COMPOUNDS CONTAINING CARBON-CARBON LINKER AS GPR120 AGONISTS
Field of the Invention
The present invention relates to compounds containing carbon-carbon linker
represented by the compounds of Formula (I) (as described herein); processes for their
preparation; pharmaceutical compositions comprising said compounds; and methods of
using said compounds for the treatment or prophylaxis of the diseases or disorders
mediated by GP 120 receptor.
Background of the Invention
Metabolic diseases or disorders are caused by an abnormal metabolic process and
may either be congenital due to an inherited enzyme abnormality, or acquired due to a
disease of an endocrine organ or failure of a metabolically important organ such as the
liver or the pancreas.
Among the metabolic disorders, diabetes mellitus is the most prevalent and is
considered to be one of the five leading causes of death in the world (Diabetes Care, vol.
27, 2004, pp. 1047-1053). Diabetes mellitus is typically classified into two main
subtypes: Type 1 and Type 2 diabetes mellitus. Type 1 diabetes mellitus (otherwise
known as Insulin Dependent Diabetes Mellitus, IDDM), which generally occurs in
adolescents under 20 years of age, is an auto-immune disease causing an insulitis with
the subsequent destruction of insulin-producing -cells of the pancreas. Further, in latent
autoimmune diabetes in adults (LADA), -cells are destroyed due to autoimmune attack.
The subsequent lack of insulin leads to elevated levels of blood and urine glucose
(hyperglycemia). Although the exact trigger for this autoimmune response is not known,
patients with Type 1 diabetes have high levels of antibodies against pancreatic beta cells
(hereinafter "beta cells"). However, it cannot be ascertained that all patients with high
levels of these antibodies develop Type 1 diabetes. Type 2 diabetes mellitus or noninsulin-
dependent diabetes mellitus (NIDDM) is developed when human muscles, fat and
liver cells are not able to respond normally to insulin that body secretes. This inability to
respond, otherwise known as insulin resistance, may be due to restriction on the
numbers of insulin receptors on these cells, or a dysfunctional behaviour of signalling
pathways within the cells, or both. Initially, the -cells which are responsible for the
production of insulin, compensate for this insulin resistance by increasing their insulin
secretion. However, gradually these cells become unable to produce enough insulin to
facilitate the normal glucose homeostasis, causing the progression to Type 2 diabetes
(Am J Med. 108(6), Supplement 1, 2000, pp. 2S-8S). Type 2 diabetes (T2D) is
characterised by fasting hyperglycemia which occurs as an effect of the combined lesions
of insulin resistance and -cell dysfunction. There are two types of defects associated
with the -cells: the first component, an increase in the basal insulin release which
usually occurs in the presence of low, non-stimulatory glucose concentrations. The
second component is a failure to enhance the insulin release in response to a
hyperglycaemic challenge.
Obesity is another risk factor for developing metabolic diseases or disorders such
as diabetes, cardiovascular disorders, hypertension, hyperlipidemia and an increased
mortality. Diabetes caused by insulin resistance and obesity are part of the "metabolic
syndrome" which is defined as the linkage between several diseases (also referred to as
syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the
same patients and are major risk factors for the development of Type 2 diabetes and
cardiovascular diseases (Frontiers in Endocrinology, vol. 4, 2013, pp. 1 - 11). It has
been suggested that the control of lipid levels and/or glucose levels is required to treat
type 2 diabetes and cardiovascular diseases. Even though lifestyle changes like exercise
and healthy diet are regarded as the most efficient ways to prevent and manage the
disease, pharmaceutical intervention is frequently necessary.
Current treatment options for diabetes, particularly T2D include use of
hypoglycaemic agents and insulin. Metformin is one such hypoglycaemic agent, which is
used in the treatment of Type 2 diabetes. It is, in fact, one of the oldest drugs used for
the treatment of T2D and it continues to remain the drug of choice despite associated
gastrointestinal (GI) side effects including anorexia, nausea, diarrhoea and vomiting
commonly associated with it. In fact, metformin should be used with caution in patients
with renal impairment because of the slight risk of lactic acidosis. Sulfonylureas (SUs)
e.g. glihnepiride, glipizide, are insulin secretagogues, which act on -cells to increase
insulin release, are commonly used in the treatment of Type 2 diabetes. However, use of
sulfonylureas is also associated with adverse effects in that they increase the risk of
hypoglycaemia and lead to weight gain. Insulin treatment also carries the same sideeffects.
Thiazolidinedione compounds e.g. rosiglitazone, pioglitazone, are insulin
sensitizers which bind to peroxisome proliferator-activated receptors (PPARs) in cells and
thereby increase the insulin sensitivity. Though, thiazolidinedione compounds have also
been widely used, the enhanced risks of cardiovascular disease and hepatotoxicity have
resulted in stringent limitations on their use. Relatively recently, regulatory authorities
approved new classes of anti-diabetic agents such as GLP-1 agonists (exenatide and
liraglutide) and DPP-4 inhibitors (linagliptin and alogliptin).
It is a known fact that metabolic processes are regulated by fatty acids which are
important biological molecules that serve both as a source of energy and as signalling
molecules. Generally, it is believed that fatty acids produce their biological effects
through interacting with intracellular targets including, for example, the family of
peroxisome proliferator-activated receptors (PPARs). However, in the recent years it has
become clear that fatty acids also serve as agonists for a group of cell surface G proteincoupled
receptors (GPCRs). Free fatty acids (FFAs) have been demonstrated to act as
ligands of several GPCRs including GPR40 (FFAR1), GPR43, GPR84, GPR119 and
GPR120. One of the GPCR namely GPR40 facilitates glucose-stimulated insulin secretion
from pancreatic -cells, whereas the other GPC namely GPR120 regulates the secretion
of glucagon-like peptide-1 (GLP-1) in the intestine, as well as insulin sensitivity in
macrophages. GPR120 is localized to intestinal enteroendocrine cells, such as colonic L
cells. Certain research studies conducted relative recently, identified that loss-of-function
GPR120 human variant is associated with obesity, diabetes and other insulin resistance,
and related metabolic disorders, and also with inflammatory disorders. These findings
establish GPR120 as a potential target for the treatment of diabetes, other metabolic
disorders, and inflammatory disorders as well (Trends Pharmacol Scl. vol. 32(9), 2011
pp.543-550).
Various patent documents describe compounds which are reported to be GPR120
modulators. Examples of patent documents describing GPR120 modulators include PCT
Application Publications WO2008103500, WO2009038204, WO2010008831,
WO2010048207, WO2010080537, WO2010104195, WO2011072132, WO2013 139341
and WO2013185766; European Published Patent Application EP2125758A1; US
Published Patent Application US2011065739 and US Patent No. 8367708.
Thus, in view of the role of GPR120 receptor in potentiating metabolic disorders
such as diabetes and related disorders, and also, inflammatory disorders, there is a
continuing need to develop compounds that act by modulating the GPR120 receptor
pathways.
Summary of the Invention
In one aspect, the present invention relates to a compound of Formula (I) (as
described herein), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a
pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a
carboxylic acid isostere thereof.
I n another aspect, the present invention relates to a process for the preparation
of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
I n a further aspect, the present invention relates to a pharmaceutical composition
comprising a therapeutically effective amount of a compound of Formula (I) or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a pharmaceutically
acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or
excipient.
In a further aspect, the present invention relates to a pharmaceutical composition
comprising a therapeutically effective amount of a compound of Formula (I) or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a pharmaceutically
acceptable solvate thereof; and one further therapeutically active agent and at least one
pharmaceutically acceptable carrier or excipient.
I n an aspect, the present invention relates to the compound of Formula (I) or a
tautomer, a stereoisomer, a pharmaceutically acceptable salt or a pharmaceutically
acceptable solvate thereof; for use as GPR120 agonist.
I n another further aspect, the present invention relates to a method for
modulating GPR120 function in a cell, comprising contacting a cell with an effective
amount of a compound of Formula (I) or a stereoisomer, a tautomer or a
pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.
I n yet another further aspect, the present invention relates to a method for the
treatment or prophylaxis of a disease or a disorder mediated by GPR120, comprising
administering to a subject in need thereof; a therapeutically effective amount of the
compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable
salt, or a pharmaceutically acceptable solvate thereof.
In yet another aspect, the present invention relates to a compound of Formula
(I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
pharmaceutically acceptable solvate thereof; for use in the treatment or prophylaxis of a
disease or a disorder mediated by GPR120.
In a still further aspect, the present invention relates to use of the compound of
Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof; in the manufacture of a medicament, for
the treatment or prophylaxis of a disease or a disorder mediated by GPR120.
In another further aspect, the present invention relates to use of the compound
of Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof; in combination with one further
therapeutically active agent for the treatment or prophylaxis of a disease or a disorder
mediated by GPR120.
These and other objectives and advantages of the present invention will be
apparent to those skilled in the art from the following description.
Detailed Description of the Invention
It should be understood that the detailed description and specific examples, while
indicating embodiments of the invention, are given by way of illustration only, since
various changes and modifications within the spirit and scope of the invention will
become apparent to those skilled in the art.
One skilled in the art, based upon the definitions herein, may utilize the present
invention to its fullest extent. The following specific embodiments are to be construed as
merely illustrative, and not limitative of the remainder of the disclosure in any way
whatsoever.
Except as defined herein, all the technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art to which
the invention relates.
Definitions
For the purpose of the disclosure, listed below are definitions of various terms
used to describe the present invention. Unless otherwise indicated, these definitions
apply to the terms as they are used throughout the specification and the appended
claims, either individually or as part of a larger group. These definitions should not be
interpreted in the literal sense as they are not general definitions, and are relevant only
for this application.
The singular forms "a", "an" and "the" include plural aspects unless the context
clearly dictates otherwise. For instance, the terms "a", "an" and "the" refers to "one or
more" when used in the subject specification, including the claims. Thus, for example,
reference to "a compound" may include a plurality of such compounds, or reference to "a
disease" or " a disorder" includes a plurality of diseases or disorders.
Also, use of "(s)" as part of a term, includes reference to the term singly or in '
plurality, for example the term salt(s) indicates a single salt or more than one salt of the
compound of formula (I).
The term "or" is generally employed in its sense including "and/or" unless the
content clearly dictates otherwise.
A symbol ( - ) is used to indicate a point of attachment to the atom, for example
- COOH is attached through the carbon atom.
Unless indicated otherwise, the term "optionally substituted" when used means
"substituted or unsubstituted," and therefore, the generic structural formulae described
herein encompasses compounds containing the specified optional substituent as well as
compounds that do not contain the optional substituent. For example, the phrase
"heteroaryl is optionally substituted with one or more groups" encompasses
unsubstituted heteroaryl ring, and heteroaryl ring substituted with one or more groups
as described.
Within the context of the present application and as used herein, the term
"unsaturated" means that a moiety has one or more units of unsaturation.
Within the context of the present application and as used herein, the term
"partially unsaturated" refers to a ring moiety that includes at least one double bond
between ring atoms but is not aromatic.
The term "independently" when used in the context of selection of substituents
for a variable, it means that where more than one substituent is selected from a number
of possible substituents, those substituents can be the same or different.
As used herein, the term "halogen" refers to chlorine, fluorine, bromine or iodine
atom.
As used herein, the term "(Ci-C 6)alkyl" or "alkyl" alone or as part of a substituent
group, refers to the radical of saturated aliphatic groups, including straight or branchedchain
alkyl groups. A straight-chain or branched chain alkyl has six or fewer carbon
atoms in its backbone, for instance, Ci-C6 for straight chain and C3-C for branched
chain. As used herein, (Ci-C 6)alkyl refers to an alkyl group having from 1 to 6 carbon
atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl,
n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, ferf-butyl, isopentyl,
2-methylbutyl and 3-methylbutyl. In the " (Ci - alky " group, one or more carbon atoms
can be optionally replaced with one or more heteroatoms independently selected from
the group consisting of N, O and S.
Furthermore, unless stated otherwise, the alkyl group can be unsubstituted or
substituted with one or more groups, for example, from one to four groups,
independently selected from the group consisting of (Ci-C )alkyl, (Ci-C )alkenyl,
halogen, halo(Ci-C6)alkyl, hydroxy, (Ci-C )alkoxy, halo(Ci-C )alkoxy, (C3-Ci 0)cycloalkyl,
(C6-Cio)aryl, (C6-Ci 0)aryloxy, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Cialkyl,
-N[(C 1-C6)alkyl] 2, -C OX - alkyl, -C(0)0(C -C6)alkyl, -C(0)NH 2, -
C O H -C alkyl, -C O Ci -C alkyl and -C O HSO Ci -Ce alkyl.
Examples of substituted alkyl include, but are not limited to, hydroxymethyl, 2-
chlorobutyl, trifluoromethyl, aminoethyl or benzyl.
As used herein, the term "halo - alkyl" or "haloalkyl" refers to alkyl groups as
defined above wherein one or more hydrogen atom of same or different carbon atoms of
the alkyl group are substituted with same or different halogens. A monohalo(Ci-C )alkyl
radical, for example, can have a chlorine, bromine, iodine or fluorine atom. Dihalo or
polyhalo(C1-C6)alkyl radicals can have two or more of the same or different halogen
atoms. Representative examples of halo(Ci-C 6)alkyl include, but are not limited to,
chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl,
fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl or difluoropropyl.
As used herein, the term "(Ci-C 6)alkoxy" or "alkoxy" refers to a (CrC )alkyl
having an oxygen radical attached thereto. The terms "(Ci-C )alkoxy" or -0(Ci-C 6)-
alkyl" or alkoxy wherever used in this specification have the same meaning.
Representative examples of alkoxy groups include, but are not limited to, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and teri-butoxy. Furthermore, unless
stated otherwise, the alkoxy groups can be unsubstituted or substituted with one or
more groups. A substituted alkoxy refers to a (Ci-C )alkoxy substituted with one or
more groups, particularly one to four groups independently selected from the groups
indicated above as the substituents for the alkyl group.
As used herein, the term (C3-Ci0)cycloalkyl" or "cycloalkyl" whether used alone or
as part of a substituent group, refers to a saturated or partially unsaturated cyclic
hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 10 carbon
atoms; preferably 3 to 8 carbon atoms forming the rings i.e. (C3-Ci0)cycloalkyl or (C3-
C8)cycloalkyl group. The term cycloalkyl includes bridged, fused and spiro ring systems.
For example, (C3-Ci0)cycloalkyl refers to a cycloalkyl group having 3 to 10 (both
inclusive) carbon atoms. Representative examples of cycloalkyl include, but are not
limited to, cyclobutyl, cyclopentyl, cyclohexyl, l,2,3,3a-tetrahydropentalene, adamantyl,
norbornyl, tetrahydronaphthalene, bicyclo[2.1.0]pentane, bicyclo[4.2.0]octane,
bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane, and the like. Unless
stated otherwise, (C4-C8)cycloalkyl may be unsubstituted or substituted with one or
more groups independently selected from the group consisting of (Ci-C )alkyl, halogen,
halo(Ci-C6)alkyl, hydroxy, -0 (Ci-C )alkyl, halo(Ci-C6)alkoxy, (C3-Ci )cycloalkyl, (C6-
C )aryl, heterocyclyl, heteroaryl, amino and cyano.
The term "(C -C 0)aryl " or "aryl" as used herein refers to a monocyclic or bicyclic
hydrocarbon groups having 6 to 10 ring carbon atoms, wherein at least one carbocyclic
ring is having a electron system. Examples f (C6-C10)aryl ring include, but are not
limited to, phenyl or naphthyl. Unless indicated otherwise, aryl group may be
unsubstituted or substituted with one or more groups. A substituted aryl refers to a (C6-
Cio)aryl substituted with one or more groups, preferably 1 to 7 groups, and more
preferably 1 to 3 groups independently selected from the group consisting of (C -
C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(d -C6)alkyl, hydroxy, -0 -(Ci-
C6)alkyl, halo(Ci-C )alkoxy, (C3-Ci )cycloalkyl, (C6-Ci0)aryl , heterocyclyl, heteroaryl,
amino and cyano. Aryl groups can be substituted in any desired position. For example, in
monosubstituted aryl such as phenyl, the substituent can be located in the 2-position,
the 3-position, the 4-position or the 5-position. If the phenyl carries two substituents,
they can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position
or 3,5-position. Examples of monosubstituted phenyl groups include, but are not limited
to, 2-fluorophenyl, 2-ethoxyphenyl, 2-ethylphenyl, 4-morpholinophenyl, (4-
ethylpiperazin-l-yl)phenyl or 4-(2-dimethylaminoethyl)phenyl. Examples of disubstituted
phenyl groups include, but are not limited to, 2,6-difluorophenyl or 3,5-difluorophenyl.
As used herein, the term "heteroaryl", whether used alone or as part of a
substituent group, refers to saturated or partially unsaturated 5- to 12-membered,
preferably 5- to 10-membered monocyclic or bicyclic aromatic ring system containing 1,
2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen,
nitrogen and sulfur atom. Representative examples of heteroaryls include, but are not
limited to, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole,
benzofuran, indole, benzoxazole, benzothiazole, isoxazole, triazine, purine, pyridine,
pyrazine, quinoline, isoquinoline, phenazine, oxadiazole, pteridine, pyridazine,
quinazolinyl, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, pyrido[2,3-
b]pyrazine. The oxidized form of the ring nitrogen and sulfur atom contained in the
heteroaryl to provide the corresponding N-oxide, S-oxide or S,S-dioxide is also
encompassed in the scope of the present invention.
Furthermore, the heteroaryl groups can be unsubstituted or substituted with one
or more groups; preferably 1 to 7 groups, more preferably 1 to 3 groups independently
selected from the group consisting of halogen, hydroxy, (Ci-C 6)alkyl, halo(Ci-C )alkyl,
(Ci-C6)alkoxy, halo(Ci-C 6)alkoxy, (C3-Ci0)cycloalkyl, (C6-Ci 0)aryl , heterocyclyl,
heteroaryl, amino, cyano and oxo. The representative examples of heteroaryl include,
but are not limited to, pyrrole, pyrazole, imidazole, isothiazole, pyrazine, furan,
thiophene, triazole, benzothiazole, benzofuran, indole, purine, pyridine, quinoline,
isoquinoline, pyridazine, quinazolinyl, pyrimidine and azocine.
The term "heteroatom" as used herein, includes nitrogen (N), oxygen (O) and
sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom
to satisfy the valency or when the heteroatom is N, it may be substituted with a group
selected from ( - alkyl, -C OXd - alkyl, -C(0)0(d-C 6)alkyl or -S O d -Ce lkyl.
Suitable (Ci-C )alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl,
pentyl, hexyl, isopropyl or isobutyl.
As used herein, the term "heterocycloalkyl" refers to saturated or partially
unsaturated 5- to 12 membered, preferably 5- to 10-membered monocyclic or bicyclic
ring containing at least one heteroatom, preferably, 1, 2, 3 or 4 heteroatoms
independently selected from the group consisting of nitrogen, oxygen, and sulfur. The
representative examples of heterocyclyl include, but are not limited to,
tetrahydropyranyl, piperidinyl, piperidino, N-methylpiperidin-3-yl, piperazinyl, Nmethylpyrrolidin-
3-yl, 3-pyrrolidinyl, 2-pyrrolidon-l-yl, pyrrolidinyl, aziridinyl, pyrrolidino,
piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl,
tetrahydrothiofuranyl, and pyranyl.
Furthermore, the heterocycloalkyl groups can be unsubstituted or substituted
with one or more groups; preferably 1 to 7 groups, more preferably 1 to 3 groups
independently selected from the group consisting of halogen, hydroxy, (Ci-C6)alkyl,
halo(C -C6)alkyl, ( - alkoxy, halo(d-C 6)alkoxy, (C3-Ci0)cycloalkyl, (C6-C10)aryl,
heterocyclyl, heteroaryl, amino, cyano and oxo
As used herein, the term "isotopic forms" or "isotopically labeled forms" is a
general term used for isotopic forms of the compounds of Formula (I), wherein one or
more atoms of the compounds of Formula (I) are replaced by their respective isotopes.
All isotopes of any particular atom or element as specified are contemplated within the
scope of the compounds of the invention. Examples of isotopes that can be incorporated
into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen
such as H (deuterium or D) and 3H, carbon such as C, 13C and 14C, nitrogen such as
1 N and N, oxygen such as 1 0 , 170 and 180 , chlorine such as 3 CI, fluorine such as 18F
and sulfur such as 3 S. Substitution with heavier isotopes, for example, replacing one or
more key carbon-hydrogen bonds with carbon-deuterium bond may show certain
therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo
half life or reduced dosage requirements), improved safety or greater effectiveness and
hence, may be preferred in certain circumstances.
In the context of the present invention, the term "the compounds of the present
invention" or "the compounds encompassed in the present invention" are used
interchangeably; and refer to the compounds of Formula (I) and/or the compounds of
Formula (IA) and/or the compounds of Formula (IB) and/or the compounds of Formula
(IC) as described herein, and encompass within its/their scope a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a
prodrug, a polymorph or an N-oxide thereof. The compound(s) of the present invention
can also be referred to herein as "the active compound" or "the active ingredient".
Within the context of the present invention and as used herein, the term
"stereoisomer" is a general term used for all isomers of individual compounds that differ
only in the orientation of their atoms in space. The term stereoisomer includes mirror
image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic
mixtures), geometric (cis/trans, syn/anti or E/Z) isomers, and isomers of compounds
with more than one chiral center that are not mirror images of one another
(diastereoisomers).
As used herein, the term "tautomer" refers to the coexistence of two or more
compounds that differ from each other only in the position of one (or more) mobile
atoms and in electron distribution. For example, proton tautomers (also known as
prototropic tautomers) include interconversions via migration of a proton, such as ketoenol
and imine-enamine tautomers.
Within the context of the present invention and as used herein, the term
"pharmaceutically acceptable" means that the carrier, diluent, excipients, and/or salt
must be compatible with the other ingredients of the formulation or composition, and not
deleterious to the recipient thereof.
The term "pharmaceutically acceptable salt(s)" as used herein includes a salt or
salts of the active compounds i.e. the compounds of Formula (I) and are prepared with
suitable acids o bases, depending on the particular substituents found on the
compounds described herein.
As used herein, the term "pharmaceutically acceptable solvate" or "solvate(s)"
describe a complex wherein the compound of Formula (I) of the present invention, is
coordinated with a proportional amount of a solvent molecule. Specific solvates, wherein
the solvent is water, are referred to as hydrates.
As used herein, the term "prodrug" refers to a compound that is drug precursor,
which, when administered to a subject undergoes transformation through metabolic
process or chemical transformation in vivo to form an active compound, for example, a
prodrug after being brought to the physiological pH or through enzyme action is
converted to active compounds, that is, compound of Formula (I) of the present
invention. In context of the present invention prodrugs can be esters of the compound
of Formula (I), which on metabolism can form an active compound of Formula (I).
As used herein, the term "polymorph" or "polymorphic form" or "polymorphs"
refers to crystals of the same compound that differs only in the arrangement and/or
conformation of the molecule in the crystal lattice.
As used herein, the term "N-oxide" refers to the oxide of the nitrogen atom of a
nitrogen-containing heteroaryl or heterocycloalkyl. N-oxide can be formed in the
presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or
hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and
is a chemical compound that contains N->0 bond.
As used herein, the term "S-oxide" refers to an oxide of the sulfur atom (S-oxide)
or a dioxide of the sulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl or
heterocycloalkyl. S-oxide and S,S-dioxides can be formed in the presence of an oxidizing
agent, for example, a peroxide such as m-chloro-perbenzoic acid or oxone.
As used herein, the term "carboxylic acid isostere" refers to a functional group or
a moiety that elicits similar physical, biological and/or chemical properties as a
carboxylic acid moiety. Representative examples of carboxylic acid isostere include, but
are not limited to:
The term "pharmaceutically acceptable carrier" as used herein means a nontoxic,
inert, solid, semi-solid, diluent, encapsulating material or formulation auxiliary of any
type. few examples of materials, which can serve as pharmaceutically acceptable
carriers include, sugars such as lactose, glucose, and sucrose; starches such as corn
starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc; as well as other non
toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as
well as coloring agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents; preservatives and antioxidants can also be used in the composition,
according to the judgment of the formulator.
As used herein, the term "a disease or a disorder mediated by GPR120" or
"GPR120 mediated disease(s) or disorder(s)" refers to a disease or a disorder or a
condition characterized by inappropriate, for example, less than or greater than normal
GPR120 activity. A GPR120-mediated disease or disorder may be completely or partially
mediated by inappropriate GPR120 activity.
The term "metabolic disorder" as used herein refers to a disorder relating to
abnormality of metabolism. Accordingly, in the context of the present invention all the
disorders relating to abnormality of metabolism are encompassed in the term "metabolic
disorders".
The term "metabolic syndrome" refers to a cluster of metabolic abnormalities
including abdominal obesity, insulin resistance, glucose intolerance, diabetes,
hypertension and dyslipidemia. These abnormalities are known to be associated with an
increased risk of vascular events.
The term "diabetes mellitus" or "diabetes" refers t o a chronic disease or
condition, which occurs when the pancreas does not produce enough insulin, or when the
body cannot effectively use the insulin it produces. This leads to an increased
concentration of glucose in the blood (hyperglycaemia). Two major forms of diabetes are
Type 1 diabetes (Insulin-dependent diabetes mellitus) and Type 2 diabetes (Non-insulin
dependent diabetes mellitus (NIDDM)). Type 1 diabetes is an autoimmune condition in
which the insulin-producing -cells of the pancreas are destroyed which generally results
in an absolute deficiency of insulin, the hormone that regulates glucose utilization., Type
2 diabetes often occurs in the face of normal or even elevated levels of insulin and can
result from the inability of tissues to respond appropriately to insulin. Other categories of
diabetes include gestational diabetes (a state of hyperglycemia which develops during
pregnancy) and "other" rarer causes (genetic syndromes, acquired processes such as
pancreatitis, diseases such as cystic fibrosis, exposure to certain drugs, viruses, and
unknown causes).
The term "subject" as used herein refers to an animal, preferably a mammal, and
most preferably a human. The term "mammal" used herein refers to warm-blooded
vertebrate animals of the class 'mammalia', including humans, characterized by a
covering of hair on the skin and, in the female, milk-producing mammary glands for
nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear,
fox, wolf, monkey, deer, mouse, pig and human. In the context of the present invention,
the phrase "a subject in need thereof" means a subject (patient) in need of the
treatment for the disease or disorder that is mediated by GPR120. Alternatively, the
phrase "a subject in need thereof" means a subject (patient) diagnosed having a disease
or a disorder that is mediated by GPR120.
As used herein, the terms "treatment", "treat", "treating" and "therapy" and the
like refer to alleviate, slow the progression, attenuation, or cure of existing diseases or
condition (e.g. diabetes). Treatment also includes curing, preventing development of or
alleviating to some extent, one or more of the symptoms of the diseases or condition.
As used herein, the term "prophylaxis", used interchangeably with the terms
"prevention" or "preventing" means preventing or reducing the probability of the
occurrence of a clinical disease-state. Subjects are selected for preventative therapy
based on factors that are known to increase risk of suffering a clinical disease state or a
condition .compared to the general population. "Prophylaxis" therapies can be divided
into (a) primary prevention and (b) secondary prevention. Primary prevention is defined
as treatment in a subject that has not yet presented with a clinical disease state or a
condition, whereas secondary prevention is defined as preventing a second occurrence of
the same or similar clinical disease state.
The term "compound(s) for use" as used herein embrace any one or more of the
following: (1) use of compound(s), (2) method of use of compound(s), (3) use in the
treatment of, (4) the use for the manufacture of pharmaceutical composition /
medicament for treatment/treating or (5) method of treatment / treating / preventing /
reducing / inhibiting comprising administering an effective amount of the compound of
the present invention t o a subject in need thereof.
As used herein, the term, "therapeutically effective amount" refers to an amount
of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a
composition comprising a compound of Formula (I) or a salt thereof, effective in
producing the desired therapeutic response in a subject suffering from a disease or
disorder mediated by GPR120. An example of a disease or disorder mediated by GPR120
is diabetes such as type 2 diabetes. Particularly, the term "therapeutically effective
amount" includes the amount of a compound (in the context of the present invention,
the compound of Formula (I) or a pharmaceutically acceptable salt thereof), when
administered that induces a positive modification in the disease or disorder t o be treated
or is sufficient to prevent development of, or alleviate to some extent one or more of the
symptoms of the disease or disorder being treated in a subject. In respect of the
therapeutic amount of the compound, consideration is also given that the amount of the
compound used for the treatment of a subject is low enough to avoid undue or severe
side effects, within the scope of sound medical judgment. The therapeutically effective
amount of the compound or composition will vary with the particular condition (in the
context of the present invention, the disease or disorder that is mediated by GPR120)
being treated, the age and physical condition of the subject, the severity of the condition
being treated or prevented, the duration of the treatment, the nature of concurrent
therapy, the specific compound or composition employed, the particular
pharmaceutically acceptable carrier utilized and other related factors.
As used herein, the term "GPR120 agonist(s)" refers to the compound(s) of
Formula (I) of the present invention or a tautomer, a stereoisomer, a pharmaceutically
acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, an Noxide,
a S-oxide or a carboxylic acid isostere thereof; which binds to, activates,
increases, stimulates, potentiates, sensitizes or upregulates GPR120 receptor and
promotes insulin sensitization.
In one aspect, ),
Formula (I)
wherein,
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyi; (C6-
Cio)aryl or 5- to 12-membered heteroaryl; wherein the heterocycloalkyi and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
, consisting of N, O and S;
to 12-membered heterocycloalkyi; or two R are combined together with Ring A to form
a 3- to 6-membered cycloalkyl or 5- to 12-membered heterocycloalkyi;
R4 and R7 are independently selected from the group consisting of hydrogen and ( -
C6)alkyl;
R5 and R are independently selected from the group consisting of hydrogen, halogen
and (Ci-C6)alkyl;
m, n and p are each integer independently selected from 1, 2 and 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted it h one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (CiC6)
alkyl, halo(d -C6 )alkyl, -0 (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-C10)aryl,
heterocycloalkyl and heteroaryl ;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independantly selected from the group consisting of ( .-
C6)alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C6-C1 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C6-C10 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C6-G10 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is unsubstituted or substituted 3- to 10-membered cycloalkyl .
In one embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is unsubstituted or substituted 5- to 12-membered heterocycloalkyl
containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of
N, O and S.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is unsubstituted or substituted (C6-Cio)aryl .
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is 5- to 12-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms
independently selected from the group consisting of N, O and S.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is unsaturated or partially unsaturated (C -C 0)aryl .
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring A is unsaturated or partially unsaturated 5- to 12-membered
heteroaryl .
I n an embodim a compound of Formula
(I), wherein Ring A is
represents a point of attachment to Ring B.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted (C -Cio)aryl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is 5- to l Tembered heteroaryl containing 1, 2 or 3 heteroatoms
independently selected from the group consisting of N, O and S.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted phenyl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted phenyl, and R2 is located at para
position to Ring A and is as defined above; and n is 1.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is phenyl and R2 is halogen located at para position to Ring A and is
as defined above; and n is 1.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is unsubstituted or substituted (C -Ci 0)aryl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is 5- to 12-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently selected from the group consisting of N, O and S.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 5- to 6- membered heteroaryl.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is unsubstituted or substituted phenyl.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is unsubstituted or substituted 5- to 6- membered heteroaryl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 6-membered heteroaryl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein two R1 are combined together with Ring A to form a 3- to 6-membered
cycloalkyl or 5- to 12-membered heterocycloalkyl.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein two R are combined together with Ring A to form a 3- to 6-membered
cycloalkyl .
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted phenyl ; Ring C is unsubstituted or
substituted phenyl, or unsubstituted or substituted 5- to 6- membered heteroaryl ; R2 is
located at para position to Ring A and is as defined above; R3 is hydrogen ; and m &' n
are 1.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted phenyl ; Ring C is unsubstituted or
substituted phenyl, R2 is halogen located at para position to Ring A; R3 is hydrogen ; and
m & n are 1.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted phenyl ; Ring C is unsubstituted or
substituted 5- to 6- membered heteroaryl; R2 is located at para position to Ring A and is
as defined above; R3 is hydrogen; and m & n are 1.
I n an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted (C6 -Ci 0)aryl or 5- to 12-membered
heteroaryl ; Ring C is unsubstituted or substituted (C -Ci 0)aryl or 5- to 12-membered
heteroaryl ; Ring A is saturated or partially unsaturated 5- to 12-membered bicyclic
heteroaryl or 5- to 12-membered bicyclic heterocycloalkyl ; X, R , R2, R3, m, n & p are as
defined above.
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein Ring B is unsubstituted or substituted (C -Ci 0)aryl or 5- to 12-membered
heteroaryl ; Ring C is unsubstituted or substituted (C -Ci 0)aryl or 5- to 12-membered
heteroaryl; Ring A is 5- to 6-membered monocyclic heteroaryl ; R is 3- to 10-membered
a compound of Formula
attachment.
a compound of Formula
defined above, and
In an embodiment, the present invention encompasses a compound of Formula
(I), wherein X is wherein R4, R5, R6 and R7 are as defined above, and
' represents a point of attachment.
I n another embodiment, the present invention encompasses a compound of
Formula (I), wherein R is hydrogen.
I n another embodiment, the present invention encompasses a compound of
Formula (I), wherein R is ( - alky .
I n an embodiment, the compound of Formula I encompasses a compound of
Formula IA;
wherein,
Ring A is 3- to 10-membered cycloalkyi, 5- to 12-membered heterocycloalkyl; (C -
Cio)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, O and S;
Ring B and Ring C are independently selected from (C -Ci0)aryl or 5- to 12-membered
heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group
consisting of N, 0 and S
R is hydrogen or (Ci-C6)alkyl;
R , R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci-C6)alkyl, halo(Ci-C )alkyl, 3- to 10-membered cycloalkyi and 5-
to 12-membered heterocycloalkyl;
m, n and p are each an integer independently selected from 1, 2 and 3;
wherein,
(GrC 6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (CiC6)
alkyl, halo(Ci-C6)alkyl, -0 (Ci-C6 )alkyl, (C3-Ci0)cycloalkyl, (C6-Ci )aryl ,
heterocycloalkyl and heteroaryl ;
cycloalkyl js a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (C -
C )alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C -C1 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is .a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0-(C -C6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci- 6)alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-C10)cycloalkyl, (C -C 0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a
pharmaceutically acceptable solvate, a prodrug, a, polymorph, N-oxide, S-oxide, or a
carboxylic acid isostere thereof.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered
, heterocycloalkyl ; (C -Cio)aryl or 5- to 12-membered heteroaryl;
Ring C is (C -Ci0)aryl or 5- to 12-membered heteroaryl;
R1, R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, ( -C )alkyl, 3- to 10-membered cycloalkyl and 5- to 12-membered
heterocycloalkyl ;
m, and p are each integer independently selected from 1 or 2, and
R is hydrogen or (Ci-C )alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl, (C6-Ci0)aryl or 5- to
12-membered heteroaryl ;
Ring B is (C6-C10 )aryl ;
Ring C is (C -Cio)aryl or 5- to 6-membered heteroaryl ;
R1 is hydrogen, halogen, (Ci-C6)alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl ;
R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen and (Ci-C )alkyl;
m, n and p are each integer independently selected from 1 or 2; and
R is hydrogen or (Ci-C6)alkyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl or 5- to 12-
membered heteroaryl;
Ring B is phenyl;
Ring C is phenyl or 5- to 6-membered heteroaryl;
R1 is hydrogen, halogen, (Gi-C )alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl;
R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen and halogen;
m, n and p are 1; and
R is hydrogen or (Ci-C )alkyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring A is 5- to 12-membered heterocycloalkyl or 5- to 12-
membered heteroaryl;
Ring B is phenyl;
Ring C is phenyl or 6-membered heteroaryl;
R is hydrogen, halogen, ( -C )alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl;
R2 is halogen;
R3 is hydrogen or halogen;
m, n and p are 1; and
R is hydrogen or (Ci-C6)alkyl.
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring B is unsubstituted or substituted phenyl.
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring B is unsubstituted or substituted phenyl, and R2 is located at
para position to Ring A and is as defined above; and n is 1.
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring B is phenyl and R2 is halogen located at para position to Ring
A; and n is 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 5- to 6- membered heteroaryl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring C is unsubstituted or substituted phenyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring C is unsubstituted or substituted 5- to 6- membered
heteroaryl .
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6- membered
heteroaryl ; R2 is located at para position to Ring A and is as defined above; R3 is
hydrogen; and m & n are 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IA, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 6-membered
heteroaryl ; R2 is halogen located at para position to Ring A; R3 is hydrogen ; and m & n
are 1.
In another aspect, the compound of Formula I encompasses a compound of
Formula IB;
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyl ; (C6-
Cio)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, 0 and S;
Ring B and Ring C are independently selected from the group consisting of (C6-Ci0)aryl
or 5- to 12-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected from the group consisting of N, 0 and S;
R is hydrogen or (Ci-C6)alkyl;
R , R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci-C6)alkyl, halo(Ci-C )alkyl, 3- to 10-membered cycloalkyl, and 5-
to 12-membered heterocycloalkyl; '
R4 is independently selected from hydrogen or (Ci-C6)alkyl ;
R5 is independently selected from hydrogen, halogen or ( -C6)alkyl ;
m, and p are each an integer independently selected from 1, 2 and 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (Ci-
C6)alkyl, halo(Ci-C )alkyl, -0(C -C6)alkyl, (C3-Ci0)cycloalkyl, (C5-Ci0)aryl ,
heterocycloalkyl and heteroaryl;
cyeloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Cr
C )alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C -C10)cycloalkyl, (C6-Cio)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-C10)cycloalkyl, (C6-C 0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C )alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-C10 )cycloalkyl, (C -Ci0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is selected from chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring A is 3- to 10- membered cyeloalkyl, 5- to 12-membered
heterocycloalkyl; (C6-C10)aryl or 5- to 12-membered heteroaryl;
Ring C is (C6-Ci0)aryl and 5- to 12-membered heteroaryl;
R1, R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci-C )alkyl, 3- to 10- membered cyeloalkyl and heterocycloalkyl;
m, n and p are each integer independently selected from 1 or 2,
R is independently selected from hydrogen or (Ci-C )alkyl;
R5 is independently selected from hydrogen, halogen or (Ci-C )alkyl and
R is hydrogen or (Ci-C6)alkyl.
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring A is 5- to 10-membered heterocycloalkyl or 5- to 10-
membered heteroaryl;
Ring C is (C6-Cio)aryl or 5- to 6-membered heteroaryl;
R1 is hydrogen, halogen, (Ci-C )alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heteroeycloalkyl ;
R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen and (Ci-C )alkyl;
m, n and p are each integer independently selected from 1 or 2;
R4 an R5 are hydrogen, and
R is hydrogen or (Ci-C )alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring A is 5- to 10-membered heteroeycloalkyl or 5- to 10-
membered heteroaryl;
Ring B is (C -C10 )aryl ;
Ring C is (C6-Ci0)aryl or 5- to 6-membered heteroaryl;
R1 is hydrogen, halogen, (C -C6)alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered rfeterocycloalkyl ;
R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen and halogen;
m, n and p are 1;
R and R are hydrogen, and
R is hydrogen or (Ci-C6)alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring A is 5- to 12-membered heteroeycloalkyl or 5- to 12-
membered heteroaryl;
Ring B is phenyl ;
Ring C is phenyl or 5- to 6-membered heteroaryl ;
R is hydrogen, halogen, (Ci-C )alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heteroeycloalkyl ;
R2 and R3 are independently selected from the group consisting hydrogen and halogen ;
, n and p are 1;
R4 and R5 are hydrogen, and
R is hydrogen or ( -C6)alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring A is 5- to 10-membered heteroeycloalkyl or 5- to 10-
membered heteroaryl;
Ring B and Ring C are phenyl ;
R is hydrogen, halogen, (Ci-C6)alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heteroeycloalkyl ;
R2 and R3 are independently selected from hydrogen or halogen ;
m, n and p are 1;
R4 and R are hydrogen, and
R is hydrogen or (Ci-C )alkyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is unsubstituted or substituted phenyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is unsubstituted or substituted phenyl, and R2 is located at
para position to Ring A; and n is 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is phenyl and R2 is halogen located at para position to Ring
A; and n is 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 5- to 6- membered heteroaryl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring C is unsubstituted or substituted phenyl.
I n an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring C is unsubstituted or substituted 5- to 6- membered
heteroaryl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6- membered
heteroaryl; R2 is located at para position to Ring A and is as defined above; R3 is
hydrogen; and m & n are 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6- membered
heteroaryl; R2 is halogen located at para position to Ring A; R3 is hydrogen; and m & n
are 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IB, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 6- membered
heteroaryl; R2 is halogen located at para position to Ring A; R3 is hydrogen; m & n are 1;
and R4 and R5 are hydrogen.
In another aspect, the compound of Formula I encompasses a compound of
Formula IC,
wherein,
Ring A is 3- to 10-membered cycloalkyi, 5 - to 12-membered heterocycloalkyl ; (C6-
Cio)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, 0 and S;
Ring B and Ring C are independently selected from the group consisting of (C -Ci0)aryl
or 5- to 12-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected from the group consisting of N, O and S;
R is hydrogen or (Ci-C )alkyl ;
R1, R2 and R3 at each occurrence is independently selected from the group consisting of
hydrogen, halogen, (Ci-C6)alkyl, halo(Ci-C )alkyl, 3- to 10-membered cycloalkyi and 5-
to 12-membered heterocycloalkyl ;
R4 and R7 are independently selected from hydrogen or (Ci-C6)alkyl;
R5 and R5 are independently selected from the group consisting of hydrogen, halogen
and (Ci-C )alkyl ;
m, n and p are each an integer independently selected from 1, 2 or 3 ;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C -
C )alkyl, halo(C1-C6)alkyl, -0 (C1-C6)alkyl, (C3-C10)cycloalkyl, (C -Ci0)aryl , heterocyclyl
and heteroaryl ;
cycloalkyi js a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 - ( -C6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl , heterocyclyl,
heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0 -(C!-C )alkyl, (C3-Cio)cycloalkyl, (C6-Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
( -C6)alkyl, halogen, hydroxy, -0 -(Ci -C6)alkyl, (C3-Ci 0)cycloalkyl, (C -Ci )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is selected from chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered
heterocycloalkyl; (C -Ci 0)aryl or 5- to 12-membered heteroaryl;
Ring B is (C -C 0)aryl;
Ring C is (C -Ci 0)aryl or 5- to 12-membered heteroaryl;
R , R and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (d-C )alkyl, 3- to 10-membered cycloalkyl and heterocycloalkyl;
m, n and p are each integer independently selected from 1 or 2,
R4 and R7 are independently selected from hydrogen or (Ci -C )alkyl;
R5 and R6 are independently selected from hydrogen or halogen; and
R is hydrogen or (Ci -C6)alkyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring A is 3- to 8-membered cycloalkyl, 5- to 10-membered
heterocycloalkyl or 5- to 10-membered heteroaryl;
Ring B is (C -C10)aryl;
Ring C is (C -Ci6)aryl or 5- to 6- membered heteroaryl;
R1 is hydrogen, halogen, (Ci -C6)alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl;
R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen and (Ci -C6)alkyl;
m, n and p are each integer independently selected from 1 or 2;
R4 and R7 are hydrogen;
R5 and R6 are independently selected from hydrogen or halogen; and
R is hydrogen or (Ci -C6)alkyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring A is 5- t o 10-membered heterocycloalkyl or 5- to 10-
membered heteroaryl;
Ring B is phenyl;
Ring C is phenyl or 5- to 6- membered heteroaryl;
R is hydrogen, halogen, (Ci -C )alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl ;
R2 and R3 are independently selected from hydrogen or halogen ;
m, n and p are 1;
R4 and R7 are hydrogen;
R5 and R6 are halogen; and
R is hydrogen or (Ci -C )alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring A is 5- to 10-membered heterocycloalkyl or 5- t o 10-
membered heteroaryl;
Ring B and Ring C are phenyl ;
R1 is hydrogen, halogen, (C -C6)alkyl, 3- to 10-membered cycloalkyl or 5- to 12-
membered heterocycloalkyl ;
R and R3 are hydrogen or halogen ;
m, n and p are 1;
R4 and R are hydrogen ;
R5 and R6 are halogen; and
R is hydrogen or (Ci -C )alkyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is unsubstituted or substituted phenyl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is unsubstituted or substituted phenyl, and R2 is located at
para position to Ring A and is as defined above; and n is 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is phenyl and R2 is halogen located at para position to Ring
A; and n is 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 5- to 6- membered heteroaryl .
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring C is unsubstituted or substituted phenyl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring C is unsubstituted or substituted 5- to 6-membered heteroaryl.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6-membered
heteroaryl; R2 is located at para position to Ring A and is as defined above; R3 is
hydrogen; and m & n are 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6- membered
heteroaryl; R2 is halogen located at para position to Ring A; R3 is hydrogen; and m & n
are 1.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula IC, wherein Ring B is unsubstituted or substituted phenyl; Ring C is
unsubstituted or substituted phenyl, or unsubstituted or substituted 5- to 6- membered
heteroaryl; R2 is halogen located at para position to Ring A; R3 is hydrogen; m & n are 1;
R4 and R7 are hydrogen; and R5 and R are halogen.
In an embodiment, the compound of Formula (I) encompasses the compound of
Formula ID,
Formula ID
wherein,
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyl; (C6-
Cio)aryl or 5- to 12-membered heteroaryl; wherein the heterocycloalkyl and the
pendent ly selected from the group
(C6-Cio)aryl or 5- to 12-membered
pendent ly selected from the group
wherein represents a point of attachment;
R is hydrogen or (Ci-C6)alkyl;
R , R2 and R3 a each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, 3- to 10-membered cycloalkyl and 5-
to 12-membered heterocycloalkyl ;
R4 and R7 are independently selected from the group consisting of hydrogen and (Ci-
C6)alkyl ;
R5 a d R6 are independently selected from the group consisting of hydrogen, halogen
and (C -C6)alkyl ;
, n and p are each integer independently selected from 1, 2 and 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (Ci-
C6)alkyl, halo(Ci-C6)alkyl, -0 (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-C 0)aryl,
heterocycloalkyl and heteroaryl ;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-C10)cycloalkyl, (C6-C10 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
Representative compounds of Formula (I) encompassed in accordance with the
present invention include :
4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid;
4-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic acid ;
4-(5-((5-Fluoro-2-(5-methylthiophen-2-y|)phenyl)ethynyl)pyridin-2-yl)butanoic acid ;
4-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoic acid ;
4-(4-(i, l-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoic
acid ;
4-(4-(l,l-Difluoro-2-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-
yl)phenyl)ethyl)phenyl)butanoic acid;
4-(4-(l,l-Difluoro-2-(4-fluoro-4 ,-methyl-[l,l'-biphenyl]-2-yl)ethyl)phenyl)butanoic acid;
4-(4-(2-(2-(5-Cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid;
4-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid;
4-(4-(2-(4'-Cyclopropyl-4-fluoro-tl,l'-biphenyl]-2-yl)-l,l-difluoroethyl)phenyl)butanoic
acid;
4-(4-((2-(5-(l-Cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic
acid;
4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenethyl)phenyl)butanoic
acid;
4-(4-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenethyl)phenyl)butanoic acid;
4-(4-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-yl)styryl)phenyl)butanoic acid;
4-(4-(2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-fluorostyryl)phenyl)butanoic acid;
4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)styryl)phenyl)butanoic acid;
4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)styryl)phenyl)butanoic acid;
4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic acid;
4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-
yl)phenyl)ethynyl)phenyl)butanoic acid;
4-(4-(l,l-difluoro-2-(5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethyl)phenyl)butanoic
acid;
4-(4-(l,l-difluoro-2-(5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-
yl)phenyl)ethyl)phenyl)butanoic acid;
4-(4-(2-(2-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically
acceptable solvate thereof.
Specific compounds encompassed in the present invention can also be found in the
examples set out below.
The compounds of the present invention also include stereoisomeric and
tautomeric forms and mixtures thereof and their pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs,
pharmaceutically acceptable polymorphs and N-oxides thereof.
In an aspect of the present invention, there are provided processes for the
preparation of the compounds of Formula (I) or pharmaceutically acceptable salts
thereof.
The compounds of Formula (I) can be prepared by various methods including
using methods well known to a person skilled in the art. Examples of processes for the
preparation of a compound of Formula (I) are described below and illustrated in the
following schemes but are not limited thereto. It will be appreciated by the persons
skilled in the art that within the processes described herein, the order of the synthetic
steps employed may be varied and will depend inter alia on factors such as the nature of
functional groups present in a particular substrate and the protecting group strategy (if
any) to be adopted. Clearly, such factors will also influence the choice of reagents such
as bases, solvents, coupling agents to be used in the reaction steps.
The reagents, reactants and intermediates used in the following processes are
either commercially available or can be prepared according to standard procedures
known in the art, for instance those reported in the literature references.
In the following schemes and the description of the processes, the starting
compounds and the intermediates used for the synthesis of the compounds of the
present invention are referred to by the symbols la, lb, lc, Id, le, If, lg, lh, li, lj,
lk, II, lm, In, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2j, 2k, 21, 2m, 2n, 3a, 3b, 3c, 3d,
3e, 3f and 3g respectively, for ease f reference.
Unless stated otherwise, throughout the process description, the corresponding
substituent groups in the various formulae representing starting compounds and/or
intermediates have the same meaning as that of the compound of Formula I as
described in one or more embodiments of the invention.
Processes for the preparation of the compounds of Formula I in one or more
embodiments as described above, are depicted in schemes, as presented herein below.
For ease of reference, the reaction steps shown in the Schemes, are referred to by using
general Symbols namely 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 3.1, 3.2, 3.3, 3.4 and 3.5 respectively.
The compounds of the present invention were purified by either flash
chromatography (ISCO Combiflash® chromatography instrument from Teledyne Isco,
Inc.) or silica gel column chromatography. Mass spectrometry (MS) was performed using
a Esquire 4000 Mass spectrometer (from Bruker Daltonics), Nuclear magnetic resonance
spectroscopy (NM ) was performed using a Bruker Avance NMR spectrometer (for the 
NMR spectra acquired at 300 MHz and 500MHz) and the chemical shifts were reported in
(ppm).
Scheme 1: Preparation of the compound of Formula I [referred to in Scheme 1
as compound la, lb, lc, Id, le, If, lg, lh, li, lj, lk, II, l m and I n wherein R1 , R2, R3,
m, n and p are as defined in any one of the embodiments of the compound of Formula I
as described herein].
Scheme 1
urs.
Step 1.2: PBr3 (Phosphorus tribromide) at 0°C for 0.5 hours.
Step 1.3: NaBH4 (Sodium borohydride), Methanol at -5°C for 0.5 hours
Step 1.4: Cul (Copper Iodide), TBAI (Tetrabutyiammonium iodide), K C0 3 (Potassium
carbonate), AC (Acetonitrile), 40°C for 24 hours.
Step 1.5: H2, Pd/C, Methanol
Step 1.6: PBr3 (Phosphorus tribromide) at 0°C for 0.5 hours.
: Step 1.7: PPh3 (Triphenylphosphine), Toluene, 60°C for 2 hours
Step 1.8: NaOMe (Sodium methoxide), Methanol, 1 hour
Step 1.9: H , P , C, Methanol
Step 1.10: LiOH.H20/THF: MeOH (4:1), 24 hours.
Step 1.11: LiOH.H20/THF: MeOH (4:1), 24 hours.
Step 1.12: Suzuki coupling: Tetrakis(triphenylphosphine)palladium(0), Sodium
bicarbonate, water, dioxane, DMF (Dimethylformamide)
Step 1.1:
Compound l a (wherein R5 is hydrogen or methyl; R3 and p are as defined in any
one of the embodiments of the compound of Formula I described herein) is reacted with
0.25 equivalents of NaBH4 (Sodium borohydride) and a solvent mixture THF:Ethanol
(40:28) at a temperature of -5°C for 6 hours to obtain the compound l b (wherein R5,
R3 and p are as defined for compound la).
Step 1.2:
I n this process step, the compound l b is treated with 0.4 equivalents of PBr3
(Phosphorus tribromide) at a temperature of 0°C for 0.5 hours to obtain the compound
l c (wherein R5; R3 and p are as defined for compound la).
Step 1.3:
In this process step, the compound l c is treated with NaBH4 (Sodium
borohydride) and a solvent such as methanol at a temperature of -5°C for 0.5 hours to
obtain the compound I d (wherein R5; R3 and p are as defined for compound la).
Step 1,4:
I n this process step, the compound I d is subjected to Sonogashira coupling.
Compound I d is treated with a compound of formula le, COOEt in the presence of
copper(I) iodide, a base such as TBAI (tetrabutylammonium iodide), K C0 3 (potassium
carbonate) and a solvent such as acetonitrile to obtain the compound I f (wherein R5; R3
and p are as defined for compound la).
Step 1.5:
The compound I f is treated with hydrogen, palladium catalyst in a solvent such
as methanol to obtain compound l g (wherein R5; R3 and p are as defined for compound
la).
Step 1.6:
The compound l g is treated with 0.4 equivalents of PBr3 (Phosphorus tribromide)
at a temperature of 0°C for 0.5 hours to obtain the compound l h (wherein R5, R3 and p
are as defined for compound la).
Step 1.7:
Treatment of the compound l h with triphenylphosphine and toluene at a
temperature of 60°C for 2 hours resulted in compound of formula li, a Wittig salt
(wherein R5 R3 and p are as defined for compound la).
Step 1.8:
I n this process step, the compound l i is treated with a compound of formula lj,
( ij)
in the presence of NaOMe (Sodium methoxide) and a solvent such as methanol for 1
hour to obtain compound l k (wherein R4 and R5 are hydrogen or methyl; R1, R2, R3, m
and p are as defined in any one of the embodiments of the compound of Formula I
described herein).
Step 1.9:
The compound l k is treated with Pd/C under hydrogen in a solvent such as
methanol to obtain compound I I (wherein R4 and R5 are hydrogen or methyl; R1, R2, R3,
m and p are as defined in any one of the embodiments of the compound of Formula I
described herein).
Step 1.10:
The compound I I is treated lithium hydroxide in a solvent mixture such as
THF: methanol- (4:1) for 24 hours to obtain compound l m (wherein R4 and R5 are
hydrogen or methyl; R1, R2, R3, m and p are as defined in any one of the embodiments
of the compound of Formula I described herein).
Step 1.11:
The compound l k is treated with lithium hydroxide in a solvent mixture such as
THF: methanol (4:1) for 24 hours to obtain compound I n (wherein R4 and R5 are
hydrogen or methyl; R1, R2, R3, m and p are as defined in any one of the embodiments
of the compound of Formula I described herein).
Step 1.12:
Preparation of compound of formula lj: Suzuki coupling reaction of substituted
bromobenzaldehyde compound (lo) (wherein R2 and n are as defined in any one of the
embodiments of the compound of Formula I described herein) using
tetrakis(trjphenylphosphine)palladium(0), sodium bicarbonate in water, in solvent
dioxane, DMF (dimethylformamide) resulted in compound (lj) (wherein R1, R2, m and n
are as defined in any one of the embodiments of the compound of Formula I described
herein).
Scheme 2: Preparation of the compound of Formula I [referred in Scheme 2 as the
compound 2n (wherein R4 and R5 are hydrogen or methyl; R1, R2, R3, m and p are as
defined in any one of the embodiments of the compound of Formula I described herein)].
Reaction condition:
Step 2.1: Suzuki coupling, Tetrakis(triphenylphosphine)palladium(0), Sodium
bicarbonate, water, dioxane, D F (Dimethylformamide)
Step 2.2: Dimethyl (l-diazo-2-oxopropyl)phosphonate, K C0 3 (potassium carbonate),
methanol.
Step 2.3: PEPPSI-IPr catalyst [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-
chloropyridyl)palladium(II) dichloride or Pd(0) .
Step 2.4: Hydrogen, Pd/C, ethanol
Step 2.5: Trifluoromethanesulfonic anhydride (Tf 20), Pyridine
Step 2.6: Cul (Copper Iodide), LiCI (Lithium chloride), TEA (Triethanolamine),
Pd(PPh3) CI2 (Bis(triphenylphosphine)palladium(II) dichloride)
Step 2.7: LiOH.H 0 , THF: methanol (4:1) for 24 hours.
Step 2.8: H2, Lindlar catalyst, 5% palladium on calcium carbonate; poisoned with lead.
Step 2.9: LiOH.H20 , THF:methanol (4:1), 24 hours.
Step 2.10: H , Pd/C
Step 2.11: LiOH.H 0 , THF:methanol (4:1), 24 hours.
Step 2.1:
Suzuki coupling reaction of substituted bromobenzaldehyde compound (2a)
(wherein R2 and n are as defined in any one of the embodiments of the compound of
Formula I described herein) with a suitably substituted boronic acid compound, using
tetrakis(triphenylphosphine)palladium(0) resulted in compound (2b) (wherein R1, R2, m
and n are as defined in any one of the embodiments of the compound of Formula I
described herein).
Step 2.2:
I n this process step, the compound 2b is treated with dimethyl (l-diazo-2-
oxopropyl)phosphonate or trimethylsilyldiazomethane, LDA (Lithium diisopropylamide) in
the presence of a base selected from K C0 3 or NaHC03 in THF and a solvent such as
methanol to obtain an ethynyl compound (2c) (wherein R1, R2 , m and n are as defined
in any one of the embodiments of the compound of Formula I described herein).
Step 2.3:
In this process step, bromo compound of formula (2d) (wherein R3 and p are as
defined in any one of the embodiments of the compound of Formula I described herein)
is subjected to Negishi Coupling with (4-ethoxy-4-oxobutyl)zinc(II) bromide compound
(2e) in the presence of PEPPSI-IPr catalyst [l,3-Bis(2,6-diisopropylphenyl)imidazol-2-
ylidene](3-chloropyridyl)palladium(II) dichloride or Pd(0), under argon atmosphere in
THF to obtain compound (2f) (wherein R3 and p are as defined in any one of the
embodiments of the compound of Formula I described herein).
Step 2.4:
In this process step, the compound 2f is treated with Pd/C under hydrogen in
ethanol to obtain the corresponding hydroxyl compound (2g) (wherein R3 and p are as
defined in any one of the embodiments of the compound of Formula I described herein).
Step 2.5:
The Compound 2g is reacted with triflic anhydride and pyridine under an inert
atmosphere to obtain compound 2h (wherein R3 and p are as defined in any one of the
embodiments of the compound of Formula I described herein).
Step 2.6:
The ethynyl compound 2c obtained in the process step 2.2 was reacted with the
compound 2h, which is obtained in process step 2.5, in the presence of copper(I) iodide,
LiCI (Lithium chloride), TEA (Triethanolamine), Pd(PPh3) 2Cl2
(Bis(triphenylphosphine)palladium(II) dichloride) to obtain an ester compound 2i
(wherein R5 is hydrogen or methyl; R3 and p are as defined in any one of the
embodiments of the compound of Formula I described herein).
Step 2.7:
The compound 2i was hydrolyzed using LiOH.H20 and a solvent THF:MeOH (4:1)
for 24 hours to obtain the corresponding acid compound 2j (wherein R , R2, R3, p, m and
n are as defined in any one of the embodiments of the compound of Formula I described
herein).
Step 2.8:
I n this process step, the compound 2i was subjected to reduction using Lindlar
catalyst and hydrogen to obtain compound 2k (wherein R4 and R are hydrogen or
methyl; R , R2, R3, m and p are as defined in any one of the embodiments of the
compound of Formula I described herein).
Step 2.9:
The compound 2k was hydrolyzed using LiOH.H20 and a solvent mixture such as
THF:MeOH (4:1) for 24 hours to obtain compound of formula 2 1 (wherein R4 and R5 are
hydrogen or methyl; R1, R2, R3, m and p are as defined in any one of the embodiments
of the compound of Formula I described herein).
Step 2.10:
In this process step, the compound 2k is treated with Pd/C under hydrogen in
ethanol to obtain compound (2m) (wherein R4 and R5 are hydrogen or methyl; R , R2, R3,
m and p are as defined in any one of the embodiments of the compound of Formula I
described herein).
Step 2.11:
The compound 2m is treated with lithium hydroxide and a solvent mixture such
as THF:methanol (4:1) for 24 hours to obtain compound 2n (wherein R4 and R are
hydrogen or methyl; R1, R2, R3, m and p are as defined in any one of the embodiments
of the compound of Formula I described herein).
Scheme 3: Preparation of the compound of Formula I [referred to in Scheme 3 as the
compound 3g (wherein R , R2, R3 and p are as defined in any one of the embodiments of
the compound of Formula I described herein)].
e), DCM
), -78°C
Step 3.4: Suzuki coupling: Tetrakis(triphenylphosphine)palladium(0), Sodium
bicarbonate, water, dioxane, DMF (Dimethylformamide)
Step 3.5: LiOH.H20 , THF:MeOH (4:1), 6 hours.
Step 3.1:
Compound (3a) is reacted with the compound (3b) (wherein R3 and p are as defined in
any one of the embodiments of the compound of Formula I described herein) with AICI3
(Aluminium chloride) to obtain compound (3c) (wherein R3 and p are as defined for the
compound (3b)).
Step 3.2:
The compound (3c) obtained in step 3.1 is treated with ethane-l,2-dithiol, boron
trifluoride diethyl etherate and a solvent DCM (dichloromethane) at room temperature
for overnight to obtain compound (3d) (wherein R3 and p are as defined for the
compound (3b)).
Step 3.3:
The compound (3d) is treated with Olah's Reagent (hydrofluoric acid-pyridine solution),
N-iodosuccinamide and a solvent such as DCM (dichloromethane) at -78°C to obtain
compound (3e) (wherein R3 and p are as defined for the compound (3b)).
Step 3.4:
Suzuki coupling reaction of compound (3e) (wherein R3 and p are as defined in any one
of the embodiments of the compound of Formula I described herein) with the compound
of formula 3f, using tetrakis(triphenylphosphine)palladium(0), sodium bicarbonate in.
water and solvent dioxane and DMF (Dimethylformamide) resulted in compound (3g)
(wherein R1, R3, m and p are as defined in any one of the embodiments of the compound
of Formula I described herein).
Step 3.5:
The compound (3g) is hydrolysed with LiOH and a solvent mixture such as
THF:MeOH (4:1) for 6 hours to obtain the compound (3h) (wherein R1, R3 and p are as
defined for the compound (3b)).
The compounds of formula (I) encompassed in the present invention as recited
in one or more embodiments as described above can be converted into their
pharmaceutically acceptable salts by following procedure known to persons skilled in the
art.
The pharmaceutically acceptable salt of the compounds of Formula (I) are
prepared with relatively non-toxic acids or bases, depending on the particular
substituents found on the compound described herein. When the compounds of Formula
(I) of the present invention contain an acidic group they can form an addition salt with a
suitable base. For example, pharmaceutically acceptable base addition salts of the
compounds of the present invention may include their alkali metal salts such as sodium,
potassium, calcium, magnesium, ammonium or an organic base addition salt. Examples
of pharmaceutically acceptable organic base addition salts of the compounds of the
present invention include those derived from organic bases like lysine, arginine,
guanidine, diethanolamine, metformin or other organic bases known t o the person skilled
in the art.
When the compounds of Formula (I) of the present invention contain one or
more basic groups, they can form an addition salt with an inorganic or an organic acid.
Examples of pharmaceutically acceptable acid addition salts include those derived from
inorganic acids like boric acid, perchloric acid, hydrochloric acid, hydrobromic acid,
hydrofluoric acid, hydriodic acid, nitric acid, carbonic acid, monohydrogencarbonic acid,
phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric
acid, monohydrogensulfuric acid, phosphorous acids or other inorganic acids known to
the person skilled in the art. Furthermore, examples of pharmaceutically acceptable acid
addition salts include the salts derived from organic acids such as acetic acid, propionic
acid, isobutyric acid, oxalic acid, malic acid acid, tartaric acid, citric acid, ascorbic acid,
maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid,
mandelic acid, phthalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic
acid, glucuronic acid, galacturonic acid, naphthoic acid, camphoric acid or other organic
acids known to the person skilled in the art. Certain specific compounds of the present
invention contain both basic and acidic functionalities that allow the compounds to be
converted into either base or acid addition salts.
The pharmaceutically acceptable salts of the present invention can be
synthesized from the subject compound i.e. the compound of Formula (I) which contains
a basic or acidic moiety by conventional chemical methods. Generally, the salts are
prepared by contacting the free base or acid with an appropriate salt-forming inorganic
or organic acid or a base in a suitable solvent or dispersant or by anion exchange or
cation exchange with other salts. Suitable solvents are, for example, ethyl acetate,
ethers, alcohols, acetone, or mixtures of these solvents.
The compounds encompassed in the present invention can be regenerated from
their corresponding salts by contacting the said salt with an appropriate base or acid
depending on the type of salt and isolating the parent compound in the conventional
manner. The corresponding salts of the compounds differ from their parent compounds
with respect to certain physical properties, for example solubility.
I n an embodiment of the present invention, the compound of Formula (I) or the
compound of Formula (IA) or the compound of Formula (IB) or the compound of Formula
(IC) is provided as its corresponding pharmaceutically acceptable salt.
Those skilled in the art will recognize that the compounds of Formula (I) of the
present invention contain asymmetric or chiral centres, and therefore exist in different
stereoisomer^ forms, as racemic mixtures of enantiomers, mixtures of diastereomers or
enantiomerically or optically pure compounds. The term "chiral" refers to molecules
which have the property of non-superimposability of the mirror image cohort, while the
term "achiral" refers to molecules which are superimposable on their mirror image
partner. It is intended that all stereoisomeric forms of the compounds of the invention,
including but not limited to, diastereomers and enantiomers, as well as mixtures thereof
such as racemic mixtures, geometric isomers form part of the present invention.
When the compounds of Formula (I) of the present invention contain one chiral
centre, the compounds exist in two enantiomeric forms and the present invention
includes both enantiomers and mixtures of enantiomers, such as the specific 50:50
mixture referred to as a racemic mixtures. The enantiomers can be resolved by methods
known to those skilled in the art, such as formation of diastereoisomeric salts which may
be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions
via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of
diastereoisomeric derivatives or complexes which may be separated, for example, by
crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer
with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid
or liquid chromatography in a chiral environment, for example on a chiral support for
example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be
appreciated that where the desired enantiomer is converted into another chemical entity
by one of the separation procedures described above, a further step is required to
liberate the desired enantiomeric form. Alternatively, specific enantiomers can be
synthesized by asymmetric synthesis using optically active reagents, substrates,
catalysts or solvents, or by converting one enantiomer into the other by asymmetric
transformation. Designation of a specific absolute configuration at a chiral carbon of the
compounds of the invention is understood to mean that the designated enantiomeric
form of the compounds is in enantiomeric excess (ee) or in other words is substantially
free from the other enantiomer. For example, the "R" forms of the compounds are
substantially free from the "S" forms of the compounds and are, thus, in enantiomeric
excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free
of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms.
Enantiomeric excess, as used herein, is the presence of a particular enantiomer at
greater than 50%. I n a particular embodiment when a specific absolute configuration is
designated, the enantiomeric excess of depicted compounds is at least about 90%. When
a compound of Formula (I) of the present invention has two or more chiral carbons it can
have more than two optical isomers and can exist in diastereoisomeric forms. For
example, when there are two chiral carbons, the compound can have up to 4 optical
isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of
enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The
stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The
diastereoisomeric pairs may be separated by methods known to those skilled in the art,
for example chromatography or crystallization and the individual enantiomers within
each pair may be separated as described above. The present invention includes each
diastereoisomer of such compounds and mixtures thereof.
I n one embodiment, the compounds of Formula (I) exist as tautomers, and it is
intended to encompass all the tautomeric forms of the compounds within the scope of
the present invention.
The present invention furthermore includes all the solvates of the compounds of
Formula (I), for example, hydrates and the solvates formed with other solvents of
crystallisation, selected from alcohols such as methanol, ethanol, 1-propanol or 2-
propanol, ethers such as diethyl ether, isopropyl ether or tetrahydrofuran, esters such as
methyl acetate or ethyl acetate, ketone such as acetone or their mixtures thereof.
Certain compounds of the present invention can exist in unsolvated forms as well as
solvated forms, including hydrated forms.
It is further intended to encompass various polymorphs of the compounds of
Formula (I) within the scope of the present invention. Various polymorphs of the
compounds of the present invention can be prepared by standard crystallisation
procedures known in the art. The crystallisation technique employed can utilize various
solvents or their mixtures, temperature conditions and various modes of cooling, ranging
from very fast to very slow cooling. The presence of polymorphs can be determined by,
IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance)
spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other
standard techniques.
Furthermore, the present invention also includes prodrugs of the compounds of
Formula (I). The prodrugs of the compounds of the present invention are derivatives of
the aforesaid compounds of the invention which upon administration to a subject in need
thereof undergoes chemical conversion by metabolic or chemical processes to release
the parent drug in vivo from which the prodrug is derived. The preferred prodrugs are
pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl
esters, benzyl esters, mono- or di-substituted alkyl esters convertible by solvolysis under
physiological conditions to the parent carboxylic acid, and those conventionally used in
the art.
The present invention further relates to carboxylic acid isosteres of the
compounds of Formula (I). '
The present invention also relates to N-oxide derivatives of the compounds of
Formula (I).
The present invention also relates to S-oxide derivatives of the compounds of
Formula (I).
I n one aspect of the present invention, the compounds of Formula (I) are
GP 120 agonists.
I n an embodiment of the present invention, the compounds of Formula (I) find
use in the treatment or prophylaxis of a disease or a disorder mediated by GPR120.
I n another aspect, the present invention relates to a method for the treatment
or prophylaxis of a disease or a disorder mediated by GPR120, comprising administering
to a subject in need thereof, a therapeutically effective amount of a compound of
Formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
I n an embodiment, the present invention relates to use of the compound of
Formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof;
for the treatment or prophylaxis of a disease or a disorder mediated by GPR120.
According t o one embodiment, the present invention relates to use of the
compounds of Formula (I) or a stereoisomer, a tautomer or a pharmaceutically
acceptable salt thereof; in the manufacture of a medicament for the treatment or
prophylaxis of a disease or a disorder mediated by GPR120.
I n an embodiment of the invention, the disease or disorder mediated by GPR120
is selected from the group consisting of diabetes, obesity, hyperglycemia, glucose
intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension,
hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic
syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease,
polycystic ovary syndrome, ketoacidosis, thrombotic disorders, diabetic nephropathy,
diabetic neuropathy, diabetic retinopathy, sexual dysfunction, fatty liver development,
dermatopathy, dyspepsia, hypoglycemia, cancer, edema, pancreatic beta cell
degeneration, and a disorder associated with pancreatic beta cell degeneration.
I n an embodiment of the invention, the disease or disorder mediated by GPR120
is selected from the group consisting of diabetes, obesity, insulin resistance,
hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia,
dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic
nephropathy, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, syndrome
X, hypertension and pancreatic beta cell degeneration.
I n an embodiment of the invention, the disease or disorder mediated by GPR120
is selected from the group consisting of diabetes, obesity, insulin resistance,
hyperglycemia, glucose intolerance, metabolic syndrome, syndrome X and pancreatic
beta cell degeneration.
I n an embodiment, diabetes is Type 2 diabetes.
I n an embodiment, the disease or disorder mediated by GPR120 is a metabolic
disorder which refers to one or more diseases or disorders as identified above.
I n an embodiment, the disease or disorder mediated by GPR120 is an
inflammatory disorder.
Accordingly, the present invention relates to a method for the treatment or
prophylaxis of a metabolic disorder, comprising administering to a subject in need
thereof a therapeutically amount of a compound of Formula (I) or a stereoisomer, a
tautomer or a pharmaceutically acceptable salt thereof.
I n an embodiment, the present invention provides use of the compound of
Formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof;
for the treatment or prophylaxis of a metabolic disorder.
According to one embodiment, the present invention relates to use of the
compound of Formula (I) or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament, for the treatment or prophylaxis of a metabolic disorder.
In one embodiment, the metabolic disorder is selected from the group
consisting of diabetes, obesity, cardiovascular disease, hypertension, ketoacidosis,
insulin resistance, glucose intolerance, hyperglycemia, hypertriglylceridemia, polycystic
ovary syndrome, hypercholesterolemia, hyperlipoproteinemia, dyslipidemia, metabolic
syndrome, syndrome X, hyperlipidemia, diabetic nephropathy, diabetic neuropathy,
diabetic retinopathy, edema and related disorders associated with abnormal plasma
lipoprotein, triglycerides, pancreatic beta cell degeneration; and a disorder associated
with pancreatic beta cell degeneration.
In an embodiment, the metabolic disorder is selected from the group consisting
of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance,
hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia,
hyperinsulinemia, atherosclerosis, diabetic nephropathy, diabetic neuropathy, diabetic
retinopathy, metabolic syndrome, syndrome X, hypertension and pancreatic beta cell
degeneration.
I n an embodiment, the metabolic disorder is selected from the group consisting
of diabetes, obesity, insulin resistance, glucose intolerance, dyslipidemia,
hyperinsulinemia, syndrome X, metabolic syndrome and pancreatic beta cell
degeneration.
In an embodiment, the metabolic disorder is Type 2 diabetes.
The present invention furthermore relates to pharmaceutical compositions that
contain a therapeutically effective amount of at least one compound of Formula (I) or its
pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable
carrier, and to a process for the production of a pharmaceutical composition, which
includes bringing at least one compound of Formula (I), into a suitable administration
form using a pharmaceutically suitable and physiologically tolerable excipient and, if
appropriate, further additives or auxiliaries.
According to one embodiment, the present invention relates to a pharmaceutical
composition comprising the compound of Formula (I) or a pharmaceutically acceptable
salt thereof; and one or more pharmaceutically acceptable excipients; for use in the
treatment or prophylaxis of a disease or a disorder mediated by GPR120.
It is further intended t o include within the scope of the present invention the use
of the compounds of Formula (I) or its pharmaceutically acceptable salts thereof in
combination with at least one further therapeutically active agent.
According to one embodiment, the present invention provides a pharmaceutical
composition, comprising a therapeutically effective amount of a compound of Formula (I)
or a pharmaceutically acceptable salt thereof; and at least one further therapeutically
active agent, together with a pharmaceutically acceptable excipient.
In an embodiment, the present invention relates to use of the compound of
Formula (I) or a pharmaceutically acceptable salt thereof; in combination with a further
therapeutically active compound, in the treatment or prophylaxis of a disease or a
disorder mediated by GPR120.
The therapeutically active agent used in combination with one or more of the
compounds of Formula (I) can be selected from the compounds or therapeutically active
substances known to be used in the treatment of diabetes and other conditions/disorders
such as obesity, insulin resistance, hyperglycemia, glucose intolerance,
hypercholesterolemia, hypertriglyceridemia, dyslipidemia, hyperlipoproteinemia,
hyperinsulinemia or atherosclerosis. According to the present invention, the
therapeutically active agent, used in combination with the compounds of Formula (I) of
the present invention can be selected from, but not limited to, insulin, sulfonylureas,
biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase
inhibitors, inhibitors of glycogen phosphorylase, glucagon antagonists, HMGCoA
reductase inhibitor, GLP-1 (Glucogen-like peptide-1) agonists, potassium channel
openers, inhibitors of dipeptidylpeptidase IV (DPP-IV), diglyceride acyltransferase
(DGAT) inhibitor, insulin sensitizers, modulators of glucose uptake, modulators of
glucose transport and modulators of glucose reabsorption, modulators of the sodiumdependent
glucose transporter 1 or 2 (SGLT1, SGLT2), compounds which alter lipid
metabolism such as antihyperlipidemic active ingredients and antilipidemic active
ingredients, PPARgamma agonists and agents with combined PPARalpha and gamma
activity and active ingredients which act on the ATP-dependent potassium channel of the
beta cells.
I n an embodiment, the compound of Formula (I) can be used in combination with
a PPAR gamma agonist selected from rosiglitazone, pioglitazone, rivoglitazone, and the
like.
In an embodiment, the compound of Formula (I) can be used in combination
with a HMGCoA reductase inhibitor selected from simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin, and the like.
I n an embodiment, the compound of Formula (I) can be used in combination with
a sulfonylurea selected from tolbutamide, glibenclamide, glipizide, glimepiride, and the
like.
I n another embodiment, the compound of the Formula (I) can be used in
combination with a meglitinide selected from repaglinide, nateglinide, mitiglinide, and
the like.
I n another embodiment, the compound of the Formula (I) can be used in
combination with GLP-1 agonist selected from exenatide, jiraglutide, taspoglutide
albiglutide, lixisenatide, and the like.
In another embodiment, the compound of the Formula (I) can be used in
combination with DPP-IV inhibitor selected from alogliptin, gemigliptin, linagliptin,
saxagliptin, sitagliptin, vildagliptin, and the like.
Accordingly, in an embodiment the further therapeutically active agent that can
be used in combination with one or more compounds of Formula (I) encompassed in the
present invention, can be selected from one or more of the agents including, but not
limited to, insulin, rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin,
pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, tolbutamide,
glibenclamide, glipizide, glimepiride, repaglinide, nateglinide, mitiglinide, exenatide,
liraglutide, taspoglutide albiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin,
saxagliptin, sitagliptin, vildagliptin, and the like.
The pharmaceutical compositions according to the present invention are prepared
in a manner known and familiar to one skilled in the art. Pharmaceutically acceptable
inert inorganic and/or organic carriers and/or additives can be used in addition to the
compound of Formula (I) and/or its pharmaceutically acceptable salts. For the production
of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for
example, lactose, corn starch or derivatives thereof, gum arabic, magnesia or glucose,
etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes,
natural or hardened oils, etc. Suitable carriers for the production of solutions, for
example injection solutions, or of emulsions or syrups are, for example, water,
physiological sodium chloride solution or alcohols, for example, ethanol, propanol or
glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of
the various solvents which have been mentioned.
Further, the pharmaceutical composition of the present invention can also contain
additives such as fillers, antioxidants, emulsifiers, preservatives, flavours, solubilisers or
colourants. The pharmaceutical composition of the present invention may also contain
two or more compounds of Formula (I) and/or its pharmaceutically acceptable salts, the
pharmaceutical compositions can also contain one or more other therapeutically or
prophylactically active ingredients.
The pharmaceutical compositions normally contain about 1 to 99%, for example,
about 10 to 80%, by weight of the compounds of Formula (I) or their pharmaceutically
acceptable salts.
The amount of the active ingredient i.e. the compound of Formula (I) or its
pharmaceutically acceptable salt in the pharmaceutical compositions can, for example,
vary from about 1 to 500 mg. In case of higher body weight of the mammal in need of
the treatment, the pharmaceutical composition may contain the compound of Formula
(I) or its pharmaceutically acceptable salt in an amount ranging from 5 mg to 1000 mg.
The desirable dosage of the compounds of Formula (I) or its pharmaceutically acceptable
salt can be selected over a wide range. The daily dosage to be administered is selected
to achieve the desired therapeutic effect in subjects being treated for metabolic
disorders. A dosage of about 0.05 to 50 mg/kg/day of the compounds of Formula (I) or
its pharmaceutically acceptable salt may be administered. I n case of higher body weight
of the mammal in need of the treatment, a dosage of about 0.1 to 100 mg/kg/day of the
compound of Formula (I) or its pharmaceutically acceptable salt may be administered. I
required, higher or lower daily dosages can also be administered. Actual dosage levels of
the active ingredients in the pharmaceutical composition of this present invention can be
varied so as to obtain an amount of the active ingredient, which is effective to achieve
the desired therapeutic response for a particular patient (subject), composition, and
mode of administration without being toxic to the patient. The selected dosage level can
be readily determined by a skilled medical practitioner in the light of the relevant
circumstances, including the condition (diseases or disorder) to be treated, the chosen
route of administration depending on a number of factors, such as age, weight and
physical health and response of the individual patient, pharmacokinetics, severity of the
disease and the like, factors known in the medical art.
The pharmaceutical compositions according to the present invention can be
administered orally, for example in the form of pills, tablets, coated tablets, capsules,
granules or elixirs. Administration, however, can also be carried out rectally, for example
in the form of suppositories, or parenterally, for example intravenously, intramuscularly
or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically,
for example in the form of solutions or transdermal patches, or in other ways, for
example in the form of aerosols or nasal sprays.
It is understood that modifications that do not substantially affect the activity of
the various embodiments of this invention are included within scope of the invention
disclosed herein. Accordingly, the following examples are intended to illustrate but not to
limit scope of the present invention.
Experimental
Nomenclature of the compounds exemplified in the present invention was derived
from Chemdraw Ultra version 9.0.1 CambridgeSoft Corporation, Cambridge.
Reagents were purchased from commercial suppliers such as Combi-Blocks Inc.,
CA; and CombiPhos Catalysts, Inc; and were used as such.
Unless otherwise stated all temperatures are in degree Celsius. Also, in these
examples and elsewhere, abbreviations have the following meanings:
The abbreviations and terms that are used herein:
Example 1:
4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid
(Compound 1)
Step l a
Synthesis of 5-(benzyloxy)-2-bromopyridine
To 6-bromopyridin-3-ol (10 g, 57.5 mmol) and cesium carbonate (28.1 g, 86 mmol) in
acetonitrile (50 mL), benzyl bromide (8.20 mL, 69.0 mmol) was added and the reaction
mass was allowed to stir at room temperature overnight. The reaction mass was
quenched with water and extracted with ethyl acetate (2 x 100 mL), organic layer was
dried over sodium sulphate and concentrated to give crude mass which was purified
using column chromatography to provide 5-(benzyloxy)-2-bromopyridine (12.3 g, 46.1
mmol, 80% yield).
H NMR (300 MHz, CDCI3) : 8.19 (d, = 1.5 Hz, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.47-
7.32 (m, 6 H), 5.18 (s, 2 H); LCMS (m/z): 265 (M+ l).
Step lb:
Synthesis of ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate
5-(Benzyloxy)-2-bromopyridine (6 g, 22.72 mmol) was stirred in dry THF (20 mL) under
argon atmosphere. (4-Ethoxy-4-oxobutyl)zinc(II) bromide (50.0 mL, 24.99 mmol) in
THF was added carefully under argon atmosphere followed by [l,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (Peppsi
catalyst) (0.772 g, 1.136 mmol) and reaction stirred at room temperature overnight.
Reaction mixture was quenched with saturated solution of ammonium chloride and
extracted with ethyl acetate (2 X 25 mL). Organic layer was washed with brine (25 mL),
dried and concentrated to obtain crude which was purified using column chromatography
to provide ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate. (4.3 g, 14.23 mmol, 62.6%
yield) .
H NMR (300 MHz, CDCI3) : 8.25 (d, J = 3.0 Hz, 1H), 7.46-7.31 (m, 6H), 7.16 (d, J -
8.4 Hz, 1 H), 5.14 (s, 2H), 4.03 (q, J = 6.9 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.66 (t, J
= 7.2 Hz, 2H), 1.93-1 .83 (m, 2H), 1, 19 (t, J = 6.9 Hz, 3H); LCMS (m/z) : 300. 1 (M+ l).
Step lc:
Synthesis of ethyl 4-(5-hydroxypyridin-2-yl)butanoate
To a solution of ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate (4.2 g, 14.03 mmol) in
ethanol (25 mL), Pd/C (0. 149 g, 1.403 mmol) was added and the flask was shaken
under hydrogen atmosphere at 40 psi for 4 hours. After completion of the reaction, it
was filtered through celite and concentrated to provide ethyl 4-(5-hydroxypyridin-2-
yl)butanoate.(2.7 g, 12.79 mmol, 91% yield) .
H NMR (300 MHz, CDCI3) : 9.7 (s, l H), 8.02 (d, J = 2.1 Hz, 1H), 7.08-7.01 (m, 2H),
4.03 (q, J = 6.0 Hz, 2H), 2.61 (t, J = 7 .5 Hz, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.90-1 .30
(m, 2H), 1.19 (t, J = 6.9 Hz, 3H); MS (m/z) : 210. 1 (M+l ) .
Step I d:
Synthesis of ethyl 4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate
To a solution of ethyl 4-(5-hydroxypyridin-2-yl)butanoate (250 mg, 1.195 mmol) in DCM
(10 mL) was added pyridine (0.773 mL, 9.56 mmol), triflic anhydride (0.505 mL, 2.99
mmol) under nitrogen atmosphere and allowed to stir overnight. After completion of
reaction, the reaction mass was concentrated and purified using column chromatography
to provide ethyl 4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate. (0.3 15 g,
0.917 mmol, 77% yield).
H NM (300 MHz, CDCI3) : 8.68 (d, J = 2.7 Hz, 1H), 7.95 (dd, J = 3.0 Hz, J = 5.7 Hz,
1H), 7.48 (d, J = 7.2 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.33 (t,
J = 7.5 Hz, 2H), 1.93 (m, 2H), 1.71 (t, J = 6.9 Hz, 3H) ; MS (m/z) : 342. 1 (M+ l ) .
Steple :
Synthesis of 5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde
2-Bromo-5-fluorobenzaldehyde (2 g, 9.85 mmol) was added to a stirred solution of (6-
methoxypyridin-3-yl)boronic acid (1.808 g, 11.82 mmol), sodium bicarbonate (1.655 g,
19.70 mmol) in l,4-dioxane:water (16 mL:4 mL). The reaction mass was degassed and
flushed with nitrogen, tetrakis(triphenylphosphine)palladium(0) (1.138 g, 0.985 mmol)
was then added. I t was flushed with nitrogen and stirred at 111 °C for 3 hours. Reaction
mixture was cooled, diluted with water and extracted with ethyl acetate (2 X 25 mL).
Ethyl acetate layer was washed with brine (25 mL), dried over sodium sulphate and
concentrated to get crude. The crude obtained was purified by column chromatography
to provide 5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde. (1.7 g, 7.35 mmol, 74.6%
yield).
H N R (300 MHz, CDCI3) : 9.85 (d, J = 3.0 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.84
(dd, J = 2.4 Hz, J = 6.3 Hz, 1H), 7.69-7.57 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H),3.92 (s,
3H); MS (m/z): 232.1 (M+ l).
Step If:
Synthesis of 5-(2-ethynyl-4-fluorophenyl)-2-methoxypyridine
Dimethyl (l-diazo-2-oxopropyl)phosphonate (1.246 mL, 0.519 mmol) was added
dropwise to a solution of 5-fluoro-2-(6-methoxypyridin-3-yl)benzaldehyde (100 mg,
0.432 mmol) and potassium carbonate (120 mg, 0.865 mmol) in dry methanol (5 mL) at
room temperature under argon, and the mixture was stirred at room temperature for 15
minutes. The reaction was quenched with brine (15 mL), and the mixture was extracted
with ethyl acetate (2 x 25 mL). The combined organic layer was washed with brine (30
mL), dried over Na S0 4. Solvent was removed under reduced pressure and the crude
obtained was purified by column chromatography to provide 5-(2-ethynyl-4-
fluorophenyl)-2-methoxypyridine. (0.071 g, 0.309 mmol, 75.1% yield).
H NMR (300 MHz, CDCI3) : 8.31 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 2.4 Hz, J = 6.0 Hz,
1H), 7.51-7.46 (m, 2H), 7.40-7.57 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.33 (s, 1H), 3.90
(s, 3H); MS (m/z): 228.0 (M+ l).
Step lg:
Synthesis of ethyl 4-(5-((5-fluoro-2-(6-meth0xypyridin-3-yl)phenyl)ethynyl)pyridin-2-
yl)butanoate
To a solution of ethyl 4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate (50
mg, 0.146 mmol), 5-(2-ethynyl-4-fluorophenyl)-2-methoxypyridine (56.6 mg, 0.249
mmol), lithium chloride (9.32 mg, 0.220 mmol), copper (I) iodide (1.395 mg, 7.32
pmol), triethanolamine (0.306 mL, 2.197 mmol) in DMF (2 mL) was added
bis(triphenylphosphine)palladium(II) chloride (2.057 mg, 2.93 ) under nitrogen
atmosphere. The reaction vessel was degassed, flushed with nitrogen and heated at 60
°C overnight. The reaction mass was distilled off and the crude was purified using
column chromatography to provide ethyl 4-(5-((5-fluoro-2-(6-methoxypyridin-3-
yl)phenyl)ethynyl)pyridin-2-yl)butanoate. (0.053 g, 0.124 mmol, 84% yield).
H NMR (300 MHz, CDCI3) : 8.52 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 2.4
Hz, J = 6.3 Hz, 1H), 7.57 (dd, J = 1.8 Hz, J = 6.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.19-
7.12 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 2.85 (t, J
= 7.5 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.12-2.02 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H); MS
(m/z): 419.1 (M+l).
Step lh:
Synthesis of 4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-
yl)butanoic acid
To a solution of ethyl 4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-
2-yl)butanoate (50 mg, 0.119 mmol) in THF (4 mL), methanol (1.0 mL) was added LiOH
(17.17 mg, 0.717 mmol) and allowed to stir at RT overnight. The .reaction mass was
distilled under vacuum, quenched with water (25 mL) and brine (25 mL) and extracted
with ethyl acetate (2x25 mL). Combined organic layer was dried over sodium sulphate
and concentrated to provide 4-(5-((5-fluoro-2-(6-methoxypyridin-3-
yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid. (0.032 g, 0.082 mmol, 68.5% yield).
H NMR (300 MHz, CDCI3) : 12.09 (s, lH), 8.48 (s, lH), 8.37 (d, J = 2.1 Hz, 1H), 8.03
(dd, J = 2.4 Hz, J = 6.3 Hz, 1H), 7.70 (dd, J = 2.1 Hz, J = 6.0 Hz, 1H), 7.59-7.54 (m,
2H), 7.43-7.38 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 6.7 Hz, 1H), 3.91 (s,
3H), 2.76 (t, = 7.5 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 1.90-1.88 (m, 2H); MS (m/z):
391,1 (M+l).
Example 2:
4-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic acid
(Compound 2)
Step 2a:
Synthesis of ethyl 4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-
yl)butanoate
To a solution of ethyl 4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-
2-yl)butanoate (70 mg, 0.167 mmol) in ethanol (25 mL), Pd/C (1.780 mg, 0.017 mmol)
was added and the flask was stirred under hydrogen atmosphere at RT overnight. After
completion of reaction, reaction mixture was filtered through celite and concentrated to
provide ethyl 4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoate.
(0.060 g, 0.137 mmol, 82% yield).
H NMR (300 MHz, CDCI3) : 8.08 (s, IH), 8.01 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 2.4
Hz, J = 6.3 Hz, 1H), 7.30-7.06 (m, 5 H), 6.86 (d, J = 9.0 Hz, 1H), 4.02 (q, = 9.0 Hz,
2H), 3.89 (s, 3H), 2.86-2.61 (m, 6H), 2.28 (t, J = 6.0 Hz, 2H), 1.91-1.82 (m, 2H), 1.16
(t, J = 6.0 Hz, 3H); MS (m/z): 423.1 (M+l).
Step 2b:
Synthesis of 4-(5-(5-fiuoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic
acid
The title compound was prepared in an analogous manner as the compound of Step l h
of Example 1, by using ethyl 4-(5-(5-fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-
2-yl)butanoate (50 mg, 0.118 mmol) instead of ethyl 4-(5-((5-fluoro-2-(6-
methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoate to obtain 4-(5-(5-fluoro-2-
(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic acid. (0.015 g, 0.036 mmol,
30.2% yield).
H NMR (CDCI3, 300 MHz): 8.16 (s, 1H), 7.96 (s, 1H), 7.42 (dd, J = 2.4 Hz, J = 6.0 Hz,
1H), 7.25 (s, 1H), 7.17-7.09 (m, 2H), 7.01 (d, J = 6.0 Hz, 2H), 6.80 (s, 1H), 3.99 (s,
3H), 2.95-2.73 (m, 6H), 2.40 (t, J = 6.0 Hz, 2H), 2.07 (t, J = 6.0 Hz, 2H), 1.26 (t, J =
3.0 Hz, 2H); MS (m/z): 395.2 (M+l).
Example 3
4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid
(Compound 3)
Step 3a:
Synthesis of 5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde
2-Bromo-5-fluorobenzaldehyde ( 1 g, 4.93 mmol) was added to a stirred solution of
4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-l,3,2-dioxaborolane (1.987 g, 8.87
mmol) and sodium bicarbonate (0.828 g, 9.85 mmol) in 20 mL of l,4-Dioxane:water
(4:1). The reaction mass was degassed and flushed with nitrogen.
Tetrakis(triphenylphosphine)palladium(0) (0.569 g, 0.493 mmol) was added to it and
stirred at 111 °C for 3 hours/ Reaction mixture was cooled, diluted with water and
extracted with ethyl acetate (2 X 25 mL). The organic layer was washed with water (25
mL), brine (25 mL) and dried over sodium sulphate to obtain crude which was purified
by column chromatography to provide 5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde.
(0.650 g, 2.82 mmol, 57.2% yield).
H NMR (300 MHz, CDCI3) : 10.04 (d, J = 3.3 Hz, 1H), 7.66-7.57 (m, 3H), 7.05 (d, J =
3.3 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 2.51 (s, 3H); MS (m/z): 221 (M+l).
Step 3b:
Synthesis of 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene
Dimethyl (l-diazo-2-oxopropyl)phosphonate (2.62 mL, 1.090 mmol) was added
dropwise to a solution of 5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde (200 mg,
0.908 mmol) and potassium carbonate (251 mg, 1.816 mmol) in dry methanol (2 mL) at
RT under argon, and the mixture was stirred at room temperature for 15 minutes. The
reaction was quenched with brine (15 mL), and the mixture extracted with ethyl acetate
(2 x 25 mL). The combined organic layer was washed with brine (30 mL), dried over
Na2S0 4. Solvent was removed under reduced pressure and crude residue was purified by
column chromatography to provide 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene.
(0. 143 g, 0.658 mmol, 72.5% yield) .
H MR (CDCI3, 300 MHz) : 7.58-7. 54 (m, 1H), 7.42 (dd, 3 = 6.6 Hz, J = 2.7 Hz, 1H),
7.31-7.27 (m, 2H), 6.83 (d, J = 2.7 Hz, 1H), 4.52 (s, 1H), 2.5 1 (s, 3H) ; MS (m/z) : 217
(M+ l ) .
Step 3c:
Synthesis of ethyl 4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-
yl)butanoate
To a solution of ethyl 4-(5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)butanoate (50
mg, 0.146 mmol), 2-(2-ethynyl-4-fluorophenyl)-5-methylthiophene (53.9 mg, 0.249
mmol), lithium chloride (9 .32 mg, 0.220 mmol), copper(I) iodide (1.395 mg, 7.32
pmol), triethylamine (0.306 mL, 2.197 mmol) in dimethylformamide (2 mL),
bis(triphenylphosphine)palladium(II) chloride (2.057 mg, 2.93 mo ) was added under
nitrogen atmosphere. The reaction vessel was degassed and flushed with nitrogen and
heated at 60 °C overnight. The reaction mass was distilled off and the crude was purified
using column chromatography to provide ethyl 4-(5-((5-fluoro-2-(5-methylthiophen-2-
yl)phenyl)ethynyl)pyridin-2-yl)butanoate. (0. 055 g, 0.131 mmol, 89.0% yield).
NMR (300 MHz, CDCI3) : 8.66 (s, 1H), 8.04 (s, 1H), 7.70 (dd, J = 6.0 Hz, J = 2.1 Hz,
1H), 7.5 1 (q, J = 5.7 Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.12-
7.05 (m, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.86 (d, J = 7.8 Hz,
2H), 2.55 (s, 3H), 2.39 (t, J = 7.5 Hz, 2H), 2.15-2.05 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H);
HPLC (%) : 96.81 %; MS (m/z) : 408. 1 (M+ l ) .
Step 3d :
Synthesis of 4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-
yl)butanoic acid
To a solution of ethyl 4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-
2-yl)butanoate (40 mg, 0.098 mmol) in THF (4 mL) and methanol (1.0 mL), LiOH (14. 10
mg, 0.589 mmol) was added and allowed to stir at RT overnight. The reaction mass was
concentrated under vacuum, quenched with water (25 mL) and brine (25 mL) and
extracted with ethyl acetate (2x25 mL) . Combined organic layer was dried over sodium
sulphate and concentrated to provide 4-(5-((5-fluoro-2-(5-methylthiophen-2-
yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid . (0.01 1 g, 0.029 mmol, 29.5% yield).
NMR (300 MHz, CDCI ) : 12.05 (s, 1H), 8.64 (s, 1H), 7.86 (dd, J = 2.7 Hz, J = 6.0
Hz, 1H), 7.67 (q, J = 5.7 Hz, 1H), 7.53 (q, J = 6.0Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H),
7.37-7.32 (m, 2H), 6.88 (d, J = 2.7 Hz, 1H), 3.81 (s, 3H), 2.79 (t, J = 7.2 Hz, 2H), 2.26
(t, J = 7.2 Hz, 2H), 1.99-1.88 (s, 2H); MS (m/z): 380.1 (M+l).
Example
4-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoic acid
(Compound 4)
Step 4a:
Synthesis of ethyl 4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-
yl)butanoate
To a solution of ethyl 4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-
2-yl)butanoate (45 mg, 0.110 mmol) in ethanol (25 mL), Pd/C (1.175 mg, 0.011 mmol)
was added and the flask was shaken under hydrogen atmosphere at RT overnight. After
completion of reaction, it was filtered through celite and concentrated to provide ethyl 4-
(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoate. (0.040 g,
0.095 mmol, 86% yield).
H NMR (300 MHz, CDCI3) : 8.27 (s, 1H), 7.43-7.42 (m, 1H), 7.34-7.31 (m, 1H), 7.20
(d, = 7.8 Hz, 1H), 6.96-6.63 (m, 2H), 6.73-6.71 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H),
3.06-2.80 (m, 6H), 2.54 (s, 3H), 2.39 (t, J = 7.5 Hz, 2H), 2.12-2.07 (m, 2H), 1.27 (t, J
= 7.2 Hz, 3H); MS (m/z): 411.5 (M+l).
Step 4b:
Synthesis of 4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoic
acid
To a solution of ethyl 4-(5-(5-fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-
yl)butanoate (35 mg, 0.085 mmol) in THF (4 mL) and methanol (1.000 mL) was added
LiOH (12.22 mg, 0.510 mmol) and allowed to stir at RT overnight. The reaction mass
was distilled under vacuum, quenched with water (10 mL) and brine (10 mL) and
extracted with ethyl acetate (2x25 mL). Combined organic layer was dried over sodium
sulphate and concentrated to provide 4-(5-(5-fluoro-2-(5-methylthiophen-2-
yl)phenethyl)pyridin-2-yl)butanoic acid. (0.021 g, 0.054 mmol, 63.4% yield).
H NMR (300 MHz, CDCI3) : 8.22 (s, 1H), 7.29-7.28 ( , 2H), 7.15 (d, J = 8.1 Hz, 1H),
6.93 (d, J = 8.7 Hz, 2H), 6.73 (s, 2H), 3.04-2.95 (m, 4H), 2.82 (t, J = 8.7 Hz, 2H), 2.41
(t, J = 8.2 Hz, 2H), 2.07 (s, 3H), 1.25-1.27 (m, 2H); MS (m/z): 384.3 (M+ l).
Example 5
4-(4-(l,l-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoic
acid (Compound 5)
Step 5a:
Synthesis of 2-(3-bromophenyl)acetyl chloride
To a solution 2-(3-bromophenyl)acetic acid (3.5 g, 16.28 mmol) in THF (20 mL),
catalytic dimethylformamide was added followed by addition of oxalyl chloride (1.396
mL, 16.28 mmol), the reaction mixture was allowed t o stir for 2 hours followed by
concentration under reduced pressure to provide 2-(3-bromophenyl)acetyl chloride as
yellow oil (3.6 g, 15.42 mmol, 95 % yield).
Step 5b:
Synthesis of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate
To a solution Of methyl 4-phenylbutanoate (2.2 g, 12.34 mmol) in anhydrous l-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (10 ml), Aluminium chloride (1.975 g, 14.81
mmol) was added at -30 °C {obtained with dry ice and excess of ethyl acetate}.
Reaction mixture was allowed t o stir for 30 minutes at this temperature. To the resulting
suspension 2-(2-bromo-5-fluorophenyl)acetyl chloride (3.10 g, 12.34 mmol) was added
in anhydrous l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10 mL) and reaction was
allowed to stir for 3 hours then at RT overnight. After complete consumption of starting
material, reaction mixture was poured into crushed ice and extracted with
dichloromethane. Organic layer was washed with brine, dried over sodium sulphate and
concentrated. The residue obtained was purified by column chromatography to provide
methyl 4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate (1.7 g, 4.32 mmol,
35.0 % yield) as white solid.
N R (300 MHz, CDCI3) : 8.00 (d, J = 6.2 Hz, 2H), 7.58 (dd, J = 5.4 Hz, 8.7 Hz, 1H),
7.34 (d, J = 8.7 Hz, 2H), 7.04 (dd, J = 2.7 Hz, 8.7 Hz, 1H), 6.92 (t, J = 2.7 Hz, 8.4 Hz,
1H), 4.43 (s, 2H), 3.70 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.50 Hz, 2H), 2.01
(t, J = 7.50, 2H); MS (m/z): 395 (M+2).
Step 5c:
Synthesis of methyl 4-(4-(2-(2-bromo-5-fluorobenzyl)-l,3-dithiolan-2-
yl)phenyl)butanoate
To a solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate (3 g,
7.63 mmol), ethane-l,2-dithiol (0.934 g, 9.92 mmol) in dichloromethane (10 mL), Boron
trifluoride diethyl etherate (1.257 mL, 9.92 mmol) was added. Reaction was allowed to
stir at room temperature overnight. After complete consumption of starting material,
reaction mixture was concentrated and purified by column chromatography to provide
methyl 4-(4-(2-(2-bromo-5-fluorobenzyl)-l,3-dithiolan-2-yl)phenyl)butanoate (3.2 g,
6.82 mmol, 89 % yield) as yellow solid.
NMR (300 MHz, CDCI3) : 7.56 (d, J = 6.2 Hz, 2H), 7.48-7.43 (dd, J = 5.4 Hz, 8.7 Hz,
1H), 7.13 (d, J = 8.7 Hz, 2H), 6.84-6.79 (m, 2H), 3.73 (s, 2H), 3.69 (s, 3H), 3.37-3.20
(m, 4H), 2.66 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 7.50 Hz, 2H), 2.01-1.92 (m, J = 7.50,
2H); MS (m/z): 370 (M+ l).
Step 5d:
Synthesis of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)acetyl)phenyl)butanoate
To a suspension of l-iodopyrrolidine-2,5-dione (613 mg, 2.73 mmol) and methyl 4-(4-
(2-(2-bromo-5-fluorobenzyl)-l,3-dithiolan-2-yl)phenyl)butanoate (320 mg, 0.682 mmol)
in dichloromethane (10 mL) was added pyridine, hydrogen fluoride 30% solution (772
mg, 5.45 mmol) at -78 °C and reaction mixture was allowed to stir at same temperature
for 4 hours. The reaction mixture was then allowed to stir overnight at RT after which
reaction mass was quenched with addition of saturated sodium bicarbonate. Reaction
mixture was extracted with dichloromethane, washed with brine, dried over sodium
sulphate and concentrated to give crude which was purified using column
chromatography to provide methyl 4-(4-(2-(2-bromo-5-
fluorophenyl)acetyl)phenyl)butanoate (10 mg, 0.025 mmol, 3.73 % yield) along with
formation of methyl 4-(4-methoxyphenyl)-4-oxobutanoate.
NMR (300 MHz, CDCI3) : 7.51 (dd, J = 5, 4 Hz, 1H), 7.35 (d, 3 = 8.1 Hz, 2H), 7.23
(d, J = 8.1 Hz, 2H), 7.12 (dd, J = 2.4 Hz, 8.7 Hz, 1H), 6.93 (t, J = 2.7 Hz, 8.7 Hz, 1H),
3.69 (s, 3H), 3.61 (t, = 15.6 Hz, HF coupling, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.34 (t, J
= 7.5 Hz, 2H), 2.02-1.92 (m, 2 H); MS (m/z): 415 (M+l).
Step 5e:
Synthesis of methyl 4-(4-(l,l-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-
yl)phenyl)ethyl)phenyl)butanoate
In a mixture of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate (30.6 mg, 0.074 mmol), 4,4,5,5-tetramethyl-2-(5-
methylthiophen-2-yl)-l,3,2-dioxaborolane (33.0 mg, 0.147 mmol) and sodium
bicarbonate (12.38 mg, 0.147 mmol) in dioxane:water (4:1),
tetrakis(triphenylphosphine)palladium(0) (1.064 mg, 3.68 mol) was added. Reaction
mixture was heated in microwave at 111 °C for 11 minutes and was quenched with
water (10 mL) and extracted with ethyl acetate (2x25 mL). Combined organic layer was
dried and concentrated. Crude residue obtained was purified by column chromatography
using 5 ethyl acetate in petroleum ether to provide methyl 4-(4-(l,l-difluoro-2-(5-
fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoate. (10 mg, 0.035 mmol,
31.3 % yield)
H NMR (300 MHz, CDCI3) : 7.31 (d, = 5.4 Hz, 1H), 7.22-7.14 (m, 5H), 7.03 (dd, J =
2.7 Hz, 8.1 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 3.69 (s, 3H),
3.60 (t, J = 15.6 Hz, 2H), 2.67 (t, J = 7. Hz, 2H), 2.50 (s, 3H), 2.32 (t, J = 7.5 Hz,
2H), 2.08-1.92 (m, 2H); MS (m/z): 433.1 (M+l).
Step 5f:
Synthesis of 4-(4-(l ,l-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-
yl)phenyl)ethyl)phenyl)butanoic acid
To solution of methyl 4-(4-(l, l-difluoro-2-(5-fluoro-2-(5-methylthiophen-2-
yl)phenyl)ethyl)phenyl)butanoate (20 mg, 0.046 mmol) in THF:methanol (4 :1) was
added lithium hydroxide hydrate (185 _, 0.277 mmol) at RT. Reaction mixture was
allowed to stir at RT for 4 hours/ After complete consumption of starting material,
solvent was evaporated under reduced pressure and was washed with 5% ethyl acetate
in petroleum ether. Reaction mixture was then quenched with addition of saturated
ammonium chloride and extracted with ethyl acetate. Organic layer was dried over
sodium sulphate and concentrated to provide 4-(4-(l, l-difluoro-2-(5-fluoro-2-(5-
methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoic acid (13 mg, 0.031 mmol, 67.2 %
yield) .
1H NMR (300 MHz, CDCI3) : 7.31 (d, J = 5.4 Hz, 1H), 7.22-7. 14 (m, 5H), 7.03 (dd, J =
2.7 Hz, 8.1 Hz, 1H), 6.67 (d, 2 = 2.4 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 3.55 (t, J =
15.6 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.50 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 2.08-1 .92
(m, 2H) ; MS (m/z) : 419 .1 (M+ l ) .
Example 6:
4-(4-(l ,l-Difluoro-2-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-
yl)phenyl)ethyl)phenyl)butanoic acid (Compound 6)
Step 6a :
Synthesis of methyl 4-(4-( l , l-difluoro-2-(5-fluoro-2-(5-(l -methylcyclopropyl)thiophen-
2-yl)phenyl)ethyl)phenyl)butanoate
A solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l , l -
difluoroethyl)phenyl)butanoate (70 mg, 0.169 mmol), 4,4,5,5-tetramethyl-2-(5-(lmethylcyclopropyl)
thiophen-2-yl)-l,3,2-dioxaborolane (111 mg, 0.421 mmol), sodium
bicarbonate (28.3 mg, 0.337 mmol) in dioxane and water (4 :1, 4 mL) was degassed
under argon . To the resulting mixture tetrakis(triphenylphosphine)palladium(0) (2.435
mg, 8.43 mol) was added and reaction mixture was heated in microwave at 111 °C for
10 min . Reaction mixture was concentrated under reduced pressure and the crude
product was purified by colum n chromatography to provide methyl 4-(4-(l,l-difluoro-2-
(5-fluoro-2-(5-(l -methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)phenyl)butanoate (35
mg, 0.074 mmol, 43.9 % yield) .
NMR (300 MHz, CDCI3) : 7.30-7.25 (m, 1H) 7.21-7. 14 (m, 5H), 7.01 (t, J = 2 Hz,
8Hz, 1H), 6.65 (d, J = 2.2 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 3.69 (s, 3H), 3.54 (t, J =
12.2 Hz, 2H), 2.68 (t, J =6 Hz, 2H), 2.32 (d, J = 2.2 Hz, 2H), 2.02-1 .94 (m, 2H), 1.60
(3H), 0.95-0.94 (m, 2H), 0.88-. 87 (m, 2H) ; MS (m/z) : 473.
Step 6b:
Synthesis of 4-(4-(l, l -difluoro-2-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-
yl)phenyl)ethyl)pheny|)butanoic acid
To a solution of methyl 4-(4-(l, l-difluoro-2-(5-fluon>2-(5-(lmethylcyclopropyl)
thiophen-2-yl)phenyl)ethyl)phenyl)butanoate (20 mg, 0.042 mmol) in
THF (4 mL) and methanol ( 1 mL), aqueous lithium hydroxide (6.08 mg, 0.254 mmol)
was added and allowed to stir at RT for 6 hours. Reaction mixture was concentrated,
quenched with dilute ammonium chloride and extracted with ethyl acetate. Organic layer
was dried over sodium sulfate and concentrated. The residue obtained was diluted with
ethyl acetate (1 mL) followed by precipitation with n-hexane. The precipitate was dried
under vacuum to obtain desired 4-(4-(l, l-difluoro-2-(5-fluoro-2-(5-(lmethylcyclopropyl)
thiophen-2-yl)phenyl)ethyl)phenyl)butanoic acid (12 mg, 0.026
mmol, 61.8 % yield) .
H NMR (300 MHz, CDCI3) : 7.30-7. 14 (m, 6H), 7.20 t , J = 8 Hz, 2.5 Hz, 1H), 6.66 (d,
= 2.2 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 3.49 (t, J = 13 Hz, 2H), 2.70 (t, J = 6.2 Hz,
2H), 2.35 (t, J = 6.5 Hz, 2H), 2.02-1 .94 (m, = 6.4 Hz, 2H), 1.27 (s, 3H), 0.95-0.94
(m, 2H), 0.8-0.87 (m, 2H) ; MS (m/z): 459 (M+ l).
Example 7
4-(4-(l, l-Difluoro-2-(4-fluoro-4'-methyl-[l, l'-biphenyl]-2-yl)ethyl)phenyl)butanoic acid
(Compound 7)
Step 7a :
Synthesis of methyl 4-(4-(l, l-difluoro-2-(4-fluoro-4'-methyl-[l, l'-biphenyl]-2-
yl)ethyl)phenyl)butanoate
To a degassed solution of methyl 4-(4-(2-(2-bromo-5-fIuorophenyl)-l, l -
difluoroethyl)phenyl)butanoate (80 mg, 0.193 mmol), 4,4,5,5-tetra methyl-2-(p-tolyl)-
1,3,2-dioxaborolane (84 mg, 0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol)
in dioxane iwater (4 mL: l mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg,
0.019 mmol) was added and the reaction mass was heated in microwave at 111 °C for
10 minutes. Reaction mixture was then concentrated and purified by column
chromatography to obtain methyl 4-(4-(l, l -difluoro-2-(4-fluoro-4'-methyl-[l, l'-
biphenyl]-2-yl)ethyl)phenyl)butanoate. (65 mg, 0.152 mmol, 79 % yield)
NMR (300 MHz, CDCI3) : 7.20-7.00 (m, 8H), 6.87-6.84 (m, 3H), 3.69 (s, 3H), 3.45
(t, J = 15.9 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.40 (s, 3H), 2.37 (t, J = 7.5 Hz, 2H),
1.99-1 .94 (m, 2H); MS (m/z) : 449 (M+Na) .
Step 7b:
Synthesis of 4-(4-(l , l-difluoro-2-(4-fluoro-4'-methyl-[l, l '-biphenyl]-2-
yl)ethyl)phenyl)butanoic acid
To a solution of methyl 4-(4-(l,l-difluoro-2-(4-fluoro-4'-methyl-[l,l'-biphenyl]-2-
yl)ethyl)phenyl)butanoate (58 mg, 0.136 mmol) in 4 mL of THF:Methanol (4:1) was
added lithium hydroxide monohydrate (453 L, 0.680 mmol) and the reaction mixture
was allowed to stir at RT overnight. After complete consumption of starting material,
solvent was removed under reduced pressure. The reaction mixture was neutralized with
saturated ammonium chloride and extracted with ethyl acetate, dried over sodium
sulphate to obtain 4-(4-(l,l-difluoro-2-(4-fluoro-4'-methyl-[l,l'-biphenyl]-2-
yl)ethyl)phenyl)butanoic acid (56 mg, 0.136 mmol)
H NMR (300 MHz, DMSO-d ) : 7.16-7.13 (m, 7H), 7.08 (d, J = 8.1 Hz, 2H), 6.94 (d, J
= 7.8 Hz, 2H), 3.60 (t, J = 14.4 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.23 (t,
J = 7.2 Hz, 2H), 1.81-1.76 (m, 2H); MS (m/z): 413 (M+ l).
Example 8:
4-(4-(2-(2-(5-Cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid (Compound 8)
Step 8a:
Synthesis of methyl 4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate
To a degassed solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate (80 mg, 0.193 mmol), 2-(5-cyclopropylthiophen-2-yl)-
4,4,5,5-tetramethyl-l,3,2-dioxaborolane (96 mg, 0.385 mmol), sodium bicarbonate
(32.4 mg, 0.385 mmol) in dioxane (4 mL):water ( 1 mL),
tetrakis(triphenylphosphine)palladium(0) (5.57 mg, 0.019 mmol) was added and the
reaction mixture was heated in microwave at 111 °C for 10 minutes. Reaction mixture
was concentrated and purified by column chromatography to provide methyl 4-(4-(2-(2-
(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,l-difluoroethyl)phenyl)butanoate (72
mg, 0.157 mmol, 82 % yield).
H NMR (300 MHz, DMSO-d6) : 7.32-7.30 (m, 1H), 7.22-7.15 (m, 6H), 6.76 (d, J = 3
Hz, IH), 6.67 (d, J = 3.3 Hz, 1H), 3.70 (t, J = 13.5 Hz, 2H), 3.58 (s, 3H), 2.64 (t, J =
7.5 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 2.11-2.10 (m, 1H), 1.85-1.80 (m, 2H), 1.02-0.99
(m, 2H), 0.68-0.66 ( , 2H); MS (m/z): 481 (M+Na).
Step 8b:
Synthesis of 4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid
To a solution of methyl 4-(4-(2-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate (62 mg, 0.135 mmol) in 4 mL of THF:methanol (4:1)
was added lithium hydroxide monohydrate (451 L, 0.676 mmol) and the reaction
mixture was allowed to stir at RT overnight. After complete consumption of starting
material, solvent was removed under reduced pressure. The reaction mixture was
neutralized with saturated ammonium chloride and extracted with ethyl acetate, dried
over sodium sulphate to obtain 4-(4-(2-(2-(5-cydopropylthiophen-2-yl)-5-fluorophenyl)-
l,l-difluoroethyl)phenyl)butanoic acid (60 mg, 0.135 mmol).
H N R (300 MHz, DMSO-d6) : 12.12 (s, 1H), 7.32-7.15 (m, 7H), 6.75-6.66 (m, 2H),
3.70 (t, J = 16.8 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.24-2.11 (m, 3H), 1.82-1.77 (m,
2H), 1.01-0.98 (m, 2H), 0.68-0.66 (m, 2H); MS (m/z): 443 (M+l).
Example 9
4-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid (Compound 9)
Step 9a:
Synthesis of methyl 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate
To a degassed solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate (80 mg, 0.193 mmol), (2,3-dihydrobenzofuran-5-
yl)boronic acid (63.2 mg, 0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol) in
dioxane (4 mL):water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg, 0.019
mmol) was added and the reaction mixture was heated in microwave at 111 °C for 10
minutes. Reaction mixture was concentrated and purified by column chromatography to
provide methyl 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butandate (58 mg, 0.128 mmol, 66.2 % yield).
H NMR (300 MHz, CDCI3) : 7.42-6.96 (m, 7H), 6.74-6.65 (m, 3H), 4.65 (t, J = 8.7 Hz,
2H), 3.68 (s, 3H), 3.44 (t, J = 15.9 Hz, 2H), 3.23 (t, J = 8.7Hz, 2H), 2.69 (t, J = 7.5
Hz, 2H), 2.37 9 (t, J =7.5 Hz, 2H), 2.01-1.91 (m, 2H); MS (m/z): 477 (M+Na).
Step 9b:
Synthesis of 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid
To a solution of methyl 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoate (58 mg, 0.128 mmol) in 4 mL of THF: Methanol (4:1)
was added lithium hydroxide monohydrate (26.8 mg, 0.638 mmol) and the reaction
mixture was allowed t o stir at RT overnight. After complete consumption of starting
material, solvent was removed under reduced pressure. The reaction mixture was
neutralized with saturated ammonium chloride and extracted with ethyl acetate, dried
over sodium sulphate to provide 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-
fluorophenyl)-l,l-difluoroethyl)phenyl)butanoic acid (43 mg, 0.098 mmol, 76 % yield).
NMR (300 MHz, DMSO-d6) : 12.10 (s, 1H), 7.21-7.13 (m, 5H), 7.07-7.04 (m, 2H),
6.72 (s, 3H), 4.58 (t, J = 8.7 Hz, 2H), 3.54 (t, J = 16.5 Hz, 2H), 3.19 (t, J = 8.7 Hz,
2H), 2.63 (t, J = 7.5 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 1.81-1 .76 (m, 2H) ; MS (m/z) :
439 (M-l).
Example 10 :
4-(4-(2-(4'-Cyclopropyl-4-fluoro-[l,l '-biphenyl]-2-yl)-l ,l-difluoroethyl)phenyl)butanoic
acid (Compound 10)
Step 10a :
Synthesis of methyl 4-(4-(2-(4'-cyclopropyl-4-fluoro-[l, l'-biphenyl]-2-yl)-l, l -
difluoroethyl)phenyl)butanoate
To a degassed solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l, l -
difluoroethyl)phenyl)butanoate (80 mg, 0.193 mmol), sodium bicarbonate (32.4 mg,
0.385 mmol), (4-cyclopropylphenyl)boronic acid (62.4 mg, 0.385 mmol) in dioxane (4
mL) and water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg, 0.019 mmol)
was added and the reaction mass was heated in microwave at 111 °C for 10 minutes.
Reaction mixture was concentrated and purified by column chromatography to provide
methyl 4-(4-(2-(4'-cyclopropyl-4-fluoro-[l, l'-biphenyl]-2-yl)-l, l -
difluoroethyl)phenyl)butanoate (73 mg, 0.161 mmol, 84 % yield).
H NMR (300 MHz, CDGI3) : 7.19-6.96 (m, 9H), 6.86 (d, J = 8.1 Hz, 2H), 3.69 (s, 3H),
3.45 (t, J = 15.9 Hz, 2H), 2.69 (t, J = 7.2Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.01-1 .89'
(m, 3H), 1.06-0.99 (m, 2H), 0.77-0.72 (m, 2H) ; MS (m/z) : 475 (M+Na) .
Step 10b :
Synthesis of 4-(4-(2-(4'-cyclopropyl-4-fluoro-[l, l'-biphenyl]-2-yl)-l, l -
difluoroethyl)phenyl)butanoic acid
To a solution of methyl 4-(4-(2-(4'-cyclopropyl-4-fluoro-[l, l'-biphenyl]-2-yl)-l, l -
difluoroethyl)phenyl)butanoate (70 mg, 0.155 mmol) in 4 mL of THF: Methanol (4 :1)
was added lithium hydroxide monohydrate (32.5 mg, 0.773 mmol) and the reaction
mixture was allowed to stir at RT overnight. After complete consumption of starting
material, solvent was removed under reduced pressure. The reaction mixture was
neutralized with saturated ammonium chloride and extracted with ethyl acetate, dried
over sodium sulphate to provide 4-(4-(2-(4'-cyclopropyl-4-fluoro-[l, l'-biphenyl]-2-yl)-
l,l-difluoroethyl)phenyl)butanoic acid (46 mg, 0.105 mmol, 67.8 % yield) .
NMR (300 MHz, DMSO-d ) : 12. 18 (s, 1H), 7.19-7.05 (m, 9H), 6.92 (d, J = 7.4 Hz,
2H), 3.55 (t, J = 16.5 Hz, 2H), 2.62 (t, J = 7.2Hz, 2H), 2.23 (t, = 7.2 Hz, 2H), 1.94-
1.76 (m, 3H), 0.98-0.96 (m, 2H), 0.71-0.69 (m, 2H); MS (m/z) : 437 (M+ l).
Example 11
4-(4-((2-(5-( l-Cyanocycloprqpyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic
acid (Compound 11)
Step 11a
Synthesis of l-(5-(4-fluoro-2-formylphenyl)thiophen-2-yl)cyclopropanecarbonitrile
To a degassed solution of 5-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)benzaldehyde (411 mg, 1.644 mmol), l-(5-bromothiophen-2-
yl)cyclopropanecarbonitrile (250 mg, 1.096 mmol) and sodium bicarbonate (184 mg,
2.192 mmol) in dioxane (4 mL) : water (1 mL), tetrakis(triphenylphosphine)palladium(0)
(31.7 mg, 0.110 mmol) was added and reaction mass was heated in microwave at 111
°C for 10 minutes. The reaction mixture was then concentrated and purified by column
chromatography t o provide l-(5-(4-fluoro-2-formylphenyl)thiophen-2-
yl)cyclopropanecarbonitrile (297 mg, 1.095 mmol).
H NMR (300 MHz, DMSO-d6) : 10.13 (s, 1H), 7.72-7.71 (m, 1H), 7.69-7.68 (m, 2H),
6.52-6.51(m, 2H), 1.85 (s, 2H), 1.53 (s, 2H); MS (m/z): 272 (M+ l).
Step lib:
Synthesis of l-(5-(2-ethynyl-4-fluorophenyl)thiophen-2-yl)cyclopropanecarbonitrile
To a solution of l-(5-(4-fluoro-2-formylphenyl)thiophen-2-yl)cyclopropanecarbonitrile
(0.050 g, 0.184 mmol) in dry methanol (5 ml) was added potassium carbonate (0.051 g,
0.369 mmol) and dimethyl (l-diazo-2-oxopropyl)phosphonate (0.531 mL, 0.221 mmol)
at RT under argon, and the mixture was stirred at RT for 1 hour. The reaction was
quenched with brine (15 mL), and the mixture extracted with ethyl acetate (2 x 25 mL).
The combined organic layer was washed with brine (30 mL), dried over sodium sulfate.
Solvent was removed under reduced pressure to give crude which was purified by
column chromatography to give l-(5-(2-ethynyl-4-fluorophenyl)thiophen-2-
yl)cyclopropanecarbonitrile (0.035 g, 0.131 mmol, 71.0 % yield) as liquid.
¾ NMR (300 MHz, CDCI3) : 7.46-7.41(m, 1H), 7.45-7.41 (m, 1H), 7.37-7.35 (m, 1H),
7.32-7.31 (m, lH), 7.13-7.04 (m, lH), 3.32 (s, 1H), 1.80-1.78 (m, 2H), 1.51-1.48 (m,
2H); MS (m/z): 268 (M+l).
Step lie:
Synthesis of methyl 4-(4-((2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-
fluorophenyl)ethynyl)phenyl)butanoate
To a solution of methyl 4-(4,-iodophenyl)butanoate (150 mg, 0.493 mmol), l-(5-(2-
ethynyl-4-fluorophertyl)thiophen-2-yl)cyclopropanecarbonitrile (158 mg, 0.592 mmol) in
DMF, triethylamine (0.207 ml, 1.480 mmol) was added and the reaction mixture was
degassed with argon and bis(triphenylphosphine)palladium(II) dichloride (34.6 mg,
0.049 mmol) added followed by addition of copper(I) iodide (9.39 mg, 0.049 mmol).
Reaction was stirred at 85 °C for 4 hours. After completion of reaction, reaction mass
was concentrated to give crude, which was purified column chromatography to provide
methyl4-(4-((2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-
fluorophenyl)ethynyl)phenyl)butanoate (185 mg, 0.417 mmol, 85 % yield) .
H NMR (300 MHz, CDCI3) : 7.51-7.48 (m, 1H), 7.45-7.42 (m, 2H), 7.38 (dd, J = 3.6,
8.4. Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.08-7.05 (m, 3H), 3.69 (s, 3H), 2.72 (t, J = 7.2
Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.03-1 .96 (m, 2H), 1.83-1 .79 (m, 2H), 1.53-1 .48 (m,
2H); MS (m/z) : 444(M + 1).
Step l i d:
Synthesis of 4-(4-((2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)-
phenyl) butanoic acid
To a solution of methyl 4-(4-((2-(5-( l-cyanocyclopropyl)thiophen-2-yl)-5-
fluorophenyl)ethynyl)phenyl)butanpate (30 mg, 0.068 mmol) in 4 mL of THF : methanol
(4 : 1), LiOH .H20 (225 L, 0.338 mmol) was added and the reaction mixture was allowed
to stir at RT overnight. After complete consumption of starting material, solvent was
removed under reduced pressure. The reaction mixture was neutralized with saturated
ammonium chloride, extracted with ethyl acetate and dried over sodium sulphate to get
4-(4-((2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic
acid (25 mg, 0.058 mmol, 86 % yield) .
H NMR (300 MHz, DMSO-d6) : 7.73-7.70 (m, 1H), 7.51-7.49 (m, 4H), 7.34-7.27 (m,
3H), 7.15 (d, J = 3.6 Hz, 1H), 2.63 (t, J = 7.2 Hz, 2H), 2.24 (t, J = 7.5 Hz, 2H), 1.86-
1.80 (m, 2H), 1.83-1 .79 (m, 2H), 1.53-1 .48 (m, 2H); MS (m/z) : 430. 1(M + 1) .
Compounds 12 to 22 were prepared analogous to Compounds 1 t o 11 and are provided
in Table 1
Table 1:
yl)styryl)phenyl)butanoic acid

Biological Assays
Representative compounds of Formula (I) of the present invention (referred to as
test compounds) were tested for their activity using the assays and the methods
described below.
Beta () arrestin 2 Interaction Assay (BRET assay) was performed using CHO-K1
cells stably expressing the GPR120L (Long Isoform) receptor using -galactosidase (Beta
gal) enzyme fragment complementation assay. The measurement of GPR120 activation
upon agonist activation was directly provided by -arrestin recruitment. One day before
the -arrestin 2 assay, CHO-K1 cells were seeded and incubated overnight at 37°C in a
5% C0 2 humidified atmosphere. Cells were treated with the test compounds in various
concentrations ranging from 30to InM and incubated for 2 hours for GPCR (GPR120)
activation. Extent of Arrestin recruitment was measured by adding detection reagents
for Beta gal complementation assay, and was further incubated for 1 hour. The
chemiluminescent signal was detected on Polar Star (BMG Labtech). The dose-response
curve was analyzed using Sigma Plot/ Graph Pad. The EC 0 (concentration of the test
compounds where 50% of compounds' maximal activity is observed) values were
calculated from the dose-response curve. Similar procedure was followed for HEK 293
cells and results obtained are tabulated in Table 2.
Table - 2: EC5 values of compounds of Examples
Compound No. C (nM)
Compound 3 +
Compound 5 +++
Compound 6 ++
Compound 11 ++
Compound 12 +++
Compound 13 ++
Compound 1 +++
Compound 18 +++
Compound 20 +++
The EC50 (nM) values of the compounds are presented in Table 1 wherein:
+++ corresponds to EC50 ranging from 50 nM t o 500 nM;
+ + corresponds t o EC5 ranging from 500 nM to 5000 nM;
+ corresponds to EC50 ranging from 5000 nM t o 10000 nM;
Conclusion: The EC50 values determined for the compounds of the present invention
indicative of GPR120 agonist activity of the compounds of the present invention.
We Claim :
1. A compound of formula (I) ;
wherein,
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyi; (C -
Cio)aryl or 5- to 12-membered heteroaryl ; wherein the heterocycloalkyi and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, O and S;
Ring B and Ring C are independently selected from (C -Cio)aryl or 5- to 12-membered
heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group
roup consisting of
cycloalkyl and 5-
th Ring A to form
R and R7 are independently selected from hydrogen or (Ci-C6)alkyl ;
R5 and R6 are independently selected from the group consisting of hydrogen, halogen
and (Ci-C6)alkyl ;
m, n and p are each integer independently selected from 1, 2 and 3;
wherein,
(Ci-G6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (CiC6)
alkyl, halo(Ci-C )alkyl, -0 (Ci-C 6)alkyl, (C3-C8)cycloalkyl, (C -Ci 0)aryl
heterocycloalkyl and heteroaryl ;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of C -
C6)alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-Ci 0)cycloalkyl, (C6-C10)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)a1kyl, halogen, hydroxy, -0 -( -C6)alkyl, (C3-Ci 0)cycloalkyl, (C6 -Ci 0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C 6)alkyl, halogen, hydroxy, -C -C alky , (C3-Ci 0)cycloalkyl, (C -C )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
2. The compound of Formula (I) according to claim 1, wherein Ring A is unsubstituted or
substituted 3- to 10-membered cycloalkyl or unsubstituted or substituted 5- to 12-
membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected
from the group consisting of N, O and S or unsubstituted or substituted (C -Ci 0)aryl or 5-
to 12-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected
from the group consisting of N, O and S or unsaturated or partially unsaturated (C -
Cio)aryl or unsaturated or partially unsaturated 5- to 12-membered heteroaryl.
ccording to claim 1, wherein Ring A is
4. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted or
substituted (C6-Ci 0)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3
heteroatoms independently selected from the group consisting of N, O and S.
5. The compound of Formula (I) according to claim 4, wherein Ring B is unsubstituted or
substituted phenyl.
6. The compound of Formula (I) according to claim 5, wherein Ring B is unsubstituted or
substituted phenyl and R2 is located at para position to Ring A and n is 1.
7. The compound of Formula (I) according to claim 6, wherein Ring B is phenyl and R2 is
halogen located at para position to Ring A and n is 1.
8. The compound of Formula (I) according to claim 1, wherein Ring C is unsubstituted or
substituted (C -Ci 0)aryl or 5- to 12-membered heteroaryl containing 1, 2 or 3
heteroatoms independently selected from the group consisting of N, O and S.
9. The compound of Formula (I) according to claim 8, wherein Ring C is unsubstituted or
substituted phenyl, or unsubstituted or substituted 5- to 6- membered heteroaryl.
'
10. The compound of Formula (I) according to claim 1, wherein two R1 are combined
together with Ring A to form a 3- to 6-membered cycloalkyl or 5- to 12-membered
heterocycloalkyl.
11. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted
or substituted phenyl ; Ring C is unsubstituted or substituted phenyl, or unsubstituted or
substituted 5- to 6- membered heteroaryl; R2 is located at para position to Ring A; R3 is
hydrogen ; and m & n are 1.
12. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted
or substituted phenyl; Ring C is unsubstituted or substituted phenyl, R2 is halogen
located at para position to Ring A; R3 is hydrogen ; and & n are 1.
13. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted
or substituted phenyl; Ring C is unsubstituted or substituted 5- to 6- membered
heteroaryl ; R2 is located at para position to Ring A; R3 is hydrogen ; and m & n are 1.
14. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted
or substituted (C6-Ci 0)aryl or 5- to 12-membered heteroaryl; Ring C is unsubstituted or
substituted (C6-Ci0)aryl or 5- to 12-membered heteroaryl and Ring A is saturated or
partially unsaturated 5- to 12-membered bicyclic heteroaryl or 5- to 12-membered
bicyclic heterocycloalkyl .
15. The compound of Formula (I) according to claim 1, wherein Ring B is unsubstituted
or substituted (C6-Ci0)aryl or 5- to 12-membered heteroaryl ; Ring C is unsubstituted or
substituted (C6-Cio)aryl or 5- to 12-membered heteroaryl ; Ring A is 5- to 6-membered
monocyclic heteroaryl and R is 3- to 10-membered cycloalkyl.
16. A compound of Formula IA;
Formula IA
wherein,
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyl ; (C6-
Cio)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, O and S;
Ring B and Ring C are independently selected from (C6-Cio)aryl or 5- to 12-membered
heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group
consisting of N, O and S;
R is hydrogen or (C -C )alkyl ;
R , R and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci -C6)alkyl, halo (Ci-C6)alkyl, 3- to 10-membered cycloalkyl and 5-
to 12-membered heterocycloalkyl;
m, n and p are each an integer independently selected from 1, 2 and 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (CiC
)alkyl, halo(Ci-C )alkyl, -0 (Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C6-C10 )aryl,
heterocycloalkyl and heteroaryl ;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0 -(Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C -Ci )aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 -(Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C -Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C -Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a
pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a
carboxylic acid isostere thereof.
17. A compound
Formula IB
Ring A is 3- to- 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyl ; (C6-
Ci0)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, O and S;
Ring B and Ring C are independently selected from the group consisting of (C6-C 0 )aryl
or 5- to 12-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected from the group consisting of N, 0 and S;
R is hydrogen or (Ci-C6)alkyl ;
R , R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (C1-C )alkyl, halo(C].-C6 )alkyl, 3- to 10-membered cycloalkyl, and 5-
to 12-membered heterocycloalkyl ;
R4 is independently selected from hydrogen or (Ci-C6)alkyl;
R5 is independently selected from hydrogen, halogen or (Ci-C )alkyl ;
m, n and p are each an integer independently selected from 1, 2 and 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (Cialkyl,
halo(Ci-C6)alkyl, -0(C -C6)alkyl, (C3-Ci0)cycloalkyl, (C -Ci0)aryl,
heterocycloalkyl and heteroaryl ;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of C -
C )alkyl, halogen, hydroxy, -0 -(Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-C10)cycloalkyl, (C -Ci0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is selected from chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
18. A compound of Formula IC;
wherein,
Ring A is 3- to 10-membered cycioalkyl, 5- to 12-membered heterocycloalkyl; (C6-
C10)aryl or 5- to 12-membered heteroaryl, wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, 0 and S;
Ring B and Ring C are independently selected from the group consisting of (C -Cio)aryl
or 5- to 12-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected from the group consisting of N, O and S;
R is hydrogen or (Ci-C6)alkyl;
R1, R2 and R3 at each occurrence is independently selected from the group consisting of
hydrogen, halogen, ( -C6)alkyl, halo(Ci-C6)alkyl, 3- to 10-membered cycioalkyl and 5-
to 12-membered heterocycloalkyl;
R4 and R7 are independently selected from hydrogen or (Ci-C )alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen, halogen
and (Ci-C )alkyl;
m, n and p are each an integer independently selected from 1, 2 or 3;
wherein,
(Ci-C6)alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (Ci-
C6)alkyl, halo(Ci-C6)alkyl, -0 (Ci-C6)alkyl, (C3-Ci0)cycloalkyl, (C -C10)aryl, heterocyclyl
and heteroaryl;
cycioalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of C -
C6)alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C6-Cio)aryl , heterocyclyl,
heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -0 -(Ci-C )alkyl, (C3-Ci0)cycloalkyl, (C6-C10 )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci-C 6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl ,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is selected from chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
Formula ID
wherein,
Ring A is 3- to 10-membered cycloalkyl, 5- to 12-membered heterocycloalkyl; (C -
Cio)aryl or 5- to 12-membered heteroaryl; wherein the heterocycloalkyl and the
heteroaryl contain 1, 2, 3 or 4 heteroatoms independently selected from the group
consisting of N, O and S;
Ring B and Ring C are independently selected from (C6-Ci0)aryl or 5- to 12-membered
pendent ly selected from the group
R is hydrogen or (Ci-C )alkyl;
R , R2 and R3 at each occurrence are independently selected from the group consisting of
hydrogen, halogen, (Ci-C )alkyl, halo(Ci-C6)alkyl, 3- to 10-membered cycloalkyl and 5-
to 12-membered heterocycloalkyl;
R4 and R7 are independently selected from the group consisting of hydrogen and (Cialkyl;
R5 and R6 are independently selected from the group consisting of hydrogen, halogen
and (Ci-C )alkyl;
m, n and p are each integer independently selected from 1, 2 and 3;
wherein,
(C -C )alkyl is unsubstituted or substituted with one or more groups
independently selected from the group consisting of halogen, hydroxy, cyano, nitro, ( -
C6)alkyl, halo(Ci-C )alkyl, -0 (Ci-C6)alkyl, (C3-C8)cycloalkyl, (C -Ci0)aryl ,
heterocycloalkyl and heteroaryl;
cycloalkyl is a 3- to 10-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C )alkyl, halogen, hydroxy, -0 -(Ci -C6)alkyl, (C3-Ci0)cycloalkyl, (C6-C10)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heteroaryl is a 5- to 12-membered ring, which is unsubstituted or substituted
with one or more groups independently selected from the group consisting of (Ci-
C6)alkyl, halogen, hydroxy, -C C -CeJalkyl, (C -Ci0)cycloalkyl, (C6-Ci )aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
heterocycloalkyl is a 5- to 12-membered ring, which is unsubstituted or
substituted with one or more groups independently selected from the group consisting of
(Ci-C6)alkyl, halogen, hydroxy, -0 -(Ci -C6)alkyl, (C3-Ci0)cycloalkyl, (C6-Ci0)aryl,
heterocycloalkyl, heteroaryl, amino and cyano;
halogen is chlorine, bromine, iodine or fluorine;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
20. The compound according to claims 1, 16, 17, 18 and 19selected from;
4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid;
4-(5-(5-Fluoro-2-(6-methoxypyridin-3-yl)phenethyl)pyridin-2-yl)butanoic acid;
4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)phenyl)ethynyl)pyridin-2-yl)butanoic acid;
4-(5-(5-Fluoro-2-(5-methylthiophen-2-yl)phenethyl)pyridin-2-yl)butanoic acid;
4-(4-(l,l-Difluoro-2-(5-fluoro-2-(5-methylthiophen-2-yl)phenyl)ethyl)phenyl)butanoic
acid;
4-(4-(l,l-Difluoro-2-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-yl)phenyl)ethyl)-
phenyl)butanoic acid;
4-(4-(l,l-Difluoro-2-(4-fluoro-4'-methyl-[l,l'-biphenyl]-2-yl)ethyl)phenyl)butanoic acid,
4-(4-(2-(2-(5-Cyclopropylthiophen.-2-yl)-5-fluorophenyl)-l,l-difluoroethyl)phenyl)-
butanoic acid;
4-(4-(2-(2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,l-difluoroethyl)phenyl)-
butanoic acid;
4-(4-(2-(4'-Cyclopropyl-4-fluoro-[l,l'-biphenyl]-2-yl)-l,l-difluoroethyl)phenyl)butanoic
acid;
4-(4-((2-(5-(l-Cyanocyclopropyl)thiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)-
butanoic acid;
4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenethyl)phenyl)butanoic
acid;
4-(4-(2-(5-cyclopropylthiophen-2-yl)-5-fluorophenethyl)phenyl)butanoic acid;
4-(4-(5-fluoro-2-(5-(l-methylcyclopropyl)thiophen-2-yl)styryl)phenyl)butanoic acid;
4-(4-(2-(5-(l-cyanocyclopropyl)thiophen-2-yl)-5-fluorostyryl)phenyl)butanoic acid;
4-(4-(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)styryl)phenyl)butanoic acid;
4-(4-(5-flu0ro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)styryl)phenyl)butanoic acid;
4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorophenyl)ethynyl)phenyl)butanoic acid;
4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)ethynyl)phenyl)-
butanoic acid;
4-(4-(14-difluoro-2-(5-fluorp-2-(6-methoxypyridin-3-yl)phenyl)ethyl)phenyl)butanoic
acid;
4-(4-(l,l-difluoro-2-(5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-
yl)phenyl)ethyl)phenyl)butanoic acid; and
4-(4-(2-(2-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-5-fluorophenyl)-l,ldifluoroethyl)
phenyl)butanoic acid;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically
acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid
isostere thereof.
21. A pharmaceutical composition comprising a therapeutically effective amount of the
compound according to any one of claims 1 to 20, or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and
at least one pharmaceutically acceptable carrier or excipient.
22. A method for the treatment or prophylaxis of a disease or a disorder mediated by
GPR120 comprising administering to a subject in need thereof; a therapeutically effective
amount of the compounds according to any one of claims 1 to 20, or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate
thereof.
23. The method according to claim 22, wherein the disease or disorder mediated by
GPR120 is a metabolic disorder.
24. The method according to claim 22, wherein the disease or disorder mediated by
GPR120 is an inflammatory disorder.
25. A compound according to any one of claims 1 to 20 or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate
thereof; for use in the treatment or prophylaxis of a disease or a disorder mediated by
GPR120.
26. The use of the compound according to any one of claims 1 to 20 or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically
acceptable solvate thereof; in the manufacture of a medicament, for the treatment or
prophylaxis of a disease or a disorder mediated by GPR.120.