24. After cooling down, the solvent is evaporated. The residue is
loaded on silica and purified by column chromatography to afford the titled compound
(2.3g) as brown oil.
Preparation 24
6-Chloro-5-methyl-pyridin-3-ol
2-Chloro-3-methyi-5-nitro-pyridine (2g, 11.6 mmol) and SnCl2«(H2O)2 (7.86g,
34.8 mmol) are refluxed in MeOH overnight. After cooled down, the mixture is diluted
with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated and
purified by column chromatography to afford 6-chloro-5-methyl-pyridin-3-ylamine
(1.7g). To the solution of 6-chloro-5-methyl-pyridin-3-ylamine (1.7g, 11.6 mmol) in IN
HC1 is added the solution of NaNO2 (960mg, 13.92mmol) in water (10ml) slowly at 0 °C.
After the addition, the solution is stirred for 20min and then heated to 90 °C for 30min.
The solution is cooled down, quenched with K2CO3, extracted with ether, dried over
MgSC>4, and purified by column chromatography to afford the titled compound (560mg)
as a yellow solid.
Preparation 25
4'-Isopropyl-2-methyl-biphenyl-4-ol
4-Bromo-3-methylphenol (1.87 g, 10 mmol), 4-isopropyl phenyl boronic acid (2.0
g, 12 mmol), potassium carbonate (4.1 g, 30 mmol) and palladium acetate (0.112 g, 0.5
mmol) are placed in water (100 mL). And the resulting mixture is stirred at room
temperature over night under open air. The mixture is filtered through Celite and
extracted with ethyl acetate (3 x 200 ml). The combined organic layers are washed with
water, IN HC1, water, brine, dried (MgSO4), concentrated and chromatographed to yield
the title compound as a white solid (1.9g).
Preparation 26
2-Bromo-5-hydroxy-benzaldehyde
To 2-bromo-5-methoxy-benzaldehyde (lOg, 31.25mmol) in dichloromethane
(30ml) at -78 °C is added BBr3 (25g, 93.75mmol) and allowed to warm to room
temperature. After 2h, the reaction is quenched with water and extracted with ethyl
acetate. The combined organic layers are washed with water, brine, dried and purified by
the column chromatography to afford 3.6g of the titled compound.
Preparation 27
2-Bromo-5-hydroxy-benzaldehyde O-tert-butyl-oxime
To the solution of 2-bromo-5-hydroxy-benzaldehyde (402mg, 2mmol) in
methanol (10ml) is added O-tert-butyl-hydroxylamine hydrochloride (125mg, lOmmol).
The mixture is stirred at room temperature overnight. The resulting mixture is diluted
with ethyl acetate, washed with brine, dried over MgSCU, and evaporated to afford the
titled compound (360mg) as colorless oil.
Preparation 28
4-Bromo-3,5-dimethyl-benzenethiol
Step A. Dimethyl-thiocarbamic acid O-(4-bromo-3,5-dimethyl-phenyl) ester
4-Bromo-3,5-dimethyl-phenol (10.0 g, 50.01 mmol) is dissolved into dry dioxane
(200 mL) and combined with 4-dimethylamino pyridine (1.0 g, 5.2 mmol), trieihylamine
(12.77 mL, 100.1 mmol), and dimethylamino-thiocarbomoyl chloride (7.69 g, 62.51
mmol). The reaction is heated to reflux under nitrogen. The reaction is monitored by
TLC until all of the phenol is consumed, approximately 20h. After cooling to room
temperature, the reaction is diluted with ethyl acetate (200 mL). Water (75 mL) is added
and the two layers are separated. The organic layer is washed with brine (75mL) then
dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified
by column chromatography, (6.4 g or 55% yield).
Step B. Dimethyl-thiocarbamic acid S-(4-bromo-3,5-dimethyl-phenyl) ester
Dimethyl-thiocarbamic acid O-(4-bromo-3,5-dimethyl-phenyl) ester (6.4 g, 22.3
mmol) is diluted with 50 mL of tetradecane and heated to reflux under nitrogen. The
reaction is monitored by TLC until all the conversion was complete, approximately 20h.
The reaction is allowed to cool to room temperature and then loaded onto silica gel
column and purified using flash column chromatography, yielding 5.78 g, or 90% of the
target product.
Step C. 4-Bromo-3,5-dimethyl-benzenethioI
Dimethyl-thiocarbamic acid S-(4-bromo-3,5-dimethyl-phenyl) ester (5.78 g, 20.14
mmol) is diluted with methanol (50 mL) and sodium methoxide (4.75 mL of 4.25M in
methanol, 20.14 mmol) is added. The reaction is heated to reflux under nitrogen and
monitored by TLC. After complete conversion, 20 hours, the reaction is allowed to cool
to room temperature. The reaction is neutralized with IN hydrochloric acid (7.5 mL) and
diluted with ethyl acetate (150 mL). The two phases are separated and the organic layer
is washed with water (75 mL), then brine (75 mL). The organic layer is dried over
anhydrous sodium sulfate, concentrated and loaded onto silica gel column. The title
compound is purified using flash column chromatography, yielding 4.0g, or 92%.
Preparation 29
(R,S) 4-(5,5,5-Trifluoro-l-hydroxy-pentyl)-benzoic acid methyl ester
This compound is made following the general method exemplified in Preparation
1 using 4-formyl-benzoic acid methyl ester and l,l,l-trifluoro-butane-4-magnesium
bromide.
Preparation 30
(R,S) 3-[4-(Cyclohexyl-hydroxy-methyl)-benzoylamino]-propionic acid methyl ester

This compound is made by the general method exemplified in Preparation 10
using 3-(4-formyl-benzoylamino)-propionic acid methyl ester and cyclohexylmagnesium
bromide.
Preparation 31
(R,S) 3-[4-(l-Hydroxy-5-methyI-hexyl)-benzoylamino]-propionic acid methyl ester
OH
This compound is made by the general method exemplified in Preparation 10
using 3-(4-formyl-benzoylamino)-propionic acid methyl ester and 4-methylpentane-l-
magnesiumbromide.
Preparation 32
4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ol
This compound is made by the general method as exemplified in Preparation 16
using 4-bromo-3,5-dimethyl-phenol and 4-tert-butyI phenyl boronic acid as reagents.
Preparation 33
2,6-DimethyI-4'-trifluoromethyI-biphenyl-4-ol
This compound is made by the general method as exemplified in Preparation 16
using 4-bromo-3,5-dimethyl-phenol and 4-trifuoromethyl phenyl boronic acid as reagents.
Preparation 34
5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol

Step A. 3-MethyI-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine
To a solution of 2-chloro-3-methyl-5-nitro-pyridine(5.0 g, 28,73 mmol) in
toluene(50 mL) is added palladium tetrakis triphenylphosphine(1.66 g, 1.44 mmol), 4-
trifluoromethy 1 phenyl boronic acid( 10.92 g, 57.46 mmol), and potassium fluoride
(3.34g, 57.46 mmol). The reaction is purged with nitrogen three times and heated to
reflux under nitrogen. At reflux, water (25 mL) is added to the reaction and the reaction is
allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon
completion, allowed to cool to room temperature. The reaction is diluted with ethyl
acetate and Celite is added, followed by water. This mixture is then filtered through a pad
of Celite. The solution is poured into a separatory funnel and the organic layer is washed
with water and brine. The organic layer is dried over anhydrous sodium sulfate and
concentrated. The product is purified by flash column chromatography (5.6 g, 19.71
mmol).
Step B. 5-Methyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-ylamine
To a solution of the 3-methyl-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine(3.5 g,
10.56 mmol) in ethanol(50 mL) is added palladium (10%) on carbon (0.700 g, 20% by
wt.). The reaction is charged to 15 psi under a hydrogen atmosphere and allowed to stir
for 4 hours. The reaction is diluted with ethyl acetate and Celite is added, followed by
water. This mixture is then filtered through a pad of celite. The solution is concentrated,
diluted with ethyl acetate, poured into a separatory funnel and the organic layer is washed
with water and brine. The organic layer is dried over anhydrous sodium sulfate and
concentrated. The product is used directly in the next step (2.74 g, 10.87 mmol).
Step C. 5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-oI
5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (2.74 g, 10.87 mmol) is
suspended in hydrochloric acid (21.74 mL, 5N) and the solution is cooled to -15 °C in a
brine/ice bath. Sodium nitrate (0.9 g, 13.04 mmol) in water (10 mL) is added slowly to
the mixture. The reaction is allowed to stir at -15 °C for ten minutes after complete
addition. Hexafluorophosphoric acid (5 mL, 21.74 mmol of a 60% wt. solution in water)
is added slowly to the mixture. The resulting slurry is filtered, rinsed with cold water,
methanol, and diethyl ether, and dried under vacuum. This solid is added in small
portions to a round bottom containing acetic acid (10 mL) at 105°C. This solution is
cooled to room temperature then treated with sodium hydroxide (25 mL, 5N) for 30 min.
The pH of this solution is adjusted to 6 with hydrochloric acid, extracted with ethyl
acetate, washed with brine, dried over anhydrous sodium sulfate, then filtered and
concentrated to provide the title product (2.2 g, 8.69 mmol).
Preparation 35
6-(4-tert-Butyl-phenyl)-5-methyl-pyridin-3-ol
This compound is made by the general method exemplified in Preparation 16
using 2-chloro-3-methyl-5-nitro-pyridine and 4-tbutyl phenyl boronic acid.
Example 1
Racemic 3-{4-[l-(4'-TrifIuoromethyl-biphenyI-4-yloxy)-propyl]-benzoylamino}-
propionic acid

Step A. 4-[l-(4'-TrifluoromethyI-biphenyl-4-yloxy)-propyl]-benzoic acid
To a solution of 4-(l-hydroxy-propyl)-benzoic acid methyl ester (300 mg, 1.55
mmol) in toluene (10 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP, 585 mg,
2.32 mmol) at 0 °C, followed by the addition of tributylphosphine (0.58 mL, 2.32 mmol)
and 4'-trifiuoromethyl-biphenyl-4-ol (442 mg, 1.86 mmol). The reaction mixture is
warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel,
eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of ethyl acetate
giving 4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid methyl ester. The
ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1
mL) for 3 hours at room temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HC1 (1.1 mL), extracted with ethyl acetate. The organic layers
are dried and concentrated giving 4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoic acid (570 mg).
Step B. Racemic methyl 3-(4-{l-[6-(4-Trifluoromethyl-phenyI)-pyridin-3-yI]-
heptyloxy}-benzoylamino)-propionoate
To a mixture of 4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid
(270 mg, 0.68 mmol) in methylene chloride (7 mL) are added triethyl amine (0.28 mL,
2.03 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (141 mg, 1.01. mmol)
and EDCI (389 mg, 2.03 mmol) at room temperature. The reaction mixture is stirred at
room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a
gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving 3-{4-[l-(4'-
trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid methyl ester
(215 mg).
Step C. Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyI]-
benzoylamino}-propionic acid
To a mixture of 3-{4-[l-(4'-TrifiuoromethyI-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid methyl ester (60 mg, 0.12 mmol) in methanol (2 mL) is
added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 hours. The reaction
mixture is concentrated and acidified by 5 N HC1 (0.5 mL), extracted with ethyl acetate.
Combined organic layers are washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (54 mg). MS (ES): 472.2 [M+H]+.
Example 2
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yIoxy)-butyI]-
benzoylaminoj-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-3-methylbutyl)-benzoic acid methyl ester and 4'-trifluoromethyI-biphenyl-4-
ol as starting materials. MS (ES): 500.2 [M+H]+.
Example 3
Racemic 3-{4-[l-(4-tert-ButyI-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-3-methyIbutyl)-benzoic acid methyl ester and 4-tert-butyl-phenol as starting
materials. MS (ES): 412.3 [M+H]+.
Example 4
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-4,4,4-trifluorobutyl)-benzoic acid methyl ester and 4'-tert-butyl-biphenyl-4-ol
as starting materials. MS (ES): 526.2 [M+H]+.
Example 5
Racemic 3-{4-[4,4,4-Trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-4,4,4-trifluorobutyl)-benzoic acid methyl ester and 4'-trifluoromethyl-
biphenyl-4-ol as starting materials. MS (ES): 538.3 [M+H]+.
Example 6
Racemic 3-{4-[(4-Bromo-phenyl)-(4'-tert-butyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-l-(4-bromophenyl)-methyl)-benzoic acid methyl ester and 4'-tbutyl-biphenyI-
4-ol as starting materials. MS (ES): 585.0.
Example 7
Racemic 3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylaminoj-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-2-methylpropyl)-benzoic acid methyl ester and 4'-trifluoromethyI-biphenyl-4-
ol as starting materials. MS (ES): 486.2 [M+H]+.
Example 8
Racemic 3-{4-[l-(4'-tert-ButyI-biphenyI-4-yloxy)-propyl]-benzoylamino}-propionic
acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-propyl)-benzoic acid methyl ester and 4'-tert-butyl-biphenyl-4-ol as starting
materials. MS (ES): 458.3 [M-H]Example 9
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-tert-butyl-biphenyl-4-ol as starting
materials. MS (ES): 516.3 [M+H]+.
Example 10
Racemic 3-{4-[l-(4'-tert-ButyI-biphenyI-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-3-methylbutyl)-benzoic acid methyl ester and 4'-tbutyl-biphenyl-4-ol as
starting materials. MS (ES): 488.3 [M+H]+.
Example 11
Racemic 3-{4-[l-(4-Cyclohexyl-phenoxy)-hexyI]-benzoylamino}-propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-hexyl)-benzoic acid methyl ester and 4-cyclohexylphenol as starting
materials. MS (ES): 452.3 [M+H]+.
Example 12
Racemic 3-{4-[l-(4-Benzyloxy-phenoxy)-hexyI]-benzoylamino}-propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-hexyl)-benzoic acid methyl ester and 4-benzyloxyphenol as starting materials.
MS (ES): 476.2 [M+H]+.
Example 13
Racemic 3-[4-(l-Phenoxy-hexyl)-benzoylamino]-propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-hexyl)-benzoic acid methyl ester and phenol as starting materials. MS (ES):
370.3 [M+H]+.
Example 14
Racemic 3-{4-[l-(4'-TrifluoromethyI-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-trifluoromethyl-biphenyl-4-ol as
starting materials. MS (ES): 528.2 [M+H]+.
Example 15
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyI-4-ylsulfanyl)-heptyl]-benzoyIamino}-
propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-trifluoromethyl-biphenyI-4-
mercaptol as starting materials. MS (ES): 542.2 [M-H]~.
Example 16
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-pentyl)-benzoic acid methyl ester and 4'-trifluoromethyl-biphenyl-4-ol as
starting materials. MS (ES): 498.2 [M-H]".
Example 17
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyI-4-yloxy)-pentyl]-benzoylamino}-propionic
acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-pentyl)-benzoic acid methyl ester and 4'-tbutyl-biphenyl-4-ol as starting
materials. MS (ES): 486.3 [M-H]'.
Example 18
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoyIamino}-
propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-butyl)-benzoic acid methyl ester and 4'-trifluoromethyI-biphenyl-4-ol as
starting materials. MS (ES): 486.2 [M+H]+.
Example 19
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoyIamino}-propionic
acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-butyl)-benzoic acid methyl ester and 4'-tert-buryl-biphenyl-4-ol as starting
materials. MS (ES): 475.2 [M+H]+.
Example 20
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]-
benzoylaminoj-propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-3-methylbutyl)-benzoic acid methyl ester and 4'-trifluoromethyl-biphenyl-4-
mercaptol as starting materials. MS (ES): 515.3 [M-H]~.
Example 21
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-
propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-nonyl)-benzoic acid methyl ester and 4'-trifluoromethyl-biphenyl-4-mercaptol
as starting materials. MS (ES): 554.2 [M-H]~.
Example 22
Racemic 3-(4-{3-MethyI-l-[4-(6-trifluoromethyl-pyridin-3-yI)-phenoxy]-butyl}-
benzoylamino)-propionic acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-3-methylbutyl)-benzoic acid methyl ester and 4-(6-Trifluoromethyl-pyridin-
3-yl)-phenol as starting materials. MS (ES): 500.3 [M-H]".
Example 23
Racemic 3-(4-{2-Methyl-l-[4-(6-trifluoromethyI-pyridin-3-yl)-phenoxy]-propyl}-
benzoylamino)-propionic acid

This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-2-methylpropyl)-benzoic acid methyl ester and 4-(6-Trifluoromethyl-pyridin-
3-yl)-phenol as starting materials. MS (ES): 487.3 [M+H]+.
Example 24
Racemic 3-(4-{l-[4'-trifluoromethoxy-biphenyl-4-ylsulfanyI]-3-methyI-butyl}-
benzoylamino)-propionic acid

Step A. 4-[l-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid
To a solution of 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1240
mg, 5.59 mmol) in toluene (10 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP,
2114 mg, 8.38 mmol) at 0 °C, followed by the additions of tributylphosphine (2.09 mL,
8.38 mmol) and 4-bromo-thiophenol (1267 mg, 6.7 mmol). The reaction mixture is
warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel,
eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of ethyl acetate
giving 4-[l-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid methyl ester. 393 mg
of the ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N
aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with
ethyl acetate, acidified with 5 N HC1 (1.1 mL), extracted with ethyl acetate. The organic
layers are dried and concentrated giving 4-[l-(4-bromo-phenylsulfanyI)-3-methyl-butyl]-
benzoic acid (379 mg).
Step B. Racemic 3-{4-[l-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester
To a mixture of 4-[l-(4-bromo-phenylsulfanyl)-3-rnethyl-butyl]-benzoic acid (379
mg, 1 mmol) in methylene chloride (10 mL) are added triethyl amine (0.42 mL, 3 mmol),
DMAP (5.0 mg), 3-amino-propionic acid methyl ester (209 mg, 1.5 mmol) and EDCI
(577 mg, 3.0 mmol) at room temperature. The reaction mixture is stirred at room
temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a
gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving 3-{4-[l-(4-Bromo-
phenylsulfanyl)-3-methyl-butyI]-benzoylamino}-propionic acid methyl ester (350 mg).
Step C. Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyI-4-yIsulfanyl)-
butyl]-benzoylamino}-propionic acid methyl ester
3-{4-[l-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid
methyl ester (350 mg, 0.75 mmol), potassium carbonate (311 mg, 2.25 mmol), 4-
triflouromethoxylphenyl boronic acid (311 mg, 1.5 mmol) and tetrakis-
(triphenylphosphine)palladium (87 mg, 0.075 mmol) are place in a flask. After the
reaction is purged with N2 for several times, THF/H2O (20ml/5ml) is added. The resulting
solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to
give 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-
benzoylamino}-propionic acid methyl ester (294 mg) as a yellow solid.
Step D. Racemic 3-(4-{l-[4'-(l-Fluoro-ethoxy)-biphenyI-4-ylsulfanyI]-3-methyl-
butyl}-benzoylamino)-propionic acid
To a mixture of 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-
butyl]-benzoylamino}-propionic acid methyl ester (20 mg) in methanol (2 mL) is added
sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is
concentrated and acidified by 5 N HC1 (0.5 mL), extracted with ethyl acetate. Combined
organic layers are washed with water and brine, dried over sodium sulfate. Concentration
gives the title compound (18 mg). MS (ES): 531.2 [M-H]~.
The following compounds are made in a substantially substantially similar manner:
Example 25
Racemic 3-{4-[l-(3',4'-dimethyI-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 3,4-dimethylphenyl boronic acid as starting material in step C. MS (ES): 477.2
[M+H]+.
Example 26
Racemic 3-{4-[l-(4'-cyano-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-cyanophenyl boronic acid as starting material in step C. MS (ES): 472.2 [M+H]+.
Example 27
Racemic 3-{4-[l-(4'-Isobutyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-isobutylphenyl boronic acid in step C. MS (ES): 505.2 [M+H]+.
Example 28
Racemic 3-(4-{l-[4-(6-Methoxy-pyridin-3-yl)-phenylsuIfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-methoxy-pyridin-3-yI boronic acid as starting material in step C. MS (ES): 480.2
[M+H]+.
Example 29
Racemic 3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-( 1-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromophenol as reagents in
step A and 4-ethylphenyl boronic acid in step C. MS (ES): 488.3 [M+H]+.
Example 30
3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 1
O
Chiral Separation: The racemic 3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-
benzoylaminoj-propionic acid methyl ester was resolved on a Chiralpak AD column (4.6
x 150 mm). Eluted with Isopropyl Alcohol/Heptane (30/70) and concentrated the
fractions to provide a purified enantiomer ester (isomer 1, 100 % ee). Hydrolysis of the
purified enantiomer of the ester provided the title compound as a white solid. MS (ES):
476.3 [M+H]+.
The following enantiomerically purifiedcompounds were obtained by substantially
similar chiral separation using Chiralpak AD column (4.6 x 150 mm) or Chiralcel OJ
column (4.6 x 250 mm):
Example 31
3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 2
O
This compound is made by the general method as exemplified in Example 30 by
resolving racemic 3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid
methyl ester on Chiralpak AD column (4.6 x 150 mm). MS (ES): 476.3 [M+H]+.
Example 32
) 3-{4-f3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 33
3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[3-methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 500.3 [M+H]+. Isomer 2 MS (ES): 500.3 [M+H]+.
Example 34
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 35
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 470.2 [M-H]". Isomer 2 MS (ES): 470.2 [M-H]Example 36
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-propyI]-benzoylamino}-propionic acid,
Isomer 1
and
Example 37
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yIoxy)-propyl]-benzoylamino}-propionic acid,
Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 458.3 [M-H]'. Isomer 2 MS (ES): 458.3 [M-H]".
Example 38
3-{4-[l-(4f-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 39
3-{4-[l-(4'-tert-ButyI-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm). Isomer 1 MS (ES):
516.3 [M+Hf. Isomer 2 MS (ES): 516.3 [M+H]+.
Example 40
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 41
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 488.3 [M+H]+. Isomer 2 MS (ES): 488.3 [M+H]+.
Example 42
3-{4-[l-(4'-TrifIuoromethyI-biphenyI-4-ylsuIfanyl)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 43
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yIsulfanyl)-heptyl]-benzoylamino}-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-
benzoylaminoj-propionic acid methyl ester on Chiralcel OD column (4.6 x 150 mm).
Isomer 1 MS (ES): 543.2 [M-H1~. Isomer 2 MS (ES): 543.2 [M-H]".
Example 44
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoyIamino}-propionic acid,
Isomer 1
and
Example 45
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic acid,
Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-tert-ButyI-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm). Isomer 1 MS (ES):
489.44 [M+H]+. Isomer 2 MS (ES): 489.44 [M+H]+.
Example 46
3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoyIamino}-
propionic acid, Isomer 1
and
Example 47
3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 486.2 [M+H]+, Isomer 2 MS (ES): 486.2 [M+H]+.
Example 48
3-{4-[l-(4'-TrifluoromethyI-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 49
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 2
O
This compound is made by the general method as exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid methyl ester on Chiralcel OJ column (4.6 x 150 mm). Isomer 1 MS (ES):
501.2 [M+H]+. Isomer 2 MS (ES): 501.2 [M+H]+.
Example 50
3-{4-[l-(4'-TrifluoromethyI-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 51
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyI]-benzoylaniino}-propionic acid,
Isomer 2
O
These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylaminoj-propionic acid methyl ester on Chiralcei OJ column (4.6 x 150 mm).
Isomer 1 MS (ES): 486.2 [M+Hf. Isomer 2 MS (ES): 486.2 [M+H]+.
Example 52
3-{4-[l-(4'-tert-Butyl-biphenyI-4-yIoxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 53
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yIoxy)-butyl]-benzoylamino}-propionic acid,
Isomer 2
These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm). Isomer 1 MS (ES):
475.2 [M+Hf. Isomer 2 MS (ES): 475.2 [M+H]+.
Example 54
3-(4-{l-[4'-(l-Fluoro-l-methyl-ethyl)-biphenyI-4-yIsulfanyl)-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 55
3-(4-{l-[4'-(l-Fluoro-l-methyl-ethyl)-biphenyl-4-yIsuIfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-(4-{l-[4'-(l-fluoro-l-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-
methyl-butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD column (4.6
x 150 mm). Isomer 1 MS (ES): 517.3 [M+H]+. Isomer 2 MS (ES): 517.3 [M+H]+.
Example 56
3-(4-{3-Methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyI}-
benzoylamino)-propionic acid, Isomer 1
and
Example 57
3-(4-{3-MethyI-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-(4-{3-methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-
butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD column (4.6 x 150
mm). Isomer 1 MS (ES): 501.2 [M+H]+. Isomer 2 MS (ES): 501.2 [M+H]+.
Example 58
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yIoxy)-nonyl]-benzoyIamino}-propionic acid,
Isomer 1
and
Example 59
3-{4-[l-(4'-TrifluoromethyI-biphenyl-4-yIoxy)-nonyl]-benzoylamino}-propionic acid,
Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-nonyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm).
Isomer 1 MS (ES): 554.2 [M-H]\ Isomer 2 MS (ES): 554.2 [M-H]".
Example 60
3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid, Isomer 1
and
Example 61
3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-propionic acid, Isomer 2

These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(4'-ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD column (4.6 x 150 mm). Isomer 1 MS (ES):
488.3 [M+H]+. Isomer 2 MS (ES): 488.3 [M+H]+.
Example 62
3-(4-{l-[6-(4-tert-Butyl-phenyI)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid, Isomer 1

Step A. 3-(4-Formyl-benzoyIamino)-propionic acid methyl ester
4-formyl-benzoic acid (20 g, 133 mmol), CDMT (24 g, 137 mmol), and 4-methyl-
morpholine (15.4 tnL, 140 mmol) are combined in anhydrous dichloromethane (DCM)
(300 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room
temperature overnight. Beta-alanine methyl ester hydrochloride (20.4 g, (147 mmol) is
then added to the reaction mixture, followed by 4-methylmorpholine (15.4 mL, 140
mmol), and allowed to stir at room temperature. Some water (<10% volume) is added to
help solubility. The reaction is monitored by HPLC, and upon complete consumption of
the acid, the reaction is diluted with DCM. The reaction is diluted with water and
extracted with IN HC1. The organic layer is washed with water and brine, followed by
drying over anhydrous sodium sulfate. The solution is filtered and concentrated and
further purified using flash column chromatography (30 g, 128 mmol).
Step B. 3-[4-(l-Hydroxy-4,4-dimethyl-pentyI)-benzoyIamino]-propionic acid methyl
ester
A solution of 3-(4-Formyl-benzoylamino)-propionic acid methyl ester (4.8 g,
20.43 mmol) is dissolved in the anhydrous tetrahydrofuran (THF) (75 mL) and cooled to
0 °C under nitrogen. 2,2-Dimethyl-butyl magnesium bromide (16.3 mL, 1.5M solution in
THF, 24.5 mmol) is then added slowly to the solution by addition funnel. The reaction is
allowed to stir at 0 °C for 1 hour and the ice bath is removed. The reaction is monitored
by TLC or HPLC to determine complete consumption of the aldehyde. The reaction is
cooled back down to 0 °C and 1 .ON hydrogen chloride solution is dropped in to quench.
The solids are dissolved with enough water and the solution is diluted with ether. The
two phases are separated and the organic layer is washed with brine, dried over anhydrous
sodium sulfate and concentrated. The alcohol (1.6 g, 4.98 mmol) is purified by column
chromatography.
Step C. 3-{4-[l-(6-ChIoro-pyridin-3-yIoxy)-4,4-dimethyl-pentyl]-benzoylamino}-
propionic acid methyl ester
3-[4-(l-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid methyl ester
(546 mg, 1.7 mmol) and 6-chloro-pyridin-3-ol (270 mg, 2.09 mmol) are combined in
anhydrous toluene (10 mL), degassed, filled with nitrogen for 3 times, and cooled in an
ice bath. Tributylphosphine (TBP) (630 uL, 2.55 mmol) is added to the reaction mixture
under nitrogen at 0 °C, followed by addition of 1,1 '-(azodicarbonyl)-dipiperidine(ADDP)
(643 mg, 2.55 mmol). The reaction mixture is allowed to warm to room temperature and
stirred over night, the mixture is loaded on silica gel column. Chromatography gave the
title compound (722 mg, 1.67 mmol).
Step D. 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid methyl ester
To a solution of 3-{4-[l-(6-chloro-pyridin-3-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid methyl ester (84 mg, 0.19 mmol) in toluene:water (1:1) (2
mL) is added palladium tetrakis triphenylphosphine (22.47 mg, 0.1 rnol%), 4-tert-
butylphenylboronic acid (58 mg, 0.39 mmol). The reaction is purged with nitrogen and
heated to reflux and the potassium fluoride (23 mg, 0.39 mmol) is added. The reaction is
monitored by HPLC, and upon completion, allowed to cool to room temperature. The
reaction is diluted with ethyl acetate and then Celite is added, followed by water. This
mixture is then filtered through a pad of Celite. The solution is separated in a seperatory
funnel and the organic layer is washed with 0.1N sodium hydoxide, water, and brine. The
organic layer is dried over anhydrous sodium sulfate and concentrated. The 5-(4-{l-[6-
(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-phenyl)-5-oxo-pentanoic
acid methyl ester (80 mg, 0.15 mmol) is purified by flash column chromatography.
Step E. Chiral separation
The racemic 3-(4-{ l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-
pentyl}-phenyl)-5-oxo-pentanoic acid methyl ester is resolved on a Chiralpak AD-H
column (4.6 x 150 mm). Eluted with Isopropyl Alcohol/Heptane (30/70) and
concentrated the fractions to provide a purified enantiomer ester (isomer 1, 98.6 % ee).
Step F. 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yIoxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid
3-(4-{l-[6-(4-tert-Butyl-phenyI)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid methyl ester (isomer 1, 80 mg, 0.15 mmol) is dissolved in
the tetrahydrofuran (1 mL) and sodium hydroxide solution (5 M, 1.0 mL, 5 mmol) is
added. The reaction is monitored by HPLC, and upon complete conversion, the reaction
is neutralized with 5N HC1, diluted with diethyl ether and water. The two phases are
separated, and the organic layer is washed, dried, and concentrated. The title compound
is used without further purification. MS (ES): 515.2 [M-H]", the structure was also
confirmed by proton NMR.
Example 63
Racemic 3-(4-{l-[6-(4-TrifluoromethyI-phenyl)-pyridin-3-yloxy]-heptyl}-
benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 62
using pentylmagnesium chloride in step B and 4-trifluromethyl phenyl boronic acid in
step D as starting materials, without chiral separation in step E. MS (ES): 527.3 [M-H]",
the structure was also confirmed by proton NMR.
Example 64
Racemic 3-(4-{4,4,4-Trifluoro-l-[6-(4-trifluoromethyI-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 62
using 3,3,3-trifluropropylmagnesium bromide in step B and 4-trifluromethyl phenyl
boronic acid in step D as starting materials, without chiral separation in step E. MS (ES):
539.2 [M-H]', the structure was also confirmed by proton NMR.
Example 65
Racemic 3-(4-{3-Methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid
This compound is made by the general method as exemplified in Example 62
using isobutylmagnesium chloride in step B and 4-trifluromethyl phenyl boronic acid in
step D as starting materials, and without chiral separation in step E. MS (ES): 499.3
[M-H]", the structure was also confirmed by proton NMR.
Example 66
Racemic 3-(4-{4,4-DimethyI-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl}-benzoylamino)-propionic acid
O
This compound is made by the general method as exemplified in Example 62
using 3,3-dimethylbutyl magnesium bromide in step B and 4-trifluromethyl phenyl
boronic acid in step D as starting materials without chiral separation in step E. MS (ES):
527.2 [M-H]', the structure was also confirmed by proton NMR.
Example 67
Racemic 3-(4-{l-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yI]-butoxy}-
benzoylamino)-propionic acid
O
This compound is made by the general method as exemplified in Example 62
using pentylmagnesium chloride in step B and 4-trifluromethyl phenyl boronic acid in
step D as starting materials without chiral separation in step E. MS (ES): 485.2 [M-H]",
the structure was also confirmed by proton NMR.
Example 68
Racemic 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-
benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 62
using 3,3,3-trifIuropropylmagnesium chloride in step B and 4-tert-butylphenyl boronic
acid in step D as starting materials. MS (ES): 527.3 [M-H]~, the structure was also
confirmed by proton NMR.
Example 69
Racemic 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-3-methyl-butyI}-
benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 62
using isobutylmagnesium chloride in step B and 4-tert-butylphenyl boronic acid in step D
as starting materials. MS (ES): 487.3 [M-H]", the structure was also confirmed by proton
NMR.
Example 70
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid, enantiomer 2

The racemic 3-(4-{ l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyI-
pentyl}-benzoylamino)-propionic acid methyl ester (80 mg, 0.15 mmol) is resolved on a
Chiralpak AD-H column (0.46 x 15 cm) with a flow rate of 0.6mL/min. and detection at
260nm. Elute with isopropyl alcohol in heptane and concentrate the fractions to provide a
purified enantiomer ester (isomer 2, 99.9% ee). Hydrolysis of the enantiomer of the ester
provided the title compound as a white solid. MS (ES): 517.3 [M+H]+, 515.2 [M-H]", the
structure was also confirmed by proton NMR.
Example 71
3-(4-{l-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-benzoylamino)-
propionic acid, Isomer 1
and
Example 72
3-(4-{l-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-benzoyIamino)-
propionic acid, Isomer 2
These compounds are made by the general method as exemplified in Example 70
by resolving racemic 3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-
benzoylamino)-propionic acid methyl ester on a Chiralpak AD-H column (4.6 x 150 mm)
with a flow rate of 0.6 mL/min. and detection at 260nm. Elute with acetonitrile in 3A
alcohol (isomer 2, 99.9% ee). Isomer IMS (ES): 527.2 [M-H]~, the structure was also
confirmed by proton NMR; Isomer 2 MS (ES): 527.2 [M-H]\ the structure was also
confirmed by proton NMR.
Example 73
3-(4-{4,4,4-Trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 74
3-(4-{4,4,4-Trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyI}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method as exemplified in Example 70
by resolving racemic 3-(4-{4,4,4-trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid methyl ester on a Chiralpak AD-H column
(4.6 x 150 mm) with a flow rate of 0.6 mL/min. and detection at 260nm. Elute with
acetonitrile in 3A alcohol (isomer 2, 99.8% ee). Isomer IMS (ES): 539.2 [M-H]\ the
structure was also confirmed by proton NMR; Isomer 2 MS (ES): 539.2 [M-H]~, the
structure was also confirmed by proton NMR.
Example 75
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoyIamino)-propionic
acid, Isomer 1
and
Example 76
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy)-butyl}-benzoyIamino)-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 70
by resolving racemic 3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid methyl ester on a Chiralpak AD-H column (0.46 x 15 cm)
with a flow rate of 0.6 mL/min. and detection at 260nm. Eluted with isopropyl alcohol in
heptane (isomer 2, >99% ee). MS (ES): 473.2 [M-H]~, the structure was also confirmed
by proton NMR; MS (ES): 473.2 [M-H]\ the structure was also confirmed by proton
NMR.
Example 77
Racemic 3-(4-{l-[6-(4-Isobutyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-
propionic acid

This compound is made by the general method as exemplified in Example 62
using propylmagnesium chloride in step B and 4-isobuphenyl boronic acid in step D as
starting materials, without chiral separation in step E. MS (ES): 473.4 [M-H]\ the
structure was also confirmed by proton NMR.
Example 78
Racemic 3-{4-[l-(3'-Trifluoromethyl-biphenyl-4-yIsulfanyl)-heptyl]-benzoylamino}-
propionic acid
H3C-
Step A. 4-[l-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid
To a solution of 4-(l-hydroxy-3-methyl-heptyl)-benzoic acid methyl ester (1760
mg, 7.04 mmol) in toluene (70 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP,
2664 mg, 10.56 mmol) at 0 °C, followed by the additions of tributylphosphine (2.63 mL,
8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The reaction mixture is
warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel,
eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of ethyl acetate
giving 4-[l-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl ester. 1700 mg of the
ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2
mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate,
acidified with 5 N HC1 (2 mL), and extracted with ethyl acetate. The organic layers are
dried and concentrated giving 4-[l-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic
acid (1700 mg).
Step B. Racemic 3-{4-[l-(4-Bromo-phenylsulfanyl)-3-methyI-heptyl]-
benzoylamino}-propionic acid methyl ester
To a mixture of 4-[l-(4-bromo-phenylsuIfanyl)-3-methyl-hepyl]-benzoic acid
(1700 mg, 4.18 mmol) in methylene chloride (42 mL) are added triethyl amine (1.75 mL,
12.53 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (875 mg, 6.27 mmol)
and EDCI (2408 mg, 12.53 mmol) at room temperature. The reaction mixture is stirred at
room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a
gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving 3-{4-[l-(4-bromo-
phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic acid methyl ester (1640 mg).
Step C. Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyl-4-ylsiilfanyl)-
heptyl]-benzoylamino}-propionic acid
3-{4-[l-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic
acid methyl ester (100 mg, 0.2 mmol), potassium carbonate (83 mg, 0.6 mmol), 3-
triflouromethoxylphenyl boronic acid (76 mg, 0.4 mmol) and tetrakis-
(triphenylphosphine)palladium (23 mg, 0.02 mmol) are placed in a flask. After the
reaction is purged with N2 for several times, THF/H2O (20 ml/ 5 ml) is added. The
resulting solution is refluxed overnight, concentrated, diluted with ethyl acetate, acidified
with 1 N HC1 (0.6 mL), extracted with ethyl acetate. The organic layers are dried and
purified with reverse phase HPLC to afford the title compound (58 mg). MS (ES): 544.1
[M+H]+.
Example 79
Racemic 3-{4-[l-(4'-Acetyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-propionic
acid
This compound is made in a substantially similar manner as Example 78 using 4-
acetylphenyl boronic acid as reagent in step C. MS (ES): 518.3 [M+H]+.
Example 80
Racemic 3-{4-[l-(3',4'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid
This compound is made in a substantially similar manner as Example 78 using
3,4-dimethylphenyl boronic acid as reagent in step C. MS (ES): 504.3 [M+H]+.
Example 81
Racemic 3-{4-[l-(4'-methylsulfonyl-biphenyl-4-yIsulfanyl)-heptyl]-benzoylamino}-
propionic acid

This compound is made in a substantially similar manner as Example 78 using 4-
methylsulfonylphenyl boronic acid as reagent in step C. MS (ES): 554.3 [M+H]+.
Example 82
Racemic 3-{4-[l-(2',3'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid

This compound is made in a substantially similar manner as Example 78 using
2,3-dimethylphenyl boronic acid as reagent in step C. MS (ES): 504.2 [M+H]+.
Example 83
Racemic 3-{4-[l-(2',6'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid

This compound is made in a substantially similar manner as Example 78 using
2,6-dimethylphenyl boronic acid as reagent in step C. MS (ES): 504.2 [M+H]+.
Example 84
Racemic 3-{4-[l-(3'-isopropyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid

This compound is made in a substantially similar manner as Example 78 using 3-
isopropylphenyl boronic acid as reagent in step C. MS (ES): 518.3 [M+H]+.
Example 85
Racemic 3-{4-[l-(3'-acetyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-propionic
acid

This compound is made in a substantially similar manner as Example 78 using
3-acetylphenyl boronic acid as reagent in step C. MS (ES): 518.3 [M+H]+.
Example 86
Racemic 3-{4-[l-(4'-pentyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-propionic
acid

This compound is made in a substantially similar manner as Example 78 using
4-pentylphenyl boronic acid as reagent in step C. MS (ES): 546.3 [M+H]*Example 87
Racemic 3-{4-[l-(4'-cyclohexyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid

This compound is made in a substantially similar manner as Example 78 using 4-
cyclohexylphenyl boronic acid as reagent in step C. MS (ES): 558.3 [M+H]+.
Example 88
Racemic 3-{4-[l-(4-AUyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid

This compound is made in a substantially similar manner as Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-allyloxy-phenol as reagents in step A.
MS (ES): 438.3 [M-H]'.
Example 89
Racemic 3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
bcnzoylaminoj-propionic acid

This compound is made in a substantially similar manner as Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 2,2,3,3-tetrafluoro-2,3-dihydro-
benzo[l,4]dioxin-6-ol as reagents in step A. MS (ES): 514.2 [M+H]+.
Example 90
Racemic 3-(4-{l-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyI}-benzoylamino)-
propionic acid

This compound is made in a substantially similar manner as Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-(4-trifluoromethyl-phenoxy)-phenol
as reagents in step A. MS (ES): 544.2 [M+H]+.
Example 91
Racemic 3-{4-[l-(4-Pentyl-phenoxy)-heptyl]-benzoylamino}-propionic

This compound is made in a substantially similar manner as Example 1 using 4-
(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-pentylphenol as reagents in step A.
MS (ES): 454.2 [M+H]+.
Example 92
Racemic 3-(4-{l-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid
Step 1.
Racemic 3-{4-[l-(4-Allyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester (1.59 g, 3.51 mmol) and triphenyl-phosphine tetrakis palladium(203 mg,
0.18 mmol) are combined with anhydrous tetrahydrofuran (10 mL) in a round bottom
flask under nitrogen. Diethyl amine (712 uL, 7.02 mmol) is added and the reaction is
allowed to stir under nitrogen at room temperature. The reaction is monitored by HPLC,
and upon complete conversion, the reaction is quenched with water. The reaction is
diluted with diethyl ether and rinsed with IN HC1, water, and brine. The ether layer is
dried over anhydrous sodium sulfate and concentrated. Racemic 3-{4-[l-(4-Allyloxy-
phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester (1.47 g, 3.50 mmol) is
obtained pure after column chromatography.
Step 2.
To 3-{4-[l-(4-Hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester (70 mg, 0.17 mmol) in anhydrous dimethyl formamide (1.0 mL) is added cesium
carbonate (110 mg, 0.34 mmol) in one portion. The mixture is allowed to stir under
nitrogen at room temperature and 4-tert-butyl-benzyl bromide is added. The reaction is
allowed to stir at room temperature for several hours and is monitored by HPLC. Upon
complete consumption of starting material, the reaction is carefully quenched with water,
extracted with ethyl acetate, washed, dried, and concentrated. 3-(4-{l-[4-(4-tert-Butyl-
benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propionic acid methyl ester is purified by
column chromatography.
Step 3.
The 3-(4-{ 1 -[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid methyl ester is dissolved in the THF (1.0 mL) and 5N NaOH (1.0 mL) is
added. The mixture is heated to reflux under nitrogen and monitored by HPLC. Upon
complete conversion, the reaction is neutralized with 5N HC1 (1.0 mL), diluted with
diethyl ether and water. The two phases are separated and the organic layer is washed,
dried, and concentrated to provide the title compound (80 mg, 0.15 mmol). MS (ES):
544.2 [M-H]~.
Example 93
Racemic 3-(4-{l-[4-(3,5-bistrifluoromethyl-benzyloxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid

This compound is made in a manner substantially similar to Example 92 using
3,5-bistrifluoromethyl-benzyl bromide. MS (ES): 624.2 [M-H]Example 94
Racemic 3-(4-{l-[4-(4-isopropyl-benzyloxy)-phenoxy]-heptyI}-benzoylamino)-
propionic acid

This compound is made in a manner substantially similar to Example 92 using 4-
isopropylbenzyl bromide. MS (ES): 530.2 [M-H]".
Example 95
Racemic 3-(4-{l-[4-(4-chloro-benzyloxy)-phenoxy]-heptyl}-benzoyIamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 4-
chlorobenzyl bromide. MS (ES): 522.2 [M-H]".
Example 96
Racemic 3-(4-{l-[4-(4-ethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 4-
ethylbenzyl bromide. MS (ES): 516.3 [M-H]".
Example 97
Racemic 3-(4-{l-[4-(4-bromo-benzyloxy)-phenoxy]-heptyI}-benzoyIamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 4-
bromobenzyl bromide. MS (ES): 566.2 [M-H]".
Example 98
Racemic 3-(4-{l-[4-(4-fluoro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 4-
fluorobenzyl bromide. MS (ES): 506.2 [M-H]'.
Example 99
Racemic 3-(4-{l-[4-(4-trifluoromethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid

This compound is made in a manner substantially similar to Example 92 using 4-
trifluoromethylbenzyl bromide. MS (ES): 556.3 [M-H]~.
Example 100
Racemic 3-(4-{l-[4-(4-phenyl-benzyloxy)-phenoxy]-heptyl}-benzoyIamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 4-
phenylbenzyl bromide. MS (ES): 564.3 [M-H]Example 101
Racemic 3-(4-{l-[4-(3-chIoro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propionic
acid

This compound is made in a manner substantially similar to Example 92 using 3-
chlorobenzyl bromide. MS (ES): 522.2 [M-H]Example 102
Racemic 3-(4-{l-[4-(3,4-dimethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid

This compound is made in a manner substantially similar to Example 92 using
3,4-dimethylbenzyl bromide as reagent. MS (ES): 516.3 [M-H]~.
Example 103
Racemic 3-(4-{l-[4-(4-isopropoxyphenoxy]-heptyl}-benzoylamino)-propionic acid
This compound is made in a manner substantially similar to Example 92 using 4-
isopropyl iodide. MS (ES): 440.2 [M-H]".
Example 104
Racemic 3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromophenol as reagents in
Step A and 3,5-bitrifluoromethylphenyl boronic acid in Step C as starting materials. MS
(ES): 594.2 [M-H]".
Example 105
Racemic 3-{4-[l-(4'-tert-ButyI-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4'-tert-butyl-biphenyl-4-ol and 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl
ester in step A as starting materials. MS (ES): 516.3 [M+H]+.
Example 106
Racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid
This compound is made by the general method as exemplified in Example 1 using
4'-trifluoromethyl-biphenyl-4-ol and 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester in step A as starting materials. MS (ES): 526.2 [M-H]Example 107
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-
propionic acid
O
This compound is made by the general method as exemplified in Example 1 using
4'-tert-butyl-biphenyl-4-ol and 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester
in step A as starting materials. MS (ES): 474.2 [M+H]+.
Example 108
Racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid
O
This compound is made by the general method as exemplified in Example 1 using
4'-trifluoromethyl-biphenyl-4-ol and 4-(l-hydroxyhexyl)-benzoic acid methyl ester in
step A as starting materials. MS (ES): 512.3 [M-H]Example 109
3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
Chiral Separation:
The racemic 3-{4-[l-(4-benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic
acid methyl ester is resolved on a Chiralpak AD-H column (4.6 x 150 mm). Elute with
Isopropyl Alcohol/Heptane (15/85 ) and concentrate the fractions to provide a purified
enantiomer ester (isomer 1, >99 % ee). Hydrolysis of the purified enantiomer of the ester
provided the title compound as a white solid. MS (ES): 594.2 [M-H]Example 110
3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
O
This compound is made by the general method as exemplified in Example 109 by
resolving racemic 3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm)
eluted with Isopropyl Alcohol/Heptane (15/85 ). MS (ES): 594.2 [M-H]".
Example 111
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 112
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyI-butyl]-benzoyIamino}-propionic acid,
Isomer 2

These compounds are made by the general method as exemplified in Example 109
by resolving racemic 3-{4-[l-(4-tert-butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm) eluted with
Methanol (100%). Isomer 1 MS (ES): 412.3 [M+H]+; Isomer 2 MS (ES): 412.3 [M+H]+.
Example 113
3-{4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic
acid, Isomer 1
or
Example 114
3-{4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 109
by resolving racemic 3-{4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm)
eluted with Isopropyl Alcohol/Heptane (50 /50 ). Isomer 1 MS (ES): 474.2 [M+H]+.
Isomer 2 MS (ES): 474.2 [M+H]+.
Example 115
3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 116
3-{4-[l-(4'-trifluoromethyI-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method as exemplified in Example 109
by resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyI]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm)
eluted with Propyl Alcohol (100% ). Isomer IMS (ES): 526.2 [M-H]\ Isomer 2 MS (ES):
526.2 [M-H]Example 117
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yIoxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
Step A. Racemic 4-[l-(4-Bromo-phenoxyl)-heptyl]-benzoic acid
To a solution of 4-(l-hydroxy-heptyl)-benzoic acid methyl ester (1800 mg, 7.2
mmol) in toluene (72 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP, 2725 mg,
10.8 mmol) at 0 °C, followed by the additions of tributylphosphine (2.69 mL, 10.8 mmol)
and 4-bromo-phenol (1503 mg, 8.64 mmol). The reaction mixture is warmed up to room
temperature and stirred overnight. The mixture is loaded on silica gel, eluted with
hexanes with a gradient from 0 % of ethyl acetate to 50 % of ethyl acetate giving 4-[l-(4-
bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. 1900 mg of the ester product is taken
into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N
HC1 (2 mL), and extracted with ethyl acetate. The organic layers are dried and
concentrated giving 4-[l-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1800 mg).
Step B. Racemic 3-{4-[l-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester
To a mixture of 4-[l-(4-bromo-phenoxyl)-heptyI]-benzoic acid (1700 mg, 4.35
mmol) in methylene chloride (43 mL) are added triethyl amine (1.82 mL, 13.4 mmol),
DMAP (5.0 mg), 3-amino-propionic acid methyl ester (910 mg, 6.52 mmol) and EDCI
(2507 mg, 13.04 mmol) at room temperature. The reaction mixture is stirred at room
temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a
gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving racemic 3-{4-[l-(4-
bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (1660 mg).
Step C. 3-{4-[l-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl
ester, isomers 1 and 2
The racemic 3-{4-[l-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester was resolved on a Chiralpak AD-H column (4.6 x 150 mm). Elute with
Isopropyl Alcohol/Heptane (50 /50 ) and concentrated the fractions to provide a purified
enantiomer ester (isomer 1, 99.5 % ee, isomer 2, 94.6 % ee).
Step D. 3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yIoxy)-heptyl]-benzoyIamino}~
propionic acid methyl ester, isomer 1
3-{4-[l-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester
(isomer 1, 100 mg. 0.21 mmol), potassium carbonate (85 mg, 0.63 mmol),
4-triflouromethoxylphenyl boronic acid (86 mg, 0.42 mmol) and tetrakis-
(triphenylphosphine)palladium (24 mg, 0.021 mmol) are place in a flask. After the
reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The
resulting solution is refluxed overnight, concentrated and acidified by 1 N HC1 (0.6 mL),
extracted with ethyl acetate. Combined organic layers are washed with water and brine,
dried over sodium sulfate, purified by reverse phase HPLC to give the title compound
(40 mg). MS (ES): 526.2 [M-H]".
Example 118
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2

This compound is made in a substantially similar manner as Example 117 using
isomer 2 of 3-{4-[l-(4-bromo-phenoxyI)-heptyl]-benzoylamino}-propionic acid methyl
ester as starting material in step D. MS (ES): 526.2 [M-H]Example 119
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-propionic
acid, Isomer 1
or
Example 120
3-{4-[l-(4'-Trifluoromethyl-biphenyI-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
These compounds are made by the general method as exemplified in Example 117
using isomer 2 of 3-{4-[l-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester and triflouromethylphenyl boronic acid as starting materials in step D.
Isomer 1 MS (ES): 528.3 [M+H]+; Isomer 2 MS (ES): 528.3 [M+H]+.
Example 121
3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 122
3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 2

This compound is made by the general method as exemplified in Example 109 by
resolving racemic 3-{4-[l-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yIoxy)-
heptyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm) eluted with Propyl Alcohol/Heptane (15/85 ). Isomer 1 MS (ES): 512.3 [M-H]";
Isomer 2 MS (ES): 514.2 [M+H]+.
Example 123
3-(4-{l-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylamino)-propionic
acid, Isomer 1
and
Example 124
3-(4-{l-[4-(4-Trifluoromethyl-phenoxy)-phenoxy)-heptyI}-benzoyIamino)-propionic
acid, Isomer 2

These compounds are made by the general method as exemplified in Example 109
by resolving racemic 3-(4-{l-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm)
eluted with Propyl Alcohol/Heptane (15 /85 ). Isomer 1 MS (ES): 542.3 [M-H]". Isomer 2
MS (ES): 542.3 [M-H]".
Example 125
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionicacid,
Isomer 1
and
Example 126
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyI]-benzoylamino}-propionic acid,
Isomer 2
These compounds are made by the general method as exemplified in Example 109
by resolving racemic 3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-
benzoylamino}-propionic acid methyl ester on Chiralcel OJ-H column (4.6 x 150 mm)
eluted with MeOH (100% ). Isomer 1 MS (ES): 512.3[M-H]\ Isomer 2 MS (ES):
512.3[M-H]Example 127
3-(4-{l-[4'-isopropyI-biphenyl-4-ylsulfanyl]-butyl}-benzoylamino)-propionic acid,
Isomer 1
This compound is made in a substantially similar manner as Example 117 using 4-
(l-hydroxy-butyl)-benzoic acid methyl ester as starting material in step A and 4-
isopropyphenylboronic acid as reagent in step D. MS (ES): 460.2 [M+H]+.
Example 128
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyI-4-yloxy)-heptyI]-
benzoylamino}-propionic acid

Step A. Racemic 4-[l-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid
To a solution of 4-( 1-hydroxy-heptyl)-benzoic acid methyl ester (1000 mg, 4.0
mmol) in toluene (40 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP, 1514mg, 6.0
mmol) at 0 °C, followed by the additions of tributylphosphine (1.49 mL, 6.0mmol) and 4-
bromo-3,5-dimethyl-phenol (965 mg, 4.8 mmol). The reaction mixture is warmed up to
room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with
hexanes with a gradient from 0 % of ethyl acetate to 50 % of ethyl acetate giving 4-[l-(4-
bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. The ester product (1800 mg) is taken
into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 5 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N
HCI (5 mL), extract with ethyl acetate. The organic layers are dried and concentrated
giving 4-[l-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg).
Step B. Racemic 3-{4-[l-(4-Bromo-3,5-dimethyI-phenoxyl)-heptyI]-benzoylamino}-
propionic acid methyl ester
To a mixture of 4-[l-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid
(1790 mg, 4.27 mmol) in methylene chloride (43 mL) are added triethyl amine (1.79 mL,
12.82 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (895 mg, 6.4 mmol)
and EDCI (2463 mg, 12.8 mmol) at room temperature. The reaction mixture is stirred at
room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a
gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving racemic 3-{4-[l-(4-
bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (945
mg).
Step C. Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-
heptyl]-benzoylamino}-propionic acid
3-{4-[l-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester (isomer 1, 100 mg, 0.2 mmol), potassium flouride (35 mg, 0.6 mmol), 4-
triflouromethoxylphenyl boronic acid (83 mg, 0.4 mmol) and
tetrakis(triphenylphosphine)palladium (23 mg, 0.02mmol) are place in a flask. After the
reaction is purged with N2 for several times, Toluene/H2O (20 ml/5 ml) is added. The
resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl
acetate to give 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, (105 mg).
Step D. 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid
To a mixture of 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-
heptyl]-benzoylamino}-propionic acid methyl ester (105 mg) in methanol (2 mL) is added
sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is
concentrated and acidified by 5 N HCI (0.5 mL), extracted with ethyl acetate. Combined
organic layers are washed with water and brine, dried over sodium sulfate. Concentration
gives the title compound (114 mg). MS (ES): 572.3 [M+Hf.
Example 129
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid

This compound is made in a substantially similar manner as Example 128 using 4-
trifluoromethylphenyl boronic acid as reagent in step C. MS (ES): 554.2 [M-H]~.
Example 130
Racemic 3-{4-[l-(2,6-Dimethyl-4'-tertbutyl-biphenyl-4-yIoxy)-heptyl]-
benzoylaminoj-propionic acid

This compound is made in a substantially similar manner as Example 128 using 4-
tertbutylphenyl boronic acid as reagent in step C. MS (ES): 542.3 [M-H]~.
Example 131
3-{4-[l-(4Mert-Butyl-biphenyl-4-yIoxy)-3-methyI-butyl]-benzoylamino}-2(R)-
hydroxy-propionic acid

Step A. 4-[l-(4'-tertbutyl-biphenyI-4-yloxy)-3-methyl-butyl]-benzoic acid
To a solution of racemic 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester
(300 mg, 1.35 mmol) in toluene (14 mL) is added l,l'-(azodicarbonyl)dipiperidine
(ADDP, 512 mg, 2.03 mmol) at 0 °C, followed by the addition of tributylphosphine (0.5
mL, 2.03 mmol) and 4'-tert butyl-biphenyI-4-oI (367 mg, 1.62 mmol). The reaction
mixture is warmed up to room temperature and stirred overnight. The mixture is loaded
on silica gel, eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of
ethyl acetate giving 4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid
methyl ester. The ester product is taken into ethanol (5 mL), treated with sodium
hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated,
diluted with ethyl acetate, acidified with 5 N HC1 (1 mL), extract with ethyl acetate. The
organic layers are dried and concentrated giving 4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-3-
methyl-butyl]-benzoic acid (400 mg).
Step B. 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
2(R)-hydroxy-propionic acid methyl ester
To a mixture of 4-f l-(4'-tertbutyl-biphenyl-4-yloxy)-3-rnethyl-butyI]-benzoic acid
(120 mg) in methylene chloride (3 mL) are added triethyl amine (0.12 mL, 0.87 mmol),
DMAP (5 mg), 3-Amino-2( R)-hydroxy-propionic acid methyl ester (67.3 mg, 0.43
mmol) and EDCI (166 mg, 0.87 mmol) at room temperature. The reaction mixture is
stirred at room temperature overnight, loaded on silica gel, eluted with eluted with
hexanes with a gradient from 0 % of ethyl acetate to 100 % of ethyl acetate giving 3-{4-
[l-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-hydroxy-
propionic acid methyl ester (60 mg).
Step C. 3-{4-[l-(4'-tert-Butyl-biphenyI-4-yloxy)-3-methyl-butyl]-benzoylamino}-
2(R)-hydroxy-propionic acid
To a mixture of 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoyIamino}-2(R)-hydroxy-propionic acid methyl ester (60 mg, 0.12 mmol) in
methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h.
The reaction mixture is concentrated and acidified by 5 N HC1 (0.5 mL), extracted with
ethyl acetate. Combined organic layers are washed with water and brine, dried over
sodium sulfate. Concentration gives the title compound (63 mg). MS (ES): 504.3 [M+H]+.
Example 132
3-{4-[l-(4'-tert-Butyl-biphenyI-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(S)-
hydroxy-propionic acid

This compound is made in a substantially similar manner as Example 131 using 3-
amino-2( S)-hydroxy-propionic acid methyl ester as reagent in step B. MS (ES): 504.2
[M+H]+.
Example 133
3-{4-[l-(4'-Pentyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid, Isomer 1

This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl
ester and 4-pentylphenylboronic acid as starting materials in step D. MS (ES): 488.3
[M+H]+.
Example 134
3-{4-[l-(4'-Isobutyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1

This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl
ester and 4-isobutylphenylbronic acid as starting materials in step D. MS (ES): 472.2 [M-
H]".
Example 135
Racemic 3-{4-[l-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid
The title compound is prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid methyl ester. MS: 429.2 [M-H]Example 136
3-{4-[l-(4'-AcetyI-biphenyl-4-yIoxy)-butyl]-benzoylamino}-propionic acid, Isomer 1
This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl
ester and 4-acetylphenylboronic acid as starting materials in step D. MS (ES): 458.3 [M-
H]Example 137
3-{4-[l-(3', 5'-dichloro-biphenyl-4-yIoxy)-butyl]-benzoylamino}-propionicacid,
Isomer 1
and
Example 138
3-{4-[l-(3', 5'-dichloro-biphenyl-4-yIoxy)-butyl]-benzoylamino}-propionic acid,
Isomer 2
O
Cl
These compounds are made in a manner substantially similar to Example 117
using isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 3', 5'-dichlorophenylboronic acid as starting materials in step D. Isomer
1 MS (ES): 484.2 [M-H]"; Isomer 2 MS (ES): 486.2 [M+H]+.
Example 139
3-{4-[l-(2', 3', 4'-trifluoro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1
This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl
ester and 2', 3', 4'-trifluorophenylboronic acid as starting materials in step D. MS (ES):
472.2 [M+H]+.
Example 140
3-{4-[l-(2\ 4'-dimethoxy-biphenyI-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1
O
i
This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl
ester and 2', 4'-dimethoxyphenylboronic acid as starting materials in step D. MS (ES):
478.3 [M+H]+.
Example 141
3-{4-[l-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid, Isomer 1
and
Example 142
3-{4-[l-(4'-t-butyl-biphenyl-4-yIoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 2
O OH
I nese compounds are made in a manner substantially similar to Example 30 by
resolving racemic 3-{4-[l-(4'-t-butyl-biphenyl-4-yIoxy)-hexyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm). Isomer 1 MS (ES): 502.2
[M+H]+; Isomer 2 MS (ES): 502.2 [M+H]+.
Example 143
3-{4-[l-(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid, Isomer 1
and
Example 144
3-{4-[l-(4'-pentylphenyl-4-yIoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 2
O OH
These compounds are made in a manner substantially similar to Example 30 by
resolving racemic 3-{4-[l-(4'-pentylphenyl-4-yIoxy)-hexyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm). Isomer IMS (ES): 454.2
[M+H]+; Isomer 2 MS (ES): 454.2 [M+H]+.
Example 145
3-(4-{l-[4-(l-Methyl-l-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-propionic
acid, Isomer 1
and
Example 146
3-(4-{l-[4-(l-Methyl-l-phenyl-ethyl)-phenoxy]-heptyl}-benzoyIamino)-propionic
acid, Isomer 2
0 OH
O
These compounds are made in a manner substantially similar to Example 30 by
resolving racemic 3-(4-{ l-[4-(l-methyl-l-phenyl-ethyl)-phenoxy]-heptyl}-
benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 502.2 [M+H]+. Isomer2 MS (ES): 502.2 [M+H]+.
Example 147
3-{4-[l-(2', 4', 6'-trimethyl-biphenyl-4-yloxy)-heptyI]-benzoylamino}-propionic acid,
Isomer 1
O
This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-brorno-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester and 2', 4', 6'-trimethylphenylboronic acid as starting materials in step D. MS (ES):
502.2 [M+H]+.
Example 148
3-{4-[l-(4'-Fluoro-2'-methyl-biphenyl-4-yIoxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
0
This compound is made in a substantially similar manner as Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step D. MS (ES):
492.3 [M+H]+.
Example 149
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 1
Chiral
This compound is made in a substantially similar manner to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-hexyI]-benzoylamino}-propionic acid methyl
ester and 4-trifluoromethoxy-phenylboronic acid as starting materials in step D. MS (ES):
530.2 [M+H]+.
Example 150
3-{4-[l-(4'-Fluoro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid, Isomer 1
O
This compound is made in a substantially similar manner to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester and 4-trifluoromethoxy-phenylboronic acid as starting materials in step D. MS (ES):
476.2 [M-H]".
Example 151
3-{4-[Cyclopropyl-(4'-trifluoromethyI-biphenyl-4-yloxy)-methyI]-benzoylamino}-
propionic acid, Isomer 1
and
Example 152
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamino}-
propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 482.2 [M-H]"; Isomer 2 MS (ES): 482.2 [M-H]'.
Example 153
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid, Isomer 1
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 528.3 [M+H]+. Isomer 2 MS (ES): 528.3 [M+H]+.
Example 155
3-{4-[l-(4'-Chloro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1
This compound is made in a substantially similar manner to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-phenoxy)-heptyl]-benzoyIamino}-propionic acid methyl
ester and 4-chIorophenylboronic acid as starting materials in step D. MS (ES): 492.3 [M-
H]".
Example 156
3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid, Isomer 1
and
Example 157
3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[ 1 -(4'-tert-butyl-2-methyl-biphenyI-4-yloxy)-3-methyl-butyl]-3-
fluoro-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 520.2 [M+H]+; Isomer2 MS (ES): 520.2 [M+H]+.
Example 158
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyI]-3-fluoro-benzoylamino}-propionic
acid, Isomer 1
and
Example 159
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-propionic
acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 534.2 [M+H]+. Isomer 2 MS (ES): 534.2 [M+H]+.
Example 160
3-{3-Fluoro-4-[l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 161
3-{3-FIuoro-4-[l-(2-methyI-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{3-fluoro-4-[ 1 -(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-
heptyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 560.2 [M+H]+; Isomer2 MS (ES): 560.2 [M+H]+.
Example 162
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yIoxy)-3-methyl-butyl]-3-fluoro-benzoylamino}-
propionic acid, Isomer 1
and
Example 163
3-{4-[l-(4'-tert-ButyI-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-benzoylaniino}-
propionic acid, Isomer 2
OH
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 506.2 [M+H]+; Isomer 2 MS (ES): 506.2 [M+H]+.
Example 164
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyI-4-yloxy)-heptyl]-benzoyIamino}-
propionic acid, Isomer 1
and
Example 165
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yIoxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 544.2 [M+H]+. Isomer2 MS (ES): 544.2 [M+H]+.
Example 166
3-{4-[l-(4'-tert-ButyI-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 167
3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-propionic
acid, Isomer 2
O OH
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 530.5 [M+H]+. Isomer 2 MS (ES): 530.5 [M+H]+.
Example 168
3-{4-[l-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 169
3-{4-[l-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2
O OH
O
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2-rnethyI-4'-trifIuoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 540.3 [M-H]\ Isomer 2 MS (ES): 540.3 [M-H]Example 170
3-{4-[l-(4'-tert-ButyI-2,6-dimethyl-biphenyl-4-yIoxy)-3-methyl-biityl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 171
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyI-butyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 516.3 [M+H]+. Isoemr2 MS (ES): 516.3 [M+H]+.
Example 172
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
Example 173
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
O 0H
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 514.2 [M-H]\ Isomer 2 MS (ES): 516.3 [M+H]+.
Example 174
3-{4-[l-(4'-FIuoro-2-methyl-biphenyI-4-yIoxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 175
3-{4-[l-(4'-Fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
OH
i
O
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm). Isomer 1 MS
(ES): 492.3 [M+H]+. Isomer 2 MS (ES): 490.2 [M-H]Example 176
3-{4-[l-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 177
3-{4-[l-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 2
0 OH
|| 1 IN" O
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm). Isomer 1 MS
(ES): 502.2 [M+H]+; Isomer 2 MS (ES): 502.2 [M+H]+.
Example 178
3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 1
and
Example 179
3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid methyl ester on Chiralcel OJ column (4.6 x 250 mm).
Isomer 1 MS (ES): 458.3 [M-H]"; Isomer 2 MS (ES): 458.3 [M-H]".
Example 180
3-{4-[l-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 181
3-{4-[l-(4'-Ethyl-2,6-dimethyl-biphenyI-4-yloxy)-3-methyI-butyI]-benzoyIamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid methyl ester on Chiralcel OJ column (4.6 x 250 mm).
Isoemr 1 MS (ES): 488.3 [M+H]+; Isomer 2 MS (ES): 488.3 [M+H]+.
Example 182
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyI-biphenyl-4-yloxy)-3-methyl-butyI]-
benzoylamino}-propionic acid, Isomer 1
and
Example 183
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yIoxy)-3-methyl-butyI]-
benzoylaminoj-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 556.3 [M+H]+. Isomer 2 MS (ES): 556.3 [M+H]+.
Example 184
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 185
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yIoxy)-heptyI]-benzoyIainino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[ 1 -(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyI]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 584.2 [M+H]+; Isomer 2 MS (ES): 584.2 [M+H]+.
Example 186
3-{4-[l-(4'-tert-Buryl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyI]-benzoyIamino}-
propionic acid, Isomer 1
and
Example 187
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 2
O OH
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 556.3 [M+H]+; Isomer 2 MS (ES): 556.3 [M+H]+.
Example 188
3-{4-[l-(4'-tert-ButyI-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyI]-
benzoylamino}-propionic acid, Isomer 1
and
Example 189
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyI-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 542.3 [M+H]+; Isomer 2 MS (ES): 542.3 [M+H]+.
Example 190
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 191
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyI]-
benzoylamino}-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-
dimethyl-pentyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 556.3 [M+H]+; Isomer 2 MS (ES): 556.3 [M+H]+.
Example 192
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyI-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid, Isomer 1
Example 193
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyI]-
benzoylaminoj-propionic acid, Isomer 2
OH
O
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 530.5 [M+H]+; Isomer 2 MS (ES): 530.2 [M+H]+.
Example 194
3-{4-[l-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyI-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 195
3-{4-[l-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2
OH
O
CN
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2-cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 499.2 [M+H]+; Isomer 2 MS (ES): 499.2 [M+H]+.
Example 196
3-{4-[l-(4'-Isopropyl-2,6-dimethyI-biphenyI-4-yloxy)-2-methyl-propyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 197
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyI-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2
OH
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 488.3 [M+H]+; Isomer 2 MS (ES): 488.3 [M+H]+.
Example 198
3-{4-[l-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 199
3-{4-[l-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-heptyI]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2-ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 556.3 [M+H]+; Isomer 2 MS (ES): 556.3 [M+H]+.
Example 200
3-{4-[l-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyI]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 201
3-{4-[l-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-chloro-2,6-dimethyl-biphenyl-4-yIoxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 522.2 [M+H]+; Isomer 2 MS (ES): 522.2 [M+H]+.
Example 202
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyI-propyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 203
3-{4-[l-(4'-tert-Butyl-2,6-dimethyI-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). MS (ES): 502.2 [M+H]+. MS (ES): 502.2 [M+H]+.
Example 204
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid, Isomer 1
Example 205
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[2-methyl-l-(2-methyl-4'-trifluorornethoxy-biphenyl-4-yloxy)-
propyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 516.3 [M+H]+; Isomer 2 MS (ES): 516.3 [M+H]+.
Example 206
3-{4-[l-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 207
3-{4-[l-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2-chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 508.3 [M+H]+; Isomer 2 MS (ES): 508.3 [M+H]+.
Example 208
3-{4-[l-(2-Chloro-4'-trifluoromethyl-biphenyI-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 209
3-{4-[l-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yIoxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2-chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 534.2 [M+H]+; Isomer 2 MS (ES): 534.2 [M+H]+.
Example 210
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-propyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 211
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid, Isomer 2

=These compounds are made by the general method exemplified in Example 30
by resolving racemic 3-{4-[2-Memyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-
propyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 500.3 [M+H]+; Isomer 2 MS (ES): 500.3 [M+H]+.
Example 212
3-(4-{3-MethyI-l-[5-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 213
3-(4-{3-Methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{3-methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 515.2 [M+H]+; Isomer 2 MS (ES): 515.2 [M+H]+.
Example 214
3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 215
3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{ l-[6-(4-isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-
butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 489.2 [M+H]+; Isomer 2 MS (ES): 489.2 [M+H]+.
Example 216
3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 217
3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyI}-
benzoylamino)-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(3-fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 519.2 [M+H]+. Isomer2 MS (ES): 519.2 [M+H]+.
Example 218
3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1
and
Example 219
3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{3-methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
MS (ES): 501.2 [M+H]+; MS (ES): 501.2 [M+H]+.
Example 220
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 1
and
Example 221
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4-tert-butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm). Isomer 1 MS
(ES): 412.3 [M+H]+. Isomer 2 MS (ES): 412.3 [M+H]+.
Example 222
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 223
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hepryl]-benzoylamino}-
propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 2-hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 542.3 [M-H]'; Isomer 2 MS (ES): 542.3 [M-H]".
Example 224
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 225
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 542.3 [M-H]"; Isomer 2 MS (ES): 542.3 [M-H]Example 226
3-(4-{l-[4-(l,l,3,3-Tetramethyl-butyI)-phenoxy]-heptyl}-benzoylamino)-propionic
acid, Isomer 1
and
Example 227
3-(4-{l-[4-(l,l,3,3-Tetramethyl-butyI)-phenoxy]-heptyl}-benzoylamino)-propionic
acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{l-[4-(l,l,3,3-tetramethyl-butyl)-phenoxy]-heptyl}-
benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 496.5 [M+H]+; Isomer 2 MS (ES): 496.5 [M+H]+.
Example 228
3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 229
3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-
heptyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x
150 mm). Isomer 1 MS (ES): 514.2 [M+H]+; Isomer2 MS (ES): 514.2 [M+H]+.
Example 230
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 231
3-{4-[l-(2,6-Dimethyl-4'-trifluoromrthyI-biphenyI-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 540.3 [M-H]"; Isomer 2 MS (ES): 542.3 [M+H]+.
Example 232
3-{4-[l-(4Mert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 233
3-{4-[l-(4'-tert-Butyl-2,6-dimethyI-biphenyl-4-yloxy)-3,3-dimethyl-butyl|-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 528.3 [M-H]"; Isomer 2 MS (ES): 528.3 [M-H]".
Example 234
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyI-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 235
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 2
Chiral
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150
mm). Isomer 1 MS (ES): 516.3 [M+Hf; Isomer 2 MS (ES): 516.3 [M+H]+.
Example 236
3-(4-{3,3-DimethyI-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 1
and
Example 237
3-(4-{3,3-Dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{3,3-dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-
3-yloxy]-butyl}-benzoyIamino)-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer IMS (ES): 529.3 [M+H]+; Isomer 2 MS (ES): 529.3 [M+H]+.
Example 238
3-{4-[l-(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 239
3-{4-[l-(4'-IsopropyI-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2
OH
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 504.2 [M+H]+; Isomer 2 MS (ES): 504.2 [M+H]Example 240
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyI-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 241
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyI-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyI]-
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column (4.6 x 150 mm).
Isomer 1 MS (ES): 488.3 [M+H]+; Isomer 2 MS (ES): 488.3 [M+H]+.
Example 242
3-{4-[l-(2,6-DimethyI-4'-trifluoromethoxy-biphenyI-4-yloxy)-3,3-dimethyl-butyI]-
benzoylamino}-propionic acid, Isomer 1
and
Example 243
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyI-butyl]-
benzoylaminoj-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 558.3 [M+H]+; Isomer 2 MS (ES): 558.3 [M+H]+.
Example 244
3-(4-{l-[2-(tert-Butoxyimino-methyI)-4'-trifluoromethyl-biphenyl-4-yloxy]-3-methyl-
butyl}-benzoylamino)-propionic acid, Isomer 1
and
Example 245
3-(4-{l-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyI-4-yloxy]-3-methyI-
butyl}-benzoylamino)-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-(4-{ l-[2-(tert-butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-
yloxy]-3-methyl-butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H
column (4.6 x 150 mm). Isomer 1 MS (ES): 599.2 [M+H]+; Isomer 2 MS (ES): 599.2
[M+H]+.
Example 246
3-{4-[l-(4Mert-Butyl-2,6-dimethyI-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1
and
Example 247
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3r3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2
These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoyIamino}-2-hydroxy-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 546.3 [M+H]+; Isomer 2 MS (ES): 546.3 [M+H]+.
Example 248
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1
and
Example 249
3-{4-[l-(4'-tert-Butyl-2,6-dimethyI-biphenyl-4-yloxy)-3,3-dimethyI-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2

These compounds are made by the general method exemplified in Example 30 by
resolving racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-2-hydroxy-propionic acid ethyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 546.3 [M+H]+; Isomer 2 MS (ES): 546.3 [M+H]+.
Example 250
3-{4-[l-(4'-Fluoro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1

This compound is made in a manner substantially similar to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester and 4-fluorophenylboronic acid as starting materials in step
D. MS (ES): 476.2 [M-H]".
Example 251
3-{4-[l-(4'-Fluoro-2,6,2'-trimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-

This compound is made in a manner substantially similar to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-heptyl]-benzoylamino}-propionic
acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step
D. MS (ES): 520.2 [M+H]+.
Example 252
3-{4-[l-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyIamino}-
propionic acid, Isomer 1

This compound is made in a manner substantially similar to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester and 4-chloro-phenylboronic acid as starting materials in step
D. MS (ES): 492.3 [M+H]+.
Example 253
3-{4-[l-(4'-IsopropyI-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1

This compound is made in a manner substantially similar to Example 117 using
isomer 1 of 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester and 4-isopropylphenylboronic acid as starting materials in
step D. MS (ES): 502.2 [M+H]+.
Example 254
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 255
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyI-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2
These compounds are made by the general method as exemplified in Example 30
by resolving racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-
methyl-butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6 x 150 mm). Isomer 1 MS (ES): 528.3 [M+H]+; Isomer 2MS (ES): 528.4 [M+H]+.
Example 256
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-hexyI]-benzoylamino}-propionic
acid
This compound is made by the general method exemplified in Example 1 using 4-
(l-hydroxy-hexyl)-benzoic acid methyl ester and 4'-tertbutyl-biphenyl-4-ol as starting
materials. MS (ES): 502.2 [M+H]+.
Example 257
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 1 usin£
3-fluoro-4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-tertbutyl-biphenyl-4-ol as
starting materials. MS (ES): 534.2 [M+H]+.
Example 258
Racemic 3-{4-[l-(4Mert-Butyl-biphenyl-4-yloxy)-3-methyl-butyI]-3-fluoro-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
3-fluoro-4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4'-tertbutyl-
biphenyl-4-ol as starting materials. MS (ES): 504.2 [M-H]Example 259
Racemic 3-{4-[l-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-hydroxy-4'-isopropyl-
biphenyl-2-carbonitrile as starting materials. MS (ES): 499.2 [M+H]+.
Example 260
Racemic 3-{4-[l-(4'-Isopropyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-isopropyl-2-trifluoromethyl-
biphenyl-4-ol as starting materials. MS (ES): 570.2 [M+H]+.
Example 261
Racemic3-{4-[l-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-heptyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 2-ethyl-4'-trifluoromethyl-biphenyl-
4-ol as starting materials. MS (ES): 556.3 [M+H]+.
Example 262
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-propionic
acid

This compound is made by the general method as exemplified in Example 1 using
4-hydroxymethyl-benzoic acid methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol
as starting materials. MS (ES): 460.2 [M+H]+.
Example 263
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-propionic
acid

This compound is made by the general method as exemplified in Example 1 using
3-(4-hydroxymethyl-benzoic acid methyl ester and 4'-trifluoromethyl-2,6-dimethyl-
biphenyl-4-ol as starting materials. MS (ES): 472.2 [M+H]+.
Example 264
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-ethyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-ethyl)-benzoic acid methyl ester and 4'-trifluoromethyl-2,6-dimethyl-
biphenyl-4-ol as starting materials. MS (ES): 486.2 [M+H]+.
Example 265
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yIoxy)-ethyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-ethyl)-benzoic acid methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-
ol as starting materials. MS (ES): 474.2 [M+H]+.
Example 266
Racemic 3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 1 using
3-fluoro-4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 6-(4-
trifluoromethyl-phenyl)-pyridin-3-ol as starting materials. MS (ES): 519.2 [M+H]+.
Example 267
Racemic 3-(4-{l-[4-(l,l>3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-benzoylamino)-
propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyI)-benzoic acid methyl ester and 4-(l,l,3,3-tetramethyI-butyl)-phenol
as starting materials. MS (ES): 494.2 [M-H]Example 268
Racemic 3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yI)-phenoxy]-butyI}-
benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-(5-trifluoromethyl-
pyridin-2-yl)-phenol as starting materials. MS (ES): 499.2 [M-H]Example 269
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyI-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4'-tert-butyl-2,6-
dimethyl-biphenyl-4-ol as starting materials. MS (ES): 530.5 [M+H]+.
Example 270
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyI]-
benzoylamino}-2-hydroxy-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4'-tert-butyl-2,6-
dimethyl-biphenyl-4-ol as starting materials. MS (ES): 546.3 [M+H]+.
Example 271
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyI-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4'-tert-butyl-2,6-
dimethyl-biphenyl-4-ol as starting materials. MS (ES): 546.3 [M+H]+.
Example 272
Chiral 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyI-4-yloxy)-3-methyI-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1

This compound is made by the general method as exemplified in Example 1 using
chiral 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 2,6-dimethyl-4'-
trifluoromethyl-biphenyl-4-ol as starting materials. MS (ES): 544.2 [M+H]+.
Example 273
Chiral 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1
I-
This compound is made by the general method as exemplified in Example 1 using
chiral 4-(l-hydroxy-3-methyl-butyI)-benzoic acid methyl ester and 2,6-dimethyl-4'-
trifiuoromethyl-biphenyl-4-ol as starting materials. MS (ES): 544.2 [M+H]+.
Example 274
Racemic 3-{4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3-[l,3]dioxan-2-yl-
phenol as starting materials. MS (ES): 521.3 [M+H]+.
Example 275
Racemic 3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-t-butyl-phenol as starting
materials. MS (ES): 412.32 [M+H]+.
Example 276
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2-
hydroxy-propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4'-tertbutyl-biphenol as
starting materials. MS (ES): 504.2 [M+H]+.
Example 277
Racemic3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2-
hydroxy-propionic acid
O
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4'-tertbutyl-biphenol as
starting materials. MS (ES): 504.2 [M+H]+.
Example 278
Racemic3-{4-[l-(4-Pentyl-phenoxy)-heptyl]-benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-pentyl-phenol as starting materials.
MS (ES): 454.2 [M+H]+.
Example 279
Racemic 3-(4-{l-[4-(l-Methyl-l-phenyl-ethyl)-phenoxy]-heptyl}-benzoyIamino)-
propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-(l-methyl-l-phenyl-ethyl)-phenol
as starting materials. MS (ES): 500.3 [M-H]".
Example 280
Racemic 2-Hydroxy-3-{4-[l-(4'-trifluoromethyI-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-trifluoromethyl-biphenol as starting
materials. MS (ES): 542.3 [M-H]'.
Example 281
Racemic 2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid
O
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-trifluoromethyl-biphenol as starting
materials. MS (ES): 542.3 [M-H]".
Example 282
Racemic 3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4'-isopropyl-2-methyl-
biphenyl-4-ol as starting materials. MS (ES): 488.3 [M+H]+.
Example 283
Racemic 3-{4-[l-(4-Chloro-3-trifluoromethyl-phenoxy)-heptyl]-benzoylamino}-2-
hydroxy-propionic acid
O
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-chloro-3-trifluoromethyl-phenol as
starting materials. MS (ES): 486.2 [M+H]+.
Example 284
Racemic 3-{4-[l-(3-Chloro-4-methyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid
^N-7 O
This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-chloro-4-methyl-phenol as
starting materials. MS (ES): 404.2 [M+H]+.
Example 285
Racemic 3-{4-[l-(2,2,3>3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 2,2,3,3-tetrafluoro-2,3-dihydro-
benzo[l,4]dioxin-6-ol as starting materials. MS (ES): 514.2 [M+H]+.
Example 286
Racemic 3-{4-[Cyclopropyl-(4Mrifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 1 using
4-(cyclopropyl-hydroxy-methyl)-benzoic acid methyl ester and 4'-trifluoromethyl-
biphenyl-4-ol as starting materials. MS (ES): 482.2 [M-H]Example 287
Racemic 3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yIoxy)-heptyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3, 5-dimethylpheno!
as reagents in step A and 4-isopropylphenyl boronic acid in step C as starting materials.
MS (ES): 530.5 [M+H]+.
Example 288
Racemic 3-{4-[l-(4'-Acetyl-2,6-dimethyl-biphenyI-4-yIoxy)-heptyl]-benzoylamino}-
propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3, 5-dimethylphenol
as reagents in step A and 4-acetylphenyl boronic acid in step C as starting materials. MS
(ES): 530.2 [M+H]+.
Example 289
Racemic 3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyI]-benzoyIamino}-
propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methylphenol as
reagents in step A and 4-tertbutylphenyl boronic acid in step C as starting materials. MS
(ES): 528.3 [M-H]".
Example 290
Racemic 3-{4-[l-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methylphenoi as
reagents in step A and 4-trifIuoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 540.3 [M-H]Example 291
Racemic 3-(4-{l-[6-(4-IsopropyI-phenyI)-5-methyl-pyridin-3-yloxy]-4,4-dimethyl-
pentyl}-benzoylamino)-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 6-chloro-5-
methyl-pyridin-3-ol as reagents in step A and 4-isopropyIphenyl boronic acid in step C as
starting materials. MS (ES): 517.3 [M+H]+.
Example 292
Racemic 3-(4-{4,4-Dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-pentyl}-benzoylamino)-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 6-chloro-5-
methyl-pyridin-3-ol as reagents in step A and 4-trifluoromethylphenyl boronic acid in
step C as starting materials. MS (ES): 529.3 [M+H]+.
Example 293
Racemic 3-(4-{4,4-Dimethyl-l-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
yloxy]-pentyl}-benzoylamino)-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 6-chloro-5-
methyl-pyridin-3-ol as reagents in step A and 4-trifluoromethoxyphenyl boronic acid in
step C as starting materials. MS (ES): 545.3 [M+H]+.
Example 294
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethoxyphenyl boronic acid in step
C as starting materials. MS (ES): 558.3 [M+H]+.
Example 295
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-3,3-dimethyI-
butyl]-benzoylamino}-2-hydroxy-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethylphenyl boronic acid in step C
as starting materials. MS (ES): 558.3 [M+H]+.
Example 296
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoyIamino}-2-hydroxy-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethylphenyI boronic acid in step C
as starting materials. MS (ES): 558.3 [M+H]+.
Example 297
Racemic 2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
di methyl-phenol as reagents in step A and 4-trifluoromethylphenyl boronic acid in step C
as starting materials. MS (ES): 532.3 [M+H]+.
Example 298
Racemic 3-{4-[l-(4'-Isopropyl-2-methoxy-biphenyI-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3-methoxy-
phenol as reagents in step A and 4-isopropylphenyl boronic acid in step C as starting
materials. MS (ES): 504.2 [M+H]+.
Example 299
Racemic 3-{3-Fluoro-4-[l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-heptyl]-
benzoylamino}-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 3-fluoro-4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-
methylphenol as reagents in step A and 4-trifluoromethylphenyl boronic acid in step C as
starting materials. MS (ES): 516.3 [M+H]+.
Example 300
Racemic 3-{4-[l-(4'-tert-Butyl-2-chIoro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid
OH
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-chloro-phenol as
reagents in step A and 4-tertbutylphenyl boronic acid in step C as starting materials. MS
(ES): 548.3 [M-H]".
Example 301
Racemic 3-{4-[l-(4'-trifluoromethyl-2-chloro-biphenyl-4-yloxy)-heptyI]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-chloro-phenol as
reagents in step A and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 560.2 [M-H]".
Example 302
Racemic 3-{4-[l-(2', 4'-bistrifluoromethyl-2-chloro-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-( 1 -hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-chloro-phenol as
reagents in step A and 2,4-bistrifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 628.3 [M-H]".
Example 303
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethylphenyl boronic acid in step C
as starting materials. MS (ES): 526.2 [M-H]Example 304
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyI-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid

i
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-t-butylphenyl boronic acid in step C as
starting materials. MS (ES): 516.3 [M+H]+.
Example 305
Racemic 3-{4-[l-(2-Hydroxy-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-benzene-l,3-
diol as reagents in step A and 4-isopropylphenyl boronic acid in step C as starting
materials. MS (ES): 490.2 [M+H]+.
Example 306
Racemic 3-{4-[l-(2-[l,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyI-butyl)-benzoic acid methyl ester and 4-bromo-3-
[l,3]dioxan-2-yl-phenol as reagents in step A and 4-isopropylphenyl boronic acid in step
C as starting materials. MS (ES): 560.2 [M+H]+.
Example 307
Racemic 3-(4-{l-[2-(tert-Butoxyimino-methyl)-4'-isopropyl-biphenyl-4-yIoxy]-3-
methyl-butyl}-benzoylamino)-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyI-butyl)-benzoic acid methyl ester and 2-bromo-5-hydroxy-
benzaldehyde O-tert-butyl-oxime as reagents in step A and 4-isopropylphenyl boronic
acid in step C as starting materials. MS (ES): 573.3 [M+H]+.
Example 308
Racemic 3-(4-{l-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]-
3-methyl-butyl}-benzoyIamino)-propionic acid
o
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 2-bromo-5-hydroxy-
benzaldehyde O-tert-butyl-oxime as reagents in step A and 4-trifluoromethylphenyI
boronic acid in step C as starting materials. MS (ES): 599.2 [M+H]+.
Example 309
Racemic 3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-niethyl-butyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and phenyl boronic acid in step C as starting
materials. MS (ES): 460.2 [M+H]+.
Example 310
Racemic 3-{4-[l-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-ethyl-phenyl boronic acid in step C as
starting materials. MS (ES): 486.2 [M-H]Example 311
Racemic 3-{4-[l-(2-Methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyI]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methyl-phenol as
reagents in step A and 4-trifluoromethoxy-phenyl boronic acid in step C as starting
materials. MS (ES): 556.3 [M-H]Example 312
Racemic 3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyi)-benzoic acid methyl ester and 4-bromo-3-methyl-phenol as
reagents in step A and 4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 516.3 [M+Hf.
Example 313
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethoxy -phenyl boronic acid in
step C as starting materials. MS (ES): 542.3 [M-H]".
Example 314
Racemic 3-{4-[l-(4'-ethyI-2-methyl-biphenyl-4-yloxy)-heptyI]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methyl-phenol as
reagents in step A and 4-ethyl-phenyl boronic acid in step C as starting materials. MS
(ES): 502.2 [M+H]+.
Example 315
Racemic 3-{4-[l-(4'-acetyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methyl-phenol as
reagents in step A and 4-acetyl-phenyl boronic acid in step C as starting materials. MS
(ES): 514.2 [M-H]".
Example 316
Racemic 3-{4-[l-(4'-fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24 using 4-(l-
hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3-methyl-phenol as reagents in
step A and 4-fluoro-phenyl boronic acid in step C as starting materials. MS (ES): 490.2
[M-H]'.
Example 317
Racemic 3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yIoxy)-heptyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-chloro-3-trifluoromethyl-
phenol as reagents in step A and 4-tertbutyl-phenyl boronic acid in step C as starting
materials. MS (ES): 582.2 [M-H]Example 318
Racemic 3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyI]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-pentyl)-benzoic acid methyl ester and 4-chloro-3-trifluoromethyl-
phenol as reagents in step A and 4-tertbutyl-phenyl boronic acid in step C as starting
materials. MS (ES): 554.2 [M-H]Example 319
Racemic 3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-chloro-3-
trifluoromethyl-phenol as reagents in step A and 4-t-butyl-phenyl boronic acid in step C
as starting materials. MS (ES): 540.3 [M-H]Example 320
Racemic 3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

p
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-chloro-3-
trifiuoromethyl-phenol as reagents in step A and 4-tertbutyl-phenyl boronic acid in step C
as starting materials. MS (ES): 554.2 [M-H]".
Example 321
Racemic 3-{4-[l-(3,5-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyI)-benzoic acid methyl ester and 4-bromo-3,5-dimethyl-phenol
as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 554.2 [M-H]".
Example 322
Racemic 3-{4-[l-(4'-Chloro-3,5-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4-bromo-3,5-dimethyl-phenol
as reagents in step A and 4-chloro-phenyl boronic acid in step C as starting materials. MS
(ES): 522.2 [M+H]+.
Example 323
Racemic 3-{4-[l-(4'-Chloro-3-methyl-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-heptyI)-benzoic acid methyl ester and 4-bromo-3-dimethyl-phenol as
reagents in step A and 4-chloro-phenyl boronic acid in step C as starting materials. MS
(ES): 506.2 [M-H]Example 324
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-fluoromethyl-phenyl boronic acid in step C
as starting materials. MS (ES): 540.3 |M-H]Example 325
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyI-4-yloxy)-4,4-dimethyI-
pentyl]-benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-fluoromethyl-phenyl boronic acid in step C
as starting materials. MS (ES): 554.2 [M-H]~.
Example 326
Racemic 3-{4-[l-(2,6-Dimethyl-4'-isopropyl-biphenyI-4-yloxy)-4,4-dimethyl-pentyI]-
benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as
starting materials. MS (ES): 530.2 [M+H]+.
Example 327
Racemic 3-{4-[l-(4'-IsopropyI-2,6-dimethyl-biphenyl-4-yloxy)-2-methyI-propyI]-
benzoylaminoj-propionic acid
O
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as
starting materials. MS (ES): 488.3 [M+H]+.
Example 328
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C
as starting materials. MS (ES): 514.2 [M+H]+.
Example 329
Racemic 3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyI-biphenyl-4-yIoxy)-propyI]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-bromo-3-methyI-
phenol as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as
starting materials. MS (ES): 500.3 [M+H]+.
Example 330
Racemic 3-{4-[l-(2,6-Dimethyl-4'-chloro-biphenyI-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester and 4-bromo-3,5-
dimethyl-phenol as reagents in step A and 4-chloro-phenyl boronic acid in step C as
starting materials. MS (ES): 522.2 [M+H]+.
Example 331
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-bromo-3-methyl-
phenol as reagents in step A and 4-tertbutyl-phenyl boronic acid in step C as starting
materials. MS (ES): 502.2 [M+H]+.
Example 332
Racemic 3-{4-[l-(4'-Isopropyl-2-methyI-biphenyl-4-yloxy)-2-methyI-propyI]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester and 4-bromo-3-methyl-
phenol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 474.2 [M+H]+.
Example 333
Racemic 3-{4-[l-(2,6-Difluoro-4'-trifluoromethyl-biphenyI-4-yloxy)-3-methyl-butyI]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-difluoro-
phenol as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as
starting materials. MS (ES): 536.2 [M+H]+.
Example 334
Racemic 3-{4-[l-(2,6-Difluoro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3,5-difluoro-
phenol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 510.2 [M+H]+.
Example 335
Racemic 3-{4-[l-(2-ChIoro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyI]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3-chloro-
phenol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 508.3 [M+H]+.
Example 336
Racemic 3-{4-[l-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 4-bromo-3-chloro-
phenol as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as
starting materials. MS (ES): 534.2 [M+H]+.
Example 337
Racemic 3-(4-{3-Methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 6-chloro-5-methyl-
pyridin-3-ol as reagents in step A and 4-trifluoro-phenyl boronic acid in step C as starting
materials. MS (ES): 515.2 [M+H]+.
Example 338
Racemic 3-(4-{l-[6-(4-IsopropyI-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 6-chloro-5-methyl-
pyridin-3-ol as reagents in step A and 4-isopropyl-phenyl boronic acid in step C as
starting materials. MS (ES): 489.2 [M+H]+.
Example 339
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-3-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-phenol as
reagents in step A and 4-tertbutyl-phenyl boronic acid in step C as starting materials. MS
(ES): 488.3 [M+H]+.
Example 340
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-3-yloxy)-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-phenol as
reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 500.3 [M+H]+.
Example 341
Racemic 3-{4-[l-(4'-Isopropyl-biphenyl-3-yloxy)-3-methyI-butyI]-benzoylamino}-
propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-phenol as
reagents in step A and 4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 474.2 [M+H]+.
Example 342
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyl-3-yIoxy)-butyl]-
benzoylamino}-propionic acid

This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-phenol as
reagents in step A and 4-trifluoromethoxy-phenyl boronic acid in step C as starting
materials. MS (ES): 516.3 [M+H]+.
Example 343
Racemic 3-{4-[3-Methyl-l-(6-methyl-4'-trifluoromethyl-biphenyl-3-yloxy)-butyl]-
benzoylaminoj-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-4-methyl-
phenol as reagents in step A and 4-trifluoromethyl-phenyl boronic acid in step C as
starting materials. MS (ES): 514.2 [M+H]+.
Example 344
Racemic 3-{4-[l-(4'-tert-Butyl-6-methyl-biphenyI-3-yloxy)-3-methyI-butyl]-
benzoylamino}-propionic acid
This compound is made by the general method as exemplified in Example 24
using 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester and 3-bromo-4-methyl-
phenol as reagents in step A and 4-t-butyl-phenyl boronic acid in step C as starting
materials. MS (ES): 502.2 [M+H]+.
Example 345
Racemic 3-{4-[l-(2-Hydroxymethyl-4'-isopropyI-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid

and
Example 346
Racemic 3-{4-[l-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid

Step A. 4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic acid
methyl ester
To a solution of 4-(l-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1600
mg, 7.21 mmol) in toluene (72 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP,
2728 mg, 10.81 mmol) at 0°C, followed by the additions of tributylphosphine (2.69 mL,
10.81 mmol) and 4-bromo-3-[l,3]dioxan-2-yl-phenol (2240 mg, 8.65 mmol). The
reaction mixture is warmed up to room temperature and stirred overnight. The mixture is
loaded on silica gel, eluted with hexanes with a gradient from 0 % of ethyl acetate to 50
% of ethyl acetate giving the titled compound (1000 mg).
Step B. 4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyI]-benzoic acid
To the solution of 4-[l-(4-bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-
benzoic acid methyl ester (1000 mg) in methanol (20 mL) is added sodium hydroxide (5
N aqueous, 2 mL) and stirred for 4 h. The reaction mixture is concentrated and acidified
by 5 N HC1 (2 mL), extracted with ethyl acetate. Combined organic layers are washed
with water and brine, dried over sodium sulfate. Concentration gives the title compound
(940 mg) as a white solid.
StepC. 3-{4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyI-butyl]-
benzoylaminoj-propionic acid methyl ester
To a mixture of 4-[l-(4-bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-
benzoic acid (940 mg, 2.09 mmol) in methylene chloride (21 mL) is added triethyl amine
(0.88mL, 6.28 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester
hydrochloride (438 mg, 3.14 mmol) and EDCI (1207 mg, 6.28mmol) at room
temperature. The reaction mixture is stirred at room temperature overnight, loaded on
silica gel, eluted with eluted with hexanes with a gradient from 0 % of ethyl acetate to
100 % of ethyl acetate giving the titled compound (670mg).
StepD. 3-{4-[l-(2-[l,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yIoxy)-3-methyl-butyI]-
benzoylamino}-propionic acid methyl ester
3-{4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester (560 mg, 1.05 mmol), potassium Fluoride (183 mg, 3.15
mmol), 4-isopropylphenyl boronic acid (344 mg, 2.1 mmol) and
tetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) are placed in a flask. After
the reaction is purged with N2 for several times, THF/H2O (20ml/5ml) is added. The
resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl
acetate to give the titled compound (570 mg).
Step E. Racemic 3-{4-[l-(2-FormyI-4'-isopropyl-biphenyl-4-yloxy)-3-methyI-butyl]-
benzoylamino}-propionic acid methyl ester, and
Racemic 3-{4-[l-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid
3-{4-[l-(2-[l,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid methyl ester (570mg) is taken into THF (10ml), treated
with 5N HC1 for 5h, neutralfied with 5N NaOH, extracted with ethyl actate, dried over
MgSCU and concentrated. The residue is purified by column chromatography to afford 3-
{4-[l-(2-formyI-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester (36mg) and 3-{4-[l-(2-formyl-4'-isopropyl-biphenyl-4-
yloxy)-3-methyI-butyl]-benzoylamino}-propionic acid (228mg). MS (ES): 502.2 [M+H]+.
Step F. 3-{4-[l-(2-Hydroxymethyl-4'-isopropyI-biphenyl-4-yloxy)-3-methyl-butyI]-
benzoyiaminoj-propionic acid
To the solution of 3-{4-[l-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid methyl ester (36mg, 0.07mmol) in methanol (5ml)
is added NaBH4 (3mg, 0.07mmol). After 2h, the mixture is diluted with ethyl actate,
washed with IN HC1, water, brine, dried over MgSCU, and concentrated. The residue is
taken into methanol (20 mL), followed by the addition of sodium hydroxide (5 N
aqueous, 1 mL), stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N
HC1 (1 mL), extracted with ethyl acetate. Combined organic layers are washed with water
and brine, dried over sodium sulfate. Concentration gives the title compound (93 mg) as a
white solid. MS (ES): 502.2 [M-H]Example 347
Racemic 3-(4-{l-[2-(Hydroxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3-
methyl-butyl}-benzoylamino)-propionic acid
o
To the solution of 3-{4-[l-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid (75mg, 0.15mmol) in methanol (10ml) is added
hydroxylamine hydrochloride (104mg, 1.5mmol). After 4h, the mixture is diluted with
ethyl actate, washed with IN HCI, water, brine, dried over MgSC>4, and concentrated. The
residue is purified by column chromatography to afford 38mg of 3-(4-{l-[2-
(hydroxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3-methyl-butyl}-benzoylamino)-
propionic acid methyl ester, which is hydrolyzed by 5N NaOH to afford the titled
compound (36mg). MS (ES): 517.2 [M+H]+.
Example 348
Racemic 3-{4-[l-(4'-Isopropyl-2-morpholin-4-ylmethyI-biphenyl-4-yloxy)-3-methyI-
butyl]-benzoylamino}-propionic acid
To the solution of 3-{4-[l-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid (240mg, 0.48mmol) and Morpholine (84 mg,
0.96mmol) in dichlorometane (20ml) is added NaBH(OAc)3 (143mg, 0.67mmol) and
acetic acid (58mg, 0.96mmol). The resulting mixture is stirred overnight, diluted with
ethyl actate, washed with IN HC1, water, brine, dried over MgSO4, and concentrated. The
residue is purified by column chromatography to afford 80mg of the titled compound as a
white solid. MS (ES): 573.5 [M+H]+.
Example 349
3-(4-{3,3-DimethyI-l-[5-methyl-l-oxy-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid

Step A. 4-[l-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic acid
methyl ester
To a solution of 4-(l-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester (450
mg, 1.91 mmol) in toluene (19 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP,
722 mg, 2.86 mmol) at 0°C, followed by the additions of tributylphosphine (0.71 mL,
2.86 mmol) and 6-chloro-5-methyl-pyridin-3-ol (327 mg, 2.29 mmol). The reaction
mixture is warmed up to room temperature and stirred overnight. The mixture is loaded
on silica gel, eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of
ethyl acetate giving the titled compound (440 mg).
Step B. 4-[l-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic acid
To the solution of 4-[l-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic
acid methyl ester (440 mg) in methanol (30 mL) is added sodium hydroxide (5 N
aqueous, 2 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by
5 N HC1 (2 mL), extracted with ethyl acetate. Combined organic layers are washed with
water and brine, dried over sodium sulfate. Concentration gives the titled compound (414
mg)-
StepC. 3-{4-[l-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-
benzoylaminoj-propionic acid methyl ester
To a mixture of 4-[l-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-
benzoic acid (414 mg, 1.19 mmol) in methylene chloride (12 mL) is added triethyl amine
(0. 5mL, 3.6 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester
hydrochloride (250 mg, 1.8mmol) and EDCI (688 mg, 3.6 mmol) at room temperature.
The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted
with eluted with hexanes with a gradient from 0 % of ethyl acetate to 100 % of ethyl
acetate giving the titled compound (400mg).
Step D. 3-(4-{3,3-Dimethyl-l-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid methyl ester
3-{4-[l-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid methyl ester (200 mg, 0.46 mmol), potassium fluoride (80
mg, 1.38 mmol), 4-trifluoromethoxyphenyl boronic acid (190 mg, 0.92 mmol) and
tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol) are placed in a flask. After
the reaction is purged with N2 for several times, THF/H2O (20ml/5ml) is added. The
resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl
acetate to give the titled compound (220 mg).
StepF. 3-(4-{3,3-Dimethyl-l-[5-methyl-l-oxy-6-(4-trifluoromethoxy-phenyl)-
pyridin-3-yloxy]-butyl}-benzoylamino)-propionic acid
To the solution of 3-(4-{3,3-Dimethyl-l-[5-methyl-6-(4-trifluoromethoxy-
phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-propionic acid methyl ester (200 mg,
0.36mmol) in chloroform (20 mL) is added the solution of mCPBA (247 mg, 1.43mmol)
in chloroform (10ml) dropwise. The resulting mixture is stirred overnight. K2CO3
(200mg) and MeOH (lml) are added. The mixture is stirred for 30min, filtrated. The solid
residue is washed with dichloromethane/MeOH(9/l). The filtrate is concentrated and
purified by column chromatography to afford 3-(4-{3,3-dimethyl-l-[5-methyl-l-oxy-6-
(4-trifluoromethoxy-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-propionic acid
methyl ester (80mg), which is hydrolyzed by sodium hydroxide (5 N aqueous, 1 mL)
giving the title compound (55 mg). MS (ES): 561.3 [M+H]+.
Example 350
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 1
Chiral
.0.
Step A. 4-[l-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester
To a solution of 4-(l-hydroxy-2-methyl-propyl)-benzoic acid methyl ester (5000
mg, 24.04 mmol) in toluene (240 mL) is added l,l'-(azodicarbonyl)dipiperidine (ADDP,
9098 mg, 36.06 mmol) at 0°C, followed by the additions of tributylphosphine (8.98 mL,
36.06 mmol) and 4-bromo-3,5-dimethyl-phenol (5798 mg, 28.85 mmol). The reaction
mixture is warmed up to room temperature and stirred overnight. The mixture is loaded
on silica gel, eluted with hexanes with a gradient from 0 % of ethyl acetate to 50 % of
ethyl acetate giving the titled compound (5540 mg).
Step B. 4-[l-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester, isomers 1 and 2
The racemic 4-[l-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic
acid methyl ester was resolved on a Chiralcel OJ-H column (4.6 x 150 mm). Eluted with
Methanol/DMEA (98/2) and concentrated the fractions to provide a purified enantiomer
ester (isomer 1, 98.4 % ee, isomer 2, >99% ee).
Step C. 4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoic
acid methyl ester, isomer 1
Isomer 1 of 4-[l-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester (500 mg, 1.28 mmol), potassium fluoride (223 mg, 3.84 mmol), 4-
isopropylphenyl boronic acid (419 mg, 2.56 mmol) and tetrakis-
(triphenylphosphine)palladium (148 mg, 0.128 mmol) are placed in a flask. After the
reaction is purged with N2 for several times, THF/H2O (20ml/5ml) is added. The resulting
solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to
give the titled compound (510 mg).
Step D. 4-[l-(4'-IsopropyI-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoic
acid, isomers 1
To the solution of isomer 1 of 4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-
2-methyI-propyl]-benzoic acid methyl ester (510 mg) in methanol (10 mL) is added
sodium hydroxide (5 N aqueous, 2 mL) and stirred for 4 h. The reaction mixture is
concentrated and acidified by 5 N HC1 (2 mL), extracted with ethyl acetate. Combined
organic layers are washed with water and brine, dried over sodium sulfate. Concentration
gives the title compound (450 mg) as a white solid.
Step E. 2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid methyl ester, isomer 1
To a mixture of 4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propylj-benzoic acid (150 mg, 0.36 mmol) in methylene chloride (4 mL) is added triethyl
amine (0.15mL, 1.08 mmol), DMAP (5.0 mg), 3-Amino-2-hydroxy-propionic acid
methyl ester (83 mg, 0.54 mmol) and EDCI (208 mg, 1.08 mmol) at room temperature.
The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted
with eluted with hexanes with a gradient from 0 % of ethyl acetate to 100 % of ethyl
acetate giving the titled compound (150mg).
Step F. 2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyI-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid, isomer 1
To the solution of isomer 1 of 2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-
biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic acid methyl ester (150
mg) in methanol (10 mL) is added sodium hydroxide (5 N aqueous, 1 mL) and stirred for
4 h. The reaction mixture is concentrated and acidified by 5 N HC1 (1 mL), extracted with
ethyl acetate. Combined organic layers are washed with water and brine, dried over
sodium sulfate. Concentration gives the title compound (93 mg) as a white solid. MS
(ES): 504.2 [M+H]+.
The following compounds are made in a manner substantially similar to Example 350
using appropriate starting materials:
Example 351
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2
MS (ES): 504.2 [M+H]+.
Example 352
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yIoxy)-2-methyl-propyI]-
benzoylaminoj-propionic acid, Isomer 1
MS (ES): 504.2 [M+H]+.
Example 353
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylaminoj-propionic acid, Isomer 2

MS (ES): 504.2 [M+H]+.
Example 354
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1
MS (ES): 530.2 [M+H]+.
Example 355
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2

MS (ES): 530.2 [M+H]+.
Example 356
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1
MS (ES): 530.2 [M+H]+.
Example 357
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2
MS (ES): 530.2 [M+H]+.
Racemic 3-{4-[l-(2,6-dimethyl-4Mrifluoromethyl-biphenyl-4-yIsulfanyl)-5,5,5-
trifluoro-pentyl)-benzoylamino}-propionic acid
F
Step A. Racemic 4-[l-(4-Bromo-3,5-dimethyI-phenyIsulfanyl)-5,5,5-trifluoro-
pentyl]-benzoic acid methyl ester
A solution of the 4-bromo-3,5-dimethyl-benzenethiol (0.572 g, 2.26 mmol) and
(R,S) 4-(5,5,5-trifluoro-l-hydroxy-pentyl)-benzoic acid methyl ester (0.500 g, 1.81
mmol) in toluene(10 mL) is degassed and filled with nitrogen three times.
Tributylphosphine (0.670 mL, 2.72 mmol) is added to the reaction mixture under nitrogen
at 0 °C, followed by addition of l,l'-(azodicarbonyl)-dipiperidine (0.685 g, 2.72 mmol).
The reaction mixture is allowed to warm to room temperature and stirred overnight, the
mixture is concentrated and purified by flash column chromatography (0.424 g, 0.89
mmol).
Step B. Racemic 4-[l-(4-Bromo-3,5-dimethyl-phenyIsulfanyl)-5,5,5-trifluoro-
pentyl]-benzoic acid
Racemic 4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoic acid methyl ester (0.424 g, 0.890 mmol) is dissolved in the tetrahydrofuran (2.5
mL) and sodium hydroxide (2.5 mL, 5N) is added. The reaction is monitored by HPLC,
and upon complete conversion, the reaction is neutralized with hydrochloric acid (2.5 mL,
5N) and diluted with diethyl ether and water. The two phases are separated, and the
organic layer is washed, dried, and concentrated. The title compound (0.380 g, 0.826
mmol) is used without further purification.
Step C. Racemic 3-{4-[l-(4-Bromo-3,5-dimethyl-phenylsulfanyI)-5,5,5-trifluoro-
pentyl]-benzoylamino}-propionic acid ethyl ester
Racemic 4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoic acid(0.190 g, 0.410 mmol), 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.0747 g,
0.430 mmol) and 4-methylmorpholine (0.050 mL, 0.430 mmol) are combined in
anhydrous dichloromethane(2.0 mL) under nitrogen. The reaction is allowed to stir under
nitrogen at room temperature overnight. The beta alanine ethyl ester hydrochloride
(0.0695 g, 0.450 mmol) and 4-methylmorpholine (0.100 mL, 0.860 mmol) is added to the
reaction mixture and allowed to stir at room temperature. Some water (<10% volume) is
added to help solubility. The reaction is monitored by HPLC, and upon complete
consumption of the acid, the reaction is diluted with dichloromethane. The reaction is
diluted with water and rinsed with IN hydrochloric acid. Upon acidification, the two
layers are separated. The organic layer is washed with brine, dried over anhydrous
sodium sulfate, and concentrated. Flash column chromatography gave the title compound
(0.200 g, 0.360 mmol).
Step D. Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-
5,5,5-trifluoro-pentyl]-benzoyIamino}-propionic acid ethyl ester
To a solution of racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.200 g, 0.360 mmol) in
toluene(2 mL) is added palladium tetrakis triphenylphosphine (0.0267 g, 0.020 mmol), 4-
trifluoromethyl phenyl boronic acid(0.135 g, 0.720 mmol), and potassium fluoride
(0.0416 g, 0.720 mmol). The reaction is purged with nitrogen three times and heated to
reflux under nitrogen. At reflux, water (1.0 mL) is added to the reaction and the reaction
is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon
completion, allowed to cool to room temperature. The reaction is diluted with ethyl
acetate and celite is added, followed by water. This mixture is then filtered through a pad
of celite. The solution is poured into a separatory funnel and the organic layer is washed
with water and brine. The organic layer is dried over anhydrous sodium sulfate and
concentrated. The product is purified by flash column chromatography (0.150 g, 0.240
mmol).
Step E. Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyl-4-ylsulfanyl)-
5,5,5-trifluoro-pentyI]-benzoylamino}-propionic acid
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.150 g, 0.240 mmol) is
dissolved in tetrahydrofuran(1.0 mL) and sodium hydroxide(1.0 mL, 5N) is added. The
reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized
with hydrochloric acid (1.0 mL, 5N) and diluted with diethyl ether and water. The two
phases are separated, and the organic layer is washed, dried, and concentrated. The title
compound is used without further purification. MS (ES): 596.3 [M-H]Example 359
Racemic 3-{4-[l-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyI]-benzoylamino}-
propionic acid
0 O
Step A. Racemic 4-[l-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid
methyl ester
A solution of the 4-bromo-phenol (2.36 g, 13.61 mmol) and (R,S) 4-(5,5,5-
trifluoro-l-hydroxy-pentyl)-benzoic acid methyl ester (3.00 g, 10.89 mmol) in toluene (50
mL) is degassed and filled with nitrogen three times. Tributylphosphine (4.03 mL, 16.34
mmol) is added to the reaction mixture under nitrogen at 0°C, followed by addition of
l,l'-(azodicarbonyl)-dipiperidine (4.12 g, 16.34 mmol). The reaction mixture is allowed
to warm to room temperature and stirred overnight; the mixture is concentrated and
purified by flash column chromatography (3.0 g, 6.96 mmol).
Step B. Racemic 4-[l-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid
Racemic 4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyI]-benzoic acid methyl
ester (7.80 g, 18.1 mmol) is dissolved in the tetrahydrofuran (75 mL) and sodium
hydroxide(25 mL, 5N) is added. The reaction is heated to reflux under nitrogen. The
reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized
with hydrochloric acid (25 mL, 5N) and diluted with diethyl ether and water. The two
phases are separated, and the organic layer is washed, dried, and concentrated. The title
compound (7.46 g, 16.24 mmol) is used without further purification.
Step C. Racemic 3-{4-[l-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester
Racemic 4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid (7.46 g,
17.89 mmol), 2-chloro-4,6-dimethoxy-l,3,5-triazine (3.23 g, 18.43 mmol) and 4-
methylmorpholine (2.07 mL, 18.78 mmol) are combined in anhydrous dichloromethane
(100 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room
temperature overnight. Beta alanine methyl ester hydrochloride (2.76 g, 19.68 mmol) and
4-methyImorpholine (4.14 mL, 37.56 mmol) is added to the reaction mixture and allowed
to stir at room temperature. Some water (<10% volume) is added to help solubility. The
reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction
is diluted with dichloromethane. The reaction is diluted with water and rinsed with IN
hydrochloric acid. Upon acidification, the two layers are separated. The organic layer is
washed with brine, dried over anhydrous sodium sulfate, and concentrated. Flash column
chromatography gave the title compound (7.07 g, 14.1 mmol).
Step D. Racemic 3-(4-{5,5,5-Trifluoro-l-[4-(4,4,5,5-tetramethyl-
[l,3>2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoyIamino)-propionic acid methyl
ester
To a solution of racemic 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester (2.20 g, 4.38 mmol) in dimethyl sulfoxide(15
mL) is added [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane (1:1) (0.178 g, 0.022 mmol), bis(pinnocalado)diborane (2.22 g, 8.76
mmol), and potassium acetate(0.860 g, 8.76 mmol). The reaction is purged with nitrogen
three times and heated to reflux under nitrogen. The reaction is monitored by HPLC, and
upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl
acetate and celite is added, followed by water. This mixture is then filtered through a pad
of celite. The solution is poured into a separatory funnel and the organic layer is washed
with water and brine. The organic layer is dried over anhydrous sodium sulfate and
concentrated. The product is purified by flash column chromatography (1.78 g, 3.24
mmol).
Step E. Racemic 3-{4-[l-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyI]-
benzoylaminoj-propionic acid methyl ester
To a solution of racemic 3-(4-{5,5,5-Trifluoro-l-[4-(4,4,5,5-tetrarnethyl-
[l,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl
ester(0.300 g, 0.550 mmol) in toluene(3.0 mL) is added palladium tetrakis
triphenylphosphine(0.0316 g, 0.030 mmol), 2-bromo-l,3,5-tri-tert-butyl-benzene (0.353
g, 1.09 mmol), and potassium fluoride(0.063 g, 1.09 mmol). The reaction is purged with
nitrogen three times and heated to reflux under nitrogen. At reflux, water (1.0 mL) is
added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is
monitored by HPLC, and upon completion, allowed to cool to room temperature. The
reaction is diluted with ethyl acetate and celite is added, followed by water. This mixture
is then filtered through a pad of celite. The solution is poured into a separatory funnel
and the organic layer is washed with water and brine. The organic layer is dried over
anhydrous sodium sulfate and concentrated. The product is purified by flash column
chromatography (0.333 g, 0.500 mmol).
Step F. Racemic 3-{4-[l-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid
Racemic 3-{4-[l-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid methyl ester (0.333 g, 0.500 mmol) is dissolved in
tetrahydrofuran(3.0 mL) and sodium hydroxide(3.0 mL, 5N) is added. The reaction is
monitored by HPLC, and upon complete conversion, the reaction is neutralized with
hydrochloric acid(3.0 mL, 5N) and diluted with diethyl ether and water. The two phases
are separated, and the organic layer is washed, dried, and concentrated. The title
compound is used without further purification. MS (ES): 652.2 [M-H]Example 360
3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl}-benzoylamino)-propionic acid, Isomer 1
and
Example 361
3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl}-benzoylamino)-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(5,5,5-trifluoro-l-hydroxy-pentyl)-benzoic acid methyl ester and 5-
methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol (Preparation 34). The isomers are
resovled by methods described herein or known to one skilled in the art. Isomer 1 MS:
567.3 [M-H]"; Isomer 2 MS: 567.3 [M-H]Example 362
Racemic 3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-
benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 499.2 [M-H]~.
Example 363
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-5,5,5-trifluoro-
pentyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS:
584.2 [M-H]Example 364
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[ 1 -(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester. MS: 531.2 [M-H]".
Example 365
Racemic 3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-pentyl}-benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 1
starting from 4-(5,5,5-trifluoro-l-hydroxy-pentyl)-benzoic acid methyl ester and 5-
methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol (Preparation 34). MS: 567.3 [M-H]~.
Example 366
Racemic 3-(4-{4,4,4-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 1
starting from 3-[4-(4,4,4-trifluoro-l-hydroxy-butyl)-benzoylamino]-propionic acid methyl
ester and 5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol(Preparaton 34). MS: 553.3
[M-H]Example 367
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 368
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyI]-
benzoylamino}-propionic acid, Isomer 2

The title compound is prepared in a manner substantially similar to Example 358
starting from enatiomerically purified 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-
methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl
boronic acid. Isomer 1 MS: 542.2 [M-H]"; Isomer 2 MS: 542.2 [M-H]".
Example 369
3-{4-[l-(4'-tert-butyl-2,6-dimethyI-bipheny]-4-ylsuIfanyI)-3-methyI-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 370
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2
The title compound is prepared in a manner substantially similar to Example 367
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 530.2 [M-H]"; Isomer 2 MS: 530.2 [M-H]".
Example 371
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 372
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example
367 starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 570.2 [M-H]"; Isomer 2 MS: 570.2 [M-H]Example 373
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid, Isomer 1
Example 374
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example
358 starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid methyl ester. Isomer 1 MS: 517.3 [M-H]"; Isomer 2 MS:
517.3 [M-H]-.
Example 375
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 376
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsuIfanyl)-3-methyI-butyl]-benzoylamino}-
propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example
358 starting from enatiomers of 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-
methyl-butyl]-benzoylamino}-propionic acid methyl ester. Isomer 1 MS: 477.2 [M-H];
Isomer 2 MS: 477.2 [M-H]".
Example 377
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 378
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(6,6,6-trifluoro-l-hydroxy-hexyl)-benzoic acid methyl ester and 4'-tert-
butyl-2,6-dimethyl-biphenyl-4-ol. The isomers are resovled by methods described herein
or known to one skilled in the art. Isomer 1 MS: 580.2 [M-H]'; Isomer 2 MS: 580.2 [M-
H]".
Example 379
3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yIoxy)-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 380
3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example
128 starting from enatiomers of 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-
butyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid.
Isomer 1 MS: 540.2 [M-H]", Isomer 2 MS: 540.2 [M-H]".
Example 381
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-4,4,4-
trifluoro-butyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid.
MS: 582.3 [M-H]Example 382
Racemic 3-{4-[l-(4'-tert-butyI-2,6-dimethyI-biphenyl-4-yIsulfanyl)-4,4,4-trifluoro-
butyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid.
MS: 570.2 [M-H]Example 383
racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-
butyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid.
MS: 542.2 [M-H]Example 384
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-bipheny!-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid
The title compound is prepared in a manner
substantially similar to Example 358 starting from 3-{4-[l-(4-bromo-3,5-dimethyl-
phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-
butyl phenyl boronic acid.
MS: 530.2 [M-H]".
Example 385
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsuIfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid methyl ester. MS: 517.3 [M-H]".
Example 386
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 358
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid methyl ester. MS: 477.2 [M-H]".
Example 387
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 388
3-{4-[l-(2,6-dimethyl-4Mrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(l-hydroxy-heptyl)-benzoic acid methyl ester and 4'-tert-butyl-2,6-
dimethyl-biphenyl-4-ol. The isomers are resovled by methods described herein or known
to one skilled in the art. Isomer 1 MS: 554.3 [M-H]"; Isomer 2 MS: 554.3 [M-H]~.
Example 389
3-{4-[3-methyl-l-(2,2',4'-trichIoro-biphenyl-4-yloxy)-butyl]-benzoyIamino}-
propionic acid, Isomer 1
and
Example 390
3-{4-[3-methyl-l-(2,2',4'-trichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, isomer 2
O
The title compounds are prepared in a manner substantially similar to Example 24
starting from 3-{4-[l-(4-bromo-3-chloro-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid methyl ester and 2,4-dichlorophenyl boronic acid. The isomers are
resovled by methods described herein or known to one skilled in the art. Isomer 1 MS:
533.2 [M-H]"; Isomer 2 MS: 533.2 [M-H]".
Example 391
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 392
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(4,4,4-trifluoro-l-hydroxy-butyl)-benzoic acid methyl ester and 2,6-
dimethyl-4'-trifluoromethyl-biphenyl-4-ol. The isomers are resovled by methods
described herein or known to one skilled in the art. Isomer 1 MS: 566.3 [M-H]~; Isomer 2
MS: 566.3 [M-H]Example 393
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 1
and
Example 394
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 2
The title compounds are prepared in a manner substantially
similar to Example 1 starting from 4-(4,4,4-trifluoro-l-hydroxy-butyl)-benzoic acid
methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol. The isomers are resovled by
methods described herein or known to one skilled in the art. Isomer 1 MS: 554.2 [M-H]";
Isomer 2 MS: 554.2 [M-H]".
Example 395
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 396
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyI-4-yIoxy)-pentyl]-
benzoylamino}-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example
128 starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. Isomer
1 MS: 554.2 [M-H]"; Isomer 2 MS: 554.2 [M-H]Example 397
Racemic 3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS:
554.2 [M-H]'.
Example 398
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
benzoylamino}-propionic acid, Isomer 1
andExample 399
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yIoxy)-5-methyl-hexyl]-
benzoylamino}-propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(I-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and 2,6-dimethyl-
4'-trifluoromethyl-biphenyl-4-ol. The isomers are resovled by methods described herein
or known to one skilled in the art. Isomer 1 MS:554.2 [M-H]~; Isomer 2 MS:554.2[M-H]Example 400
3-{4-[5-methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexylJ-benzoylamino}-
propionic acid, Isomer 1
and
Example 401
3-{4-[5-methyl-l-(4'-trifluoromethyI-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid, Isomer 2
The title compounds are prepared in a
manner substantially similar to Example 1 starting from 4-(l-hydroxy-5-methyl-hexyl)-
benzoic acid methyl ester and 4'-trifluoromethyl-biphenyl-4-ol. The isomers are resovled
by methods described herein or known to one skilled in the art. Isomer 1 MS: 526.2 [M-
HT; Isomer 2 MS: 526.2 [M-H]Example 402
3-(4-{l-[6-(4-tert-butyl-phenyI)-pyridin-3-yloxy]-5-methyl-hexyl}-benzoylamino)-
propionic acid, Isomer 1
and
Example 403
3-(4_{l-[6-(4-tert-buryl-phenyl)-pyridin-3-yloxy]-5-methyI-hexyl}-benzoylamino)-
propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 515.2 [M-
H]"; Isomer 2 MS: 515.2 [M-H]Example 404
Racemic 3-(4-{5-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-
benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yIoxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 527.2[M-H]Example 405
Racemic 3-{4-[l-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid

The title compound is prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid methyl ester. MS: 417.3 [M-H]".
Example 406
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyI-hexyl]-
benzoylamino}-propionic acid
The title compound is prepared in a manner substantially similar to Example 1
starting from 4-(l-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and 2,6-dimethyl-
4'-trifluoromethyl-biphenyI-4-ol. MS: 554.2 [M-H]".
Example 407
Racemic 3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-
benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 515.2 [M-H]".
Example 408
Racemic 3-{4-[5-methyI-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 1
starting from 4-(l-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and 4'-
trifluoromethyl-biphenyl-4-ol. MS: 526.2 [M-H]'.
Example 409
Racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-5-methyl-hexyI]-benzoylamino}-
propionic acid
The title compound is prepared in a manner substantially similar to Example I
starting from 4-(l-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and 4'-tert-butyl-
biphenyl-4-ol. MS: 514.2 [M-H]~.
Example 410
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyI}-
benzoylamino)-propionic acid, Isomer 1
and
Example 411
3-(4-{l-[6-(4-tert-butyl-phenyI)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyl}-
benzoylamino)-propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example 62
starting from 4-[l-(6-chloro-pyridin-3-yloxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl
ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 541.3 [M-H]~; Isomer 2 MS:
541.3 [M-H]Example 412
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yIoxy]-4,4,4-trifluoro-butyI}-
benzoylamino)-propionic acid, Isomer 1
and
Example 413
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-
benzoylamino)-propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 62
starting from 4-[l-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyI]-benzoic acid methyl
ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 527.2 [M-H]~; Isomer 2 MS:
527.2 [M-H]Example 414
Racemic 3-{4-[(41-tert-butyl-2,6-dimethyI-biphenyl-4-yloxy)-cyclohexyl-methyl]-
benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 1
starting from 4-(cyclohexyl-hydroxy-methyl)-benzoic acid methyl ester and 4'-tert-butyI-
biphenyl-4-ol. MS: 540.3 [M-HV.
Example 415
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyI]-
benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 1
starting from 4-(4,4,4-trifluoro-l-hydroxy-butyl)-benzoic acid methyl ester and 4'-tert-
butyl-biphenyl-4-ol. MS: 554.2 [M-H]~.
Example 416
3-{4-[4,4,4-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yIoxy)-butyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 417
3-{4-[4,4,4-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example 1
starting from 4-(4,4,4-trifluoro-l-hydroxy-butyl)-benzoic acid methyl ester and 4'-
trifluoromethyl-biphenyl-4-ol. The isomers are resovled by methods described herein or
known to one skilled in the art. Isomer 1 MS: 538.3 [M-H]~; Isomer 2 MS: 538.3 [M-H]Example 418
Racemic 3-(4-{4,4,4-trifluoro-l-[6-(4-isopropyl-phenyI)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid

The title compound is prepared in a manner substantially similar to Example 62
starting from 4-[l-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoic acid methyl
ester and 4-isopropyl phenyl boronic acid. MS: 513.2 [M-H]Example 419
Racemic 3-(4-{5,5,5-trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yIoxy]-
pentyl}-benzoylamino)-propionic acid
The title compound is prepared in a manner substantially similar to Example 62
starting from 4-[l-(6-chloro-pyridin-3-yloxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl
ester and 4-trifluoromethyl phenyl boronic acid. MS: 553.3 [M-H]Example 420
Racemic 3-(4-{[6-(4-tert-butyI-phenyl)-pyridin-3-yloxy]-cyclohexyl-methyI}-
benzoylamino)-propionic acid
The title compound is prepared in a manner substantially similar to Example 62
starting from 4-[(6-chloro-pyridin-3-yloxy)-cyclohexyl-methyl]-benzoic acid methyl ester
and 4-tert-butyl phenyl boronic acid. MS: 513.2 [M-H]".
Example 421
Racemic3-(4-{5,5,5-trifluoro-l-[6-(4-isopropyl-phenyl)-pyridin-3-yIoxy]-pentyl}-
benzoylamino)-propionic acid
F F
The title compound is prepared in a manner substantially similar to Example 62
starting from 4-[l-(6-chloro-pyridin-3-yIoxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl
ester and 4-isopropyl phenyl boronic acid. MS: 527.2 [M-H]".
Example 422
Racemic3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-
butyl]-benzoylamino}-propionic acid
F
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid methyl ester and 4-trifiuoromethyl phenyl boronic acid.
MS: 566.2 [M-H]-.
Example 423
Racemic 3-(4-{cyclohexyl-[6-(4-isopropyI-phenyl)-pyridin-3-yloxyl-methyI}-
benzoylamino)-propionic acid
N'
The title compound is prepared in a manner substantially similar to Example 62
starting from 4-[(6-chloro-pyridin-3-yloxy)-cyclohexyl-methyl]-benzoic acid methyl ester
and 4-isopropyl phenyl boronic acid. MS: 499.2 [M-H]~.
Example 424
Racemic 3-{4-[cycIohexyl-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[(4-bromo-3,5-dimethyl-phenoxy)-cyclohexyl-methyl]-
benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS:
526.2 [M-H]".
Example 425
Racemic 3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyI-4-yloxy)-butyl]-
benzoylamino}-propionic acid
Q
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS:
540.3 [M-H]".
Example 426
3-{4-[cyclohexyl-(4Mrifluoromethyl-biphenyI-4-yloxy)-methyl]-benzoyIamino}-
propionic acid, Isomer 1
and
Example 427
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamino}-
propionic acid, Isomer 2

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. The isomers are resovled by
methods described herein or known to one skilled in the art. Isomer 1 MS: 524.3 [M-H]~;
Isomer 2 MS: 524.3 [M-H]".
Example 428
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 429
3-{4-[5,5,5-trifluoro-l-(4'-isopropyI-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 2

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester and 4-isopropyl phenyl boronic acid. The isomers are
resovled by methods described herein or known to one skilled in the art. Isomer 1 MS:
526.2 [M-H]"; Isomer 2 MS: 526.2 [M-H]".
Example 430
Racetnic 3-{4-[(4'-tert-butyl-biphenyl-4-yIoxy)-cyclohexyl-methyl]-benzoylamino}-
propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic
acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 512.3 [M-H]Example 431
Racemic3-{4-[5,5,5-trifluoro-l-(2'-3'-fluoro-4'-trifluoromethyl-biphenyI-4-y!oxy)-
pentyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 359
starting from 3-(4-{5,5,5-trifluoro-l-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and l-bromo-2,3-difluoro-
4-trifluoromethyl-benzene. MS: 588.3 [M-H]Example 432
Racemic3-{4-[cycIohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 128 starting
from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 524.3 [M-H]~.
Example 433
Racemic 3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylarnino}-
propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 526.2 [M-H]~.
Example 434
Racemic 3-{4-[l-(4'-ethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid
The title compound is prepared in a manner
substantially similar to Example 128 starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-ethyl phenyl boronic
acid. MS: 572.3 [M-H]Example 435
Racemic 3-{4-[5,5,5-trifluoro-l-(3'-fluoro-4'-trifluoromethyl-biphenyl-4-yloxy)-
pentyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 359
starting from 3-(4-{5,5,5-trifluoro-l-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 4-bromo-2-fluoro-l-
trifluoromethyl-benzene. MS: 570.2 [M-H]~.
Example 436
Racemic 3-{4-[l-(2,4,6-triisopropyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid
The title compound is prepared in a manner substantially similar to Example 359
starting from 3-(4-{5,5,5-trifluoro-l-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaboroIan-2-yl)-
phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 2-bromo-1,3,5-
triisopropyl-benzene. MS: 610.2 [M-H]".
Example 437
Racemic 3-{4-[l-(2,3,4,5,6-pentamethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 359
starting from 3-(4-{5,5,5-trifluoro-l-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and l-bromo-2,3,4,5,6-
pentamethyl-benzene. MS: 554.2 [M-H]".
Example 438
Racemic 3-{4-[l-(2,4,6-tri-t-butyI-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid

The title compound is prepared in a manner substantially similar to Example 359
starting from 3-(4-{5,5,5-trifluoro-l-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenoxy]-pentyl}-benzoy!amino)-propionic acid methyl ester and 2-bromo-l,3,5-tri-tert-
butyl-benzene. MS: 652.2 [M-H]".
Example 439
Racemic 3-{4-[l-(3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester. MS: 436.2 [M-H]Example 440
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid, Isomer 1
and
Example 441
3-{4-[l-(4'-tert-butyI-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid, isomer 2

The title compounds are prepared in a manner substantially similar to Example
128 starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyI]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 568.2 [M-H]'; Isomer 2 MS: 568.2 [M-H]~.
Example 442
Racemic 3-{4-[l-(4-ethyI-3, 5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyI]-
benzoylaminoj-propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid methyl ester and ethyl boronic acid. MS: 464.2 [M-H]Example 443
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-5,5,5-trifluoro-
pentyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid.
MS: 580.3 [M-H]Example 444
Racemic 3-(4-{l-[4-(4-methyl-pentyloxy)-phenoxy]-heptyl}-benzoyIamino)-propionic
acid
The title compound is prepared in a manner substantially similar to Example 92
starting from 3-{4-[l-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester and l-bromo-4-methyl-pentane. MS: 484.2 [M-H]".
Example 445
Racemic 3-{4-[l-(4-pentyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 92
starting from 3-{4-[l-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester and 1-bromo-pentane. MS: 468.2 [M-H]".
Example 446
3-{4-[5,5,5-trifluoro-l-(4'-trifluoromethyI-biphenyl-4-yloxy)-penryl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 447
3-{4-[5,5,5-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 2
F
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS:
552.2 [M-H]"; Isomer 2 MS: 552.2 [M-H]".
Example 448
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyI-4-yIoxy)-5,5;5-trifluoro-
pentyl]-benzoylamino}-propionic acid
0
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS:
568.2 [M-H]".
Example 449
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid methyl ester. MS: 516 [M-H]'.
Example 450
3-{4-[l-(4'-tert-butyl-biphenyI-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid, Isomer 1
and
Example 451
3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example
128 starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 540.3 [M-
H]"; Isomer 2 MS: 540.3 [M-H]".
Example 452
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yIoxy]-hexyl}-benzoylamino)-
propionic acid, Isomer 1
and
Example 453
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-benzoylamino)-
propionic acid, Isomer 2
The title compounds are prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-hexyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 513.3 [M-H]";
Isomer2 MS: 513.3 [M-H].
Example 454
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoylamino)-
propionic acid, Isomer 1
and
Example 455
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoyIamino)-
propionic acid, Isomer 2

The title compounds are prepared in a manner substantially similar to Example 62
starting from 3-{4-[l-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 499.2 [M-H]';
Isomer 2 MS: 499.2 [M-H]".
Example 456
Racemic 3-{4-[5,5,5-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid
The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 552.2[M-H]".
Example 457
Racemic 3-{4-[l-(4'-tert-butyl-biphenyl-4-yIoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 540.3[M-H]Example 458
Racemic 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid

The title compound is prepared in a manner substantially similar to Example 128
starting from 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid methyl ester. MS: 488 [M-H]".
Example 459
Racemic 3-{4-[l-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid

The title compound is prepared in a manner substantially similar to Example 92
starting from 3-{4-[l-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl
ester. MS: 398.3 [M-H]".
Example 460
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyI-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, isomer 1
and
Example 461
3-{4-[l-(2,6-Dimethyl-4MrifluoromethyI-biphenyl-4-yIoxy)-2-methyI-propylj-
benzoylamino}-propionic acid, isomer 1

The racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-
methyl-propyl]-benzoylamino}-propionic acid is resolved on a Chiralpak OJ-H column
(0.46 x 15 cm) with a flow rate of 0.6mL/min. and detection at 250nm. Elute with
Methanol and concentrate the fractions to provide a purified enantiomer ester isomer 1
(100 % ee) and enantiomer ester isomer 2 (99.3 % ee). Hydrolysis of the purified
enantiomer of the ester provided the title compound as a white solid. The structure was
confirmed by proton NMR.
Example 462
3-{4-[l-(2,6-DimethyI-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoyIamino}-
propionic acid, isomer 1
and
Example 463
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, isomer 1

The racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-
heptyl]-benzoylamino}-propionic acid is resolved on a Chiralpak OJ-H column (0.46 x 15
cm) with a flow rate of 0.6mL/min. and detection at 250nm. Elute with Methanol and
concentrate the fractions to provide a purified enantiomer ester isomer 1 (100 % ee) and
enantiomer ester isomer 2 (99.2 % ee). Hydrolysis of the purified enantiomer of the ester
provided the title compound as a white solid. The structure was confirmed by proton
NMR.
The compound of Formula I is preferably formulated in a unit dosage form prior
to administration. Therefore, yet another embodiment of the present invention is a
pharmaceutical composition comprising a compound of Formula I and one or more
pharmaceutically acceptable carriers, diluents or excipients.
The present pharmaceutical compositions are prepared by known procedures
using well-known and readily available ingredients. In making the formulations of the
present invention, the active ingredient (Formula I compound) will usually be mixed with
a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of
a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be
a solid, semisolid or liquid material that acts as a vehicle, excipient, or medium for the
active ingredient. Thus, the compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a
solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile
injectable solutions and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,
magnesium stearate and mineral oil. The formulations can additionally include
lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents,
sweetening agents or flavoring agents. The compositions of the invention may be
formulated so as to provide quick, sustained or delayed release of the active ingredient
after administration to the patient.
The compositions of the present invention may be formulated in sustained release
form to provide the rate controlled release of any one or more of the components or active
ingredients to optimize the therapeutic effects, i.e., antihistaminic activity and the like.
Suitable dosage forms for sustained release include layered tablets containing layers of
varying disintegration rates or controlled release polymeric matrices impregnated with the
active components and shaped in tablet form or capsules containing such impregnated or
encapsulated porous polymeric matrices.
Liquid form preparations include solutions, suspensions and emulsions. As an
example may be mentioned water or water-propylene glycol solutions for parenteral
injections or addition of sweeteners and opacifiers for oral solutions, suspensions and
emulsions. Liquid form preparations may also include solutions for intranasal
administration.
Aerosol preparations suitable for inhalation may include solutions and solids in
powder form, which may be in combination with a pharmaceutically acceptable carrier
such as inert compressed gas, e.g. nitrogen.
For preparing suppositories, a low melting wax such as a mixture of fatty acid
glycerides such as cocoa butter is first melted, and the active ingredient is dispersed
homogeneously therein by stirring or similar mixing. The molten homogeneous mixture
is then poured into convenient sized molds, allowed to cool and thereby solidify.
Also included are solid form preparations which are intended to be converted,
shortly before use, to liquid form preparations for either oral or parenteral administration.
Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The
transdermal compositions may take the form of creams, lotions, aerosols and/or
emulsions and can be included in a transdermal patch of the matrix or reservoir type as a
re conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form,
the preparation is subdivided into suitably sized unit doses containing appropriate
quantities of the active components, e.g., an effective amount to achieve the desired
purpose.
The quantity of the inventive active composition in a unit dose of preparation may
be generally varied or adjusted from about 0.01 milligrams to about 1,000 milligrams,
preferably from about 0.01 to about 950 milligrams, more preferably from about 0.01 to
about 500 milligrams, and typically from about 1 to about 250 milligrams, according to
the particular application. The actual dosage employed may be varied depending upon
the patient's age, sex, weight and severity of the condition being treated. Such techniques
are well known to those skilled in the art. Generally, the human oral dosage form
containing the active ingredients can be administered 1 or 2 times per day.
There is increasing evidence that glucagon plays an important role in glucose
homeostasis. Compounds of Formula I are effective as antagonists or inverse agonists of
the glucagon receptor, and thus inhibit the activity of the glucagon receptor. More
particularly, these compounds are selective antagonists or inverse agonists of the
glucagon receptor. As selective antagonists or inverse agonists, the compounds of
Formula I are useful in the treatment of diseases, disorders, or conditions responsive to
the inactivation of the glucagon receptor, including but not limited to diabetic and other
glucagon related disorder. It is postulated that selective antagonists or inverse agonists of
the glucagon receptor will lower plasma glucose levels and thus prevent or treat diabetic
and other glucagon related metabolic disorders.
PHARMACOLOGICAL METHODS
In the following section binding assays as well as functional assays useful for
evaluating the efficiency of the compounds of the invention are described.
Binding of compounds to the glucagon receptor may be determined in a
competition binding assay using the cloned human glucagon receptor, and selectivity
against the hGlpl receptor. Antagonism may be determined as the ability of the
compounds to inhibit the amount of cAMP formed in in the assay in the presence of 5 nM
glucagon.
Glucagon Receptor (hGlucR) Binding Assay
The receptor binding assay used cloned human glucagon receptor (Lok S, Kuijper JL,
Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH,
Rosenberg GB, et al.Gene 140 (2), 203-209 (1994)) isolated from 293HEK membranes.
The hGlucR cDNA was subcloned into the expression plasmid phD (Trans-activated
expression of fully gamma-carboxylated recombinant human protein C, an antithrombotic
factor. Grinnell, B.W., Berg, D.T., Walls, J. and Yan, S.B. Bio/Technology 5: 1189-1192
(1987)). This plasmid DNA was transfected into 293 HEK cells and selected with 200
ug/mL Hygromycin.
Crude plasma membranes are prepared using cells from suspension culture. The
cells are lysed on ice in hypotonic buffer containing 25 mM Tris HCL, pH 7.5, 1 mM
MgC12, DNAsel, 20 u/mL, and Roche Complete Inhibitors-without EDTA. The cell
suspension is homogenized with a glass dounce homogenizer using a Teflon pestle for 25
strokes. The homogenate is centrifuged at 4 degrees C at 1800 x g for 15 mins. The
supernate is collected and the pellet is resuspended in hypotonic buffer and
rehomogenized. The mixture is centrifuged at 1800 x g for 15 mins. The second
supernate is combined with the first supernate. The combined supernates are
recentrifuged at 1800 x g for 15 mins to clarify. The clarified supernate is transferred to
high speed tubes and centrifuged at 25000 x g for 30 minutes at 4 degrees C. The
membrane pellet is resuspended in homogenization buffer and stored as frozen aliquots at
-80 degree C freezer until needed.
Glucagon is radioiodinated by I-125-lactoperoxidase procedure and purified by
reversed phase HPLC at Perkin-Elmer/NEN (NEX207). The specific activity is 2200
Ci/mmol. Kd determination is performed by homologous competition instead of
saturation binding due to high propanol content in the 1-125 glucagon material. The Kd is
estimated to be 3 nM and is used to calculate Ki values for all compounds tested.
The binding assays are carried out using a Scintillation Proximity Assay
(Amersham) with WGA beads previously blocked with 1% fatty acid free BSA (ICN).
The binding buffer contains 25 mM Hepes, pH 7.4, 2.5 mM CaC12, 1 mM MgC12, 0.1%
fatty acid free BSA, (ICN), 0.003% tween-20, and Roche Complete Inhibitors without
EDTA. Glucagon is dissolved in 0.01 N HC1 at 1 mg/mL and immediately frozen at -80
degrees C in 30 ul aliquots. The glucagon aliquot is diluted and used in binding assays
within an hour. Test compounds are dissolved in DMSO and serially diluted in DMSO.
10 ul diluted compounds or DMSO is transferred into Corning 3632, opaque clear bottom
assay plates containing 90 ul assay binding buffer or cold glucagon (NSB at 1 uM final).
50 ul of 1-125 glucagon (0.15 nM final in reaction), 50 ul of membranes (300 ug/well),
and 40 ul of WGA beads (150 ugs/well) are added, covered, and mixed end over end.
Plates are read with a MicroBeta after 14 hours of settling time at room temp.
Results are calculated as a percent of specific I-125-glucagon binding in the
presence of compound. The absolute EC50 dose of compound is derived by non-linear
regression of percent specific binding of I-125-glucagon vs. the dose of compound added.
The EC50 dose is converted to Ki using the Cheng-Prusoff equation (Cheng Y., Prusoff
W. H., Biochem. Pharmacol. 22, 3099-3108, 1973).
Glucagon -Like - Peptide 1 (Glpl-R) Receptor Binding Assay
The receptor binding assay used cloned human glucagon-like peptide 1 receptor
(hGlpl-R). (Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD, Biochem
Biophys Res Commun. 1993 Oct 15; 196(1): 141-6) isolated from 293HEK membranes.
The hGlpl-R cDNA was subcloned into the expression plasmid phD (Trans-activated
expression of fully gamma-carboxylated recombinant human protein C, an antithrombotic
factor. Grinnell, B.W., Berg, D.T., Walls, J. and Yan, S.B. Bio/Technology 5: 1189-
1192 (1987)). This plasmid DNA was transfected into 293 HEK cells and selected with
200 ug/mL Hygromycin.
Crude plasma membrane is prepared using cells from suspension culture. The
cells are lysed on ice in hypotonic buffer containing 25 mM Tris HC1, pH 7.5, 1 mM
MgC12, DNAse, 20 u/mL, and Roche Complete Inhibitors without EDTA. The cell
suspension is homogenized with a glass dounce homogenizer using a Teflon pestle for 25
strokes. The homogenate is centrifuged at 4 degrees C at 1800 x g for 15 mins. The
supernate is collected and the pellet is resuspended in hypotonic buffer and
rehomogenized. The mixture is centrifuged at 1800 x g for 15 mins. The second
supernate is combined with the first supernate. The combined supernates are
recentrifuged at 1800 x g for 15 mins to clarify. The clarified supernate is transferred to
high speed tubes and centrifuged at 25000 x g for 30 minutes at 4 degrees C. The
membrane pellet is resuspended in homogenization buffer and stored as frozen aliquots in
-80 degree C freezer until use.
Glucagaon-like peptide 1 (Glp-1) is radioiodinated by the I-125-lactoperoxidase
procedure and purified by reversed phase HPLC at Perkin-Elmer/NEN (NEX308). The
specific activity is 2200 Ci/mmol. Kd determination is performed by homologous
competition instead of saturation binding due to high propanol content in the 1-125 Glp-1
material. The Kd is estimated to be 3 nM and is used to calculate Ki values for all
compounds tested.
The binding assays are carried out using a Scintillation Proximity Assay
(Amersham) with wheat germ agglutinin (WGA) beads previously blocked with 1% fatty
acid free BSA (ICN). The binding buffer contains 25 mM Hepes, pH 7.4, 2.5 mM CaCI2.
1 mM MgC12, 0.1% fatty acid free BSA, (ICN), 0.003% tween-20, and Roche Complete
Inhibitors without EDTA. Glucagon-like peptide 1 is dissolved in PBS at 1 mg/mL and
immediately frozen at -80 degrees C in 30 ul aliquots. The glucagon-like peptide aliquot
is diluted and used in binding assays within an hour. Test compounds are dissolved in
DMSO and serially diluted in DMSO. 10 ul diluted compounds or DMSO is transferred
into Corning 3632, opaque clear bottom assay plates containing 90 ul assay binding
buffer or cold glucagon-like peptide 1 (NSB at 1 uM final). 50 ul of 1-125 glucagon-like
peptide 1 (0.15 nM final in reaction), 50 ul of membranes (600 ug/well), and 40 ul of
WGA beads (150 ugs/well) are added, covered, and mixed end over end. Plates are read
with a MicroBeta after 14 hours of settling time at room temp.
Results are calculated as a percent of specific I-125-glucagon-like peptide 1
binding in the presence of compound. The absolute EC50 dose of compound is derived
by non-linear regression of percent specific binding of I-125-glucagon-like peptide 1 vs.
the dose of compound added. The EC50 dose is converted to Ki using the Cheng-Prusoff
equation (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22, 3099-3108, 1973).
Glucagon-Stimulated cAMP Functional Antagonist Assay
The cAMP functional assay uses the same cloned human glucagon receptor cell
line isolated for the hGlucR binding assay described above. Cells are stimulated with a
mixture of an EC80 dose of glucagon in the presence of compound. The cAMP generated
within the cell is quantitated using an Amplified Luminescent Proximity Homogeneous
Assay, Alpha Screen, from Perkin Elmer (6760625R).
Briefly, cAMP within the cell competes for binding of biotinylated cAMP from the kit to
a coated anti-cAMP antibody Acceptor bead and a strepavidin coated Donor bead. As the
cAMP level within the cell increases, a disruption of the Acceptor bead-biotinlyated
cAMP -Donor bead complex occurs and decreases the signal.
Glucagon is dissolved in 0.01 N HC1 at 1 mg/mL and immediately frozen at -80
degrees C in 30 ul aliquots. The glucagon aliquot is diluted and used in the functional
assay within an hour. Cells are harvested from sub-confluent tissue culture dishes with
Enzyme-Free Cell Dissociation Solution, (Specialty Media 5-004-B). The cells are
pelleted at low speed and washed 3 times with assay buffer [25 mM Hepes in HBSS-with
Mg and Ca (GIBCO, 14025-092) with 0.1% Fatty Acid Free BSA (ICN)] then diluted to a
final concentration of 250,000 cells per mL. Compounds are serially diluted into DMSO
then diluted into assay buffer with a 3X concentration of glucagon and 3% DMSO. The
EC80 of glucagon is pre-determined from a full glucagon dose response and represents
the dose at which glucagons produces an 80% of the maximal glucagon response. A
mixture of biotinylated cAMP (1 unit/well final) from the Alpha Screen Kit and 3X
IBMX (1500 uM) is prepared in Assay Buffer.
The functional assay is performed in 96 well, low-volume, white, poylstyrene
Costar Plates (3688). The biotinylated cAMP/IBMX mixture, 0.02 mLs, is placed into
each well, followed by addition of 0.02 mLs of glucagon dose response, cAMP standard
curve, or compound/glucagon mixtures. The reaction is started by addition of 0.02 mLs
of cells (5000/well final). After 60 minutes at room temperature, the reaction is stopped
by the addition of 0.03 mLs of Lysis Buffer [10 mM Hepes, pH 7.4, 1% NP40, and 0.01%
fatty acid free BSA (ICN) containing 1 unit each/well of Acceptor and Donor beads from
the Alpha Screen Kit]. Lysis Buffer addition is performed under a green light to prevent
bleaching of the detection beads. The plates are wrapped in foil and left to equilibrate
overnight at room temperature. The plates are read on a Packard Fusion™-" Instrument.
Alpha screen units are converted to pmoles cAMP generated per well based upon
the cAMP standard curve. The pmoles cAMP produced in the presence of compound are
converted to % of a maximal response with the EC80 dose of glucagon alone. With each
experiment, the dose of glucagon needed to produce a 50% response of pmoles cAMP is
determined. This EC50 dose is used to normalize results to a Kb using a modified
Cheng-Prusoff equation (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22, 3099-3108,
1973), where Kb = (EC50 compound)/ [1 + (pM glucagon used/ EC50 in pM for
glucagon dose response)].
The compounds according to the invention preferably have a Ki value of no
greater than 50uM as determined by the Glucagon Receptor (hGlucR) Binding Assay
disclosed herein. More preferably, the compounds according to the invention have a Ki
value of less than 5|iM, preferably of less than 500 nM and even more preferred of less
than 100 nM as determined by the Glucagon Receptor (hGlucR) Binding Assay disclosed
herein. Generally, the compounds according to the invention show a higher affinity for
the glucagon receptor compared to the GLP-1 receptor, and preferably have a higher
binding affinity to the glucagon receptor than to the GLP-1 receptor.
The results are given below for the indicated compound.
Table 1:
From the above description, one skilled in the art can ascertain the essential
characteristics of the present invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
various usages and conditions. Thus, other embodiments are also within the claims.
We Claim:
1. A compound structurally represented by Formula I

or a pharmaceutically acceptable salt thereof wherein:
Y is -O- or -S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the
optional substituents as indicated herein), or nitrogen (optionally substituted with
oxygen), provided that no more than two of Q, D, X, and T are nitrogen;
Rl is -H, -OH, or -halogen;
R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);
R3 and R4 are independently
- H, -halogen, -CN, -OH, -(CrC7) alkoxy, -(CrC7) alkyl(optionally
substituted with 1 to 3 halogens), or -(C2-C7) alkenyl;
R5 is selected from the group consisting of
-H, -(C1-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl,
-aryl, -aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl,
-(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl, -heterocycloalkyl,
-aryl-(C2-C10)alkenyl,-heteroaryl-(C2-C10)alkenyl,-(C2-Ci2)alkynyl,
-(C3-C12)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, and
-heteroaryl-(C2-Ci2)alkynyl, and wherein -(Ci-C|2)alkyl,
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl,
-aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(CrCi2)alkyl,
-heterocycloalkyl, -(C2-Ci2)alkenyl, -(C3-C|2)cycloalkenyl,
-aryl-(C2-C|0)alkenyl,-heteroaryl-(C2-C10)alkenyl,-(C2-Ci2)alkynyl,
-(C3-C12) cycloalkynyl, -aryl-(C2-Ci2)alkynyl, -heteroaryl-(C2-Ci2)alkynyl,
are each optionally substituted with from one to three substituents each
independently selected from the group consisting of-hydrogen, -hydroxy,
-cyano, -nitro, -halo, -oxo, -(C]-C7)alkyl (optionally substituted with 1 to 3
halogens), -(C1-C7)alkyl-C(O)OR12, -(CrC7)alkoxy, -(C3-C7)cycloalkyl,
-C(O)R12, -C(O)OR12, -OC(O)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12, -S(O)2R12, and
-S(O)2N(R12)2;
R6 and R7 are independently at each occurrence selected from the group
consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl,
-(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, tert-butoxyiminomethyl, l,3-dioxan-2-yl,
hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl,
4-methylpentyloxy, and pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not
attached to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6 or R7
are not attached to Q, and provided that wherein X is nitrogen, then R6 or
R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the
atoms to which they are attached, and the ring so formed may optionally
contain up to two oxygens, and further the ring so formed may optionally
be substituted with up to four halogens;
R8 and R9 are independently at each occurrence selected from the group
consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C|-C7)alkyl(optionally
substituted with 1 to 3 halogens), -(C1-C7)alkoxy, -(C3-C7)cycloalkyl,
-aryl, -aryl-(C]-C7)alkyl, -heteroaryl, -heteroaryl-(C1-C7)alkyl, -aryloxy,
-C(0)R12, -C00R12, -0C(0)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O)R12, -NR12SO2R12, -SR12, -S(0)R12, -S(O)2R12,
-O(C2-C7)alkenyl, and -S(O)2N(R12)2; and wherein -(C1-C7)alkyl,
-(C1-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl,
-heteroaryl-(C1-C7)alkyl, -aryloxy, and -O(C2-C7)alkenyl are each
optionally substituted with from one to three substituents independently
selected from the group consisting of -hydrogen, -hydroxy, -cyano, -nitro,
-halo, -oxo, -(C1-C7)alkyl, -(CrC7)alkyl-C(O)OR12, -(C1-C7)alkoxyl,
-(C3-C7)cycloalkyl, -heterocycloalkyl, -C(0)R12, -COOR12, -0C(0)R12,
-OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12,
-S(O)R12, -S(O)2R12, and -S(O)2N(R12)2;
RIO is selected from the group consisting of
-H, halogen, -(CrCi2)alkyl(optionally substituted with 1 to 3 halogens),
-cycloalkyl, -aryl, -aryl-(C1-C7)alkyl, -heteroaryl, -heteroaryl-(C1-C7)alkyl,
-(C2-C12)alkenyl, -(C3-C12)cycloalkenyl, -aryl-(C2-C10)alkenyl,
-heteroaryl-(C2-Cio)alkenyl, -(C2-Ci2)alkynyl, -(C3-C12)cycloalkynyl,
-aryl-(C2-Ci2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl;
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A, G, and
E are nitrogen;
provided however that wherein A is nitrogen, then R8, R9, and R14 are
not attached to A, and provided that wherein G is nitrogen, then R8, R9,
and R14 are not attached to G, and provided that wherein E is nitrogen,
then R8, R9, and R14 are not attached to E,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3,
and when m is 0 then (CF^m is a bond, and
wherein the zig-zag mark shows the point of attachment
to the parent molecule,
provided however that wherein D is nitrogen, then Rl 1 is not attached to
D, and provided that wherein T is nitrogen, then Rl 1 is not attached to T,
and provided that wherein Q is nitrogen, then Rl 1 is not attached to Q,
and provided that wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), and
-aryl;
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), phenyl, and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3
halogens).
'.. A compound of Formula I, as claimed in claim 1, or a pharmaceutically
acceptable salt thereof, wherein:
Y is -O- or -S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the
optional substituents as indicated herein), or nitrogen, provided that no more than
two of Q, D, X, and T are nitrogen;
Rl is -H, -OH, or -halogen;
R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);
R3 and R4 are independently
- H, -halogen, -CN, -(C1-C7) alkoxy, -(CrC7) alkyl(optionally substituted
with 1 to 3 halogens), or -(C2-C7)alkenyl;
R5 is selected from the group consisting of
-(C1-C12) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-C]2)alkyl,
-(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl, -heterocycloalkyl,
-(C2-Ci2)alkynyl, and -(C3-C12)cycloalkynyl, and wherein -(Ci-Ci2)alkyl,
-(C3-C12)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl,
-heterocycloalkyl, -(C2-Ci2)alkenyl, -(C3-C12)cycloalkenyl,
-(C2-C|2)alkynyl, and -(C3-C12) cycloalkynyl, are each optionally
substituted with from one to three substituents each independently selected
from the group consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo,
-oxo, -(C1-C7)alkyl (optionally substituted with 1 to 3 halogens);
R6 and R7 are independently at each occurrence selected from the group
consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl,
-(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens),
-(C3-C12)cycloalkyl, tert-butoxyiminomethyl, l,3-dioxan-2-yl,
hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl,
4-methylpentyloxy, and pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not
attached to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6 or R7
are not attached to Q, and provided that wherein X is nitrogen, then R6 or
R7 are not attached to X;
wherein R6 and R7 may optionally form a six membered ring with the
atoms to which they are attached, and the ring so formed may optionally
contain up to two oxygens, and further the ring so formed may optionally
be substituted with up to four halogens;
R8 and R9 are independently at each occurrence selected from the group
consisting of
-hydrogen, -hydroxy, -CN, -nitro, -halo, -(C1-C7)alkyl(optionally
substituted with 1 to 3 halogens), -(C1-C7)alkoxy, -(C3-Cv)cycloalkyl,
-C(O)R12, -C(O)OR12, -OC(O)R12, -OS(O)2R12, -N(R12)2,
-NR12C(O)R12, -NR12SO2 R12, -SR12, -S(O)R12, -S(O)2R12,
-O(C2-C7)alkenyl, and -S(O)2N(R12)2; and wherein -(C1-C7)alkyl,
-(Ci-Cv)alkoxy, -(C3-C7)cycloalkyl, and -O(C2-C7)alkenyl are each
optionally substituted with from one to three substituents independently
selected from the group consisting of-hydrogen, -hydroxy, -cyano, -nitro,
-halo, -oxo, and -(CpCT^lkyl;
RIO is selected from the group consisting of
-H, halogen, and -(Ci-Ci2)alkyl(optionally substituted with 1 to 3
halogens);
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A, G, and
E are nitrogen;
provided however that wherein A is nitrogen, then R8, R9, and R14 are
not attached to A, and provided that wherein G is nitrogen, then R8, R9,
and R14 are not attached to G, and provided that wherein E is nitrogen,
then R8, R9, and R14 are not attached to E,
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein m is an integer of 0, 1, 2, or 3,
and when m is 0 then (CH2)m is a bond, and
wherein the zig-zag mark shows the point of attachment
to the parent molecule,
provided however that wherein D is nitrogen, then Rl 1 is not attached to
D, and provided that wherein T is nitrogen, then Rl 1 is not attached to T,
and provided that wherein Q is nitrogen, then Rl 1 is not attached to Q,
and provided that wherein X is nitrogen, then Rl 1 is not attached to X;
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, and -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens);
R13 is independently at each occurrence selected from the group consisting of
-hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), phenyl, and -(C2-C7)alkenyl; and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3
halogens).
A compound of Formula I, as claimed in claim 2, or a pharmaceutically
acceptable salt thereof, wherein:
Yis-O-, or-S-;
Q, D, X, and T independently represent carbon (substituted with hydrogen or the
optional substituents as indicated herein);
Rl is -H, -OH, or -halogen;
R2 is -H;
R3 and R4 are independently -H, -halogen, or -(C1-C7) alkyl(optionally
substituted with 1 to 3 halogens);
R5 is selected from the group consisting of
-(C1-C12) alkyl(optionally substituted with 1 to 3 halogens), and
-(C3-C12)cycloalkyl(optionally substituted with 1 to 3 halogens);
R6 and R7 are independently at each occurrence selected from the group
consisting of
-H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C7)alkenyl,
-(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens),
-(C.-rCi2)cycloalkyl, tert-butoxyiminomethyl, l,3-dioxan-2-yl,
hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl,
4-methylpentyloxy, and pentyloxy;
provided however that wherein D is nitrogen, then R6 or R7 are not
attached to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6 or R7
are not attached to Q, and provided that wherein X is nitrogen, then R6 or
R7 are not attached to X;
R8 and R9 are independently at each occurrence selected from the group
consisting of
-hydrogen, -halogen, -(C1-C7)alkyl(optionally substituted with 1 to 3
halogens), -(CrC7)alkoxy, -(C3-C7)cycloalkyl, -C(O)R12, -C(O)OR12,
-OC(O)R12, -OS(O)2R12, -SR12, -S(O)R12, -S(O)2R12, and
-O(C2-C7)alkenyl;
RIO is-H;
Rl 1 is independently at each occurrence selected from the group consisting of
-H, -halogen, and
wherein the zig-zag mark shows the point of
attachment to the parent molecule, wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional substituents as
indicated herein);
R12 is independently at each occurrence selected from the group consisting of
-hydrogen, and -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens);
and
R14 is independently at each occurrence
-H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3
halogens).
A compound as claimed in any of claims 1, 2, or 3, wherein Y is -O- or -S-; Rl is
hydrogen or -OH; R2 is hydrogen; R3 and R4 are independently hydrogen or
halogen; R5 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, octyl, 3,3-
dimethylbutyl, 2-methylpropyl, 4-methylpentyl, 2,2-dimethylpropyl, 3-
trifluoropropyl, 4-trifluorobutyl, cyclohexyl, or 4-bromo- phenyl; R6 and R7 are
independently hydrogen, methyl, ethyl, 1,1,3,3-tetramethylbutyl, tert-butyl,
cyclohexyl, pentyl, isopropoxy, chloro, fluoro, bromo, hydroxy, trifluoromethyl, -
CN, methoxy, tertbutoxyiminomethyl, l,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morpholino-4-yl-methyl, 4-methylpentyloxy, and
pentyloxy, and wherein R6 and R7 combine to form, with the phenyl to which
they are attached, a fused benzodioxin moiety; R8 and R9 are independently
hydrogen, fluoro, chloro, methyl, ethyl, pentyl, isopropyl, tert-butyl,
trifluoromethyl, acetyl, 2-methylpropyl, methoxy, cyclohexyl, allyloxy, or
trifluoromethoxy; RIO is hydrogen; Rl 1 is hydrogen, halogen, phenyl
(substituted, independently at each occurrence, once with R8, once with R9, and
twice with R14), pyridinyl (substituted, independently at each occurrence, once
with R8, once with R9, and twice with R14), or benzoxy (substituted twice with
R13); R13 is hydrogen, trifluoromethyl, tertbutyl, isopropyl, chloro, fluoro,
bromo, methyl, ethyl, or phenyl, T is -CH-, -CR6-, or N; X is -CH- or -CR11-; D
is -CH-, -CR6-, -CR11-, or N; and Q is -CH-, -CR6-, or N; R14 is hydrogen,
bromo, fluoro, methyl, tertbutyl, or isopropyl.
A compound as claimed in any of claims 1, 2, 3, or 4 wherein Y is -O-.
A compound as claimed in any of claims 1, 2, 3, or 4 wherein Y is -S-.
'. The compound as claimed in claim 5 or 6 wherein Rl, R2, R3, R4, and RIO are -
H.
!. The compound as claimed in any of claims 1, 2, 3, 4, 5, 6, or 7 wherein D, X, Q,
and T are carbon (substituted with hydrogen or the optional substituents as
indicated herein).
>. The compound as claimed in any of claims 1, 2, 3, 4, 5, 6, or 7 wherein D is
nitrogen, and T, Q, and X are carbon (substituted with hydrogen or the optional
substituents as indicated herein).
0. The compound as claimed in any of claims 1, 2, 3, 4, 5, 6, or 7 wherein R6 and
R7 are independently hydrogen or methyl; X is carbon substituted with Rl 1; and
A, G, and E are carbon (substituted with hydrogen or the optional substituents as
indicated herein); and R5 is -(C1-Q2) alkyl(optionally substituted with 1 to 3
halogens), or -(C3-C12)cycloalkyl.
1. A compound as claimed in claim 1 selected from the group consisting of:
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[4,4,4-Trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[(4-Bromo-phenyl)-(4'-tert-butyl-biphenyl-4-yloxy)-methyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid;
Racemic3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-Cyclohexyl-phenoxy)-hexyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid;
Racemic 3-[4-(l-Phenoxy-hexyl)-benzoylamino]-propionic acid;
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3- {4-[ 1 -(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-
propionic acid;
Racemic 3-(4-{3-Methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{2-Methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-propyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{1 -[4'-trifluoromethoxy-biphenyl-4-ylsulfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[ 1 -(3',4'-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-cyano-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-Isobutyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-(4-{l-[4-(6-Methoxy-pyridin-3-yl)-phenylsulfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid;
3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid, Isomer 2;
3 - {4- [ 3 -Methyl-1 -(4'-tri fluoromethyl -biphenyl-4-yloxy)-butyl] -benzoyl amino} -
propionic acid, Isomer 1;
3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid,
Isomer 2;
3- {4-[l -(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 2;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionicacid,
Isomer 2;
3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[2-Methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-
propionic acid, Isomer 2;
3- {4-[ 1 -(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 2;
3-{4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 2;
3-(4-{l-[4'-(l-Fluoro-l-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{l-[4'-(l-Fluoro-l-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 2;
3-(4-{3-Methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{3-Methyl-l-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-propionic
acid, Isomer 2;
3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 2;
3 -(4- {1 - [6-(4-tert-Butyl-phenyl)-pyridin-3 -yloxy] -4,4-dimethyl-pentyl} -
benzoylamino)-propionic acid, Isomer 1;
Racemic 3 -(4- {1 - [6-(4-Trifluoromethyl-phenyl)-pyridin-3 -yloxy] -heptyl} -
benzoylamino)-propionic acid;
Racemic 3-(4- {4,4,4-Trifluoro-1 -[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxyJ-
butyl}-benzoylamino)-propionic acid;
Racemic 3-(4-{3-Methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl} -benzoylamino)-propionic acid;
Racemic 3-(4-{4,4-Dimethyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl} -benzoylamino)-propionic acid;
Racemic 3-(4-{l-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-
benzoylamino)-propionic acid;
Racemic 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid;
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-
benzoylamino)-propionic acid, Isomer 2;
3-(4- {1 -[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl }-benzoylamino)-
propionic acid, Isomer 1;
3-(4- {1 -[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl] -benzoylamino)-
propionic acid, Isomer 2;
3-(4-{4,4,4-Trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{4,4,4-Trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2;
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-
propionic acid, Isomer 1;
3-(4-{l-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-
propionic acid, Isomer 2;
Racemic 3-(4-{l-[6-(4-Isobutyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-
propionic acid;
Racemic 3-{4-[l-(3'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-Acetyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(3',4'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3- {4-[ 1 -(4'-methylsulfonyl-biphenyl-4-ylsulfanyl)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2',3'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(2',6'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[ 1 -(3'-isopropyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(3'-acetyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-pentyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[ 1 -(4'-cyclohexyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4-Allyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-
heptyl]-benzoylamino}-propionic acid;
Racemic 3-(4-{l-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[ 1 -(4-Pentyl-phenoxy)-heptyl]-benzoylamino}-propionic
acid;Racemic 3-(4-{l-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{l-[4-(3,5-bistrifluoromethyl-benzyloxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{l-[4-(4-isopropyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-chloro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-ethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-bromo-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-fluoro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-trifluoromethyl-benzyloxy)-phenoxy]-heptyl}-
benzoylamino)-propionic acid;
Racemic 3-(4- {1 -[4-(4-phenyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(3-chloro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4- {1 -[4-(3,4-dimethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 3-(4-{l-[4-(4-isopropxyphenoxy]-heptyl}-benzoylamino)-propionic
acid;
Racemic 3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid;
Racemic 3- {4-[ 1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[ 1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid;
3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[ 1 -(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[ 1 -(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 2;
3-{4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-
propionic acid, Isomer 2;
3- {4-[ 1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2;
3- {4-[ 1 -(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[ 1,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-(4- {1 -[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl} -benzoylamino)-
propionic acid, Isomer 1;
3-(4- {1 -[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylamino)-
propionic acid, Isomer 2;
3- {4-[ 1 -(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 2;
3-(4-{l-[4'-isopropyl-biphenyl-4-ylsulfanyl]-butyl}-benzoylamino)-propionic
acid, Isomer 1;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-tertbutyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-
hydroxy-propionic acid;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(S)-
hydroxy-propionic acid;
3-{4-[l-(4'-Pentyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[ 1 -(4'-Isobutyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1;
Racemic 3-{4-[l-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid;
3-{4-[l-(4'-Acetyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(3', 5'-dichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionicacid,
Isomer 1;
3-{4-[l-(3', 5'-dichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic acid,
Isomer 2;
3-{4-[l-(2', 3', 4'-trifluoro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(2',4' -dimethoxy-biphenyl-4-yloxy)-butyl] -benzoylamino} -propionic
acid, Isomer I;
3-{4-[l-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid,
Isomer 2;
3-{4-[ 1 -(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid, Isomer
1;
3-{4-[l-(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic acid, Isomer
2;
3-(4- {1 -[4-(l -Methyl-1 -phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-
propionic acid, Isomer 1;
3-(4-{l-[4-(l -Methyl- l-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-
propionic acid, Isomer 2;
3-{4-[l-(2', 4', 6'-trimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Fluoro-2'-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Fluoro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Chloro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionicacid,
Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid, Isomer 1;
3. {4_[ i -(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-
propionic acid, Isomer 2;
3-{3-Fluoro-4-[l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{3-Fluoro-4-[l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-2,6-dimemyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino} -
propionic acid, Isomer 2;
3- {4-[ 1 -(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3- {4-[ 1 -(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3_{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino} -propionic acid, Isomer 1;
3_ {4-[ l -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino} -
propionic acid, Isomer 1;
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1;
3- {4-f l-(4'-Fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino} -propionic
acid, Isomer 2;
3-{4-[l-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1;
3-{4-[l-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2;
3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid, Isomer 2;
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-f 1 -(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[l-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
benzoylamino}-propionic acid, Isomer l;3-{4-[l-(4'-Chloro-2,6-dimethyl-
biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid, Isomer 2;
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]-
benzoylaminoj-propionic acid, Isomer l;3-{4-[2-Methyl-l-(2-methyl-4'-
trifluoromethoxy-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid,
Isomer 2;
3- {4-[ 1 -(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[l-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-
benzoylamino}-propionic acid, Isomer 2;
3-(4-{3-Methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 1;
3-(4-{3-Methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 2;
3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
benzoylamino)-propionic acid, Isomer 2;
3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 1;
3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-bcnzoylamino)-propionic acid, Isomer 2;
3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid, Isomer 2;
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 1;
3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid,
Isomer 2;
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 1;
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 2;
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 1;
2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 2;
3 -(4- {1 -[4-( 1,1,3,3 -Tetramethyl-butyl)-phenoxy]-heptyl} -benzoylamino)-
propionic acid, Isomer 1;
3-(4-{ 1 -[4-(l, 1,3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-benzoylamino)-
propionic acid, Isomer 2;
3- {4-[ 1 -(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[ 1,4]dioxin-6-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[ 1,4]dioxin-6-yloxy)-heptyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(4'-terl-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3-(4-{3,3-Dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 1;
3-(4-{3,3-Dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
butyl}-benzoylamino)-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid, Isomer 2;
3-(4-{l-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]-3-
methyl-butyl}-benzoylamino)-propionic acid, Isomer 1;
3-(4- {1 -[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]-3-
methyl-butyl}-benzoylamino)-propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
3-{4-[ 1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2;
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-Fluoro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[l-(4'-Fluoro-2,6,2'-trimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer l;3-{4-[l-(2,6-Dimethyl-4'-
trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 2;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Isopropyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-
propionic acid;
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-
propionic acid;
Racemic 3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-
benzoylamino}-propionic acid;
Racemic 3-(3-Fluoro-4-{3-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid;
Racemic 3-(4-{l-[4-(l,l,3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{3-Methyl-l-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-2-hydroxy-propionic acid;
Racemic3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
butyl]-benzoylamino}-2-hydroxy-propionicacid;
Chiral 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
Chiral 3-{4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
Racemic 3-{4-[l-(4-Bromo-3-[l,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-2-hydroxy-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butylJ-
benzoylamino} -2-hydroxy-propionic acid;
Racemic 3-{4-[ 1 -(4-Pentyl-phenoxy)-heptyl]-benzoylaminoj -propionic acid;
Racemic 3-(4- {1 -[4-( 1 -Methyl-1 -phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-
propionic acid;
Racemic 2-Hydroxy-3- {4-[ 1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 2-Hydroxy-3-{4-[l-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butylj-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(4-Chloro-3-trifluoromethyl-phenoxy)-heptyl]-benzoylamino}-
2-hydroxy-propionic acid;
Racemic 3-{4-[l-(3-Chloro-4-methyl-phenoxy)-3-methyl-butyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-
heptyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;Racemic 3-{4-[l-(4'-Acetyl-2,6-dimethyl-
biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-4,4-
dimethyl-pentyl}-benzoylamino)-propionic acid;
Racemic 3-(4-{4,4-Dimethyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-pentyl}-benzoylamino)-propionic acid;
Racemic 3-(4-{4,4-Dimethyl-l-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-
3-yloxy]-pentyl}-benzoylamino)-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-2-hydroxy-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-2-hydroxy-propionicacid;
Racemic 2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl]-benzoylamino}-propionicacid;
Racemic 3-{4-[ 1 -(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3- {3-Fluoro-4-[ 1 -(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-
heptyl]-benzoylamino}-propionicacid;
Racemic 3-{4-[l-(4'-tert-Butyl-2-chloro-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3- {4-[ 1 -(4'-trifluoromethyl-2-chloro-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2', 4'-bistrifluoromethyl-2-chloro-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(2-Hydroxy-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-[l,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-(4-{l-[2-(tert-Butoxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3-
methyl-butyl}-benzoylamino)-propionic acid;
Racemic 3-(4- {1 -[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-
yloxy]-3-methyl-butyl}-benzoylamino)-propionicacid;
Racemic 3-{4-[l-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(2-Methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-acetyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4'-fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(3,5-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Chloro-3,5-dimethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-Chloro-3-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-
dimethyl-butyl] -benzoylamino} -propionic acid;
Racemic 3-{4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-
dimethyl-pentyl]-benzoylamino}-propionicacid;
Racemic 3- {4-[ 1 -(2,6-Dimethyl-4'-isopropyl-biphenyl-4-yloxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[2-Methyl-l-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-
propyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,6-Dimethyl-4'-chloro-biphenyl-4-yloxy)-4,4-dimethyl-
pentyl]-benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-propionic acid;
Racemic 3- {4-[ 1 -(2,6-Difluoro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,6-Difluoro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionicacid;
Racemic 3-(4-{3-Methyl-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionic acid;
Racemic 3-(4-{l-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-
butyl}-benzoylamino)-propionicacid;
Racemic 3-{4-[l-(4'-tert-Butyl-biphenyl-3-yloxy)-3-methyl-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethyl-biphenyl-3-yloxy)-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4'-Isopropyl-biphenyl-3-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[3-Methyl-l-(4'-trifluoromethoxy-biphenyl-3-yloxy)-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[3-Methyl-l-(6-methyl-4'-trifluoromethyl-biphenyl-3-yloxy)-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-tert-Butyl-6-methyl-biphenyl-3-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(2-Hydroxymethyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-
benzoylaminoj-propionic acid;
Racemic 3-(4-{l-[2-(Hydroxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3-
methyl-butyl}-benzoylamino)-propionic acid;
Racemic 3- {4-[ 1 -(4'-Isopropyl-2-morpholin-4-ylmethyl-biphenyl-4-yloxy)-3-
methyl-butyl]-benzoylamino}-propionic acid;
3-(4-{3,3-Dimethyl-l-[5-methyl-l-oxy-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
yloxy]-butyl}-benzoylamino)-propionicacid;
2-Hydroxy-3- {4-[ 1 -(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid, Isomer 1;
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid, Isomer 2;
2-Hydroxy-3- {4-[ 1 -(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid, Isomer 1;
2-Hydroxy-3-{4-[l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-
propyl]-benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 1;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylamino}-2-hydroxy-propionic acid, Isomer 2;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid;Racemic 3-{4-[l-(2,4,6-tri-t-
butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid;
3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl}-benzoylamino)-propionic acid, Isomer 1;
3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl }-benzoylamino)-propionic acid, Isomer 2;
Racemic 3-{4-[I-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid;
Racemic3-{4-[I-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-(4-{5,5,5-trifluoro-l-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-
3-yloxy]-pentyl}-benzoylamino)-propionicacid;
Racemic 3-(4- {4,4,4-trifluoro-l -[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-
3-yloxy]-butyl}-benzoylamino)-propionic acid;
3- {4-[ 1 -(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3- {4-f 1 -(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[ 1 -(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-
propionic acid, Isomer 2;3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-
yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-
pentyl]-benzoylamino}-propionic acid, Isomer 2;
3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-butyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid, Isomer 2;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-4,4,4-
trifluoro-butyl]-benzoylamino}-propionic acid;
Racemic 3- {4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-
trifluoro-butyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-
methyl-butyl]-benzoylamino}-propionicacid
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-
butyl]-benzoylamino} -propionic acid;
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-
benzoylamino}-propionic acid;
3- {4-[ 1 -(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
benzoylamino}-propionic acid, Isomer 2;
3-{4-[3-methyl-l-(2,2',4'-trichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[3-methyl-l-(2,2',4'-trichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-
propionic acid, isomer 2;
3- {4-[ 1 -(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino} -propionic acid, Isomer 1;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-
benzoylamino}-propionic acid, Isomer 2;
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid, Isomer 2;
Racemic 3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-
pentyl]-benzoylamino}-propionic acid;
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
benzoylaminoj-propionic acid, Isomer 2;
3-{4-[5-methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[5-methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
propionic acid, Isomer 2;
3-(4- {1 -[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4- {1 -[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-
benzoylamino)-propionic acid, Isomer 2;
Racemic 3-(4-{5-methyl-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
hexyl} -benzoylamino)-propionic acid;
Racemic 3-{4-[l-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-
hexyl]-benzoylamino}-propionic acid;
Racemic 3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[5-methyl-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[ 1 -(4'-tert-butyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
benzoylamino}-propionic acid;
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyl}-
benzoylamino)-propionic acid, Isomer 1;
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyl}-
benzoylamino)-propionic acid, Isomer 2;
3-(4- {1 -[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl} -
benzoylamino)-propionic acid, Isomer 1;
3-(4-{l-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-
benzoylamino)-propionic acid, Isomer 2;
Racemic 3-{4-[(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-cyclohexyl-methyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-
butyl]-benzoylamino}-propionic acid;
3- {4-[4,4,4-trifluoro-1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid, Isomer 1;
3- {4-[4,4,4-trifluoro-1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-
benzoylamino}-propionic acid, Isomer 2;
Racemic 3-(4-{4,4,4-trifluoro-l-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-butyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{5,5,5-trifluoro-l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-
pentyl} -benzoylamino)-propionic acid;
Racemic 3-(4-{[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-cyclohexyl-methyl}-
benzoylamino)-propionic acid;
Racemic 3-(4-{5,5,5-trifluoro-l-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-
pentyl} -benzoylamino)-propionic acid;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-
trifluoro-butyl]-benzoylamino}-propionic acid;
Racemic 3-(4-{cyclohexyl-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-methyl}-
benzoylamino)-propionic acid;
Racemic 3-{4-[cyclohexyl-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-methyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[4,4,4-trifluoro-l-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-
butyl]-benzoylamino}-propionic acid;
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamino}-
propionic acid, Isomer 2;
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-
propionic acid, Isomer 2;
Racemic 3-{4-[(4'-tert-butyl-biphenyl-4-yloxy)-cyclohexyl-methyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[5,5,5-trifluoro-l-(2'-3'-fluoro-4'-trifluoromethyl-biphenyl-4-
yloxy)-pentyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[5,5,5-trifluoro-l-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4'-ethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[5,5,5-trifluoro-l-(3'-fluoro-4'-trifluoromethyl-biphenyl-4-yloxy)-
pentyl] -benzoylamino} -propionic acid;
Racemic 3-{4-[l-(2,4,6-triisopropyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,3,4,5,6-pentamethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid;
3- {4-[ 1 -(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid, Isomer 1;
3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid, isomer 2;
Racemic 3-{4-[l-(4-ethyl-3, 5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
Racemic 3-{4-[l-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-
trifluoro-pentyl]-benzoylamino}-propionic acid;
Racemic 3-(4- {1 -[4-(4-methyl-pentyloxy)-phenoxy]-heptyl} -benzoylamino)-
propionic acid;
Racemic 3-{4-[l-(4-pentyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid;
3-{4-[5,5,5-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylaminoj-propionic acid, Isomer 1;
3-{4-[5,5,5-trifluoro-l-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid, Isomer 2;
Racemic 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-
pentyl]-benzoylamino}-propionic acid;
Racemic 3-{4-[l-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-
benzoylamino}-propionic acid;
3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid, Isomer 1;
3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid, Isomer 2;
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-benzoylamino)-
propionic acid, Isomer 1;
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-benzoylamino)-
propionic acid, Isomer 2;
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoylamino)-
propionic acid, Isomer 1;
3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoylamino)-
propionic acid, Isomer 2;
Racemic 3- {4-[5,5,5-trifluoro-1 -(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
benzoylamino}-propionic acid;
Racemic3-{4-[l-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-
benzoylaminoj-propionic acid;
Racemic 3-{4-[l-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
propionic acid;
Racemic 3-{4-[l-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid;
Racemic 3-(4-{l-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-
benzoylamino)-propionic acid;3-{4-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-
4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic acid, isomer 1;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
benzoylaminoj-propionic acid, isomer 1;
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, isomer 1; and
3- {4-[ 1 -(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-
benzoylaminoj-propionic acid, isomer 1,
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition which comprises a compound, or a
pharmaceutically acceptable salt thereof, as claimed in any of claims 1-11 and a
pharmaceutically acceptable carrier, wherein the amount of compound is in range
of 0.01 to 1000 mg by weight of the total composition.
13. A compound of formula I, or a salt thereof, as claimed in any one of claims 1-11,
for use in treating a diabetic or other glucagon related metabolic disorder.
14. A compound as claimed in claim 1 of the formula
or a pharmaceutically acceptable salt thereof.
15. A compound as claimed in claim 14 which is 3-{4-[l-(4'-tert-butyl-2,6-dimethyl-
biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid, Isomer 1,
or a pharmaceutically acceptable salt thereof.
16. A compound as claimed in claim 1 of the formula

or a pharmaceutically acceptable salt thereof.
17. A compound as claimed in claim 16 which is 3-{4-[l-(2,6-Dimethyl-4'-
trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-propionic
acid, Isomer 1, or a pharmaceutically acceptable salt thereof.
18. A compound as claimed in claim 1 of the formula

or a pharmaceutically acceptable salt thereof.
19. A compound as claimed in claim 18 which is 3-{4-[l-(4'-tert-Butyl-2,6-dimethyl-
biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-propionic acid, Isomer 1, or
a pharmaceutically acceptable salt thereof.
20. A compound of Formula (I) and/or a pharmaceutical composition comprising the
same, substantially as hereinbefore described with reference to the foregoing
examples.

The present invention discloses novel compounds of Formula I,
or pharmaceutically acceptable salts thereof, which have glucagon receptor
antagonist or inverse agonist activity, as well as methods for preparing such compounds.
In another embodiment, the invention discloses pharmaceutical compositions comprising
compounds of Formula I as well as methods of using these compounds and compositions
to treat diabetic and other glucagon related metabolic disorders, and the like.