HETEROCYCLIC COMPOUNDS
Related applications
This application claims the benefit of Indian patent applications No. 1335/KOL/2010,
filed on November 26, 2010 and 0539/KOL/201 1, filed on April 14 201 1 all of which is
hereby incorporated by reference.
Field of the invention
The invention relates to heterocyclic compounds and their stereoisomers or
pharmaceutically acceptable salts thereof. The invention also relates to a process for the
preparation of the compounds of invention. The invention also relates to methods of treating,
preventing and/or managing diseases, disorders, syndromes or conditions associated with the
modulation of the GPR1 9 receptor. The invention also relates to combination therapy for
treating, preventing and/or managing diseases and disorders associated with the modulation
of GPR1 19 receptors.
Background of the invention
Diabetes mellitus can be classified into two types: Type I (also referred to as insulin
dependent diabetes mellitus) and Type II (also referred to as non-insulin dependent diabetes
mellitus). Type I diabetes is an autoimmune disease wherein there is an extensive loss of the
insulin producing b-cells of the pancreas. The resulting insulin deficiency leads to
hyperglycemia (abnormally high glucose levels in the blood).
Type II diabetes mellitus develops as a result of non-responsiveness of muscle, fat
and liver cells to insulin. This phenomenon is referred to as insulin resistance and could arise
due to a reduced number of insulin receptors on the surface of these cells, or a defective
insulin-mediated signaling, or a combination of both. Chronic Type II diabetes leads to
pancreatic b-cell dysfunction. Surprisingly, there is no cure for diabetes. The current
treatments focus on disease management, by controlling blood glucose levels and delaying
complications that arise due to hyperglycemia. Treatments that target insulin resistance
include metformin and TZDs (Thiazolidinediones), and those that stimulate insulin secretion,
such as sulfonylureas and GLP-1 agonists. Sulfonylureas often lead to hypoglycemia due to
excessive insulin secretion. Moreover, the insulin secretion, in this case, is independent of the
blood glucose concentration. GLP-1 agonists stimulate insulin secretion only in the presence
of glucose, but it is not orally bioavailable and has to be given intravenously. DPP-IV
inhibitors work by increasing the levels of GLP-1 which in turn leads to insulin secretion.
(Jones PvM, et al, Expert Opin. Ther. Patents (2009) 19(10):1339-1359).
GPR1 19 (G protein-coupled receptor) is a member of the rhodopsin family of GPCRs
and is a G s coupled receptor. It is expressed predominantly in the pancreas (b-cells) and
gastrointestinal tract (enteroendocrine cells) in humans (Overton HA, et al., British Journal
of Pharmacology (2008) 153 S76-S81). GPR1 19 activation by endogenous ligands (e.g.,
oleoylethanolamide, OEA) leads to an increase in the intracellular concentrations of cAMP,
which subsequently leads to increased secretion of glucose-dependent insulinotropic peptide
(GIP) and glucagon-like peptide (GLP-1). This mechanism is responsible for the glucose
stimulated insulin secretion (GSIS) from the b-cells of the pancreas. Treatments that increase
GLP-1 secretion may be useful for various conditions and disorders including, but not limited
to, metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic,
depressive and neuropsychiatric diseases.
GPR1 19 is reported to be involved in various diseases in addition to Type 2 diabetes.
These include but are not limited to obesity (Overton HA, et al., British Journal of
Pharmacology (2008) 153 S76-S81) and osteoporosis (WO2007/1 20689 A2).
As reported in the literature, the agonists of GPR1 19 receptors are useful as
therapeutic agents for treating or preventing a condition modulated by PYY(peptide YY),
such as a condition modulated by stimulation of NPY Y2 receptor (Y2R). Conditions
modulated by PYY include but are not limited to bone-related conditions, metabolic
disorders, angiogenesis-related conditions, ischemia-related conditions, convulsive disorders,
malabsorptive disorders, cancers, and inflammatory disorders. PCT application WO
2009/126245 Al discloses GPR1 19 receptors to be involved in inflammation, inflammatory
bowel disease and atherosclerosis.
Obesity is a condition in which individuals have high body mass index (BMI).
Overweight conditions and obesity are closely linked to Type 2 diabetes, heart disease,
increased cholesterol, dislipidemia, high blood pressure, insulin resistance, glucose
intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart
failure, strokes, gallstones, cholecystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep
apnea, respiratory problems, certain forms of cancers (endometrial, breast, prostate and
colon) and psychological disorders (e.g., depression, eating disorder, low self-esteem).
Osteoporosis is characterized by the loss of bone mass and the deterioration of
skeletal structure leading to decreased bone strength. Patients have an enhanced risk of
fractures. Osteoporosis leads to morbidity, mortality and decreased quality of life.
Osteoporotic fractures therefore cause substantial mortality, morbidity, and economic cost.
With an ageing population, the number of osteoporotic fractures and their costs will at least
double in the next 50 years unless effective preventive strategies are developed. (Cole et al.,
Curr. Rheum. Reports (2008); 10; 92-96; Reginster, Bone (2006) 38:S4-S9); Boonen, Curr.
Med. Res. Opin. (2008); 24; 1781-1788).
Atherosclerosis is a condition involving inflammation, lipid accumulation, cell death
(necrosis) and fibrosis. Foam cell formation results from monocyte infiltration and
cholesterol deposition in the subendothelial space. Complications of atherosclerosis lead to
myocardial infarction and stroke. Atherosclerosis is one of the major causes of death in many
countries (Ruggeri, Nat. Med. (2002); 8; 1227-1234; Li, Nat. Med. (2002); 8; 1234-1242).
Inflammatory bowel disease (IBD) is a term that includes diseases leading to
inflammation of intestine. The diseases that are classified under this category are Crohn's
disease, ulcerative colitis and ulcerative proctitis.
Several patent applications disclose compounds that modulate GPR1 19 receptor
activity and their use in the treatment of various diseases and disorders. Some of the patent
applications disclosing compounds modulating GPR1 19 receptor activity are PCT
publications JP 201 1136942, WO 2010/1 19881, WO 2010/149685, WO 2010/128425, WO
2010/128414, WO 2010/095663, WO 2010/075271, WO 2010/075269, WO 2010/008739,
WO 2009/050523, WO 2009/050522, WO 2008/054675, WO 2008/025800, WO
2007/1 16230, WO 2008/005576, WO 2008/005569, WO 2008/070692, WO 2007/035355,
WO 2006/076243, WO 2004/065380, WO 2006/083491, WO 2006/070208, WO
2005/007647, WO 2005/121 121, WO 2004/076413. Pyrimidyl indoline compounds having
hypoglycemic effect are disclosed in WO 2009/051 119 and WO 2009/141238.
Summary of the invention
In accordance with one aspect, the invention provides the compounds of Formula (I):
(I)
wherein,
is a single or double bond; provided that
when = is a double bond W is selected from group A and group B, and,
when is a single bond W is selected from group A;
group A is selected from the group consisting of a 6-membered aromatic ring,
wherein the 6-membered aromatic ring is selected from the group consisting of
a 5-membered heteroaryl, a cycloalkyl, a heterocyclyl, a bicyclic aryl and a bicyclic
heteroaryl, and a member of group A may be optionally substituted with one or more Ri ;
group B is selected from the group consisting of
wherein, R at each occurrence is selected from the group consisting of haloalkyl, alkoxy,
cycloalkyl and N R aR ;
R , R2 are each independently selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, halo, hydroxyalkyl, haloalkyl, -OR a, -NR aRb, -C (0)ORa and -
C (0)NR aR b ;
or when 'b' is single bond, R i may be oxo (=0);
R 3 is selected from the group consisting of - S (0 )pR , -C (0)ORa , -(CH ) qC (0)NR R b, -
(CH ) qN(R a)C (0)R , -N(R a)C (0)ORb , -N(R a)C (0)NR aR b, - S (0 )2N R aR b , -N(R a) S (0 ) R , -
CN, alkoxy, hydroxyalkyl, heterocyclyl and heteroaryl;
Y is N or C ;
Ra and R b are each independently selected from the group consisting of hydrogen,
alkyl, halo, haloalkyl, hydroxy, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryl,
heteroaryl, arylalkyl, and heterocyclyl; or R a and R b may join together with the nitrogen atom
to which they are attached to form a heterocyclic ring;
R 4 is selected from the group consisting of hydrogen, alkyl, halo, haloalkyl, cyano
and -OR a;
Z is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl,
arylalkyl, haloalkyl, hydroxyalkyl, -(CH 2 ) C (0)ORa,
(CH ) C (0)OR R dRe , -(CH 2 ) C (0)R a, -C (0)(CH2 ) N R aR , -(CH 2 ) C (0)NR R , - S (0 ) R , -
S (0 )2N R aR , -C (0)CRcRdRe and -(CH 2 ) C R cR dR ;
Rc, R and R e are each independently selected from the group consisting of hydrogen,
halogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,
and heterocyclyl; or R c and may join together with the carbon atom to which they are
attached to form a 3 to 7 membered carbocyclic or heterocyclic ring;
R , R7, R are each independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cylcoalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, haloalkyl,
alkoxy, -C(0)OR a, -OC(0)R a, -C(0)NR aRb, -N(Ra)C(0)R b, -S(0) pRa, -S(0) 2NRaRb, and -
N(Ra)S(0) 2Rb; wherein R , R6,R7, and R may be present on same or different carbon atom;
or any two of R4, R , R6 R7, R and Z may join together to form a cycloalkyl or heterocyclyl
ring; or any two of R , R^, R7 and R8, when they are attached to the same carbon, may
together form oxo (=0);
X is selected from the group consisting of -(CRioRii)qO(CRi0R ) ,
-(CR10R,,) qS(0) p(CR,oRn )t- and -(CR,oRii )qNR9 (CR ORii)r;
R is hydrogen or alkyl;
R o and R are each independently selected from the group consisting of hydrogen,
halogen, alkyl and haloalkyl; or Ri0 and R may join together with the carbon atom to which
they are attached to form a 3 to 7 membered carbocyclic ring;
R12 at each occurrence is independently selected from hydrogen, alkyl, halogen,
haloalkyl, alkoxy, cycloalkyl and NRaRb;
'm', 'n' and 'p' are each independently selected from 0, 1 or 2;
'q' is an integer ranging from 0 to 4, both inclusive;
't' is an integer ranging from 0 to 4, both inclusive;
with the proviso that when is double bond and
W is
, then X is not -NH- or -NHCH(Ri 1);
and
wherein, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl wherever
they occur may optionally be substituted with one or more substituents independently
selected from hydroxy, halo, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic
ring, heterocyclylalkyl, heteroarylalkyl, -C(0)OR x, -C(0)R , -C(S)R , -C(0)NR xRy, -
NRxC(0)NRyR , -N(Rx)S(0)Ry, -N(Rx)S(0)2Ry, -NRxRy, -NRxC(0)Ry, -NRxC(S)Ry, -
NRxC(S)NR R , -S(0)NRxR , -S(0) 2NRxRy, -ORx, -OC(0)Rx, -OC(0)NRxR , -RxC(0)OR ,
-RxC(0)NRyR , -RxC(0)R , -SRX, -S(0)Rx, and -S(0) Rx; wherein each occurrence of R , R
and R are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and
heteroarylalkyl;
or pharmaceutically acceptable salt thereof.
The below embodiments are illustrative in nature only and are not intended to limit
the scope of the invention.
According to one embodiment there are provided compounds of Formula (I):
(I)
or pharmaceutically acceptable salt thereof;
wherein,
i is a single or double bond;
W is selected fro -membered aromatic ring selected from the group consisting
X, Z, Ri, R , R3, R , R5, R , R7, R$, 'n' and 'm' are as defined herein above.
According to another embodiment there are provided compounds of Formula (I) in
which is a double bond and W is selected from 6-membered aromatic ring selected from
the group consisting of:
According to another embodiment there are provided compounds of Formula (II):
or pharmaceutically acceptable salt thereof;
wherein,
i is a single or double bond;
X, Z, R , R3, R , R^, R , R , 'n' and 'm' are as defined herein above.
According to another embodiment there are provided compounds of Formula (III):
or pharmaceutically acceptable salt thereof;
wherein,
is a single or double bond;
R3 is selected from the group consisting of -S(0) pRa, -C(0)OR a, -(CH2) C(0)NR aRb, -
(CH2)qN(Ra)C(0)R , -N(Ra)C(0)OR , -N(Ra)C(0)NR aRb, -S(0) NRaR , -N(Ra)S(0) 2R ,
hydroxyalkyl and heterocyclyl;
X, Z, R2, R , R , R7, R , 'n' and 'm' are as defined herein above.
According to another embodiment there are provided compounds of Formula (IV):
or pharmaceutically acceptable salt thereof;
wherein,
--^ is a single or double bond;
X, Z, R2, R3, R , R , R , R , 'n' and 'm' are as defined herein above.
According to another embodiment there are provided compounds of Formula (V):
or pharmaceutically acceptable salt thereof;
wherein,
i is a single or double bond;
X, Z, R2, and R3 are as defined herein above.
It should be understood that Formula (I), (II), (III), (IV) and (V) structurally
encompass all N-oxides, tautomers, stereoisomers and pharmaceutically acceptable salts that
may be contemplated from the chemical structures described herein.
According to one sub embodiment there are provided a compound of Formula (I) in
which W is selected from
According to another sub embodiment there are provided a compound of Formula
(II), (III), (IV) and/or (V) in which X is -(CRioRn) qO(CRIORiOr and -
(CRi0Rii)q R9(CRioRii)t- ; wherein 'q' is 0 or 1; 't' is 0 or 1; and each of Rio and R are
independently selected from hydrogen, halogen or alkyl.
According to another sub embodiment there are provided a compound of Formula
(II), (III), (IV) and/or (V) in which R2 is hydrogen or halogen.
According to another sub embodiment there are provided a compound of Formula
(II), (IV) and/or (V) in which R3 is -CN, alkoxy, hydroxyalkyl, C(0)ORa, -S(0)2Ra, -
C(0)NRaR , -N(Ra)C(0)R , -CH2N(Ra)C(0)R , -N(Ra)C(0)OR , -S(0)2NRaR , -
N(Ra)S(0)2Rb, heterocyclyl or heteroaryl wherein Ra and R are each and independently a
hydrogen, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclyl; or R
and Rb may join together with the nitrogen atom to which they are attached to form a
heterocyclic ring.
According to another sub embodiment there are provided a compound of Formula
(III) in which R3 is hydroxyalkyl, C(0)ORa, -S(0)2Ra, -C(0)NRaRb, -N(R )C(0)Rb, -
CH2N(Ra)C(0)Rb, -N(Ra)C(0)ORb, -S(0)2NRaRb, -N(R )S(0) 2Rb, heterocyclyl wherein Ra
and Rb are each and independently a hydrogen, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl,
aryl, heteroaryl or heterocyclyl; or Ra and Rb may join together with the nitrogen atom to
which they are attached to form a heterocyclic ring.
According to another sub embodiment there are provided a compound of Formula
(II), (III), (IV) and/or (V) in which Z is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl,
aryl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, -C(0)ORa, -
C(0)Ra, -C(0)CR RdRe, -(CH )qCRcR Re, -S(0)2Ra or -S(0) 2NRaRb wherein Ra, R , Rc, Rd
and R are each and independently a hydrogen, alkyl, halo, haloalkyl, hydroxy, cycloalkyl,
hydroxyalkyl, aryl, heteroaryl, arylalkyl, and heterocyclyl; or Ra and Rb may join together
with the nitrogen atom to which they are attached to form a heterocyclic ring; or Rc and
may join together with the carbon atom to which they are attached to form a 3 to 7 membered
carbocyclic or heterocyclic ring.
According to another sub embodiment there are provided a compound of Formula
(II), (III) and/or (IV) in which 'm' is 0 or 1; and 'n' is 0 or 1.
According to another sub embodiment there are provided a compound of Formula
(II), (III) and/or (IV) in which R5, ¾ R7 and R are each and independently selected from the
group consisting of hydrogen, alkyl, cyano, hydroxy, haloalkyl or alkoxy; or any two of R ,
R , R R7, R and Z may join together to form a cycloalkyl or heterocyclyl ring; or any two
of R5, R6, R7 and R8, when they are attached to the same carbon, may together form oxo
(=0).
According to another sub embodiment there are provided a compound of Formula (I),
(II), (III), (IV) and/or (V) in which is a single or double bond; W is selected from group
A as defined herein above or 5-membered heteroaryl; R2 is hydrogen or halogen; R3 is -
S(0 ) Ra, -C(0)NR aRb, -N(R a)C(0)R b, -N(R a)C(0)OR b, heterocyclyl, heterocyclylalkyl or
heteroaryl wherein Ra and b are each independently a hydrogen, alkyl; X is -O, -NH-; Z is
alkyl, haloalkyl, heteroaryl, heterocyclyl, -C(0)Oalkyl, -C(0)CR cRdRe, -(CH 2) CRcRdRe; R5,
R6 R7 and Rg are hydrogen or halogen or any two of R4, R5, R6, R7, R and Z may join
together to form a cycloalkyl or heterocyclyl ring; Rc, R , and are as defined herein above;
'm' is 1; and 'n' is 1.
In another embodiment of the invention there is provided a pharmaceutical
composition comprising at least one compound of Formula (I) and one or more
pharmaceutically acceptable excipients such as a carrier or a diluent. Preferably, the
pharmaceutical composition comprises a therapeutically affective amount of at least one
compound of Formula (I).
In another embodiment of the invention there is provided a pharmaceutical
composition comprising a compound of Formula (I) for treating, preventing, and/or
managing diseases, disorders, syndromes or conditions associated with the modulation of the
GPR1 19 receptor.
In another embodiment of the invention, the compounds of Formula (I) may be used
either alone or in combination with one or more therapeutically active agents described
herein for treating, preventing, managing diseases, disorders, syndromes or conditions
associated with the modulation of the GPR1 19 receptor.
In another embodiment, the invention further provides methods of treating,
preventing, and/or managing diseases, disorders, syndromes or conditions associated with the
modulation of the GPR1 1 receptor.
In another embodiment, the invention is related to a pharmaceutical composition
comprising a therapeutically effective amount of at least one of the compound of Formula (I)
or its stereoisomers, or pharmaceutically acceptable salts thereof, and one or more
pharmaceutically acceptable carriers or diluents for treating, preventing, managing diseases,
disorders, syndromes or conditions associated with the modulation of the GPR1 19 receptor.
In another embodiment of the invention there are provided processes for the
preparation of compounds of the invention havin the structure of Formula (I):
(I)
comprising,
a) reacting a compound of formula (2) where L is a leaving group, with a compound of
formula (7), where L' is a leaving group PG is protecting group, in the presence of
suitable base to give a compound of formula (8),
(2) (7) (8)
b) treating the compound of formula (8) with a compound of formula (5) in the presence
of palladium catalyst to ive a compound of formula (9),
(5) (9)
c) deprotecting the compound of formula (9) with a suitable reagent to give a compound
of formula (10), and
(10)
d) coupling the compound of formula (10) with Z-L where L is a leaving group, to obtain
the compound of formula (I).
The details of one or more embodiments of the inventions are set forth in the
description below. Other features, objects and advantages of the inventions will be apparent
from the description and claims.
Detailed description of the invention
Unless otherwise stated, the following terms used in the specification and claims have
the meanings given below:
For purposes of interpreting this specification, the following definitions will apply
and whenever appropriate, terms used in the singular will also include the plural and vice
versa.
The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.
The term "oxo" means the C(=0) group. Such an oxo group may be a part of either a
cycle or a chain in the compounds of the present invention.
The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely
carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to
six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g.,
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (tbutyl)
and the like. Unless set forth or recited to the contrary, all alkyl groups described or
claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon
atoms and including at least one carbon-carbon double bond. Non-limiting Examples of
alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-lpropenyl,
1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all
alkenyl groups described or claimed herein may be straight chain or branched, substituted or
unsubstituted.
The term "alkynyl" refers to a hydrocarbon radical containing at least one carboncarbon
triple bond, and having 2 to about 10 carbon atoms. Non- limiting examples of
alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to
the contrary, all alkynyl groups described or claimed herein may be straight chain or
branched, substituted or unsubstituted.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest
of the molecule. Representative examples of such groups are -OCH3 and -OC2H5.
Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may
be straight chain or branched, substituted or unsubstituted.
The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of 3
to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like. Examples of multicyclic cycloalkyl groups include, but are not limited to,
perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic
groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all
cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, directly
bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl etc. Unless set forth or recited to the
contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or
unsubstituted.
The term "cycloalkenyl" refers to a monocyclic or bicyclic nonaromatic carbocyclic
radical containing at least one double bond and having from 3 to 10 ring members, and refers
in particular cyclobutenyl, cyclopentenyl or cyclohexenyl radicals. Unless set forth or recited
to the contrary, all cycloalkyl groups described or claimed herein may be substituted or
unsubstituted.
The term "haloalkyl" refers to an alkyl, as defined herein, that is substituted by one or
more halogen groups as defined herein. Preferably, the haloalkyl may be monohaloalkyl,
dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine,
bromine, chlorine or fluorine substituent. Dihaloalkyl and polyhaloalkyl groups can be
substituted with two or more of the same halogen atoms or a combination of different
halogen groups. Preferably, a polyhaloalkyl is substituted with up to 12, 10, 8, 6, 4, 3, or 2
halogen groups. Non-limiting examples of haloalkyl include fluoromefhyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl
having all hydrogen atoms replaced with halogen atoms.
The term "hydroxyalkyl" refers to an alkyl, as defined herein, that is substituted by
one or more hydroxy groups. Preferably the hydroxyalkyl can be monohydroxyalkyl or
dihydroxyalkyl. Non-limiting examples of hydroxyalkyl include 2- hydroxyethyl, 3-
hydroxypropyl, 2-hydroxypropyl, and the like.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms, including
monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl,
tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the
contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
The term "arylalkyl" refers to an aryl group as defined above, directly bonded to an
alkyl group as defined above, e.g., -CH2C6H and -C H4C6H . Unless set forth or recited to
the contrary, all arylalkyl groups described or claimed herein may be substituted or
unsubstituted.
The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise
specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which
consists of carbon atoms and with one or more heteroatom(s) independently selected from N,
O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may
include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms
in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition,
the nitrogen atom may be optionally quatemized, the heterocyclic ring or heterocyclyl may
optionally contain one or more olefmic bond(s), and one or two carbon atoms(s) in the
heterocyclic ring or heterocyclyl may be interrupted with -C(O)-, -C(=N-alkyl)-, or -C(=Ncycloalkyl),
etc. In addition the heterocyclic ring may be fused with aromatic ring. Nonlimiting
examples of heterocyclic rings include azepinyl, azetidinyl, benzodioxolyl,
benzodioxanyl, benzopyranyl, chromanyl, dioxolanyl, dioxaphospholanyl,
decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl,
isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-
oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl,
quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl,
thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and the
like. The heterocyclic ring may be attached to the main structure at any heteroatom or carbon
atom that results in the creation of a stable structure. Unless set forth or recited to the
contrary, all heterocyclyl groups described or claimed herein may be substituted or
unsubstituted.
A "carbocyclic ring" or "carbocycle" as used herein refers to a 3- to 10- membered saturated
or unsaturated, monocyclic, fused bicyclic, spirocyclic or bridged polycyclic ring containing
carbon atoms, which may optionally be substituted, for example, carbocyclic rings include
but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene,
cyclohexanone, aryl, naphthyl, adamentyl etc. Unless set forth or recited to the contrary, all
carbocyclic groups or rings described or claimed herein may be aromatic or non aromatic.
The term "heteroaryl" unless otherwise specified, refers to substituted or
unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more
heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or
tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any
heteroatom or carbon atom that results in the creation of a stable structure. Examples of such
heteroaryl ring radicals include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl,
indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl,
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl,
benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl,
quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl,
isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless
set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be
substituted or unsubstituted.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to
an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any
carbon atom in the alkyl group that results in the creation of a stable structure. Unless set
forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may
be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an
alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon
atom in the alkyl group that results in the creation of a stable structure. Unless set forth or
recited to the contrary, all heteroarylalkyl groups described or claimed herein may be
substituted or unsubstituted.
Unless otherwise specified, the term "substituted" as used herein refers to a group or
moiety having one or more substituents attached to the structural skeleton of the group or
moiety. Such substituents include, but are not limited to hydroxy, halo, carboxyl, cyano,
nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclic ring, heterocyclylalkyl,
heteroarylalkyl, -C(0)OR x, -C(0)R x, -C(S)RX, -C(0)NR Ry, -NRxC(0)NR yR , -
N(R )S(0)R y, -N(Rx)S(0) 2Ry, -NRxR , -NRxC(0)R , -NR C(S)R , -NRxC(S)NR R , -
S(0)NR xR , -S(0) 2NRxR , -ORx, -OC(0)R x, -OC(0)NR xR , -RxC(0)OR , -
R C(0)NR R , -RxC(0)R , -SRX, -S(0)R x, and -S(0) 2R ; wherein each occurrence of R , R
and Rz are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and
heteroarylalkyl.
"May optionally be substituted" means that the moiety or group may or may not be
substituted. For example, "optionally substituted aryl" means that the aryl radical may or may
not be substituted and that the description includes both substituted aryl radicals and aryl
radicals having no substitution.
Unless otherwise stated, in the present application "protecting group" (PG) refers to the
groups intended to protect an otherwise labile group, e.g., an amino group, a carboxy group
and the like, under specific reaction conditions. Various protecting groups alongwith the
methods of protection and deprotection are generally known to a person of ordinary skilled in
the art. Incorporated herein in this regard as reference is Greene's Protective Groups in
Organic Synthesis, 4th Edition, John Wiley & Sons, New York. In the present invention,
preferred amino protecting groups are t-butoxycarbonyl, benzyloxycarbonyl, acetyl and the
like; while preferred carboxy protecting groups are esters, amides and the like.
A "stereoisomer" refers to a compound made up of the same atoms bonded by the
same bonds but having different three-dimensional structures, which are not interchangeable.
The invention contemplates various stereoisomers and mixtures thereof and includes
"enantiomers", which refers to two stereoisomers whose molecules are non-superimposable
mirror images of one another.
The term "treating" or "treatment" of a state, diseases, disorders, syndromes or
conditions includes: (a) preventing or delaying the appearance of clinical symptoms of the
state, disease, disorder, condition or syndrome developing in a subject that may be afflicted
with or predisposed to the state, disease, disorder, condition or syndrome but does not yet
experience or display clinical or subclinical symptoms of the state, disease, disorder,
condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e.,
arresting or reducing the development of the disease or at least one clinical or subclinical
symptom thereof; and/or (c) slowing the progression of a disease, disorder, condition or
syndrome or at least one of its clinical or subclinical symptoms thereof.
The term "modulate" or "modulating" or "modulation" refers to an increase or
decrease in the amount, quality, or effect of a particular activity, function or molecule; by
way of illustration and not limitation, agonists, partial agonists, inverse agonists, and
antagonists of a G protein-coupled receptor are modulators of the receptor. For example, the
compounds of invention are useful as modulators of the GPR1 19 receptor.
The term "subject" includes mammals preferably humans and other animals, such as
domestic animals; e.g., household pets including cats and dogs and non- domestic animals.
A "therapeutically effective amount" means the amount of a compound that, when
administered to a subject for treating a state, disease, disorder, condition or syndrome, is
sufficient to cause the effect in the subject which is the purpose of the administration. The
"therapeutically effective amount" will vary depending on the compound, the disease and its
severity and the age, weight, physical condition and responsiveness of the subject to be
treated.
The compounds of the invention may form salts. Non-limiting examples of
pharmaceutically acceptable salts forming part of this invention include salts derived from
inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and
salts of non-natural amino acids. With respect to the overall compounds described by the
Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. The
different stereoisomeric forms of the present patent application may be separated from one
another by the method known in the art, or a given isomer may be obtained by stereospecific
or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are
also contemplated.
Screening of compounds of invention for GPR1 19 receptor modulation activity may
be achieved by using various in-vitro and in-vivo protocols mentioned herein below or
methods known in the art.
Pharmaceutical Compositions
The invention relates to pharmaceutical compositions containing the compounds of
the Formula (I) disclosed herein. In particular, pharmaceutical compositions containing a
therapeutically effective amount of at least one compound of Formula (I) described herein
and at least one pharmaceutically acceptable excipient such as a carrier or diluent. Preferably,
the contemplated pharmaceutical compositions include the compound(s) described herein in
an amount sufficient to modulate GPR1 19 receptor mediated diseases described herein when
administered to a subject.
The compounds of the invention may be associated with a pharmaceutically
acceptable excipient such as a carrier or a diluent or be diluted by a carrier, or enclosed
within a carrier which can be in the form of a capsule, sachet, paper or other container. The
pharmaceutically acceptable excipient includes pharmaceutical agents that do not induce the
production of antibodies harmful to the individual receiving the composition, and which may
be administered without undue toxicity.
Examples of suitable carriers include, but are not limited to, water, salt solutions,
alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil,
gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin,
amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl
ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides
and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose
and polyvinylpyrrolidone.
The pharmaceutical composition may also include one or more pharmaceutically
acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents,
preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents,
flavoring agents, stabilizers, surfactants, colorants, or any combination of the foregoing. The
pharmaceutical composition of the invention may be formulated so as to provide quick,
sustained, or delayed release of the active ingredient after administration to the subject by
employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared by conventional
techniques known in the art. For example, the active compound of Formula (I) can be mixed
with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form
of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a
diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or
medium for the active compound. The active compound can be adsorbed on a granular solid
container, for example, in a sachet.
The pharmaceutical compositions may be in conventional forms, for example,
capsules, tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active
compound of the invention, to the appropriate or desired site of action. Suitable routes of
administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal,
intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such
as with a topical ointment).
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard
gelatin), dragees (containing the active ingredient in powder or pellet form), troches and
lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or
the like are particularly suitable for oral application. Liquid formulations include, but are not
limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or
non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable
are injectable solutions or suspensions formulation.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the
preparation is subdivided into unit doses containing appropriate quantities of the active
component. The unit dosage form can be a.packaged preparation; the package containing
discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it
can be the appropriate number of any of these in packaged form.
For administration to subject patients, the total daily dose of the compounds of the
invention depends, of course, on the mode of administration. For example, oral
administration may require a higher total daily dose, than an intravenous (direct into blood).
The quantity of active component in a unit dose preparation may be varied or adjusted from
0.1 mg to 10000 g, according to the potency of the active component or mode of
administration.
Suitable doses of the compounds, for use in treating the diseases and disorders
described herein, can be determined by those skilled in the relevant art. Therapeutic doses are
generally identified through a dose ranging study in subject based on preliminary evidence
derived from the animal studies. Doses must be sufficient to result in a desired therapeutic
benefit without causing unwanted side effects for the patient. For example, the daily dosage
of the GPR1 19 modulator can range from about 0.1 to about 30.0 mg/kg. Mode of
administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also
be well used and adjusted by those skilled in the art. All changes and modifications are
envisioned within the scope of the invention.
In one embodiment of the invention, the compound of Formula (I) and / or the
pharmaceutical compositions of Formula (I) may be used either alone or in combination with
one or more additional therapeutic agents for treating, preventing, managing diseases,
disorders, syndromes or conditions associated with the modulation of the GPR1 19 receptor.
The compounds and compositions of the invention and the additional therapeutic
agent as described herein may be administered simultaneously, sequentially or separately.
The combination of the compound of Formula (I) with any one or more additional
therapeutic agent may be given to the subject in the same or separate dosage formulation.
Where separate dosage formulations are used, the compound of Formula (I) and one
or more additional therapeutic agents can be administered at essentially the same time i.e.,
concurrently, or at separately staggered times i.e., sequentially. Combination therapy is
understood to include all these regimens. Selection of additional therapeutic agents will, in
large part, depend on the desired target therapy. Turner N, et al, Prog. Drug Res. (1998) 5 1
:33-94; Haffner S, Diabetes Care (1998) 2 1 :160- 178; and DeFronzo R, et al. (eds.),
Diabetes Reviews (1997) Vol. 5 No. 4. A number of studies have investigated the benefits of
combination therapies with oral agents {see, e.g., Mahler R, J. Clin. Endocrinol. Metab.
(1999) 84:1 165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28,
Diabetes Care (1998) 2 1 :87-92; Bardin CW (ed.), Current Therapy in Endocrinology and
Metabolism, 6th Ed. (Mosby - Year Book, Inc., St. Louis, MO 1997); Chiasson J, et al., Ann.
Intern. Med. (1994) 121 :928-935; Coniff R, et al, Clin. Ther. (1997) 19:16-26; Coniff R, et
al., Am. J . Med. (1995) 98:443-451; and Iwamoto Y, et al, Diabet. Med. (1996) 13:365-370;
Kwiterovich P, Am. J. Cardiol. (1998) 82(12A):3U-17U).
The additional therapeutic agent which can be used in combination with the
compounds of invention include, but not limited to, anti-diabetic agents, anti-hyperglycemic
agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, antinephropathic
agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive
agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, antihypertriglyceridemic
agents, anti-hypercholesterolemic agents, anti-restenotic agents, antipancreatic
agents, anti-metabolic syndrome agents, lipid lowering agents, anti-lipodystrophy
agents, appetite suppressants, treatments for heart failure, treatments for peripheral arterial
disease and anti-inflammatory agents.
A combination therapy may be used in modulating, including preventing, the onset of
the symptoms or complications associated with diabetes or treating, preventing or reducing
the risk of developing diabetes and its related symptoms, complications, and disorders,
wherein the compounds of the invention can be effectively used in combination with, one or
more additional therapeutic agents. One or more additional therapeutic agents for diabetes
includes but not limited to insulin and insulin analogs; insulin secretagogues such as
sulfonylureas and analogs; meglitinides; insulin sensitizers such as biguanides;
thiazolidinediones (PPAR); PPAR alpha/gamma dual agonists; alpha-glucosidase inhibitors;
dipeptidyl peptidase-IV (DPP4) inhibitors; glucagon-like peptide- 1 (GLP-1) receptor
agonists including glucagon-like peptides and its analogues, amylin agonists; glucagon
antagonists; alpha2-antagonists and imidazolines; SGLT2 inhibitors; insulin signaling
agonists, insulin mimetics, aldose reductase inhibitors; 11-beta-hydroxysteroid
dehydrogenase Type I inhibitors; RXR agonists; fatty acid oxidation inhibitors; betaagonists;
phosphodiesterase inhibitors, both cAMP and cGMP type; lipoxygenase inhibitors;
PTP1B inhibitors; gluconeogenesis inhibitors; somatostatin and its analogs and antagonists;
antilipolytic agents; glucose transport stimulating agents; glucose synthase kinase inhibitors;
galanin receptor agonists; chemokine receptor antagonist; glucokinase activators; GDIR
agonists; GPR40 modulators and other GPR1 19 modulators.
Insulin and its analogs include insulin from animal source and recombinant insulin
and its derivatives, for e.g., short acting derivatives Lispro, aspart, glulisine and their
protamine solutions and mixtures thereof, or the long acting derivatives, for e.g., glargine,
detemir, and their modified formulations, for e.g., inhaled formulations comprising insulin,
insulin via buccal route and the like. Sulfonylureas and analogs includes, but not limited to,
chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide,
glimepiride and the like. Meglitinides such as repaglinide, mitiglinide and the like.
Biguanides includes, but not limited to, metformin, phenformin, buformin and the like.
Thiazolidinediones for e.g., ciglitazone, pioglitazone, troglitazone, rosiglitazone and the like.
PPAR-alpha agonists for e.g., fenofibrate, gemfibrozil and the like. PPAR alpha/gamma dual
agonists, for e.g., muraglitazar, peliglitazar, and the like. Dipeptidyl peptidase-IV (DPP4)
inhibitors includes saxagliptin, sitagliptin, vildagliptin, denagliptin and the like. Glucagonlike
peptide-1 (GLP-1) receptor agonists, for e.g., Exenatide, Liraglutide, AVE0010, R1583,
SUN E7001, GSK-716155 and Exendin-4 (PC-DACTM) and the like. Alpha2-antagonists
and imidazolines include, but are not limited to, midaglizole, isaglidole, deriglidole,
idazoxan, efaroxan, fluparoxan and the like. SGLT2 inhibitors include, but are not limited to,
dapagliflozin, sergliflozin, canagliflozin, LX421 1, BI-10773, BI-44847, ASP- 1941, TS-071
and the like. Alpha-glucosidase inhibitors include, but are not limited to, acarbose, miglitol,
voglibose and the like. Amylin analogs such as pramlintide and its derivatives. Other insulin
secretagogues, for e.g., linogliride, insulinotropin, exendin-4, N,N-dimethyl-N'-[2-(4-
morpholinyl)phenyl]guanidine (E)-2-butenedioate salt (BTS-675820), (-)-N-(trans-4-
isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166)) and the like.
In another embodiment, the compound of Formula (I) may be used in combination
therapy for treating obesity or obesity- related disorders, wherein the compound of Formula
(I) can be effectively used in combination with one or more therapeutic agents having
synergistic effects such as anti-obesity agents, anorectic agents, appetite suppressant and
related agents. Diet and/or exercise can also have synergistic effects.
Anti-obesity agents include but are not limited to b-3 adrenoceptor agonist agents;
gastrointestinal lipase inhibitors, leptins, cannabinoid-1 ("CB-1") receptor antagonists (such
as rimonabant); PPAR delta agonists or partial agonists; dual PPAR alpha, PPAR delta
agonists or partial agonists; dual PPAR delta, PPAR gamma agonists or partial agonists; pan
PPAR agonists or partial agonists; neuropeptide Y; enterostatin; cholecytokinin; bombesin;
amylin; histamine H3 receptors; serotonin 2C receptor agonists (5HT2c), dopamine D2
receptors; melanocyte stimulating hormone; corticotrophin releasing factor; galanin; gamma
amino butyric acid (GABA), apolipoprotein-B secretion/micro somal triglyceride transfer
protein (apo-B/MTP) inhibitors, MCR-4 agonists, MCR-4 antagonists; cholescystokinin-A
(CCK-A) agonists, serotonin, galanin receptor antagonists; urocortin mimetics, CRF
antagonists, CRF binding proteins and norepinephrine reuptake inhibitors (for example,
sibutramine), sympathomimetic agents, b3 adrenergic receptor agonists, dopamine agonists
(for example, bromocriptine), melanocyte-stimulating hormone receptor analogs, melanin
concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin
receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.,
Orlistat), anorectic agents (such as a bombesin agonist), europeptide-Y antagonists,
thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor
agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists,
glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors (such as AXOKINE,
human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor
antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic
agents (for example, phentermine, mazindol and the like) and appetite suppressants (for
example, bupropion). Some of the compounds- that can be used in combination with the
compounds of the invention include, but are not limited to, phenylpropanolamine,
phentermine; orlistat, rimonabant, dexamphetamine, diethylpropion, mazindol, fenfluramine,
dexfenfluramine, sibutramine, QNEXA (combination of phentermine and topiramate),
Lorcaserin, CONTRAVE (combination of naltrexone and bupropion) and the like.
In a further embodiment, the compound of Formula (I) may be used in combination
therapy for treating, preventing, and/or managing lipodystrophy including HIV protease
associated lipodystrophy. Accordingly, the compound of Formula (I) may be used in
combination with HIV protease inhibitors, including but not limited to, REYATAZ and
KALETRA and the like.
In a further embodiment, the compound of Formula (I) may be used in combination
therapy for modulating metabolic syndrome for e.g., treating metabolic syndrome and its
related symptoms, complications and disorders, wherein the compound of Formula (I) may
be effectively used in combination with, for example, the active agents discussed above for
modulating or treating diabetes, obesity, hyperlipidemia, atherosclerosis, and/or their
respective related symptoms, complications and disorders. Metabolic Syndrome or
"Syndrome X" is described in Ford et al., J. Am. Med. Assoc., 287:356-359 (2002) and
Arbeeny et al., Curr. Med. Chem.-Imm., Endoc. & Metab. Agents, 1:1-24 (2001).
In a further embodiment, the compound of Formula (I) may be used in combination
therapy in modulating hyperlipidemia. Examples of suitable lipid lowering agents and antiatherosclerotic
agents, for use in combination with the compounds of Formula (I) include
one or more MTP/ApoB secretion inhibitors (e.g., dirlopatide, N-(2,2,2-trifluoroethyl)-9-[4-
[4- [[[4'-(trifluoromethyl) [1,1 '-biphenyl]-2-yl]carbonyl-]amino]-1-piped dinyl]butyl] -9Hfluorene-
9-carboxamide methane sulfonate, CP-741952, SLx-4090; HMG CoA reductase
inhibitors (e.g., atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin);
squalene synthetase inhibitors, PPAR alpha agonists and fibric acid derivatives (e.g.,
fenofibrate, gemfibrozil); ACAT inhibitors; lipoxygenase inhibitors; cholesterol absorption
inhibitors (e.g., ezetimibe); Ileal Na+/bile acid cotransporter inhibitors (e.g., compounds as
disclosed in Drugs of the Future, 24:425-430 (1999); upregulators of LDL receptor activity
(e.g., (3R)-3-[(13R)-13-hydroxy-10-oxotetradecyl]-5,7-dimethoxy-l(3H)-isobenzofuranone
and (3alpha,4alpha,5alpha)-4-(2-propenyl)-cholestan-3-ol; bile acid sequestrants (e.g.,
WELCHOL, COLESTID, LOCHOLEST and QUESTRAN; and fibric acid derivatives, such
as ATROMID, LOPID and TRICOT); cholesterol ester transfer protein inhibitors (e.g.,
torcetrapib and (2R)-3-{ [3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-(l , ,2,2-tetrafluoroethoxy)
phenyl]methyl]amino}-l,l,l-trifluoro-2-propanol); nicotinic acid and derivatives thereof
(e.g., niacin, acipimox); PCSK9 inhibitors; LXR agonists; lipoxygenase inhibitors as
disclosed by Sendobry et al., "Attenuation of diet-induced atherosclerosis in rabbits with a
highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J.
Pharmacology, 120:1 199-1206 (1997), and Cornicelli et al., "15-Lipoxygenase and its
Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical
Design, 5:1 1-20 (1999)).
Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin,
fluvastatin, cerivastatin, atavastatin, and rosuvastatin.
Examples of suitable anti-hypertensive agents for use in combination with the
compounds of the invention include beta adrenergic blockers, calcium channel blockers (Ltype
and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics
(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendrofiumefhiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,
ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,
triamtrenene, amiloride, spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors
(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril,
quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,
valsartan), ET receptor antagonists, Dual ET/AII antagonist , neutral endopeptidase (NEP)
inhibitors, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and
gemopatrilat), nitrates, central alpha agonists (e.g., clonidine), alphal blockers (e.g.,
prazosine), arterial vasodilators (e.g., minoxidil), sympatolytics (e.g., resperine), renin
inhibitors (e.g., Aliskiren).
In a further embodiment, the compound of Formula (I) may be used in combination
therapy with therapeutic agents showing therapeutic benefits of GPR 119 activity modulators
derived from increasing levels of GIP and PPY.
In a further embodiment, the compound of Formula (I) may be used either alone or in
combination with one or more therapeutically active drug for treating, preventing and/or
managing a disease or disorder caused by low bone mass such as osteoporosis, and for
increasing bone mass in an individual. WO 2007/120689A2 discloses that administration of a
GPR1 19 agonist to an individual, such as by oral administration, can act at the GPR1 19
receptor to increase the GIP level in the individual. One or more therapeutically active drugs
can be selected from the group consisting of calcium, vitamin D, estrogen, tibolone, selective
estrogen receptor modulator (SERM; e.g., raloxifene, tamoxifen), biphosphonate (e.g.,
etidronate, alendronate, risedronate), calcitonin, la-hydroxylated metabolite of vitamin D,
fluoride, thiazide, anabolic steroids, ipriflavone, vitamin K, parathyroid hormone (PTH),
strontium, statin, osteoprotererin, EP4 receptor selective agonists, cannabinoid receptor type
2 (CB2) selective agonists, and p38 MAP kinase inhibitors. (World Health Organization
Technical Report Series 921 (2003), Prevention and Management of Osteoporosis).
In a further embodiment, the compound of Formula (I) may be used either alone or in
combination with one or more therapeutically active drug for treating, preventing and/or
managing a disease or disorder associated with inflammation. Examples of suitable antiinflammatory
agents for use in combination with the compounds of the invention include,
but are not limited to, NSAIDS, prednisone, acetaminophen, aspirin, codeine, fentanyl,
ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, sufentanyl,
sunlindac, prednisolone, methylprednisolone, dexamethazone, flucatisone, betamethasone,
hydrocortisone, and beclomethasone.
The above other therapeutic agents, when employed in combination with the
compounds of the invention may be used, for example, in those amounts indicated in the
Physicians' Desk Reference, or as otherwise determined by one of ordinary skill in the art.
In one embodiment, the compounds of the invention can be administered in
therapeutically effective amounts in combination with one or more therapeutic active agents
(pharmaceutical combinations) as described above. Where compounds of the invention are
administered in conjunction with other therapies, dosages of the co-administered compounds
will of course vary, depending on the type of co-drug employed, on the specific drug
employed, on the condition being treated and so forth. In general, compounds of the
invention will be administered in therapeutically effective amounts via one or more
acceptable modes known in the art, either alone or in combination with one or more
therapeutic agents. A therapeutically effective amount can vary widely depending on the
severity of the disease, the age and relative health of the subject, the potency of the
compound used and other factors.
Method of treatment
In one embodiment, the invention provides a compound of Formula (I) and
pharmaceutical compositions thereof that are useful in treating diseases, disorders or
conditions associated with the modulation of GPR1 19 receptors which includes, but are not
limited to, treating, preventing, managing and/or slowing the progression of diabetes and
related conditions, microvascular complications associated with diabetes, macrovascular
complications associated with diabetes, obesity, cardiovascular diseases, and metabolic
syndrome and its component conditions.
The invention further provides methods of treating diseases, disorders syndromes or
conditions associated with the modulation of the GPR1 19 receptor in a subject in need
thereof by administering to the subject a therapeutically effective amount of a compound of
Formula (I) or a pharmaceutical composition thereof.
In a further embodiment the diseases, disorders or conditions associated with the
modulation of the GPR1 19 receptors include Type 2 diabetes, Type 1 diabetes,
hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, wound
healing, retinopathy, neuropathy, nephropathy, obesity, Metabolic Syndrome, lipodystrophy
including HIV protease associated lipodystrophy, lipid disorders, hypertension, dyslipidemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, vascular
restenosis, peripheral arterial disease, and its sequela for example acute coronary syndrome,
myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication,
myocardial ischemia, stroke and heart failure.
In a further embodiment the diseases, disorders or conditions associated with the
modulation of GPR1 19 receptor includes inflammatory diseases such as psoriasis,
rheumatoid arthritis and osteoarthritis, inflammatory bowel diseases, atherosclerosis and
bone diseases including osteoporosis.
General Methods of Preparation
The compounds described herein may be prepared by techniques known in the art. In
addition, the compounds described herein may be prepared by following the reaction
sequence as depicted in Schemes 1 to 3. Further, in the following schemes, where specific
bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that
other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used
and are therefore included within the scope of the present invention. Variations in reaction
conditions, for example, temperature and/or duration of the reaction, which may be used as
known in the art are also within the scope of the present invention. All the isomers of the
compounds described are these schemes, unless otherwise specified, are also encompassed
within the scope of this invention.
Compounds of Formula (I) may be prepared as shown in the following reaction
schemes and the brief description thereof. Exemplary reagents and procedures for these
reactions appear hereinafter and in the working examples. Protection and deprotection, in the
schemes below, may be carried out by procedures generally known in the art (for example,
Greene, T. W. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 3rd Edition, 1999
[Wiley]).
As shown in Scheme 1 wherein = , W, X, Z, Rl R , R3, R , R , R6, R7, R , 'n' and
'm' are as defined herein above, the compounds of formula (I) may be obtained by treating
substituted compound (2) where L is a leaving group, with a piperidine compound of formula
(3), where L' is a leaving group, in the presence of a base to give a compound of formula (4).
This compound of formula (4) is further treated with the compound of formula (5) in the
presence of palladium catalyst to give a compound of formula (I).
Scheme 1
)
Alternatively, compounds of formula (I) may also be prepared by following the procedure as
depicted in Scheme 2 wherein -^, W, X, Z, R , R2, R3, R4, R5, R6, R7, R8, 'n' and 'm' are as
defined herein above. The compound (2) can be reacted with the compound of formula (5) in
the presence of palladium catalyst to give a compound of formula (6), which on further
reaction with a compound of formula (3) in the presence of a base results in a compound of
formula (I).
Scheme 2
(I)
Another alternative approach to prepare the compound of formula (I), wherein W, X, Z,
Ri, R2, R3, R4, R5, R^, R7, R , 'n' and 'm' are as defined herein above, is depicted in Scheme
3. A compound of formula (2) can be reacted with a piperidine compound of formula (7) in
the presence of a base to give a compound of formula (8). This compound of formula (8),
where PG is a protecting group, is further treated with the compound of formula (5) in
presence of palladium catalyst to give a compound of formula (9). Deprotection of
intermediate (9) can be carried out with appropriate reagents known to a person skilled in the
art of organic synthesis.
The deprotected compound of formula (10) is then treated with Z-L where L is a leaving
group such as halide, mesylate, triflate etc., by methods known in the art of organic synthesis
to give compounds of formula (I).
Scheme 3
(2) (7) (8) (5)
Experimental
Some of the representative examples of the present invention were prepared by
following one or more reaction schemes as described above.
The invention is further illustrated by the following examples which are provided
merely to be exemplary of the invention and do not limit the scope of the invention. The
examples set forth below demonstrate the synthetic procedures for the preparation of the
relative compounds. Certain modifications and equivalents will be apparent to those skilled
in the art and are intended to be included within the scope of the invention. The
aforementioned patents and patent applications are incorporated herein by reference.
Nomenclature of the compounds of the invention is according to ChemBioDraw
version 12. Structures of the intermediates as well as the final compounds were confirmed by
spectral data.
Intermediate-1: N-(lH-indol-5-yl)pivalamide
To a stirred solution of 5-Indole amine (0.6 g, 4.54 mmol) in anhydrous dichloromethane (15
mL), triethylamine (1.3 mL, 9.0 mmol) and pivaloyl chloride (0.45 mL, 5.4 mmol) were
added and stirred at room temperature for 2 h. The reaction mixture was diluted with water;
the organic layer was separated and concentrated in vacuo. The resultant residue was purified
by flash column chromatography to give N-(lH-indol-5-yl)pivalamide (0.88g, 89%); MS:
217.0 (M+l).
Intermediate-2: N-(lH-indol-5-yl)cyclopropanecarboxamide
The title compound was prepared by following the similar procedure as described in
Intermediate-1, using lH-indol-5-amine and cyclopropanecarbonyl chloride; MS: 201.1
(M+l).
Intermediate-3: N-((lH-indol-5-yl) methyl) isobutyramide
The title compound was prepared by following the similar procedure as described in
intermediate-1, using (lH-indol-5-yl) methanamine and isobutyryl chloride (169 mg, 99 %);
MS: 217.0 (M+l).
Intermediate-4: (2-chloropyridin-4-yl)methyl methanesulfonate.
To a stirred solution of (2-chloropyridin-4-yl)methanol (0.500 g, 3.496 mmol) in
dichloromethane (15 mL), triethylamine (0.424 g, 4.195 mmol) and methanesulfonylchloride
(0.440g, 3.846 mmol) were added at 0°C and stirred at room temperature for 2-3 h. The
reaction was quenched with water and extracted with dichloromethane. The organic layer
was concentrated in vacuo to give (2-chloropyridin-4-yl)methyl methanesulfonate (0.530 g,
68 %); MS: 221.9 (M+l).
Intermediate-5: t rt-butyl 4-((6-bromopyridin-3-yl)amino)piperidine- 1-carboxylate
To a mixture of tert-butyl 4-oxopiperidine-l -carboxylate (1.15 g, 5.78 mmol) and 6-
bromopyridin-3 -amine (0.5 g, 2.89 mmol) in dichloroethane (20 mL), acetic acid (8 mL,
2.89 mmol) was added and the contents were stirred at room temperature for 3 h. Sodium
triacetoxy borohydride (1.225 g, 5.78 mmol) was added and the contents were stirred at room
temperature for 12 h. The reaction was diluted with ethyl acetate and washed with brine; the
organic layer was separated and concentrated in vacuo. The resulting residue was purified by
flash column chromatography to give rt-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-lcarboxylate
(0.638g, 62%); MS: 357.1(M+1)
Intermediate-6: rt-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine- 1-carboxylate.
To a mixture of 4-hydroxy-piperidine-l-carboxylic acid rt-butyl ester (15.5 g, 77 mmol), 2-
Chloro-5-hydroxy-pyridine (9.9g, 77mmol) and triphenylphosphine (24.24 g, 92.4 mmol) in
THF, diisopropylazodicarboxylate (18.6 g, 92.4 mmol) was added at 0°C and stirred for 18 h.
The reaction was quenched with water and the mixture was extracted with ethyl acetate. The
organic layer was concentrated in vacuo, resulting residue was purified by flash column
chromatography to give rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
( 1lg, 45%); MS: 335.2 (M+23).
Intermediate-7: cis(±)-tert-Butyl-4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-lcarboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate- 1, using 6-chloropyridin-3-ol and trans(±)-ter/-butyl 3-fluoro-4-
hydroxypiperidine-1 -carboxylate (0.490 g, 48%); MS: 332.2 (M+l).
Intermediate-8: t rt-Butyl-3-((6-chloropyridin-3-yl)oxy)pyrrolidine-l-carboxylate.
The title compound was prepared by following the similar procedure as described in
intermediate-6, using 6-chloropyridin-3-ol and tert-butyl 3-hydroxypyrrolidine-lcarboxylate;
MS: 299.0 (M+l)
Intermediate-9: t rt-Butyl-3-((6-chloropyridin-3-yl)oxy)azetidine-l-carboxylate.
The title compound was prepared by following the similar procedure as described
inIntermediate-6, using 6-chloropyridin-3-ol and tert-butyl 3-hydroxyazetidine-1 -carboxylate
(0.319 g, 64.7 % yield); MS: 284.9 (M+l).
Intermediate-10: N-(lH-indol-5-yl)isobutyramide
To a stirred solution of 5-Indole amine (0.5 g, 3.78 mmol), l-ethyl-3(3-
dimethylaminopropyl)carbodiimidehydrochloride (1.45g, 7.56 mmol), 1-hyroxybenzotriazole
(0.578 g, 3.78 mmol) in anhydrous DMF (25 niL), triethylamine (1.0 mL, 7.5 mmol) and
isobutyric acid (0.31 mL, 3.4 mmol) were added and stirred at room temperature for 12 h.
The reaction was quenched with water and the mixture was extracted with ethyl acetate. The
organic layer was concentrated in vacuo and the resultant residue was purified by flash
column chromatography to give N-(lH-indol-5-yl)isobutyramide (0.596g, 77.8%); MS:
203.1 (M+l)
Intermediate-1 1: N-Cyclopropyl- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using lH-indole-5-carboxylic acid and cyclopropanamine (0.34 g, 92%);
MS: 201.1 (M+l).
Intermediate-12: N, N-dimethyl-lH-indole-5-carboxamide.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using lH-indole-5-carboxylic acid and dimethylamine (0.330 g, 56.6 %);
MS: 189.1 (M+l).
Intermediate-13: N, N-dimethylindoline-5-carboxamide.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using indoline-5-carboxylic acid and dimethylamine; MS: 191.1 (M+l).
Intermediate-14: N-methyl-lH-indole-5-carboxamide.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using lH-indole-5-carboxylic acid and methylamine (0.320 g, 59 %); MS:
175(M+1).
Intermediate-15: N-ethyl- 1H-indole-5 -carboxamide.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using 1H-indole-5 -carboxylic acid and ethylamine; MS: 189.1(M+1).
Intermediate-16: N-isopropyl-1 H-indole-5 -carboxamide
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using 1H-indole-5 -carboxylic acid and propan-2 -amine (0.420 g, 67%).
Intermediate-17: 5-(Isopropylsulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Intermediate-20, using 5-iodo-lH-indole (0.610 g, 66%); MS: 224 (M+l)
Intermediate-18: (lH-indol-5-yl)(pyrrolidin-l-yl)methanone.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using lH-indole-5-carboxylic acid and pyrrolidine (0.210 g, 70%).
Intermediate-19: N-(2-hydroxyethyl)-lH-indole-5-carboxamide.
The title compound was prepared by following the similar procedure as described in
Intermediate- 10, using lH-indole-5-carboxylic acid and 2-aminoethanol; MS: 205 (M+l).
Intermediate-20: 3, 3-difluoro-5-(methylsulfonyl)indolin-2-one
To a stirred solution of 5-bromo-3,3-difluoroindolin-2-one (5.0 g, 20 mmol) in DMSO (50
mL), sodium methanesulfinate (3.0 g, 30 mmol), copper(I) trifluoromethane- sulfonate
benzene complex (1.52 g, 3.022 mmol) and N,N'-dimethylethylenediamine (0.33 mL, 3.022
mmol) were added and stirred at 120°C for 14 h. The reaction was quenched with water and
the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo
and resulting residue was purified by flash column chromatography to give the title product
(2.9g, 58.2%); MS: 247.9 (M+l).
Intermediate-21: 5-(Methylsulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Intermediate-20, using 5-Iodo-lH-indole. (9.200g, 57%); MS: 196 (M+l).
Intermediate-22: 7-Fluoro-5-(methylsulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Intermediate-20 using 7-fluoro-5-iodo-lH-indole (0.109g, 67%); MS: 214 (M+l).
Intermediate-23: 3-Methyl-5-(methylsulfonyl)- 1H-indole.
The title compound was prepared by following the similar procedure as described in
Intermediate-20 using 5-bromo-3 -methyl-1H-indole (0.227 g, 57 %); MS: 210 (M+l).
Intermediate-24: 5-(Cyclopropylsulfonyl)-l H-indole
The title compound was prepared by following the similar procedure as described in
Intermediate-20 using 5-iodo-1 H-indole (0.400 g, 44%); MS: 222 (M+l).
Intermediate-25: 5-(Methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine.
The title compound was prepared by following the similar procedure as described in
Intermediate-20 using 5-bromo-lH-pyrrolo[2,3-b]pyridine; MS: 196.02 (M+l).
Intermediate-26: 5-(Methylsulfonyl)indoline.
The title compound was prepared by following the similar procedure as described in
Intermediate-20, using 5-iodoindoline (0.630, 87%); MS: 198 (M+l).
Intermediate-27: tert-Butyl -(2-oxopyrrolidin- 1-yl)- 1H-indole- 1-carboxylate
To a stirred mixture of tert-butyl 5-iodo-l H-indole- 1-carboxylate (1.5 g, 4.3 mmol), Xant
Phos (0.25 g, 0.43 mmol) and 2-pyrrolidinone (0.74 g, 8.7 mmol) in anhydrous dioxane (15
mL), cesium carbonate (2.8 g, 8.7 mmol) was added and the contents were stirred for 5
minutes. Tris(dibenzylideneacetone)-dipalladium (O)chloroform adduct (0.452 g, 0.437
mmol) was added and the reaction mixture was stirred at 110-1 15°C for 6 h. The reaction
mixture was cooled to room temperature and filtered over celite and filtrate was extracted
with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified
by flash column chromatography to yield tert-butyl 5-(2-oxopyrrolidin- l-yl)-l H-indole- 1-
carboxylate (0.80 g, 61%); MS: 301 (M+l).
Intermediate-28: Ethyl-l-(5-((l -(tert-butoxycarbonyl) piperidin-4-yl) oxy) pyridin-2-yl)-
1H-indole-5-carboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-27 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate and
ethyl lH-indole-5-carboxylate (0.21g, 36%); MS: 466.2 (M+l).
Intermediate-29: t rt-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine- 1-carboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-6 using rt-butyl 4-(hydroxymethyl)piperidine-l -carboxylate and 6-
chloropyridin-3-ol (0.1 Og, 54%); MS: 271 (M-56).
Intermediate-30: tert-Butyl 4-((6-(5-pivalamido-lH-indol-l-yl)pyridin-3-yl)oxy)piperidine-
1-carboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-27, using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate and
N-(lH-indol-5-yl)pivalamide; MS: 437.6 (M-56).
Intermediate-31: ter t-Butyl 4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)amino)-
piperidine- 1-carboxylate.
The title compound was prepared by following the similar procedure as described in
lntermediate-27 using ter t-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-l -carboxylate
and 5-(methylsulfonyl)-lH-indole; MS: 415.2 (M-56).
Intermediate-32: tert-Butyl 4-((6-(5-(methylsulfonyl)indolin-l-yl)pyridin-3-yl)amino)-
piperidine- -carboxylate.
The title compound was prepared by following the similar procedure as described in
lntermediate-27 using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-l -carboxylate
and 5-(methyl-sulfonyl)indoline; MS: 473.3 (M+l).
Intermediate-33: tert-Butyl 3-((6-(5-((2-hydroxyethyl)carbamoyl)-l H-indol- 1-yl)pyridin-
3-yl)oxy)pyrrolidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
lntermediate-27 using tert-butyl 3-((6-chloropyridin-3-yl)oxy)pyrrolidine-l -carboxylate and
N-(2-hydroxyethyl)-lH-indole-5-carboxamide; MS: 466.5 (M+)
Intermediate-34: 1-(2-((l -(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)-lH-indol-5-
amine.
The title compound was prepared by following the similar procedure as described in
lntermediate-27 using 4-bromo-2-((l-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazole and
tert-butyl- lH-indol-5-ylcarbamate (0.092g, 40 %); MS: 421 .2 (M+l).
Intermediate-35 : ter t-Butyl 4-((4-(5-amino- 1H-indol- -yl)thiazol-2-yl)oxy)-piperidine- 1-
carboxylate:
The title compound was prepared by following the similar procedure as described in
lntermediate-27 using tert-butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-l -carboxylate and
tert-butyl lH-indol-5-ylcarbamate; MS: 415.1 (M+l).
Intermediate-36 : 4-((6-(5 -(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carbonitrile.
To a stirred solution of tert-butyl 4-((6-(5 -(methylsulfonyl)- 1H-indol- l-yl)pyridin-3 -yl)oxy)-
piperidine-1 -carboxylate (0.3 g, 0.63 mmol) in dichloromethane (5 mL) trifluoroacetic acid
(2.0 niL) was added at 0°C and stirred at room temperature for 2-3h. The solvent was
removed in vacuo and the resulting residue was dissolved in dichloromethane (5 mL),
triethylamine(0.193 g, 1.91 mmol ) and the cyanogen bromide (0.101 g, 0.95 mmol) were
added at 0°C and stirred at room temperature for 2-3h. The reaction was quenched with water
and the mixture was extracted with ethyl acetate. The organic layer was concentrated in
vacuo and the residue was purified by flash column chromatography to give 4-((6-(5-
(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-carbonitrile (0. 160g, 63%);
MS: 397 (M+l).
Intermediate-37: 4-((6-(5 -(Isopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carbonitrile.
The title compound was prepared by following the similar procedure as described in
Intermediate-36 using tert-b y\ 4-((6-(5 -(isopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine-l-carboxylate; MS: 425.3 (M+l).
Intermediate-38: 4-((6-(5-(Methylsulfonyl)-l H-indol- 1-yl) pyridin-3-yl) methoxy)
piperidine-1 -carbonitrile
The title compound was prepared by following the similar procedure as described in
Intermediate-36 using rt-butyl 4-((6-(5-(methylsulfonyl)-l H-indol- 1-yl)pyridin-3 -
yl)methoxy)piperidine-l-carboxylate (0.18g, 93%); MS: 4 11.2 (M+l).
Intermediate-39: 4-((6-(5-(Methylsulfonyl) indolin-l-yl) pyridin-3-yl) methoxy) piperidine-
1-carbonitrile
The title compound was prepared by following the similar procedure as described in
Intermediate-36 using rt-butyl 4-((6-(5-(methylsulfonyl)indolin-l-yl)pyridin-3-yl)
methoxy)piperidine-l-carboxylate (0.16 g, 79%); MS: 413.2 (M+l).
Intermediate-40: 4-((6-(5-(Methylsulfonyl)indolin-l-yl)pyridin-3-yl)oxy)piperidine-lcarbonitrile.
The title compound was prepared by following the similar procedure as described in
Intermediate-36 using tert-butyl 4-((6-(5-(methylsulfonyl)indolin-l-yl)pyridin-3-
yl)oxy)piperidine-l-carboxylate (0.070 g, 83 %); MS: 399.2 (M+l).
Intermediate-41: 4-Hydroxypiperidine-l -carbonitrile.
The title compound was prepared by following the described in Intermediate-36 using tertbutyl
4-hydroxypiperidine-l-carboxylate (0.340 g, 54%).
Intermediate-42: rt-Butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-l -carboxylate.
To a stirred solution of 4-Hydroxy-piperidine-l-carboxylic acid t rt-butyl ester (1.63 g, 8.1
mmol) in THF (20 mL), NaH (0.40 g, 10.1 mmol)) was added and stirred at 60 °C for 0.5 h.
2,6-dichloropyridine (1.0 g, 6.75 mmol) was added and stirred at room temperature for 3-4h.
The reaction was quenched with water and extracted with ethyl acetate. The organic layer
was concentrated in vacuo and the resultant residue was purified by flash column
chromatography to yield t r t-butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-l -carboxylate as
a pale yellow solid (0.98g, 48 %); MS: 335.1 (M+23)
Intermediate-43: r t-Butyl 4-((6-chloropyridin-3-yl) methoxy) piperidine-1 -carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-42 using 4-hydroxy-piperidine-l-carboxylic acid rt-butyl ester and (6-
chloropyridin-3-yl)methyl methanesulfonate; MS: 227 (M-100).
Intermediate-44: -Butyl 4-((2-chloropyridin-4-yl)methoxy)piperidine-l -carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-42 using (2-chloropyridin-4-yl)methylmethanesulfonate (Intermediate-4) and 4-
hydroxy-piperidine-l-carboxylic acid rt-butyl ester (0.215 g, 29 %); MS: 327.2 (M+l).
Intermediate-45: 4-Bromo-2-((l-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazole.
The title compound was prepared by following the similar procedure as described in
Intermediate-42 using l-(5-ethylpyrazin-2-yl)piperidin-4-ol and 2,4-dibromothiazole (0.480
g, 54 %); MS: 369.2 (M+l).
Intermediate-46: rt-Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine- 1-carboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-42 using tert-butyl 4-hydroxypiperidine-l -carboxylate and 2,4-dibromothiazole
(O.lg, 25 %); MS: 363.2 (M+l).
Intermediate-47: rt-Butyl 4-(((4-bromothiazol-2-yl)oxy)methyl)piperidine- 1-
carboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-42, using t rt-butyl 4-(hydroxymethyl)piperidine-l-carboxylate and 2,4-
dibromothiazole (0.124 g, 39%); MS: 377.3 (M+l).
Intermediate-48: (6-Chloropyridin-3-yl)methyl methanesulfonate
The title compound was prepared by following the similar procedure as described in
Intermediate-42 using (6-chloropyridin-3-yl)methanol; MS: 222 (M+l).
Intermediate-49: l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-ol
To a stirred solution of 4-hydroxypiperidine-l-carbonitrile (0.4 g, 3.1 mmol) in THF (10
mL), (E)-N'-hydroxyisobutyrimidamide (0.35 g, 35 mmol) and ZnCl (1M solution in THF)
(4.7 mL) were added and stirred at room temperature for lOh. The reaction mixture was
concentrated in vacuo and the resulting crude was dissolved in 4N HC1 in ethanol-water ( 1:1)
and stirred at 60-70°C for 2-3 h. The reaction was quenched by saturated NaHC0 3 and the
organic layer was separated and concentrated. The residue on column chromatography gave
the title compound. (0.280 g, 41.8%)
Intermediate-50 : N-(Indolin-5 -yl)isobutyramide
To a stirred solution of N-(lH-indol-5-yl)isobutyramide (0.42g, 2.9mmol) in acetic acid (10
mL), sodium cynoborohydride (0.29 g, 4.6 mmol) was added at 0°C, and the reaction mixture
was stirred at room temperature for 2-3 h. The reaction was quenched with water and
neutralized by 50% NaOH solution, extracted with diethyl ether. The organic layer was
separated and concentrated in vacuo to give N-(indolin-5-yl)isobutyramide (0.1 22g, 28.5%);
MS: 205.1 (M+l).
Intermediate-51: 5-Iodoindoline.
The title compound was prepared by following the similar procedure as described in
Intermediate-50 using 5-iodo-lH-indole. (0.9g, 89%); MS: 245.9 (M+l).
Intermediate-52: Ethyl lH-indol-5-ylcarbamate
To a stirred solution of lH-indol-5 -amine ( 1lg, 83.2mmol) and triethyl amine (25.22 g, 250
mmol) in dichloromethane ( 110 mL) at -10°C, ethyl-chloro-formate (13.5g 124.8 mmol) was
added dropwise and stirred at 0°C for 2-3 h. The reaction was quenched with water and the
mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and
the resultant residue was purified by flash column chromatography to give ethyl- lH-indol-5-
ylcarbamate (5.980 g, 35.2%); MS: 205 (M+l).
Intermediate-53 : 1-(4-((6-Chloropyridin-3 -yl)oxy)piperidin- 1-yl)-2-methylpropan-2-ol
To a stirred solution of rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate (1.0
g, 3.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0°C and
stirred for 3h. The reaction mixture was concentrated in vacuo and resultant residue was
dissolved in MeOH (5 mL), 2, 2-dimethyloxirane (0.246 g, 3.2 mmol) was added and stirred
at room temperature for 10-12 h. The reaction mixture was concentrated in vacuo to give the
title product (0.775, 85%); MS: 285.0 (M+l).
Intermediate-54: 2-Chloro-5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridine.
To a stirred solution l-(4-((6-chloropyridin-3-yl)oxy)piperidin-l-yl)-2-methylpropan-2-ol
(0.775 g, 2.7 mmol) in dichloromethane (15 mL), deoxofluor (0.71 mL, 3.2 mmol) was
added and stirred for 3h. The reaction was quenched by saturated NaHC0 3 and the mixture
was extracted with dichloromethane. The organic layer was separated, concentrated in vacuo
and the resulting residue was purified by flash column chromatography to yield 2-chloro-5-
((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridine; MS: 287.02 (M+l)
Intermediate-55: 5-Bromo-3 ,3-difluoroindolin-2-one
To an ice-cooled solution of 5-Bromo isatin (7.0 g, 31.0 mmol) in dichloromethane (200 mL)
in acetonitrile (20 mL), diethylaminosulfur triflouride (10.2 mL, 77.4 mmol) was added and
stirred at room temperature for 20 h. The reaction mixture was cooled to 0°C; methanol (15
mL) was added dropwise. Water (100 mL) was added to the reaction mixture and the organic
layer was extracted with dichloromethane. The organic layer was concentrated in vacuo and
the resulting residue was purified by flash column chromatography to yield title compound
(6.1g, 79.4%); MS: 249.53 (M+l).
Intermediate-56: 3-Fluoro-5-(methylsulfonyl)-lH-indole
To a stirring solution of 3, 3-difluoro-5-(methylsulfonyl)indolin-2-one (1.0 g, 4.0 mmol) in
anhydrous THF (25 mL), a solution of "BH2F.THF" (nominal concentration 1.3 M, 13ml)
was added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The
reaction mixture was brought to 0°C, aqueous HC1 (3 M, 13 mL) was added dropwise. The
reaction mixture was subsequently neutralized with aqueous NaOH (2.5M). The mixture was
extracted with ethyl acetate, separated and concentrated in vacuo. The residue was purified
by flash column chromatography to give the title compound (0.450g, 52.3%); MS: 213.9
(M+l).
Intermediate-57: 5-(lH-tetrazol-l-yl)-lH-indole
To a stirring solution of i H-indol-5-amine (0.6 g, 4.52 mmol) in acetic acid (9 mL), sodium
azide (0.42 g, 6.2 mmol) and triethoxy ethane (1.0 mL, 6.2 mmol) were added and stirred at
100 °C for 3h. The reaction was brought to room temperature and stirred for 10-12h. The
reaction was quenched with saturated NaHC0 3 and the mixture was extracted with ethyl
acetate. The organic layer was separated, washed with brine, dried over anhydrous NaS0 4
and concentrated in vacuo. Resultant residue was purified by flash column chromatography
to yield 5-(lH-tetrazol-l-yl)-lH-indole. (0.174g, 21%); MS: 186 (M+l).
Intermediate-58: 5-(1H-1,2,4-triazol- 1-yl)- 1H-indole.
To a stirred solution of 5-iodo-1 H-indole (2.0 g, 8.2 mmol), lH-l,2,4-triazole (0.51 1 g, 7.4
mmol), Cul (0.15 g, 0.82 mmol), K2C0 3 (2.27 g, 16.46 mmol) and L-proline (0.51 1 g, 7.4
mmol) in DMF (20 mL), N,N'-dimethylethylenediamine (2.375 g 16.46 mmol) was added
and stirred atl20°C for 2-3 h. The reaction was quenched with water and the mixture was
extracted with ethyl acetate. The organic layer was separated, concentrated in vacuo and the
residue was purified by flash column chromatography to give 5-(lH-l,2,4-triazol-l-yl)-lHindole
(0.790g, 52%); MS: 185 (M+l).
Intermediate-59: 3-(1H-indol-5 -yl)oxazolidin-2-one
The title compound was prepared by following the similar procedure as described in
Intermediate-58 (0.348 g, 41%); MS: 202.8 (M+l).
Intermediate-60: tert-Butyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate.
To a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (5.0 g, 25.0 mmol) in
anhydrous DMF (50 mL), trimethylsilyl chloride (3 mL, 30.1 mmol) and triethylamine (8.3
mL, 60.2 mmol) were added at 80 °C and stirred for 10-12 h. The reaction mixture was
cooled to room temperature, diluted with hexane and washed with saturated NaHC0 3.
Combined organic layers were dried over anhydrous Na2S0 4, filtered and concentrated in
vacuo and the residue was purified by flash column chromatography to give rt-butyl 4-
((trimethylsilyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate as a pale yellow oil (2.16 g,
32%); MS: 271 (M+) .
Intermediate-61: tert-Butyl-3-fluoro-4-oxopiperidine-l-carboxylate.
To a stirred solution of t rt-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-l(2H)-
carboxylate (2.15 g, 7.92 mmol) in anhydrous acetonitrile (20 mL), selectfluor (3.08 g, 8.71
mmol) was added and stirred at room temperature for 1-2 h. The reaction mixture was diluted
with ethyl acetate and washed with saturated NaHC0 3 solution. The organic layer was
separated, concentrated in vacuo and the residue was purified by flash column
chromatography to yield rt-butyl 3-fluoro-4-oxopiperidine-l-carboxylate as a white solid
(1.34 g, 78%). 1H NMR (400 MHz, CDC13) d; 1.50 (s, 9H), 2.49-2.63 (m, 2H), 3.20-3.27 (m,
2H), 4.1 1-4.21 (m, 2H), 4.76-4.80 (m, 0.5H), 4.88-4.92 (m, 0.5H).
Intermediate-62: cis (±) and trans (±) -t rt-Butyl-3-fluoro-4-hydroxypiperidine-lcarboxylate.
To a stirred solution of tert-butyl-3-fluoro-4-oxopiperidine-l-carboxylate (1.3 g, 6.0 mmol)
in methanol (15mL), NaBH4 (0.29 g, 7.7 mmol) was added at 0°C and stirred for 2-3 h.
Methanol was removed in vacuo and the residue was diluted with ethyl acetate and washed
with water. The organic layer was separated, concentrated in vacuo and the residue was
purified by flash column chromatography to give cis(±)-te rt-butyl 3-fluoro-4-
hydroxypiperidine-l-carboxylate (0.850 g, 65%) and trans(±)-fe rt-butyl 3-fiuoro-4-
hydroxypiperidine-l-carboxylate (0.315 g, 24%); MS: 242.1 (M+23).
Intermediate-63: tra n (±)-tert-butyl-4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-lcarboxylate.
The title compound was prepared by following the similar procedure as described in
Intermediate-6 using 6-chloropyridin-3-ol and cis(±) ter t-butyl-3-fluoro-4-
hydroxypiperidine-l-carboxylate; MS: 353.2 (M+23).
Intermediate-64 : N-isopropylindoline-5 -carboxamide.
46
The title compound was prepared by following the similar procedure as described in
Intermediate- 10 using indoline-5-carboxylic acid and propan-2-amine (0.315 g, 31%); MS:
205 (M+l).
Intermediate-65: tert-Butyl-4-((5-bromopyridin-2-yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-6 using 5-bromopyridin-2-ol and t rt-butyl 4-hydroxypiperidine-l -carboxylate
(1.49g, 56%); MS: 357 (M+) .
Intermediate-66: t rt-Butyl-5-(pyrrolidin- 1-yl)- 1H-indole- 1-carboxylate
To a stirred solution of pyrrolidine (1.43 mL, 17.47 mmol) in DMSO (15 mL), Cul (33.3 mg,
0.174 mmol) ), L-proline (0.20 g, 1.75 mmol) and cesium carbonate ( 1.14 mg , 3.5 mmol)
were added and stirred at 120°C for 18 h. The reaction was quenched with water and the
mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine
and dried over anhydrous sodium sulphate. The organic layer was concentrated in vacuo and
the resulting residue was triturated with diethyl ether to give the title compound. (0.4 lg,
82%); MS: 287.2 (M+l).
Intermediate-67: 2-(lH-indol-5-yl)oxazole.
To a stirred solution oxazole (0.1 g, 1.45 mmol) in anhydrous THF (3 mL), n-BuLi (1.6 mL,
1.6 mmol) was added at -78°C and stirred for 30 minutes. The reaction mixture was brought
to 0 °C, ZnCl .Et 0 (4.35 mL, 4.35mmol) was added and stirred for 1 h. 5-iodo-l H-indole
(0.352 g, 1.45 mmol) and (Ph3P)PdCl (0.050 g, 0.072 mmol) were added and stirred at 80°C
for lh. The reaction mixture was quenched with water and the mixture was extracted with
ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by
flash column chromatography to give 2-(lH-indol-5-yl)oxazole (0.060 g, 22%); MS: 185.0
(M+l).
Intermediate-68: N-(2, 2, 2-trifluoroethyl)-lH-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Intermediate- 10 using lH-indole-5-carboxylic acid and 2,2,2-trifluoroethanamine (0.93 g,
62%); MS: 243 (M+) .
Intermediate-69: rt-Butyl lH-indol-5-ylcarbamate
To a stirred solution lH-indol-5 -amine (0.5 g, 3.78 mmol) in dichloromethane (10 mL),
triethylamine (0.95g, 9.4 mmol) and di-tert-butyl dicarbonate (0.908 g, 4.166 mmol) were
added at 0°C. The reaction contents were stirred at room temperature for 4 h. The reaction
was quenched with water and the mixture was extracted with ethyl acetate. The organic layer
was concentrated in vacuo and the residue was purified by flash column chromatography to
give t rt-butyl lH-indol-5-ylcarbamate (0.380 g, 43%); MS: 233.5 (M+l).
Intermediate-70: l-(2-((l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)thiazol-4-
yl)-lH-indol-5-amine
The title compound was prepared by following the similar procedure as described in
Intermediate- 17 using 5-(4-((4-bromothiazol-2-yl)oxy)piperidin-l-yl)-3-isopropyl-l,2,4-
oxadiazole and tert-butyl lH-indol-5-ylcarbamate.
Intermediate-71 : 2-chloro- 1-(pyrrolidin- 1-yl)ethanone.
To an ice-cooled solution of pyrrolidine (0.4 g, 5.62 mmol) in dichloromethane (4 mL),
triethylamine (1.176 mL, 8.44 mmol) and chloroacetyl chloride (0.451 mL, 5.62 mmol) was
added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture
was diluted with dichloromethane and washed with water. The organic layer was
concentrated in vacuo and residue was purified by column chromatography to give title
compound (0.5g, 60.2%); MS: 147.10 (M+) .
Intermediate-72: 5-(4-((4-Bromothiazol-2-yl)oxy)piperidin-l-yl)-3-isopropyl- 1,2,4-
oxadiazole.
The title compound was prepared by following the similar procedure as described in
Intermediate-42, using l-(3-isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-ol and 2,4-
dibromothiazole
Intermediate-73: anti-ter t-Butyl-9-((6-chloropyridin-3-yl)oxy)-3-oxa-7-azabicyclo [3.3. 1]-
nonane-7-carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-5, using tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate
and 6-chloropyridin-3-ol (0.015 g, 11%); MS: 355(M+1)
Intermediate-74: syn-t rt-Butyl-9-((6-chloropyridin-3 -yl)oxy)-3-oxa-7-azabicyclo [3.3.1]-
nonane-7-carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-5, using tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate
and 6-chloropyridin-3-ol (0.020 g, 14%); MS: 355(M+1)
Intermediate-75: rt-Butyl-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl) pyridin-3 -yl)
methoxy) piperidine- 1-carboxylate.
The title compound was prepared by following a procedure described in Intermediate-27 by
using tert-butyl 4-((6-chloropyridin-3-yl)methoxy)piperidine-l -carboxylate and 5-
(methylsulfonyl)- lH-indole (0.410 g, 27.70 %); MS: 386.32 (M-100).
Intermediate-76: rt-Butyl-4-((6-(5 -methoxy- 1H-pyrrolo [2,3 -b]pyridin- 1-yl)pyridin-3 -
yl)oxy)-piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-27 using 5-methoxy-lH-pyrrolo[2,3-b]pyridine and tert-butyl 4-((6-
chloropyridin-3-yl)oxy)piperidine-l -carboxylate. (0.09 g, 45%); MS: 425(M+1).
Intermediate-77: 7 rt-Butyl-4-(4-bromophenoxy)piperidine-l -carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-5 using rt-butyl 4-hydroxypiperidine-l -carboxylate and 4-bromophenol (0.65
g, 36%); MS: 256 (M-100).
Intermediate-78: Isopropyl lH-indol-5-ylcarbamate
The title compound was prepared by following the similar procedure as described in
Intermediate-52, using lH-indol-5 -amine and isopropyl-chloro-formate (0.72g, 52%); MS:
219(M+1).
Intermediate-79: rt-Butyl-4-(((6-chloropyridin-3 -yl)methyl)amino)piperidine- 1-
carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-5 using tert-butyl-4-oxopiperidine-l -carboxylate and tert-butyl 4-
oxopiperidine-1 -carboxylate (0.15 g, 36%); MS: 326.4 (M+l).
Intermediate-80: tert-Butyl-4-(4-(5-(methylsulfonyl)indolin- 1-yl)phenoxy)piperidine- 1-
carboxylate
The title compound was prepared by following the similar procedure as described in
Intermediate-27 using rt-butyl-4-(4-bromophenoxy)piperidine-l -carboxylate and 5-
(methylsulfonyl)indoline (0.1 lg, 35%); MS: 373 (M-100).
Intermediate-8 1: 5-(Ethylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Intermediate-20 using 5-iodo-1 H-indole (0.347 g, 40%); MS: 210 (M+l).
EXAMPLES
Example-1 : rt-Butyl-4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidine- 1-carboxylate
To a mixture of 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate (intermediate-6)
(0.440g, 1.4mmol) and 5-(methylsulfonyl)-7 H-indole (intermediate-21) (0.261g, 1.3mmol)
in anhydrous dioxane (5 mL), 2-(2'-Di -tert-butylphosphine) biphenylpalladium(II)acetate
(0.130g, 0.281mmol) and NaO Bu (sodium tert.butoxide) (0.312g, 0.960mmol) were added.
The resultant reaction mixture was refluxed for 4-5h. The reaction mixture was filtered over
celite and filtrate was concentrated in vacuo. The residue was purified by flash column
chromatography to give tert-butyl 4-((6-(5-(methylsulfonyl)-l H-indol- l-yl)pyridin-3-
yl)oxy)piperidine-l -carboxylate (0.337g, 50%).
NMR (400 MHz, CDC13) d; 1.47 (s, 9H), 1.82 (bs, 2H), 1.98-2.08 (m, 2H), 3.08 (s, 3H),
3.37 (bs, 2H), 3.73 (bs, 2H), 4.55 (bs, 1H), 6.82 (bs, 1H), 7.42 (bs, 2H), 7.71 (bs, 1H), 7.79
(d, J =9.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.29 (bs, 2H); MS: 416 (M-56).
Example-2: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methyl
sulfonyl)-! H-indole
To a stirred solution of example- 1 (O.lg, 0.212 mmol) in dichloromethane (5 mL)
trifluoroacetic acid (0.5 mL) was added at 0°C and stirred at room temperature for 2-3h. The
solvent was removed in vacuo and the resulting salt was dissolved in 2-propanol (3 mL),
diisopropylethylamine (0.082 g, 0.635 mmol) and 2-chloro-5-ethylpyrimidine (0.039 g, 0.275
mmol) were added and stirred at 160°C for 3h. The suspension was passed through celite, the
filtrate was concentrated and the resulting residue was purified by flash column
chromatography to give l-(6-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole as white solid (0.054 g, 24%).
Ή NMR (400 MHz, CDC13) d; 1.20 (t, J =7.2 Hz, 3H), 1.87-1.89 (m, 2H), 2.04-2.09 (m,
2H), 2.48 (q, J =7.6 Hz, 2H) 3.09 (s, 3H), 3.65-3.70(m, 2H),4.21-4.24 (m, 2H), 4.65 (bs,
1H), 6.83 (s, 1H), 7.41-7.48 (m, 2H), 7.73 (s, 1H), 7.81 (d, J =8.4 Hz,IH), 8.20 (bs, 3H),
8.31 (bs, 2H); MS: 478 (M+l).
Example-3: t rr-Butyl-4-(4-(5-(methylsulfonyl)- 1H-indol- 1-yl)phenoxy)-piperidine- 1-
carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-l H-indole (intermediate-21) and tert-butyl-4-(4-
bromophenoxy)piperidine-l-carboxylate (intermediate-77) (0.130g, 24 %) .
NMR (400 MHz, CDC13) ; 1.49 (s, 9H), 1.85-1.86 ( , 2H), 1.96-2.01 (m, 2H ), 3.09 (s,
3H), 3.36-3.43 (m, 2H), 3.71-3.77 (m, 2H), 4.54-4.56 (m, 1H), 6.80 (dd, J = 3.2, 0.4 Hz, 1H),
7.07, (dd, J = 6.8, 2.4 Hz, 2H), 7.38 (dd, J = 6.8, 2.0 Hz, 2H), 7.42 (d, J = 3.2 Hz,IH), 7.54
(d, J = 8.8 Hz, 1H), 7.74 (dd, J = 1.6, 8.4 Hz, 1H), 8.33 (d, J = 4 Hz, 1H); MS: 471 (M+l).
Example-4: 3-Isopropyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidin- 1-yl)- 1,2,4-oxadiazole
StepA: 4-((6-(5 -(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-carbonitrile
To a stirred solution of example- 1 (0.3 g, 0.63 mmol) in dichloromethane (5 mL)
trifluoroacetic acid (2.0 mL) was added at 0°C and stirred at room temperature for 2-3 h. The
solvent was removed in vacuo and the resulting salt was dissolved in dichloromethane (5
mL). Triethylamine (0.193 g, 1.91 mmol) and the cyanogen bromide (O.lOlg, 0.95 mmol)
were added at 0°C and stirred at room temperature for 2-3 h. The reaction mixture was
quenched with water and the mixture was extracted with ethyl acetate. The organic layer was
concentrated in vacuo and purified by flash column chromatography to give 4-((6-(5-
(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-carbonitrile (intermediate-3 6)
(0.160g, 63%); MS: 397.46 (M+l).
Step B: 3-Isopropyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl) oxy)-piperidinl-
yl)-l,2,4-oxadiazole
To a mixture of 4-((6-(5 -(methylsulfonyl)- 1H-indol- l-yl)pyridin-3 yl)oxy)piperidine- 1-
carbonitrile (intermediate-3 6) (0.1 10 g, 0.27mmol) and N-hydroxy-isobutyramidine (0.05 g,
0.5 mmol) in anhydrous THF (15 mL), 1M solution of zinc chloride in THF (0.56 mL, 0.56
mmol) was added. The suspension was stirred at room temperature for 18 h. Solvent was
concentrated in vacuo, the resulting crude was dissolved in 4N HC1 in ethanol, water (1:1)
and stirred at 60-70°C for 2-3 h. The reaction was quenched by saturated NaHC0 3 and the
organic layer was separated and concentrated. The residue was purified by flash column
chromatography to give 3-isopropyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidin-l-yl)-l,2,4-oxadiazole (0.041g, 30%)
NMR (400 MHz, CDC13) d; 1.29 (d, J = 6.8 Hz, 6H), 1.98-2.01 (m, 2H), 2.07-2.10 (s,
2H), 2.88-2.92 (m , 1H), 3.09 (s, 3H), 3.65-3.69 (m, 2H), 3.84-3.88 (m, 2H), 4.66 (bs, 1H),
6.82-6.83 (d, J =2.8 Hz, IH), 7.44 (bs, 2H), 7.72 (d, J = 2.8 Hz, IH), 7.80 (d, J = 8.8 Hz,
IH ), 8.20 (d, J = 8.8 Hz, IH ), 8.30 (bs, 2H); MS: 482 (M+l).
Example-5: tert-Butyl-4-(((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)methyl)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using 5-(methylsulfonyl)-lH-indole (intermediate-21) and rt-butyl 4-(((6-
chloropyridin-3-yl)oxy)methyl)piperidine-l -carboxylate (intermediate-29) (0.188 g, 11%).
NMR (400 MHz, CDC13) d; 1.23-1.29 (m, 2H), 1.45 (s, 9H), 1.83-1.86 (m, 2H), 2.00 (bs,
IH), 2.73-2.79 (m, 2H), 3.07 (s, 3H), 3.90-3.91 (m, 2H), 4.17 (m, 2H), 6.81(s, IH), 7.39 (s,
2H), 7.69 (bs, IH), 7.77-7.79 (m, 2H), 8.14-8.16 (m , IH) , 8.24-8.28 (m, IH); MS: 430
(M-56).
Example-6: 1-(5-((l -(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-5 -
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 5 (0.012g, 11%).
NMR (400 MHz, CDC13) d; 1.22 (t, J =7.6 Hz, 3H), 1.37-1.46 (m, 2H) , 1.97-2.06 (m,
2H), 2.1 1-2.17 (m IH), 2.49 (q, J = 7.6 Hz, 2H), 2.92-2.96 (m, 2H), 3.1 (s, 3H), 3.97 (d, J
=6.4 Hz, 2H), 4.83 (m, 2H), 6.84 (dd, J = 2.8, 0.4 Hz, IH), 7.43 (d, J = 2.0 Hz, 2H ), 7.74
(d, J = 3.6 Hz, IH ), 7.82 (dd , J = 7.2, 1.6 Hz, lH), 8.17 (s, IH), 8.20 (s, IH), 8.21(bs IH),
8.29 (t, J =2.0, 1.6 Hz, IH), 8.32 (d, J =1.6, IH); MS: 492 (M+l).
Example-7: 3-Isopropyl-5-(4-(((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
methyl)piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-5 (0.012 g, 12%).
NMR (400 MHz, CDC13) d; 1.30 (d, J = 7.2 Hz, 6H), 1.49-1.56 (m, 2H), 1.97-2.00 (m,
2H), 2.05-2.14 (m, 1H), 2.87-2.94 (m, 1H), 3.09 (s, 3H), 3.10-3.17 (m, 2H), 3.96 (d, J = 6.4
Hz, 2H), 4.23-4.27 (m, 2H), 6.83 (dd, J = 3.2, 0.4 Hz, 1H ), 7.42 (d, J = 1.6 Hz, 2H ), 7.72
(d, J =3.6 Hz, 1H ), 7.80 (dd, J = 6.8, 2.0 Hz, 1H ), 8.17 (d, J = 8.8 Hz, 1H ), 8.27 (m, 1H ),
8.30 (d, J =1.6Hz, 1H ); MS: 496 (M+l).
Example-8: tert-Butyl-4-((6-(5-((ethoxycarbonyl)amino)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-06) and ethyl lH-indol-5-ylcarbamate ( intermediate-52) (6.0 g, 35%).
1H NMR (400 MHz, CDC13) d; 1.32 (t, J =7.2Hz, 3H), 1.48 (s, 9H), 1.76-1.84 ( m, 2H),
1.95-2.00 ( m, 2H), 3.33-3.39 ( m, 2H), 3.71-3.77 ( m, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.49-
4.52 ( , 1H), 6.59 (bs, 1H), 6.63 (d, J = 3.2 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 7.38 (dd, J =
10.4, 8.0 Hz, 2H), 7.60 (d, J = 3.2 Hz, 1H), 7.75 ( bs, 1H), 7.99 (d, J = 8.8 Hz, 1H), 8.23 (d,
J =2 Hz, 1H); MS: 481 (M+l).
Example-9: Ethyl (1-(5-(( 1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-8 (1.4g, 23%).
NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.33 (t, J = 6.8 Hz, 3H), 1.86-1.89
( m, 2H), 2.06-2.09 (m, 2H), 2.78 (q, J = 7.6 Hz, 2H), 3.63-3.70 ( m, 2H), 4.20-4.28 ( m,
2H), 4.60 (bs, 1H), 6.59 (bs, 1H), 6.64 (d, J = 3.2 Hz, 1H), 7.18 (d, J = 8.8-Hz, 1H), 7.41( bs,
2H), 7.62 (d, J = 3.2 Hz, 1H), 7.76 ( bs, 1H), 8.0 l(d, J = 8.8 Hz, 1H), 8.20 ( bs, 2H), 8.27 (d,
J 1.2 Hz, 1H); MS: 487 (M+l).
Example-10: tert-Butyl-4-((6-(5-(ethylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy) piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using tert-butyl-4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and 5-(ethylsulfonyl)-lH-indole (intermediate-81).
Ή NMR (400 MHz, CDC13) d; 1.27 (t, J = 7.2 Hz, 3H), 1.48 (s, 9H), 1.79-1.83 (m, 2H),
1.97-2.02 (m, 2H), 3.15 (q, J 7.2 Hz, 2H), 3.36-3.40 (m, 2H), 3.71-3.77 (m, 2H), 4.55-4.57
(m, 1H), 6.82 (dd, J =3.6, 0.8 Hz, 1H), 7.40-7.45 (m, 2H), 7.71 (d, J 3.6 Hz, 1H), 7.75 (dd,
J =8.8, 2.0 Hz, 1H), 8.18 (d, J =8.8 Hz, 1H), 8.25-8.28 (m, 2H); MS: 430.1 (M-56).
Example-1 1: 1-(5 -(( 1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(ethyl
sulfonyl)- 1H-indole.
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 10.
NMR (400 MHz, CDC13) d; 1.19 (t, J 7.2 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H), 1.86-1.89
(m, 2H), 2.06-2.09 (m, 2H), 2.47 (q, J = 7.6 Hz, 2H), 3.15 (q, J = 7.6 Hz, 2H), 3.65-3.70 (m,
2H), 4.18-4.24 (m, 2H), 4.63 (bs, 1H), 6.82 (dd, J = 3.6, 0.8 Hz, 1H), 7.43-7.47 (m, 2H),
7.71-7.72 (d, J = 3.6 Hz, 1H), 7.75 (dd, J = 8.8, 2.0 Hz, 1H), 8.18-8.20 (m, 3H), 8.25 (d, J=.
1.2 Hz, 1H), 8.30 (m, 1H); MS: 492.1 (M+l).
Example-12: 2-Methyl- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidin-l-yl)propan-2-ol
To a stirred solution of Example-1 (0.4 g, 0.848 mmol) in dichloromethane (5 mL)
trifluoroacetic acid (0.065 mL, 0.848 mmol) was added at 0°C and stirred for 3 h. The
reaction mixture was concentrated in vacuo and the resultant residue was dissolved in
methanol (5 mL), 2, 2-dimethyloxirane (0.061 g, 0.85 mmol) was added and stirred at room
temperature for 18 h. Methanol was concentrated in vacuo and the resultant residue was
purified by flash column chromatography to give 2-methyl-l-(4-((6-(5-(methylsulfonyl)-lHindol-
l-yl)pyridin-3-yl)oxy)piperidin-l-yl)propan-2-ol (0.279 g, 74%).
NMR (400 MHz, CDC13) d; 1.20 (s, 6H), 1.88-1.92 (m, 2H), 2.06 (bs, 2H), 2.39 (s, 2H),
2.59-2.63 (m, 2H), 2.93-2.95 (m, 2H), 3.10 (s, 3H), 4.43 (bs, 1H), 6.840-6.849 (m, 1H), 7.41-
7.43 (m, 2H), 7.73 (d, J 3.6 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 8.20 (d, J = 8.8 Hz,
1H), 8.28-8.31 (m, 2H); MS: 444.2 (M+l).
Example-13: 1-(4-((6-(5-(Ethylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-2-
methylpropan-2-ol
The title compound was prepared by following the similar procedure as described in
Example-12 by using Example- 10.
NMR (400 MHz, CDC13) d; 1.20 (s, 6H), 1.27 (t, J = 7.2 Hz, 3H), 1.92 (bs, 2H), 2.06 (bs,
2H), 2.35-2.39 (bs, 2H), 2.61-2.63 (m, 2H), 2.95 (bs, 2H), 3.17 (q, J = 7.6 Hz, 2H), 4.43 (bs,
1H), 6.83-6.84 (m, 1H), 7.41-7.46 (m, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.77 (dd, J = 8.8, 2.0
Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.27-8.29 (m, 2H); MS: 458.08 (M+l).
Example-14: 1-(5-((l -(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indol
To a stirred solution of example-12 (0.25 g, 0.564 mmol) in dichloromethane (15 mL)
deoxofluor (0.1 lmL, 0.62 mmol) was added at 20°C and stirred for 3 h. The reaction was
quenched by the addition of saturated NaHC0 3 solution. The mixture was extracted with
dichloromethane, concentrated in vacuo and the residue was purified by flash column
chromatography to give l-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-
5-(methylsulfonyl)-l H-indole (0.170 g, 67%).
NMR (400 MHz, CDC13) d; 1.37 (d, J = 21.6 Hz, 6H), 1.85-1.90 (m, 2H), 2.03 (bs, 2H),
2.42-2.50 (m, 4H), 2.88-2.90 (m, 2H), 3.08 (s, 3H), 4.35-4.39 (m, 1H), 6.81 (d, J = 2.8 Hz,
1H), 7.38-7.43 (m, 2H), 7.71 (d, J = 3.6 Hz, 1H), 7.79 (dd, J = 8.8, 2.0 Hz, 1H), 8.17 (d, J =
8.8Hz, 1H), 8.26-8.29 (m, 2H); MS: 446.2 (M+l).
Example-15: 5-(Ethylsulfonyl)-l-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)
pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example-13.
H NMR (400 MHz, CDC13) d; 1.27 (t, J = 7.2 Hz, 3H), 1.38 (d, J = 21.6 Hz, 6H), 1.83-1.91
(m, 2H), 2.01-2.03 (m, 2H), 2.42-2.51 (m, 4H), 2.87-2.90 (m, 2H), 3.15 (q, J 7.2 Hz, 2H),
4.36-4.40 (m, 1H), 6.82 (d, J = 3.2 Hz, 1H), 7.39-7.44 (m, 2H), 7.71 (d, J = 3.2 Hz, 1H), 7.75
(dd, J = 8.8, 2.0 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.25-8.27 (m, 2H); MS: 460.2 (M+l).
Example-16: tert-Butyl4-((6-(5-(isopropylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1, using rt-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and 5-(Isopropylsulfonyl)-lH-indole (intermediate- 17).
NMR (400 MHz, CDC13) d; .30-1.33 (m, 6H), 1.59 (s, 9H), 1.82-1 .85 (m, 2H), 1.98-2.00
( , 2H), 3.23-3.26 (m, 1H), 3.36-3.43 (m, 2H), 3.73-3.78 (m, 2H), 4.58 (bs, 1H), 6.83-6.84
(m, 1H), 7.44-7.45 (m, 2H), 7.72 (d, J = 3.6 Hz, 1H), 7.75 (dd, J = 8.8, 2.0 Hz, 1H), 8.19 (d,
J = 8.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.29-8.30 (m, 1H); MS: 500.09 (M+l).
Example-17: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(iso
propylsulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-16.
Ή NMR (400 MHz, CDC13) d; 1.22 (t, J = 7.6 Hz, 3H), 1.32 (d, J = 6.8 Hz, 6H), 1.87-1.93
(m, 2H), 2.09-2.14 (m, 2H), 2.50 (q, J = 7.6 Hz, 2H), 3.25-3.27 (m, 1H), 3.66-3.72 (m, 2H),
4.21-4.27 (m, 2H), 4.64-4.67 (m, 1H), 6.84 (d, J = 3.2 Hz, 1H), 7.43-7.50 (m, 2H), 7.73-7.77
(m, 2H), 8.19-8.25 (m, 4H), 8.32 (s, 1H); MS: 506.09 (M+l).
Example-18: 5-(4-((6-(5-(Isopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-
yl)-3 -methyl- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 16 (0.027 g, 12%).
NMR (400 MHz, CDC13) d; 1.29 (d, J = 7.2 Hz, 6H), 2.02-2.18 (m, 4H), 2.25 (s, 3H),
3.23-3.26 (m, 1H), 3.67-3.73 (m, 2H), 3.84-3.90 (m, 2H), 4.69-4.70 (m, 1H), 6.84 (d, J = 3.6
Hz, 1H), 7.46-7.47 (m, 2H), 7.73 (d, J 3.6 Hz, 1H), 7.76 (dd, J = 8.8, 1.6 Hz, 1H), 8.21 (d,
J = 8.8 Hz, 1H), 8.24 (d, J 1.6 Hz, 1H), 8.31-8.32 (m, 1H); MS: 482.17 (M+l).
Example-19: tert-Butyl-4-((6-(5-((2-hydroxyethyl)carbamoyl)- 1H-indol- l-yl)pyridin-3-
yl)amino)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using t rt-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-l -carboxylate
(intermediate-5) and N-(2-hydroxyethyl)-lH-indole-5-carboxamide (intermediate- 19)
Ή NMR (400 MHz, CDC13) d; 1.29-1.49 (m, 2H), 1.52 (s, 9H), 2.10 (d, J = 10.8 Hz, 2H),
2.97 (t, J = 12 Hz, 2H), 3.46-3.51 ( , 1H), 3.66-3.70 (m, 2H), 3.87-3.89 (m, 2H), 4.10 (m,
2H), 6.70-6.74 (m, 2H), 7.09 (dd, J = 8.8, 3.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.62 (d, J =
3.6 Hz, 1H), 7.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.93-7.99 (m, 2H), 8.14 (d, J = 1.2 Hz, 1H); MS:
482.3 (M+l).
Example-20: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N-(2-
hydroxyethyl)- H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described
Example-2 by using Example- 19.
H NMR (400 MHz, CDC13) d: 1.22 (t, J =7.6 Hz, 3H), 1.44-1.54 (m, 2H), 2.21 (d, J = 10.8
Hz, 2H), 2.50 (q, J =7.6 Hz, 2H), 3.19 (t, J = 11.6 Hz, 2H), 3.62 (m, 1H), 3.67-3.71 (m, 2H),
3.87-3.90 (m, 2H), 4.68-4.71 (m, 2H), 6.68 (s, 1H), 6:74 (d, J =3.6 Hz, 1H), 7.12 (dd, J =
8.8, 2.8 Hz, 1H), 7.32 (d, J =8.4 Hz, 1H), 7.63 (d, J =3.6 Hz, 1H), 7.69-7.71 (m. 1H), 7.96
(d, J = 8.8 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 8.22 (s, 2H); MS:
486.05 (M+l).
Example-21 : t rt-Butyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)
amino)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-l -carboxylate
(intermediate-5) and N,N-dimethyl-lH-indole-5-carboxamide (intermediate- 12) .
1H NMR (400 MHz, DMSO-d 6) d; 1.24-1.28 (m, 2H), 1.41 (s, 9H), 1.93 (m, J = 10.8 Hz,
2H), 2.89 (s, 1H), 2.99 (s, 6H), 3.53 (s, 1H), 3.89 (d, J = 11.2 Hz, 2H), 5.94 (d, J =8 Hz, 1H),
6.70 (d, J =3.2 Hz, 1H), 7.20-7.25 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J
=3.2 Hz, 1H), 7.95-7.97 (m, 1H), 8.02 (d, J =8.8 Hz, 1H); MS: 464.2 (M+l).
Example-22: l-(5-((l-(5-Ethylpyriniidin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N,Ndimethyl-
1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-21.
NMR (400 MHz, DMSO-d 6) ; 1.16 (t, J = 7.6 Hz, 3H), 1.29-1.38 (m, 2H), 2.00 (d, J =
9.6 Hz, 2H), 2.43 (q, J = 7.6 Hz, 2H), 2.99 (s, 6H), 3.14(t, J = 11.2 Hz, 2H), 3.57-3.65 (m,
1H), 4.52 (d, J = 13.6 Hz, 2H), 5.95 (d, J = 8.4 Hz, 1H), 6.71 (d, J 3.2 Hz, 1H), 7 ..22-7.26
(m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.84 (d, J = 3.2 Hz, 1H), 7.98-
8.04 (m, 2H), 8.25 (m, 2H); MS: 470.2 (M+l).
Example-23: 2-Methyl- 1-(4-((6-(5 -(methylsulfonyl) -1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidin- 1-yl)propan- 1-one
To a stirred solution of Example- 1 (0.120 g, 0.254 mmol) in dichloromethane (5 mL),
trifluoroacetic acid ( 1 mL) was added at 0°C and stirred for 2-3h. The reaction mixture was
concentrated in vacuo and the resultant residue was dissolved in dichloromethane (10 mL),
triethylamine (0.3 mL, 2.036 mmol), N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide
hydrochloride (0.073 g, 0.38 mmol) and isobutyric acid (0.025 g, 0.28 mmol) were added
sequentially and stirred at room temperature for 2 h. The reaction was quenched with water
and the organic layer was extracted with ethyl acetate, separated dried over Na2S0 and
concentrated in vacuo. The resultant residue was purified by flash column chromatography to
give 2-methyl- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)propan- 1-one (41 mg, 36 %).
NMR (400 MHz, CDC13) d; 1.14 (d, J = 6.8 Hz, 6H), 1.86-2.20 ( , 4H), 2.80-2.86 ( ,
IH), 3.07 (s, 3H), 3.45-3.51 ( m, IH), 3.63-3.66 ( m, IH), 3.76-3.87 ( m, 2H), 4.60-4.64 ( m,
IH), 6.81 (d, J = 3.2 Hz, IH), 7.41 (dd, J = 3.6, 2.8 Hz, 2H), 7.71 (d, J = 3.2 Hz, IH), 7.78
(dd, J = 8.8, 2.0 Hz, IH), 8.18 (d, J = 8.8 Hz, IH), 8.27 (dd, J = 4.0, 1.6 Hz, 2H); MS: 442
(M+l).
Example-24: (±)-t -Butyl-3-((6-(5 -(methyl sulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
pyrrolidine- 1-carboxylat
The title compound was prepared by following the similar procedure as described in
Example- 1 by using (±)-tert-butyl 3-((6-chloropyridin-3-yl)oxy)pyrrolidine-l -carboxylate
(intermediate-8) and 5-(methylsulfonyl)-lH-indole (intermediate-21).
NMR (400 MHz, CDCI3) d; 1.45 (s, 9H), 2.16-2.21 (m, 2H), 3.06 (s, 3H), 3.53-3.67 ( ,
4H), 4.96 (s, IH), 6.80 (s, IH), 7.38 (s, 2H), 7.69-7.78 (m, 2H), 8.17-8.27 (m, 3H); MS:
480.05 (M+23).
Example-25: (±)-l-(5-((l-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-24.
NMR (400 MHz, CDC13) d; 1.18 (t, J = 7.6 Hz, 3H), 2.32-2.50 (m, 4H), 3.08 (s, 3H),
3.72-3.79 (m, IH), 3.85-3.88 (m, 3H), 5.12-5.14 (m, IH), 6.82 (d, J = 3.2 Hz, IH), 7.412-
7.417 (m, 2H), 7.71 (d, J = 3.6 Hz, IH), 7.79 (dd, J = 8.8, 2.0 Hz, IH), 8.17 (d, J = 8.8 Hz,
IH), 8.20 (s, 2H), 8.26-8.29 (m, 2H); MS: 464.1 1 (M+l).
Example-26: (±)-5-(Methylsulfonyl)-l-(5-((l-(4-(trifluoromethyl)benzyl)pyrrolidin-3-
yl)oxy)pyridin-2-yl)-lH-indole
To a stirred solution of Example- 24 (0.100 g, 0.218 mmol) in dichloromethane (4 mL)
trifluoroacetic acid ( 1 mL) was added at 0°C and stirred for 2 h. The reaction contents were
concentrated in vacuo and the resultant residue was dissolved in N, N'-dimethylformamide
(5 mL), triethylamine (0.283 mL, 2.1 mmol), K2C0 3 (0.283 g, 2.1 mmol) and 1-
(chloromethyl)-4-(trifluoromethyl)benzene (0.081 g, 0.42 mmol) were added, stirred at 65°C
for 7h. The reaction contents were cooled to room temperature, quenched with water and the
organic layer was extracted with dichloromethane. The organic layer was separated,
concentrated in vacuo and the resultant residue was purified by flash column chromatography
to give 5-(methylsulfonyl)-l-(5-((l-(4-(trifluoromethyl) benzyl)pyrrolidin-3-yl)oxy)pyridin-
2-yl)-lH-indole (0.023 g, 20%).
NMR (400 MHz, CDC13) d; 2.09 (bs, 1H), 2.37-2.43 (m, 1H), 2.63 (bs, 1H), 2.87 (bs,
2H), 3.00 (bs, 1H), 3.10 (s, 3H), 3.76-3.78 (m, 2H), 4.94 (bs, 1H), 6.84 (d, J = 2.8 Hz, 1H),
7.37-7.43 (m, 2H), 7.49-7.51 (m, 2H), 7.60-7.62 (m, 2H), 7.72-7.73 (m, 1H), 7.80-7.82 (m,
1H), 8.18-8.22 (m, 2H), 8.31 (s, 1H); MS: 515.9 (M+) .
Example-27: tert-Butyl-3-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-
azetidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using tert-butyl 3-((6-chloropyridin-3-yl)oxy)azetidine-l -carboxylate
(intermediate -9) and 5-(methylsulfonyl)-lH-indole (intermediate-21).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 3.10 (s, 3H), 4.07-4.1 1 (m, 2H), 4.37-4.41 (m,
2H), 4.99-5.02 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 7.32 (dd, J = 8.8, 2.8 Hz, 1H), 7.45 (d, J =
8.8 Hz, IH), 7.74 (d, J = 3.2 Hz, IH), 7.82 (dd, J = 8.8, 2.0 Hz, IH), 8.14 (d, J = 2.8 Hz, IH),
8.22 (d, J = 8.8 Hz, IH), 8.31 (d, J = 1.6 Hz, IH); MS: 466.0 (M+23).
Exaniple-28: 1-(5 -(( 1-(5 -Ethylpyrimidin-2-yl)azetidin-3 -yl)oxy)pyridin-2-yl)-5 -
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-27.
NMR (400 MHz, CDC13) ; 1.22 (t, J = 7.6 Hz, 3H), 2.52 (q, J = 7.6 Hz, 2H), 3.1 1 (s,
3H), 4.26-4.29 (m, 2H), 4.59-4.63 (m, 2H), 5.17-5.20 (m, IH), 6.85 (dd, J = 3.2, 0.4 Hz, IH),
7.35-7.38 (m, IH), 7.46 (d, J 8.8 Hz, IH), 7.74 (d, J = 3.6 Hz, IH), 7.82 (dd, J = 8.8, 1.6
Hz, IH), 8.19-8.21 (m, 2H), 8.23 (s, 2H), 8.31 (d, J = 1.6 Hz, IH); MS: 450.0 (M+l).
Example-29: 5-(Methylsulfonyl)- 1-(5-((l -(4-(trifluoromethyl)benzyl)azetidin-3-
yl)oxy)pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-26 by using Example-27.
NMR (400 MHz, CDC13) d; 3.10 (s, 3H), 3.27-3.30 (m, 2H), 3.80 (s, 2H), 3.87-3.91 (m,
2H), 4.92-4.95 (m, IH), 6.84 (d, J = 3.6 Hz, IH), 7.30-7.33 (m, IH), 7.41-7.46 (m, 3H), 7.60-
7.62 (m, 2H), 7.72 (d, J = 3.6 Hz, IH), 7.81 (dd, J = 8.8, 2.0 Hz, IH), 8.16 (d, J = 2.8 Hz,
IH), 8.19 (d, J = 8.8 Hz, IH), 8.31 (d, J = 1.2 Hz, IH); MS: 502.0 (M+l).
Example-30: l-(5-((l-Isobutylpiperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole
To a stirred solution of Example-23 (0.350 g, 0.8 mmol) in THF (15 mL), LiAlH4 (0.060 g,
1.585 mmol) was added at 0°C and stirred at room temperature forl8h. The reaction contents
were poured into ice cold water and the organic layer was extracted with ethyl acetate,
separated and concentrated in vacuo. The resultant residue was purified by flash column
chromatography to give l-(5-((l-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)-lH-indole (0.025 g, 7.38%).
NMR (400 MHz, CDC13) d; 0.95 (d, J = 6.4 Hz, 6H), 1.93 (m, 4H), 2.13 (m, 5H), 2.83 (m,
2H), 3.10 (s, 3H), 4.48 (m, 1H), 6.84 (d, J = 3.2 Hz, 1H), 7.40-7.45 (m, 2H), 7.73 (d, J = 3.2
Hz, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 8.19 ( d, J = 8.8 Hz, 1H), 8.28-8.31 (m, 2H); MS:
428.2 (M+l).
Example-31: rt-Butyl-4-((6-(5 -(methylsulfonyl)- 1H-pyrrolo [2,3 -b]pyridin- 1-yl)-pyridin-3 -
yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and 5-(methylsulfonyl)-l H-pyrrolo [2,3 -bjpyridine (intermediate-25).
NMR (400 MHz, CDC13) d; 1.49 (s, 9H), 1.78-1.86 (m, 2H), 1.97-2.06 (m, 2H), 3.16 (s,
3H), 3.35-3.41 (m, 2H), 3.72-3.78 (m, 2H), 4.54-4.58 (m, 1H), 6.80 (d, J = 4.0 Hz, 1H), 7.48
(dd, J 9.2, 2.8 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 3.6 Hz, 1H), 8.53 (d, J = 2.4
Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.93 (d, J = 2.0 Hz, 1H); MS: 417 (M-56).
Example-32: 1-(5-(( 1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methyl
sulfonyl)- 1H-pyrrolo[2,3-b]pyridine.
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-3 1.
Ή NMR (400 MHz, CDC13) d; 1.23 (t, J = 7.6 Hz, 3H), 1.82-1.92 (m, 2H), 2.07-2.12 (m,
2H), 2.49 (q, J = 7.6 Hz, 2H), 3.16 (s, 3H), 3.67-3.72 (m, 2H), 4.19-4.25 (m,2H), 4.63-4.66
( , 1H), 6.80 (d, J = 4.0 Hz, 1H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 8.21 (s, 2H), 8.24 (d, J = 2.8
Hz, 1H), 8.43 (d, J = 3.6 Hz, 1H), 8.53 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.93 (d,
J = 2.0 Hz, 1H); MS: 479 (M+l)
Example-33: l-(5-((l-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine.
The title compound was prepared by following the similar procedure as described in
Example- 12 and Example- 14 by using Example-3 1.
NMR (400 MHz, CDC13) d; 1.39 (d, J = 21.2 Hz, 6H), 1.89 (bs, 2H), 2.04 (bs, 2H), 2.46-
2.52 ( , 4H), 2.89 (bs, 2H), 3.16 (s, 3H), 4.38 (bs, 1H), 6.80 (d, J = 3.6 Hz, 1H), 7.47 (dd, J
= 8.8, 2.8 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.52 (d, J 2.0 Hz,
1H), 8.64 (d, J = 8.8 Hz, 1H), 8.93 (d, J = 2.4 Hz, 1H); MS: 447.4 (M+l)
Example-34: 2, 2-Dimethyl- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)piperidin- 1-yl)propan- -one
The title compound was prepared by following the similar procedure as described
Example-23 by using Example- 1.
NMR (400 MHz, CDC13) ; 1.33 (s, 9H), 1.86-1.92 (m, 2H), 2.02-2.07 (m, 2H), 3.10 (s,
3H), 3.62-3.68 (m, 2H), 3.89-3.95 (m, 2H), 4.64-4.67 (m, 1H), 6.85 (d, J = 3.2 Hz, 1H), 7.45
(d, J = 2.4 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.82 (dd, J = 9.2, 2.0 Hz, 1H), 8.21 (d, J = 8.8
Hz, 1H), 8.30-8.32 (m, 2H); MS: 456.2 (M+l).
Example-35: 5-(Methylsulfonyl)- 1-(5-((l -neopentylpiperidin-4-yl)oxy)pyridin-2-yl)- 1Hindole
The title compound was prepared by following the similar procedure as described in
Example-30 by using Example-34.
NMR (400 MHz, CDC13) d; 0.89 (s, 9H), 1.84-1.90 (m, 2H), 2.01-2.04 (m, 2H), 2.1 1 (s,
2H), 2.43-2.49 (m, 2H), 2.80-2.85 (m, 2H), 3.10 (s, 3H), 4.34-4.38 (m, 1H), 6.84 (d, J = 3.2
Hz, 1H), 7.42-7.43 (m, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 8.19 (d,
J = 8.8 Hz, 1H), 8.28-8.31 (m, 2H); MS: 442.2 (M+l).
Example-36: rt-Butyl-4-((6-(5 -(methylsulfonyl)indolin- 1-yl)pyridin-3 -yl)oxy)-piperidine-
1-carboxylate:
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and 5-(methylsulfonyl)indoline (intermediate-26) (0.1 60g, 48.0 %).
NMR (400 MHz, CDC13) d; 1.49 (s, 9H), 1.71-1.79 (m, 2H), 1.91-1.96 (m, 2H), 3.02 (s,
3H), 3.24-3.34 (m, 4H), 3.70-3.76 (m, 2H), 4.12 (t, J = 2.4 Hz, 2H), 4.38-4.41 (m, 1H), 6.79
(d, J = 9.2 Hz, 1H), 7.28 (dd, J = 9.2, 3.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.8,
2.0 Hz, 1H), 8.1 1 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H); MS: 474 (M+l).
Example-37: 1-(5-((l -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methyl
sulfonyl)indoline
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-36 (0.1 5g, 25 %)
NMR (400 MHz, CDC13) d; 1.92 (t, J = 7.6 Hz, 3H), 1.79-1.83 (m, 2H), 2.01-2.04 (m,
2H), 2.47 (q, J 7.6 Hz, 2H), 3.02 (s, 3H), 3.26 (t, J = 17.2 Hz, 2H), 3.57-3.63 (m, 2H), 4.12
(t, J = 17.6 Hz, 2H), 4.18-4.23 (m, 2H), 4.48-4.49 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.32 (dd,
J = 8.8, 3.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.4, 2.0 Hz, 1H), 8.13-8.18 (m,
4H); MS: 480.2 (M+l).
Example-38: 3-Isopropyl-5 -(4-((6-(5 -(methylsulfonyl)indolin- 1-yl)pyridin-3 -yl)oxy)-
piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-36 (0.017 g, 20%).
NMR (400 MHz, CDC13) d; 1.32 (d, J 2.8 Hz, 6H), 1.93-1.97 (m, 2H), 1.98-2.08 (m,
2H), 2.80-2.95 (m, 1H), 3.05 (s, 3H), 3.29 (t, J = 17.2 Hz, 2H), 3.61-3.67 (m, 2H), 3.83-3.90
(m, 2H), 4.14 (t, J = 17.6 Hz, 2H), 4.51-4.55 (m, 1H), 6.82 (d, J = 9.2 Hz, 1H), 7.33 (dd, J =
8.8, 2.8 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 8.15 (dd, J = 8.4,
2.8 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H); MS: 484.2 (M+l).
Example-39: tert-Butyl-4-((6-(5-(dimethylcarbamoyl)-l H-indol- l-yl)pyridin-3-yl)oxy)
piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using r t-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and N,N-dimethyl-lH-indole-5-carboxamide ( intermediate- 12).
NMR (400 MHz, DMSO-d 6) d; 1.41 (s, 9H), 1.53-1.61 (m, 2H), 1.94-1.98 ( , 2H), 2.99
(s, 6H), 3.17-3.20 (m, 2H), 3.67-3.73 (m, 2H), 4.67-4.72 (m, 1H), 6.77 (d, J = 3.2 Hz, 1H),
7.28 (dd, J 8.4, 1.6 Hz, 1H), 7.70 (d, J = 1.2 Hz, 3H), 7.99 (d, J 3.6 Hz, 1H), 8.22 (d, J =
8.4, 1H), 8.33 (t, J = 1.6, 1H); MS: 465.3 (M+l).
Example-40: 1-(5 -((1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-39.
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.85-1.89 (m, 2H), 2.07-2.1 1 (m,
2H), 2.48 (q, J = 7.6 Hz, 2H), 3.08 (s, 6H), 3.65-3.70 (m, 2H), 4.19-4.25 (m, 2H), 4.60-4.63
(m, 1H), 6.72 (d, J 2.8 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H),7.44 (m, 2H),7.65 (d, J = 3.6
Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.20 (s, 2H), 8.29 (t, J = 2 Hz,
1H); MS: 471.3 (M+l).
Example-41 : ter/-Butyl-4-((6-(5-(methylsulfonyl)- 1H-indol-1 -yl)pyridin-3-yl)-methoxy)
piperidine- 1-carboxylat
The title compound was prepared by following the similar procedure as described in
Example-1 by using 5-(methylsulfonyl)-lH-indole (intermediate-21)and t rt-butyl 4-((6-
chloropyridin-3-yl) methoxy) piperidine- 1-carboxylate (intermediate-43).
Ή NMR (400 MHz, CDC13) d; 1.44 (s, 9H), 1.58-1.63 (m, 2H),1.88 (bs, 2H), 3.07 (s, 3H),
3.08-3.15 (m, 2H), 3.61-3.63 (m, 1H), 3.76 (bs, 2H), 4.61 (s, 2 H), 6.82-6.83 (m , 1H), 7.45
(d, J = 8.4 Hz, 1H), 7.77-7.81 (m, 2H), 7.87 (dd, J = 8.0, 2.0 Hz, 1H), 8.27 (d, J = 1.6 Hz,
1H) , 8.35 (d, J =8.8 Hz,IH), 8.53( bs , 1H); MS: 484.3 (M+l).
ExampIe-42: l-(5-(((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-41.
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.64-1.73 (m, 2H), 2.00-2.04 (m,
2H), 2.46 ( q, J = 7.6 Hz, 2 H) , 3.09 (s, 3H), 3.36-3.42 (m, 2H), 3.72-3.76 (m, 1H) , 4.29-
4.35 (m ,2H), 4.67 (s, 2H), 6.85 (d, J = 3.6 Hz ,1H), 7.48 (d, J = 8.4 Hz, 1H), 7.80-7.83 (m,
2H) ,7.91 (dd, J =8.8, 2.0 Hz, 1H), 8.17(s, 2H), 8.29 (s, 1H), 8.37 (d, J =8.8 Hz 1H), 8.57 (s,
1H); MS: 492.2 (M+l).
Example-43: tert-Butyl-4-((6-(5-(dimethylcarbamoyl)indolin-l -yl)pyridin-3-yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and N,N-dimethylindoline-5-carboxamide ( intermediate- 13).
NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.70-1.78 (m, 2H), 1.90-1.95 (m, 2H), 3.07 (s,
6H), 3.21 (t, J = 8.8 Hz, 2H), 3.26-3.32 (m, 2H), 3.70-3.76 (m, 2H), 4.03 (t, J = 8.4 Hz, 2H),
4.33-4.37 (m, 1H), 6.75 (d, J 8.8, 1H), 7.22-7.30 (m, 3H), 8.03 (d, J = 8.4 Hz, 1H), 8.08 (d,
J =2.8 Hz, 1H); MS: 467.3 (M+l).
Example-44: tert-Butyl-4-(((6-(5-(methylsulfonyl)indolin-l-yl)pyridin-3-yl)oxy)-
methyl)piperidine- 1-
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)indoline (intermediate-26) and r t-butyl 4-(((6-
chloropyridin-3-yl)oxy)methyl)piperidine- 1-carboxylate (intermediate-29).
H NMR (400 MHz, CDC13) d; 1.26-1.33 (m, 2H), 1.49 (s, 9H), 1.83-1.87 (m, 2H), 1.99-2.07
(m, 1H), 2.77 (m, 2H), 3.04 (s, 3H), 3.28 (t, J = 8.4 Hz, 2H), 3.86 (d, J 6.4 Hz, 2H), 4.1 1-
4.19 (m, 4H), 6.81 (d, J = 9.2 Hz, 1H), 7.27-7.30 (m, 1H), 7.67 (bs, 1H), 7.74 (dd, J = 8.4,
2.0 Hz, 1H), 8.10 (d, J =2.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H); MS: 432.2 (M-56).
Example-45: tert-butyl 4-(((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)
methyl)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- lby using N,N-dimethyl-lH-indole-5-carboxamide (intermediate- 12) and tertbutyl-
4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-l -carboxylate (Intermediate 29).
NMR (400 MHz, CDC13) d; 1.66-1.23 (m, 2H), 1.40 (s, 9H), 1.76-1.80 (m, 2H), 1.97 (bs,
1H), 2.66-2.67 ( , 2H), 2.99 (s, 6H), 3.99 (d, J = 6.4 Hz, 4H), 6.77 (d, J = 3.2 Hz, 1H), 7.28
(dd, J = 8.8, 1.6 Hz, 1H), 7.62-7.72 (m, 3H), 7.98 (d, J = 3.2 Hz, 1H), 8.20 (d, J = 8.4 Hz,
1H), 8.29 (d, J =2.8 Hz, 1H); MS: 479.3 (M+l).
ter/-Butyl-4-((6-(5 -(methylsulfonyl)indolin- -yl)pyridin-3 -yl) methoxy)
The title compound was prepared by following the similar procedure as described in
Example- 1 using 5-(methylsulfonyl)indoline ( intermediate-26) and tert-butyl 4-((6-
chloropyridin-3-yl) methoxy) piperidine-l-carboxylate (intermediate-43) (462 mg, 34%).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.59-1.63 (m, 2H), 1.88 (bs, 2H), 3.05 (s, 3H),
3.09-3.15 (m, 2H), 3.31 (t, J = 8.8 Hz, 2H), 3.57-3.63 (m, 1H), 3.77-3.79 (bs, 2H), 4.16 ( t, J
= 8.8 Hz, 2H), 4.54 (s, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.69-7.71 (bs, 2H), 7.77 (dd, J = 8.8,
2.0 Hz, 1H), 8.36-8.41 (m, 2H); MS: 488.2 (M+l).
Example-47: l-(5-(((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-N,Ndimethyl-
1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2.
NMR (400 MHz, CDC13) d; 1.19 (t, J 7.6 Hz, 3H), 1.22-1.45 (m, 2H), 1.95-1.98 (m,
2H), 2.13-2.17 (m, 1H), 2.47 (q, J =7.6 Hz, 2H), 2.90-2.97 (m, 2H), 3.08 (s, 6H), 3.94 (d, J =
6.4 Hz, 2H), 4.79-4.83 (m, 2H), 6.70-6.71 (m, 1H), 7.34-7.40 (m, 3H), 7.64 (d, J = 3.2 Hz,
1H), 7.75 (m, 1H), 8.02 (d, J =8.4 Hz, 1H), 8.18-8.25 (m, 3H); MS: 485.3 (M+l).
Example-48: (syn)-tert-Butyl-9-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy) -3-
oxa-7-azabicyclo[3 .3.1 ]nonane-7-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate-21) and anti -tert-Butyl-9-
((6-chloropyridin-3-yl)oxy)-3-oxa-7-azabicyclo[3 .3 .1]-nonane-7-carboxylate (intermediate-
73).
H NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.92-1.97 (m, 2H), 3.08-3.15 (m, 4H), 3.24-3.27
(m, IH), 3.84-3.93 (m, 2H), 4.12-4.20 (m, 2H), 4.44-4.48 ( , IH), 4.59-4.66 (m, 2H), 6.82-
6.83 (m, IH), 7.42-7.49 (m, 2H), 7.72 (d, J = 1.6 Hz, IH), 7.80 (dd, J = 8.8, 1.6 Hz, IH),
8.20 (d, J = 8.8 Hz, IH), 8.29-8.31 (m, 2H); MS: 514.2 (M+l).
Example-49: (anti) tert-Butyl- 9-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl) oxy)-3-
oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate-21) and syn-tert-Butyl-9-
((6-chloropyridin-3-yl)oxy)-3-oxa-7-azabicyclo[3 .3 .1]-nonane-7-carboxylate (intermediate-
74).
H NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 2.00-2.06 (m, 2H), 3.09 (s, 3H), 3.40-3.56 (m,
2H), 3.77-3.86 (m, 2H), 4:12-4.32 (m, 4H), 4.46-4.67 (m, IH), 6.84-6.85 (m, IH), 7.43-7.52
(m, 2H), 7.73 (d, J = 3.2 Hz, IH), 7.81 (dd, J = 8.8, 2.0 Hz, IH), 8.21 (d, J = 8.8 Hz, IH),
8.30-8.33 (m, 2H); MS: 458.1 (M-56).
Example-50: syn 7-(5-Ethylpyrimidin-2-yl)-9-((6-(5-(methylsulfonyl)-lH-indol-l -yl)
pyridin-3 -yl)oxy)-3 -oxa-7-azabicyclo[3 .3.1 jnonane
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-48.
NMR (400 MHz, CDC13) d; 1.18 (t, J = 7.6 Hz, 3H), 2.03 (s, 2H), 2.46 (q, J 7.6 Hz,
2H), 3.08 (s, 3H), 3.25-3.38 (m, 2H), 3.87 (d, J = 11.2 Hz, 2H), 4.19 (d, J = 11.6 Hz, 2H),
4.75 (t, J = 3.2 Hz, 1H), 5.1 1 (d, J = 12.8 Hz, 2H), 6.83-6.84 (m, 1H), 7.47-7.52 (m, 2H),
7.73 (d, J = 3.6 Hz, 1H), 7.80 ( dd, J = 8.8, 2.0 Hz, 1H), 8.20-8.23 (m, 2H), 8.29-8.36 (m,
2H); MS: 520.2 (M+l).
Example-51 : anti 7-(5-Ethylpyrimidin-2-yl)-9-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)
pyridin-3 -yl)oxy)-3 -oxa-7-azabicyclo[3 .3 .1]nonane
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-49.
NMR (400 MHz, CDC13) d; 1.81 (t, J = 7.6 Hz, 3H), 2.20 (bs, 2H), 2.46 (q, J = 7.6 Hz,
2H), 3.09 (s, 3H), 3.46-3.48 (m, 1H), 3.57-3.60 (m, 2H), 3.82 (d, J = 12.0 Hz, 2H), 4.20 (d, J
= 11.6 Hz, 2H), 4.71-4.74 (m, 2H), 6.83-6.84 (m, 1H), 7.43-7.50 (m, 3H), 7.73 (d, J = 3.6
Hz, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 8.18-8.23 (m, 2H), 8.30-8.36 (m, 2H); MS: 520.2
(M+l).
Example-52: ter t-Butyl-4-((6-(5-cyano- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-
carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and lH-indole-5-carbonitrile
NMR (400 MHz, CDC13) d 1.48 (s, 9H), 1.77-1.85 (m, 2H), 1.96-2.01 (m, 2H), 3.34-
3.41 (m, 2H), 3.71-3.77 (m, 2H), 4.25-4.57 (m, 1H), 6.75-6.73 (m, 1H), 7.38-7.44 (m, 2H),
7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (d, J =3.6 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 8.12 (d, J =
8.8 Hz, 1H), 8.26-8.27 (m, 1H); MS: 463.2 (M-56).
Example-53: t rt-Butyl-4-((6-(5 -(cyclopropylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and N-cyclopropyl-lH-indole-5-carboxamide ( intermediate- 11).
IH MR (400 MHz, CDC13) d; 0.64-0.67 (m, 2H), 0.86-0.91 (m, 2H), 1.48 (s, 9H), 1.79-1.83
(m, 2H), 1.96-2.01 (m, 2H), 2.92-2.97 (m, 1H), 3.34-3.40 (m, 2H), 3.76-3.78 (m, 2H), 4.52-
4.55 (m, 2H), 6.74 (dd, J =3.2, 0.4 Hz, 1H), 7.41-7.42 (m, 2H), 7.65-7.66 (m, 1H), 7.68 (d, J
= 1.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.26-8.26 (m, 1H); MS: 477
(M+l).
Example-54: N-Cyclopropyl-l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-
yl)- 1H-indole-5 -carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-53.
NMR (400 MHz, CDC13) d; 0.62-0.64 ( , 2H), 0.85-0.87 (m, 2H), 1.18 (t, J = 7.6 Hz,
3H), 1.83-1.88 (m, 2H), 2.04-2.09 (m, 2H), 2.70 (q, J = 7.6 Hz, 2H), 2.91-2.94 (m, 1H), 3.62-
3.68 ( , 2H), 4.17-4.23 (m, 2H), 4.60 (m, 1H), 6.27 (bs, 1H), 6.71-6.72 (m, 1H), 7.41-7.42
( , 2H), 7.63-7.66 (m, 2H), 8.01-8.05 (m, 2H), 8.27 (s, 2H), 8.27 (s, 1H); MS: 483.3 (M+1).
Example-55 : tert-Butyl-4-((6-(5-(oxazol-2-yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using t rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and 2-(lH-indol-5-yl)oxazole ( intermediate-67).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.79-1.85 (m, 2H), 1.96-2.02 (m, 2H), 3.34-
3.40 (m, 2H), 3.72-3.78 (m, 2H), 4.52-4.56 (m, 1H), 6.76-6.77 (m, 1H), 7.23 (s, 1H), 7.39-
7.45 (m, 2H), 7.66 (d, J = 3.6 Hz, 1H), 7.71 (s, 1H), 7.98 (dd, J 8.8, 1.6 Hz, 1H), 8.10 (d, J
= 8.8 Hz, 1H), 8.27 (s, 1H), 8.29 (s, 1H); MS: 461.2 (M+1).
ExampIe-56: t rt-Butyl-4-((6-(5-isobutyramido- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and N-(lH-indol-5-yl)isobutyramide ( intermediate- 10).
NMR (400 MHz, CDC13) d; 1.29 (d, J = 7.2 Hz, 6H), 1.48 (s, 9H), 1.81-1.81 (m, 2H),
1.95-2.01 (m, 2H), 2.50-2.57 (m, 1H), 3.33-3.39 (m, 2H), 3.71-3.77 (m, 2H), 4.50-4.52 (m,
1H), 6.64 (d, J = 3.2 Hz, 1H), 7.22 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.38-7.39 (m, 2H), 7.61
(d, J = 3.6 Hz, 1H), 7.96 (d, J = 2 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.23-8.24 (m, 1H); MS:
481 (M+l).
Example-57: N-( 1-(5 -(( 1-(3 -Isopropyl- 1,2,4-oxadiazol-5 -yl)piperidm-4-yl)oxy)pyridin-2-
yl)- 1H-indol-5-yl)isobutyramide
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example-56.
NMR (400 MHz, CDC13) d; 1.30 (d, J = 0.8 Hz, 12 H), 1.96-2.02 (m, 2H), 2.05-2.1 1 (m,
2H), 2.1 1-2.55 (m, 1H), 2.86-2.92 (m, 1H), 3.63-3.69 (m, 2H), 3.82-3.89 (m, 2H), 4.61-4.63
(m, 1H), 6.64 (d, J = 3.6 Hz, 1H), 7.19 (m, 1H), 7.26-7.29 (m, 1H), 7.38-7.43 (m, 2H), 7.61
(d, J = 3.2 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.25 (s, 1H); MS:
489.3 (M+l).
Example-58: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indole-5-
carbonitrile
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-52.
NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.85-1.89 (m, 2H), 2.06-2.10 ( ,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.64-3.70 (m, 2H), 4.18-4.24 (m, 2H), 4.62-4.63 ( 1H), 6.75-
6.76 (m, 1H), 7.39-7.51 (m, 3H), 7.69 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 8.12 (d, J = 8.8 Hz,
1H), 8.19 (s, 2H), 8.29 (s, 1H); MS: 425.3 (M+l).
Example-59: 2-( 1-(5-(( 1-(5-Ethy lpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)oxazole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-55.
NMR (400 MHz, CDC13) d; 1.18 (t, J = 7.6 Hz, 3H), 1.85-1.91 (m, 2H), 2.05-2.1 1 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.63-3.69 (m, 2H), 4.19-4.61 (m, 2H), 4.62-4.63 (m, IH), 6.76
(d, J = 3.2 Hz, IH), 7.22-7.25 (m, IH), 7.44 (d, J = 2.0 Hz, 2H), 7.66 (d, J = 3.2 Hz, IH),
7.70 (s, IH), 7.98 (dd, J = 8.8, 1.6 Hz, IH), 8.1 1 (d, J = 8.8 Hz, IH), 8.19 (s, 2H), 8.29-8.30
(m, IH), 8.35 (s, IH); MS: 467.2 (M+l).
Example-60: rt-Butyl-4-((6-(5 -(methylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)-oxy)
piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and N-methyl-lH-indole-5-carboxamide (intermediate- 14).
1H NMR (400 MHz, CDC13) d; 1.45 (s, 9H), 1.79-1.83 (m, 2H), 1.96-2.00 (m, 2H), 3.04 (s,
3H), 3.33-3.40 (m, 2H), 3.71-3.76 (m, 2H), 4.52-4.54 (m, IH), 6.19 (bs, IH), 6.73-6.74 (m,
IH), 7.41 (s, 2 H), 7.65-7.69 (m, 2H), 8.03-8.10 (m, 2H), 8.25-8.26 (m, IH); MS: 451.2
(M+l).
Example-61 : rt-Butyl-4-((6-(5-(ethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-
piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and N-ethyl-lH-indole-5-carboxamide (intermediate- 15).
NMR (400 MHz, CDC13) d; 1.28 (t, J =7.2 Hz, 3H), 1.47 (s, 9H), 1.81 (m, 2H), 1.98 ( ,
2H), 3.48 (m, 2H), 3.52-3.55 (m, 2H), 3.74 (m, 2H), 4.51 (m, IH), 6.14 (bs, IH), 6.74 (d, J
2.8 Hz, IH), 7.41 (s, 2H), 7.65-7.70 (m, 2H), 8.03-8.09 (m, 2H), 8.26 (s, IH); MS: 465.2
(M+l).
Example-62: tert-Butyl-4-((6-(5-(isopropylcarbamoyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylat
The title compound was prepared by following the similar procedure as described in
Example- 1 by using r t-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and N-isopropyl-lH-indole-5-carboxamide (intermediate- 16).
. NMR (400 MHz, CDC13) d; 1.23-1.29 (m, 6H), 1.41 (s, 9H), 1.801.82 (m, 2H), 1.96-1.97
(m, 2H), 3.34-3.40 (m, 2H), 3.72-3.75 (m, 2H), 4.34 (m, IH), 4.53 (m, IH), 5.97 (bs, IH),
6.74 (d, J = 3.2 Hz, IH), 7.39-7.43 (m, 2H), 7.65-7.69 (m, 2H), 8.02-8.07 (m, 2H), 8.26 (s,
IH); MS: 479.3 (M+l).
Example-63: 1-(5-((l -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-methyl -
1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-60.
H NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.85-1.89 (m, 2H), 2.06-2.10 (m,
2H), 2.47 (q, J =7.6 Hz, 2H), 3.05 (s, 3H), 3.64-3.69 (m, 2H), 4.19-4.25 (m, 2H), 4.61-4.62
(m, IH), 6.19 (bs, IH), 6.74-6.75 (m, IH), 7.43 (s, 2H), 7.66-7.69 (m, 2H), 8.03 (d, J = 8.8
Hz, IH), 8.10 (s, IH), 8.19 (s, 2H), 8.29 (s, IH); MS: 457.3 (M+1).
Example-64: N-Ethyl- 1-(5-((l -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindole-
5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-61.
NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.87-1.91
(m, 2H), 2.08-2.13 (m, 2H), 2.49 (q, J = 7.6 Hz, 2H), 3.54-3.57 (m, 2H), 3.66-3.71 (m, 2H),
4.21-4.27 (m, 2H), 4.64 ( , IH), 6.16 (bs, IH), 6.76-6.77 (m, IH), 7.45 (m, 2H), 7.68-7.72
(m, 2H), 8.06-8.12 (m, 2H), 8.21 (s, 2H), 8.30 (m, IH); MS: 471.3 (M+1).
Example-65: 1-(5-((l -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-isopropyllH-
indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 using Example-62.
NMR (400 MHz, CDC13) d; 1.23 (t, J =7.6 Hz, 3H), 1.30 (d, J = 6.4 Hz, 6 H), 1.88-1.91
( , 2H), 2.07-2.12 (m, 2H), 2.49 (q, J = 7.6 Hz, 2H), 3.69 (m, 2H), 4.20-4.26 ( , 2H), 4.32-
4.37 (m, IH), 4.63-4.65 (m, IH), 5.98 (bs, IH), 6.76 (d, J =3.6 Hz, IH), 7.45 (m, 2H), 7.67-
7.71 (m, 2H), 8.05-8.09 ( , 2H), 8.30 (s, 2H), 8.3 1 ( , IH); MS: 485.3 (M+1).
Example-66: tert-Butyl-4-(((6-(5-(methylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)-
oxy)methyl)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using N-methyl-lH-indole-5-carboxamide (intermediate- 14) and rt-butyl 4-
(((6-chloropyridin-3-yl)oxy)methyl)piperidine-l -carboxylate (intermediate-29).
H NMR (400 MHZ, CDCI3) d; 1.25-1.38 (m, 2H), 1.46 (s, 9H), 1.85-1.88 (m, 2H), 2.02-2.04
(m, 1H), 2.76-2.81 (m, 2H), 3.06 (s, 3H), 3.92 (d, J = 6.4 Hz, 2H), 4.74 (bs, 2H), 6.75 (d, J =
3.2 Hz, 1H), 7.37-7.44 ( , 2H), 7.66-7.70 (m, 2H), 8.03 (d, J = 8.8 Hz, 1H), 8.1 1 (s, 1H),
8.26 (s, 1H); MS: 465.08 (M+l).
Example-67: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-Nmethyl-
1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 using Example-66.
Ή NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 2H), 1.94-1.98 (m,
2H), 2.14-2.16 (m, 1H), 2.46 (q, J = 7.6 Hz, 2H), 2.89-2.96 (m, 2H), 3.05 (s, 3H), 3.93 (d, J =
6.4 Hz, 2H), 4.80 (d, J = 13.2 Hz, 2H), 6.18 (d, J = 4.4 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H),
7.39-7.42 (m, 2H), 7.65-7.69 (m, 2H), 8.03 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 8.25 (s, 3H);
MS: 471.2 (M+l).
Example-68: l-(5-((l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-Nmethyl-
lH-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example- 4 using Example-60.
Ή NMR (400 MHz, CDC13) ; 1.29 (d, J = 6.8 Hz, 6H), 1.96-2.09 (m, 2H), 2.06-2.10 (m,
2H), 2.88-2.92 (m, 1H), 3.06 (s, 3H), 3.63-3.70 (m, 2H), 3.83-3.89 (m, 2H), 4.65 (bs, 1H),
6.18 (bs, 1H), 6.75 (s, 1H), 7.43 (bs 2H), 7.66-7.70 (m, 2H), 8.05-8.10 (m, 2H), 8.28 (bs,
1H); MS: 461.2 (M+l).
Example-69: -Butyl- 4-((6-(5-(pyrrolidine-l-carbonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidine- 1-carb xylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using t rt-butyl-4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and (lH-indol-5-yl)(pyrrolidin-l-yl)methanone (intermediate- 18).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.79-1.88 (m, 4H), 1.96-1.99 (m, 4H), 3.34-3.40
(m, 2H), 3.47-3.69 (m, 2H), 3.71-3.78 (m, 4H), 4.52-4.55 (m, 1H), 6.67 (bs, 1H), 7.41-7.42
(m, 2H), 7.47 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (d, J = 3.6 Hz, 1H), 7.86 (s, 1H), 8.04 (d, J =
8.4 Hz, 1H), 8.26 ( , 1H); MS: 491.3 (M+l).
Example-70: Isopropyl 4-((6-(5 -(pyrrolidine- 1-carbonyl)- 1H-indol- -yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate
To a stirred solution of Example-69 (0.050g, 0.102 mmol) in dichloromethane (3mL)
trifluoroacetic acid (0.2 n L) was added and stirred for lh. The reaction contents were
concentrated in vacuo and the residue was dissolved in dichloromethane (3mL),
triethylamine (0.015g, 0.153mmol), isopropylchloroformate (0.012g, 0.102mmol) were
added at 0°C and stirred for lh. The reaction was quenched by water and the organic layer
was extracted with dichloromethane. The organic layer was concentrated in vacuo and the
resultant residue was purified by flash column chromatography to give isopropyl 4-((6-(5-
(pyrrolidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine-l -carboxylate (0.012 g,
25 %).
NMR (400 MHz, CDC13) d; 1.24 (d, J = 6.0 Hz, 6H), 1.80-1.87 ( , 4H), 1.94-1.99 (m,
4H), 3.38-3.44 (m, 2H), 3.49-3.52 (m, 2H), 3.65-3.74 (m, 2H), 3.75-3.78 (m, 2H), 4.51-4.91
(m, 1H), 4.92-4.94 (m, 1H), 6.69-6.70 (m, 1H), 7.37-7.40 (m, 2H), 7.44-7.50 (m, 1H), 7.63
(d, J = 3.6 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.24-8.25 (m, 1H);
MS: 476.3 (M+) .
Example-71: (l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-
yl)(pyrrolidin- 1-yl)methanone
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-69.
1H NMR (400 MHz, CDC13) d; 1.19 (t, J = 7.6 Hz, 3H), 1.85-1.91 ( , 4H), 1.96-2.00 (m,
2H), 2.07-2.08 (m, 2H), 2.48 (q, J = 7.6 Hz, 2H), 3.51-3.55 (m, 2H), 3.62-3.70 (m, 4H), 4.21-
4.25 (m, 2H), 4.62 (m, 1H), 6.72 (d, J = 3.2 Hz, 1H), 7.43-7.49 (m, 3H), 7.66 (d, J = 3.2 Hz,
1H), 7.87 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.20 (s, 2H), 8.29 (s, 1H); MS: 497.2 (M+l).
Example-72 : Isopropyl 4-((6-(5-(isopropyl carbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidine-1 -carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 using Example-62.
NMR (400 MHz, CDC13) d; 1.19-1.28 (m, 12H), 1.80-1.83 (m, 2H), 1.96-2.00 (m, 2H),
3.38-3.45 (m, 2H), 3.73-3.78 (m, 2H), 4.27-4.34 (m, IH), 4.52-4.56 (m, IH), 4.89-4.95 (m,
IH), 6.73 (d, J = 3.2 Hz, IH), 7.37-7.43 (m, 2H), 7.64-7.69 ( , 2H), 8.02-8.06 (m, 2H), 8.25
(s, IH); MS: 465.2 (M+l).
Example- 3: Ethyl-4-((6-(5 -(isopropylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 using Example-62.
NMR (400 MHz, CDC13) d; 1.21-1.28 (m, 9H), 1.82-1.86 (m, 2H), 1.98-2.03 (m, 2H),
3.42-3.49 (m, 2H), 3.75-3.81 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.31-4.36 (m, IH), 4.54-4.57
(m, IH), 5.99 (bs, IH), 6.74-6.75 (m, IH), 7.39-7.45 (m, 2H), 7.66-7.07 (m, 2H), 8.04-8.08
(m, 2H), 8.27 ( , IH); MS: 451.2 (M+l).
Example-74: Isopropyl 4-((6-(5-(dimethylcarbamoyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described
Example-70 using Example-39.
NMR (400 MHz, CDC13) d; 1.28 (d, J = 6.4 Hz, 6H), 1.81-1.86 (m, 2H), 1.99-2.03 (m,
2H), 3.09 (s, 6H), 3.41-3.52 (m, 2H), 3.77-3.82 ( , 2H), 4.54-4.59 (m, 1H), 4.92-4.98 (m,
1H), 6.72-6.73 (m, 1H), 7.37 (dd, J = 8.4, 6.4 Hz, 1H), 7.42-7.43 (m, 2H), 7.66 (d, J = 3.6
Hz, 1H), 7.77 (s, 1H), 8.06 (d, J =8.4 Hz, 1H), 8.27-8.28 (m, 1H); MS: 451.2 (M+l).
Example-75: Ethyl-4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 using Example-39.
Ή NMR (400 MHz, CDC13) d; 1.29 (t, J = 7.2 Hz, 3H), 1.82-1.89 (m, 2H), 1.98-2.04 (m,
2H), 3.10 (s, 6H), 3.43-3.50 (m, 2H), 3.76-3.82 (m, 2H), 4.17 (q, J 7.2 Hz, 2H), 4.55-4.59
(m, 1H), 6.72-6.73 (m, 1H), 7.36-7.43 (m, 3H), 7.65 (d, J 3.2 Hz, 1H), 7.77 (s, 1H), 8.06
(d, J =8.8 Hz, 1H), 8.28 (m, 1H); MS: 437.2 (M+l).
ExampIe-76: tert-Butyl-4-((6-(5-((2-hydroxyethyl)carbamoyl)-lH-indol-l-yl)-pyridin-3-
yl)oxy)piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and N-(2-hydroxyethyl)-lH-indole-5-carboxamide (intermediate- 19) (0.1 10
g, 48.0 %).
Ή NMR (400 MHz, CDCI3) d; 1.46 (s, 9H), 1.80-1.84 (m, 2H), 1.98-2.02 (m, 2H), 2.96 (bs,
2H), 3.35-3.41 (m, 2H), 3.66-3.74 (m, 2H), 3.76-3.89 (m, 2H), 4.54-4.56 (m, 2H), 6.66 (bs,
1H), 6.75-6.76 (m, 1H), 7.42 (bs, 2H), 7.66-7.73 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 8.14 (s,
1H), 8.27 (m, 1H); MS: 481.2 (M+l).
Example-77: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2-
hydroxyethyl)- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 using Example-76.
NMR (400 MHz, CDC13) d; 1.20 (t, J = 4.8 Hz, 3H), 1.87-1.91 (m, 2H), 2.08-2.12 (m,
2H), 2.49 (q, J = 22.8 Hz, 2H), 2.84 (bs, 1H), 3.67-3.71 (m, 4H), 3.87-3.90 (m, 2H), 4.21-
4.27 (m, 2H), 4.63-4.65 (m, 1H), 6.82 (t, J = 10.8 Hz, 1H), 6.77 (d, J = 3.2 Hz, 1H), 7.43-
7.46 (s, 2H), 7.68-7.74 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.21 (s, 2H), 8.31 (m,
1H); MS: 487.0 (M+l).
Example-78: tran (±)-t rt-Butyl-3 -fluoro-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl) pyridin-
3-yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate-21) and
4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-l -carboxylate (intermediate-63) (0.220 g,
37%).
NMR (400 MHz, CDC13) d; 1.51 (s, 9H), 1.78-1.82 (m, 1H), 2.14-2.20 (m, 1H), 3.07 (s,
3H), 3.32 (bs, 1H), 3.43-3.49 (m, 1H), 3.70-3.74 (m, 1H), 4.00 (bs, 1H), 4.47-4.58 (m, 1H),
4.70 (bs, 1H), 6.82 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.47-7.48 (m, 1H), 7.71 (d, J
= 3.6 Hz, 1H), 7.78-7.80 (m, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.28 (d, J 2.0 Hz, 1H), 8.32 (d,
J =2.8 Hz, 1H); MS: 434.1 (M-56).
Example-79: ' 3-Ethyl-5-((4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-
piperidin- 1-yl)methyl)- -oxadiazole
To a solution of tert-buty\ 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate (0.1 50g,
0.318mmol) in dichloromethane (15 mL), trifluoroacetic acid (0.2 mL) was added and the
reaction mixture was stirred for lh. The reaction mixture was concentrated in vacuo, the
resultant residue was dissolved in NMP (3 mL), 5-(chloromethyl)-3 -ethyl- 1,2,4-oxadiazole
(0.051g 0.350mmol) and DIPEA (0.123 g, 0.955 mmol) were added and stirred at 60°C for
3h. The reaction was quenched by water and the organic layer was extracted with ethyl
acetate. The organic layer was separated, concentrated in vacuo and the resultant residue was
purified by flash column chromatography to give 3-ethyl-5-((4-((6-(5-(methylsulfonyl)-lHindol-
l-yl)pyridin-3-yl)oxy)piperidin-l-yl)methyl)- 1,2,4-oxadiazole (0.012 g, 8%).
'H NMR (400 MHz, CDC13) d; 1.36 (t, J = 7.6 Hz, 3H), 1.99 (m, 2H), 2.1 1 (m, 2H), 2.59 (m,
2H), 2.82 (q, J = 6.4 Hz, 2H), 2.89 (m, 2H), 3.12 (s, 3H), 3.90 (s, 2H), 4.46 (bs, 1H), 6.83 (d,
J = 3.2 Hz, 1H), 7.42 (d, J = 2 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.80 (dd, J = 8.8, 1.6 Hz,
1H), 8.19 (d, J = 8.8 Hz, 1H), 8.27-8.30 (m, 2H); MS: 482.0 (M+l).
Example-80: 3-Isopropyl-5-((4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidin- 1-yl)methyl)- -oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-79 by using Example-1 and 5-(chloromethyl)-3-isopropyl-l,2,4-oxadiazole.
NMR (400 MHz, CDC13) d; 1.38 (d, J = 6.8 Hz, 6H), 1.86-1.90 (m, 2H), 2.02-2.03 (m,
2H), 2.68 (bs, 2H), 2.95-2.98 (m, 2H), 3.10-3.18 (m, 4H), 3.97 (s, 2H), 4.91 (bs, 1H), 6.84 (d,
J = 3.6 Hz, 1H), 7.43 (d, J = 1.2 Hz, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz,
1H), 8.19 (d, J 8.8 Hz, 1H), 8.28 (s, 1H), 8.32 (s, 1H); MS: 496.1 (M+l).
Example-81: l-(5-((l-(4-Fluorophenyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methyl sulfonyl)-
lH-indole
To a stirred solution of example- 1 (0.250g, 0.53mmol) in dichloromethane (5 mL)
trifluoroacetic acid (0.5 mL) was added at 0°C and stirred at room temperature for 2-3h. The
solvent was removed in vacuo and the resulting salt was dissolved in anhydrous dioxane (10
mL), and 1-bromo-4-florobenzene (0.074g, 0.424mmol), 2-{2'-D\-tertbutylphosphine)
biphenylpalladium (II) acetate (0.049g, 0.106mmol) and NaOT3u (0.120g,
1.318 mmol) were added. The resultant reaction mixture was refluxed for 4-5h. The reaction
mixture was filtered over celite and concentrated in vacuo. The residue was purified by flash
column chromatography to give the title compound.
NMR (400 MHz, CDC13) d; 2.03-2.07 (m, 2H), 2.19-2.23 (m, 2H), 3.06-3.10 (m, 5H),
3.43-3.52 (m, 2H), 4.55-4.58 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 6.93-7.02 (m, 4H), 7.43-7.49
(m, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H),
8.32 (s, 2H); MS: 466.1 (M+l).
Example-82: 1-(5-((l -(4-Fluorobenzyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methyl sulfonyl)-
lH-indole
To a stirred solution of Example-1 (0.200g, 0.424mmol) in dichloromethane (10 mL)
trifluoroacetic acid (0.2 mL) was added and stirred for lh. The reaction mixture was
concentrated in vacuo and the residue was dissolved in DMF (5 mL), Et3N (0.050 g, 0.5
mmol) was added and stirred for 15 minutes. 4-Fluoro benzaldehyde (0.057 g, 0.467 mmol),
sodium triacetoxyborohydride (0.134 g, 0.636 mmol) were added and stirred for lOh. The
reaction was quenched by water and the organic layer was extracted with ethyl acetate. The
organic layer was concentrated in vacuo and the residue was purified by flash column
chromatography to give l-(5-((l-(4-fluorobenzyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)-lH-indole (0.012 g, 6%).
NMR (400 MHz, CDC13) d; 1.92 (bs, 2H), 2.06 (bs, 2H), 2.36 (bs, 2H), 2.78 (bs, 2H),
3.10 (s, 3H), 3.48-3.54 (m, 2H), 4.44 (bs, 1H), 6.84 (d, J 3.6 Hz, 1H), 7.03 (t, 8.4 Hz, 2H),
7.32 (bs, 2H), 7.42-7.3-43 (m, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H),
8.19 (d, J = 8.8 Hz, 1H), 8.28-8.31 ( , 2H); MS: 481.1 (M+l).
Example-83: l-(5-((l-((4-Ethyloxazol-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
lH-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-79 by using Example-39.
NMR (400 MHz, CDC13) d; 1.24 (t, J = 7.6 Hz, 3H), 1.66-1.73 (m, 2H), 2.00-2.28 (m,
2H), 2.42-2.50 (m, 2H), 2.68 (q, J =7.6 Hz, 2H), 2.79-2.90 (m, 2H), 2.99 (s, 6H), 3.91 (s,
2H), 4.50-4.55 ( , 1H), 6.76 (d, J = 3.6 Hz, 1H), 7.28 (dd, J - 8.4, 1.6 Hz, 1H), 7.66-7.70
(m, 3H), 7.98 (d, J = 3.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.29 (m, 1H); MS: 475.2 (M+l).
Example-84: l-(5-((l-((4-Isopropyloxazol-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-
N,N-dimethyl- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-79 by using Example-39.
Ή NMR (400 MHz, CDC13) d; 1.27 (d, J = 6.8 Hz, 6H), 1.69-1.71 (m, 2H), 2.00-2.02 (m,
2H), 2.41-2.50 (m, 2H), 2.79-2.81 (m, 2H), 2.99 (s, 6H), 3.03-3.37 (m, 1H), 3.91 (s, 2H),
4.52 (bs, 1H), 6.76 (d, J = 3.6 Hz, 1H), 7.28 (dd, J = 8.8, 2.0 Hz, 1H), 7.37-7.70 (m, 3H),
7.98 (d, J =3.2 Hz, 1H), 8.21 (d, J =8.8 Hz, 1H), 8.29 (s, 1H); MS: 489.1 (M+l).
ExampIe-85: 3-Cyclopropyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 1 and (Z)-N-hydroxycyclopropanecarbimidic acid.
NMR (400 MHz, CDC13) ; 0.92-0.95 (m, 4H), 1.84-188 (m, 1H), 1.93-1.99 (m, 2H),
2.03-2.09 (m, 2H), 3.07 (s, 3H), 3.59-3.65 (m, 2H), 3.78-3.84 (m, 2H), 4.62-4.64 (m, 1H),
6.81 (d, J = 3.2 Hz, 1H), 7.42 (bs, 2H), 7.70 (d, J = 3.6 Hz, 1H), 7.78 (dd, J = 8.8, 2.0 Hz,
1H), 8.18 (d, J =8.8 Hz, 1H), 8.28 (s, 2H); MS: 480.1 (M+l).
Example-86: 4-Cyclopropyl-2-((4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)
oxy)piperidin- 1-yl)methyl)oxazole
The title compound was prepared by following the similar procedure as described in
Example-79 by using Example- 1.
H NMR (400 MHz, CDC13) d; 1.08-1.10 (m, 4H), 1.97 (bs, 2H), 2.10-2.16 (m, 3H), 2.56 (bs,
2H), 2.86-2.88 (m, 2H), 3.10 (s, 3H), 3.85 (s, 2H), 4.45 (bs, 1H), 6.84 (d, J = 3.2 Hz, 1H),
7.42 (s, 2H), 7.73 (d, J =3.6 Hz, 1H), 7.81 (dd, J =8.8, 1.6 Hz, 1H), 8.20 (d, J =8.8 Hz, 1H),
8.27-8.31 (m, 2H); MS: 494.1 (M+l).
Example-87: tert-Butyl-4-((6-(5-((2,2,2-trifluoroethyl)carbamoyl)-lH-indol-l-yl)-pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate- 06) and rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate- 68).
Ή NMR (400 MHz, CDC13) d; 1.49 (d, J = 9.0 Hz, H), 1.81-1.87 (m, 2H). 1.98-2.03 (m,
2H), 3.36-3.42 (m, 2H), 3.73-3.78 (m, 2H), 4.15-4.24 (m, 2H), 4.54 (bs, 1H), 6.79 (d, J = 3.2
Hz, 1H), 7.44 (s, 2H), 7.69 (d, J = 3.6 Hz, 1H), 7.73 (dd, J = 8.8, 1.6 Hz, 1H), 8.10 (d, J = 8.4
Hz, 1H), 8.16 (s, 1H), 8.29 (bs, 1H); MS: 519.3 (M+l).
Example-88: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2,2,2-
trifluoroethyl)-lH-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-87.
NMR (400 MHz, CDC13) d; 1.92 (t, J = 4.8 Hz, 3H), 1.86-1.92 (m, 2H), 2.06-2.12 (m,
2H), 2.31 (q, J = 7.6 Hz, 2H), 3.66-3.70 (m, 2H), 4.14-4.25 (m, 4H), 4.63-4.64 (m, 1H), 6.41
(t, J = 6.4 Hz, 1H), 6.77 (d, J = 3.2 Hz, 1H). 7.44-7.45 (m, 2H), 7.68-7.73 (m, 2H), 8.10 (d, J
= 8.8 Hz, 2H), 8.14-8.20 (m, 2H), 8.30 (m, 1H); MS: 525.2 (M+l).
Example-89: Isopropyl 4-((6-(5-((2-hydroxyethyl)carbamoyl)-l H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-76.
Ή NMR (400 MHz, CDC13) d: 1.25 (d, J = 6.0 Hz, 6H), 1.80-1.83 (m, 2H), 1.98-1.99 (m,
2H), 3.39-3.46 (m, 2H), 3.64-3.68 (m, 2H), 3.74-3.78 (m, 2H), 3.84-3.86 (m, 2H), 4.54-4.56
(m, 1H), 4.91-4.94 (m, 1H), 6.74 (d, J = 3.6 Hz, 1H), 7.41 (s, 2H), 7.65-7.71 (m, 2H), 8.05
(d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.25 (s, 1H); MS: 467.1 (M+l).
Example-90: Ethyl 4-((6-(5-((2-hydroxyethyl)carbamoyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-76.
NMR (400 MHz, CDC13) d: 1.26 (t, J = 7.2 Hz, 3H), 1.79-1.85 (m, 2H), 1.96-2.00 (m,
2H), 3.40-3.46 (m, 2H), 3.64-3.68 (m, 2H), 3.73-3.78 (m, 2H), 3.85 (t, J = 4.8 Hz, 2H), 4.14
(q, J = 7.2 Hz, 2H), 4.52-4.56 (m, 1H), 6.64-6.66 (m, 1H), 6.73 (d, J = 3.6 Hz, 1H), 7.40 (s,
2H), 7.64-7.70 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 8.1 1 (s, 1H), 8.25 (bs, 1H); MS: 453.2
(M+l).
Example-91: tert-Butyl-4-((6-(7-fluoro-5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 using t rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-06) and 7-Fluoro-5-(methylsulfonyl)-lH-indole (intermediate-22) (0.060 g,
23%).
' NMR (400 MHz, CDC13) d; 1.30 (s, 9H), 1.59 (bs, 2H), 1.86 (bs, 2H), 3.1 1( s, 3H), 3.38-
3.44 (m, 2H), 3.74-3.80 ( m, 2H), 4.58-4.62 ( m, IH), 6.88 (dd, J = 3.6, 2.4 Hz, IH), 7.41
(s, IH), 7.41(d, J = 1.6 Hz, IH), 7.52 (dd, J = 11.2, 1.6 Hz, IH), 7.70 (d, J = 3.2 Hz, IH),
8.13 (d, J =1.6 Hz, IH), 8.25 (d, J = 2.0 Hz, IH); MS: 434 (M-56).
Example-92: 3-Methyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) oxy)
piperidin- 1-yl)- 1, 2, 4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 using Example-1 (0.010 g, 5.84%).
NMR (400 MHz, CDC13) d; 1.95-2.01 (m, 2H), 2.05-2.10 (m, 2H), 2.20 (s, 3H), 3.07 (s,
3H), 3.63-3.69 (m, 2H), 3.79-3.86 ( m ,2H), 4.65 (bs, IH), 6.80 (d, J = 3.2 Hz, IH), 7.36-
7.44 (m, 2H), Ί .69-1.10 (m, IH), 7.76-7.84 (m, IH), 8.16-8.19 ( , IH), 8.20-8.30 (m, 2 H);
MS: 454.1 (M+l).
Example-93: Methyl- 1-(5 -((l-(tert-butoxycarbonyl) piperidin-4-yl) oxy) pyridin-2-yl)-lHindole-
5-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-6) and methyl lH-indole-5-carboxylate (0.615 g, 21%).
Ή NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.80 (bs, 2H), 1.97 (bs, 2H), 3.34-3.38 (m, 2H),
3.73 (bs, 2H), 3.93 (s, 3H), 4.53 (bs, IH), 6.76 (s, IH), 7.40 (s, 2H), 7.65 (s, IH), 7.98 (dd, J
= 8.8, 2.8 Hz, 2H), 8.26 (s, IH), 8.39 (s, IH); MS: 452.1 (M+l).
Example-94: / rt-Butyl-4-((6-(5-(hydroxymethyl)-lH-indol-l-yl) pyridin-3-yl) oxy)
piperidine -1-carboxylate
To a stirred solution of Example-96 (0.3g, 0.665 mmol) in dry THF, LiAlH 4 in THF (0.2 ml,
0.996mmol) was added at 0°C and stirred for 20 minutes. The reaction was quenched with
methanol at 0°C, the reaction mixture was concentrated in vacuo and the residue was diluted
with ethyl acetate and washed with water. The organic layer was separated, concentrated in
vacuo and the resulting residue was purified by flash column chromatography to give the title
compound (0.198 g, 70.46 %).
NMR (400 MHz, CDC13) d; 1.45 (s, 9H), 1.73-1.81 (m, 2H), 1.95-2.00 (m, 2H), 3.33-3.39
(m, 2H), 3.71-3.77 (m, 2H), 4.50-4.54 (m, 1H), 4.78 (s, 2H), 6.67 (d, J = 3.2 Hz, 1H), 7.29
(dd, J = 8.8, 1.6 Hz, 2H), 7.37-7.43 (m, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.65 (s, 1H), 8.02 (d, J
= 8.4 Hz ,1H), 8.24(bs, 1H); MS: 424.23 (M+l).
Example-95: Methyl- l-(5-((l-(5-ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lHindole-
5-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-93 (0.220 g, 74.82%).
NMR (400 MHz, CDC13) d; 1.19 (t, J =7.6 Hz, 3H), 1.83-1.90 (m, 2H), 2.04-2.1 1 (m,
2H), 2.47 (q, J =7.6 Hz, 2H), 3.63-3.69 (m, 2H), 3.93 ( s ,1H), 4.18-4.24 (m, 2H), 4.59-4.61
(m, 1H), 6.76 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 1.6 Hz, 2H), 7.66 (d, J 3.6 Hz, 2H),7.95
(dd, J = 8.8, 2.0 Hz , 2H), 8.03 (d, J = 8.8 Hz, 1H), 8.18 (s, 2H), 8.28(s, 1H), 8.40 (s, 1H);
MS: 458.1 (M+l).
Example-96: (l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indol-
5-yl) methanol
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-94 (0.008 g, 7.14%).
NMR (400 MHz, CDC13) d; 1.19 (t, J =7.6 Hz, 3H), 1.84-1.88 (m, 2H), 2.05-2.1 1 (m,
2H), 2.47 (q, J =7.6 Hz, 2H), 3.63-3.69 (m, 2H), 4.19-4.25 (m, 2H), 4.58-4.62 (m, 1H), 4.79
(s, 2H), 6.67 (d, J = 3.2 Hz, 1H), 7.29 (dd, J = 8.8, 1.6 Hz, 2H), 7.42 (bs, 2H), 7.63-7.65 (m,
2H), 8.03 (d, J = 8.4 Hz, 1H), 8.19 (s, 2H).8.27(s, 1H); MS: 430.2 (M+l).
Example-97: ter/-Butyl-4-((6-(5-(isobutyramido methyl)- lH-indol-l-yl) pyridin-3-yl)
oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using N-((lH-indol-5-yl) methyl) isobutyramide (intermediate 3) and rt-butyl 4-
((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate (intermediate 6) (0.103 g, 21.77%).
Ή NMR (400 MHz, CDC13) d; 1.18 (d, J = 4 Hz, 6H), 1.47 (s, 9H), 1.77- 1.82 (m, 2H), 1.95-
1.99 (m, 2H), 2.35-2.38 (m, 1H), 3.33-3.39 (m, 2H), 3.70-3.76 (m, 2H), 4.51-4.53 (m, 3H),
5.67 (s, 1H), 6.65 (d, J = 3.2 Hz, 1H), 7.18 (dd, J = 8.8, 1.6 Hz, 1H), 7.36-7.41 (m, 2H), 7.55
(s, 1H), 7.61 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H); MS: 452.1 (M+l).
Example-98: N-((l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lHindol-
5-yl) methyl)isobutyramide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-97 (0.070 g, 83.57%).
Ή NMR (400 MHz, CDC13) ; 1.1-1.23 (m, 9H), 1.84-1.87 (m, 2H), 2.04-2.07 (m, 2H),
2.34-2.37 (m, 1H), 2.46 (q, J = 7.6 Hz, 2H), 3.61-3.68 (m, 2H),4.17-4.22 (m, 2H), 4.52 (d, J
= 5.6 Hz, 2H), 4.58- 4.60 (m, 1H), 5.67 (s, 1H), 6.64 (dd, J - 3.2, 0.4 Hz, 1H), 7.18 (dd, J =
8.8, 2.0 Hz ,1H), 7.40 (bs, 2H), 7.55 (bs, 1H), 7.62 (d, J = 3.6 Hz, 1H), 7.98-8.00 (m, 1H),
8.18 (s, 2H), 8.25-8.26 ( , 1H); MS: 522 (M+23).
Example-99: rt-Butyl-4-((6-(5-(3-isopropyl-l, 2, 4-oxadiazol-5-yl)-lH-indol-l-yl)
pyridin-3-yl) oxy) piperidine-l-carboxylate
To a stirred solution of N'-hydroxyisobutyrimidamide (0.10g, 1.0 mmol) in dry THF (10
mL), NaH (0.078 g, 3.26 mmol) was added and stirred at 60°C for 2h. The reaction contents
were brought to room temperature, Ethyl- l-(5-((l-(tert-butoxycarbonyl) piperidin-4-yl) oxy)
pyridin-2-yl)-lH-indole-5-carboxylate (0.205 g, 0.440 mmol) was added and stirred at 60°C
for 3h. The reaction was quenched by methanol at 0°C and concentrated in vacuo. The
resultant residue was dissolved with ethyl acetate and washed with water, the organic layer
was separated, concentrated in vacuo and the resulting residue was purified by flash column
chromatography to give the title compound (0.050 g, 10.16 %).
Ή NMR (400 MHz, CDC13) d; 1.44 (d, J = 7.2 Hz, 6H), 1.50 (s, 9H),1.81-1.86 (m, 2H),
1.99-2.04 (m, 2H), 3.15-3.22 (s, 1H), 3.36-3.42 (m, 2H), 3.73- 3.79 (m, 2H), 4.55-4.59 ( m,
1H), 6.82 (dd, J = 3.2, 0.4 Hz, IH), 7.45 (bs, 2H), 7.69 (d, J = 3.6 Hz, 1H), 8.03 (dd, J = 8.8,
1.6 Hz, 1H), 8.13-8.16 (m, 1H), 8.30 (bs, 1H), 8.49 (bs, 1H); MS: 504.2 (M+l).
Example-100: 5-(l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lHindol-
5-yl)-3-isopropyl-l, 2, 4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-99 (0.052 g, 55.60%).
NMR (400 MHz, CDC13) d; 1.22 (t, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 6H), 1.87-1.92
(m, 2H), 2.09-2.13 (m, 2H), 2.50 (q, J = 7.6 Hz, 2H), 3.17-3.21 (m, IH), 3.66-3.72 (m, 2H),
4.21-4.27 (m, 2H), 4.64 - 4.66 (m, IH), 6.82 (dd, J = 3.2, 0.4 Hz, IH), 7.47-7.46 (m, 2H),
7.70 (d, J = 3.6 Hz, IH) , 8.04( dd, J = 8.8, 2.0 Hz, IH), 8.15-8.17 (m, IH), 8.21 (s, 2H),
8.32-8.33 (m , IH), 8.49 (s, IH).
Example-101: Isopropyl 4-((6-(5-(3-isopropyl-l, 2, 4-oxadiazol-5-yl)-lH-indol-l-yl)
pyridin-3-yl) oxy) piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-99 (0.035 g, 43%).
NMR (400 MHz, CDC13) d; 1.28 (d, J = 6.0 Hz, 6H) , 1.44 (d, J = 7.2 Hz, 6H), 1.82-1.87
(m, 2H), 1.99-2.03 (m, 2H), 3.15-3.21 (s, IH), 3.42-3.48 (m, 2H), 3.76-3.82 (m, 2H), 4.57-
4.60 (m, IH), 4.93-4.99 (m, IH) , 6.82 (d, J = 3.2 Hz, IH), 7.45 (s, 2H), 7.69 (d, J = 3.2 Hz,
IH), 8.03 (dd, J = 8.8, 1.2 Hz, IH), 8.14-8.16 (m, IH), 8.29-8.30 (m, IH), 8.49 (bs, IH);
MS: 490.2 (M+l).
Example-102: rt-Butyl-4-((6-(5-(3-methyl-l, 2, 4-oxadiazol-5-yl)-lH-indol-l-yl) pyridin -
3-yl)oxy) piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-99 using Ethyl-l-(5-((l -(tert-butoxycarbonyl) piperidin-4-yl) oxy) pyridin-2-yl)-
lH-indole-5-carboxylate (intermediate 28) (0.615 g, 21.30%).
NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.55-1.83 (m, 2H), 1.95-2.00 (m, 2H), 2.46 (s,
3H), 3.33-3.39 (m, 2H), 3.70-3.76 (m, 2H), 4.51-4.56 (m, 1H), 6.78 (dd, J = 3.6, 0.8 Hz, 1H),
7.41 (s, 2H), 7.66 (d, J =3.6 Hz, lH), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 8.12 (d, J =8.8 Hz, 1H),
8.26-8.27 (m, 1H), 8.44 (s, 1H); MS: 476.2 (M+l).
Example-103: 5-(l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lHindol-
5-yl)-3-methyl- -oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 102.
H NMR (400 MHz, CDC13) d; 1.20 (t, J =7.6 Hz, 3H), 1.86-1.90 (m, 2H), 2.07-2.12 (m,
2H), 2.45-2.51 (m, 5H), 3.64-3.70 (m, 2H), 4.19-4.26 (m ,2H), 4.63-4.64 (m, 1H), 6.80 (d, J
= 3.2 Hz, 1H), 7.45 (s, 1H), 7.69 (d, J = 3.2 Hz, 1H) , 8.01( dd, J = 8.8, 1.6 Hz ,2H), 8.15
(d, J = 8.8 Hz, 1H), 8.20 (s, 2H), 8.31-8.32 (m, 1H), 8.46 (s, 1H); MS: 482.2 (M+l).
Example-104: -Butyl- 4-((6-(5-(pyrrolidin-l-yl)-lH-indol-l-yl) pyridin-3-yl) oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using iert-buty\ 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate 6) and t rt-butyl-5-(pyrrolidin-l-yl)-lH-indole-l-carboxylate (intermediate 66)
(0.030 g, 10.16%).
1H NMR (400 MHz, CDC13) d; 1.49 (s, 9H), 1.81 (s, 2H), 1.97 (s, 2H), 2.04(s, 4H) , 3.20-
3.50 (m, 6H) , 3.75 (s, 2H), 4.50 (s, 1H), 6.55 ( s, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.79 (s, 1H)
, 7.35-7.41 (m, 2H), 7.57 (s, 1H), 7.96 (d, J =8.8 Hz, 1H), 8.22 (s, 1H); MS: 463.3 (M+l).
Example-105: l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-5-
(pyrrolidin- 1-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-104 (0.060 g, 64%).
Ή NMR (400 MHz, CDC13) d; 1.20 (t, J =7.6 Hz, 3H), 1.56-1.87 (m, 2H), 2.01-2.10 (m,
6H), 2.47 (q, J =7.6 Hz, 2H), 3.32-3.35 (m, 4H), 3.61-3.68 (m, 2H), 4.19-4.25 (m, 2H), 4.55-
4.57 (m, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.69 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (s, 1H) , 7.39-
7.41 (m, 2H), 7.57 (d, J = 3.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.19 (s, 2H), 8.24 (s, 1H);
MS: 469.3 (M+l).
Example-106: l-(5-(((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) methyl) pyridin-2-yl)-
5-(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 using ½rt-butyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy)
piperidine-l-carboxylate (intermediate 75) (0.055 g, 58%).
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.64-1.73 (m, 2H), 2.00-2.04 (m,
2H), 2.46 (q, J 7.6 Hz, 2H), 3.09 (s, 3H), 3.36-3.42 (m, 2H), 3.72-3.76 (m, IH) , 4.29-4.35
(m, 2H), 4.67 (s, 2H), 6.85 (d, J =3.6 Hz, IH), 7.48 (d, J = 8.4 Hz, IH), 7.80-7.83 (m, 2H),
7.91 (dd, J = 8.8, 2.0 Hz, IH), 8.17(s, 2H), 8.29 (s, IH), 8.37 (d, J = 8.8 Hz, IH), 8.57(s,
IH); MS: 492.2 (M+l).
Example-107: Ethyl 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 using tert-butyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl)
methoxy) piperidine- 1-carboxylate (intermediate 75) (0.038 g, 41%).
Ή NMR (400 MHz, CDC13) d; 1.26 (t, J = 7.2 Hz, 3H), 1.53-1.69 (m, 2H), 1.91 (bs, 2H),
3.09 (s, 3H), 3.19-3.25 ( , 2H), 3.64-3.68 (m, IH), 3.82 (bs, 2H), 4.13 (q, J = 7.2 Hz, 2H),
4.63 (s, 2 H), 6.85 (dd, J = 3.2, 0.4 Hz, IH), 7.48 (d, J = 8.4 Hz, IH), 7.80-7.83 (m, 2H),
7.89 (dd, J = 8.4, 2.4 Hz, IH), 8.29 (d, J = 1.6 Hz, IH), 8.38 (d, J = 8.8 Hz, IH), 8.56 (bs,
IH); MS: 458.1 (M+l).
ExampIe-108: Isopropyl 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl) methoxy)
piperidine - 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 using ert -butyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl)
methoxy) piperidine-l-carboxylate (intermediate 75) (0.075 g, 80%).
Ή NMR (400 MHz, CDC13) d; 1.24 (d, J = 6.4 Hz, 6H), 1.64-1.67 (m, 2H), 1.92 (bs, 2H),
3.1 1 (s, 3H), 3.18-3.24 (m, 2H), 3.65-3.71 (m, 1H), 3.84 (bs, 2H), 4.65 (s, 2H), 4.90-4.96
( , 1H), 6.87 (dd, J = 3.6, 0.8 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.82-7.85 (m, 2H), 7.91
(dd, J = 8.4, 2.4 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.56 (bs, 1H);
MS: 472.08 (M+l).
Example-109: 2-Methyl-l-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)
methoxy)piperidin- 1-yl) propan-2-ol
The title compound was prepared by following the similar procedure as described in
Example- 12 using rt-butyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl)
methoxy) piperidine-l-carboxylate (intermediate 75) (0.133 g, 48%).
Ή NMR (400 MHz, CDC13) d; 1.14 (s, 6H), 1.70 (bs, 2H), 1.92 (bs, 2H), 2.30 (s, 2 H), 2.45(
bs, 2H) , 2.88 (bs, 2H), 3.07(s, 3H), 3.48 (bs, 1H), 4.60 (s, 2H), 6.83(d, J = 3.6 Hz, 1H), 7.46
(d, J = 8 Hz, 1H), 7.78-7.80 (m, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H),
8.28 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 2 Hz, 1H); MS: 458.1 (M+l).
Example-110: l-(5-(((l-(2-Fluoro-2-methylpropyl) piperidin-4-yl) oxy) methyl) pyridin-2-
yl)-5-(methylsulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Example- 14 by using Example-109 (0.030 g, 27%).
NMR (400 MHz, CDC13) d; 1.31 (s, 3H), 1.37 (s, 3H), 1.64-1.72 (m, 2H), 1.91-1.94( ,
2H) , 2.28 (t, J = 9.6 Hz, 2H), 2.39 (s, 1H) , 2.44 (s, 1H), 2.82-2.86 (m, 2H), 3.08 (s, 3H),
3.41-3.46 ( , 1H), 4.60 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.78-7.79
(m, 1H), 7.82 (d, J = 2Hz, 1H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.35
(d, J = 9.2 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H); MS: 496.2 (M+l).
Example-Ill: 3-Isopropyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl)
methoxy) piperidin-l - - l , 2, 4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 using 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy)
piperidine-l-carbonitrile (intermediate 38) and N-hydroxy-isobutyramidine (0.010 g, 5.8%).
NMR (400 MHz, CDC13) d; 1.32 (d, J =6.8 Hz, 6H), 1.82-1 .86 (m, 2H), 2.02-2.06 (m,
2H), 2.89-2.93( m, 1H), 3.12 (s, 3H), 3.48-3.54 (m, 2H), 3.77-3.79 (m, 1H), 3.87- 3.88. (m,
2H), 4.68 (s, 2H), 6.88 (dd, J = 3.6, 0.4 Hz, 1H), 7.52 (d, J - 8.4 Hz, 1H), 7.83-7.86 (m, 2H),
7.92 (dd, J = 8.4, 2.4 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.60 (d, J =
1.6 Hz, 1H); MS: 496.2 (M+l).
Example-112: 3-Methyl-5-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy)
piperidin-l-yl)-l, 2, 4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 using 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy)
piperidine-l-carbonitrile (intermediate 38) and N-hydroxyacetimidamide (0.014 g, 8%).
NMR (400 MHz, CDC13) d; 1.85-1.88 (m, 2H), 1.99-2.07 (m, 2H), 2.23 (s, 3H), 3.1 l(s,
3H), 3.49-3.55 (m, 2H) , 3.77-3.81 (m, IH), 3.85-3.91 (m, 2H), 4.67 (s, 2H), 6.87 (d, J = 3.2
Hz, IH), 7.45-7.53 (m, 2H), 7.82-7.86 (m, IH), 7.88-7.93 (m, IH), 8.31-8.35 (m, IH), 8.39-
8.44 (m, IH), 8.58 (bs, IH); MS: 468.08 (M+l).
Example-113: l-(5-(((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-5-
(methylsulfonyl)indoline
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-46.
Ή NMR (400 MHz, CDC13) d; 1.81 (t, J = 7.6 Hz, 3H), 1.309-1.41 (m, 2H), 1.92-1.95 (m,
2H), 2.07-2.13 (m, IH), 2.46 (q, J = 7.6 Hz, 2H), 2.87-2.94 (m, 2H), 3.02 (s, 3H), 3.25 (t, J =
17.6 Hz, 2H), 3.86 (d, J 6.4 Hz, 2H), 4.1 1 (t, J = 8.8 Hz, 2H), 4.76-4.80 ( , 2H), 6.78 (d, J
= 9.2 Hz, IH), 7.25-7.28 (m, IH), 7.64 (bs, IH), 7.71 (dd, J = 8.8, 2.0 Hz, IH), 8.09 (d, J =
2.8 Hz, IH), 8.14 (s, IH), 8.17 (s, 2H); MS: 494.2 (M+l).
Example-114: ter t-Butyl-4-((6-(5-isobutyramido- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using t rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate 06) and N-(lH-indol-5-yl)isobutyramide (intermediate 10).
1H NMR (400 MHz, CDC13) d; 1.29 (d, J =7.2 Hz, 6H), 1.48 (s, 9H), 1.813-1.814 (m, 2H),
1.95-2.00 (m, 2H), 2.50-2.57 (m, 1H), 3.33-3.39 (m, 2H), 3.71-3.77 (m, 2H), 4.50-4.52 (m,
1H), 6.63(d, J = 3.2Hz, 1H), 7.21 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.38-7.39 (m, 2H),
7.60(d, J =3.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, lH), 8.00 (d, J =8.8 Hz, 1H), 8.23-8.24 (m, 1H);
MS: 481 (M+1).
Example-115: 3-Isopropyl-5-(4-((6-(5-(methylsulfonyl) indolin-l-yl) pyridin-3-yl) methoxy)
piperidin-l-yl)-l, 2, 4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-46 (0.010 g, 5%).
NMR (400 MHz, CDC13) ; 1.30 (d, J = 6.8 Hz, 6H), 1.75-1.83 (m, 2H), 1.95-2.00 (m,
2H), 2.87-2.94( m, 1H) , 3.05 (s, 3H), 3.31(t, J = 8.8 Hz, 2H), 3.44-3.50 (m, 2H), 3.69-3.85
(m, 1H), 3.86- 3.90 ( m, 2H), 4.17 ( t, J = 8.8 Hz, 2H), 4.56 (s, 2H), 6.82 (d, J =8.4 Hz, 1H),
7.70 (bs, 2H), 7.77 ( d, J =8.8 Hz, 1H), 8.37-8.42 (m, 2H); MS: 498.2 (M+l).
Example-116: tert-Butyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-2-yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate 21) and t rt-butyl 4-((6-
chloropyridin-2-yl)oxy)piperidine-l -carboxylate (intermediate 42) (0.19 g, 63%).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.79-1.85 (m, 2H), 2.02-2.06 (m, 2H), 3.10 (s,
3H), 3.30-3.36 (m, 2H), 3.78-3.82 (m, 2H), 5.26-5.30 (m, 1H), 6.69 (d, J =8.4 Hz, 1H), 6.83
(d, J = 3.2 Hz, 1H), 7.03 (d, J = 8Hz, 1H), 7.73-7.82 (m, 3H), 8.29-8.30 (m, 2H); MS: 372
(M-100)
Example-117: l-(6-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-1 16 (0.054 g, 24%).
NMR (400 MHz, CDC13) ; 1.19 (t, J = 7.6 Hz, 3H), 1.85-1.93 (m, 2H), 2.12-2.16 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.10 (s, 3H), 3.61-3.67 (m, 2H), 4.24-4.30 (m, 2H), 5.38-5.40
(m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 3.6 Hz, 1H), 7.03 (d, J 7.6 Hz, 1H), 7.74-
7.78 (m, 1H), 7.79-7.82 (m, 2H), 8.19 (s, 2H), 8.29 (d, J = 1.2 Hz, 1H), 8.35 (d, J = 8.8 Hz,
1H); MS: 478 (M+l).
Example-118: N-( 1-(5-(( 1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- Hindol-
5-yl)pivalamide
The title compound was prepared by following the similar procedure as described in
Example-2 using r t-butyl 4-((6-(5-pivalamido-lH-indol-l-yl)pyridin-3-yl)oxy)piperidine-
1-carboxylate (intermediate 30).
NMR (400 MHz, CDC13) ; 1.2 (t, J = 7.6 Hz, 3H), 1.35 (s, 9H), 1.84-1.88 (m, 2H), 2.05-
2.10 (m, 2H), 2.47 (q, J = 7.6 Hz, 2H), 3.62-3.68 (m, 2H), 4.19-4.25 (m, 2H), 4.58-4.60 (m,
1H), 7.24-7.27 (m, 2H), 7.39-7.41 (m, 3H), 7.61 (d, J = 3.2 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H),
8.01 (d, J = 8.8 Hz, 1H), 8.19 (s, 2H), 8.26 - 8.27 (m, 1H); MS: 499 (M+l).
Example-119: N-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-6-(5-(methylsulfonyl)-lH-indol-
1-yl)pyridin-3 -amine
The title compound was prepared by following the similar procedure as described in
Example-2 using t rt-butyl 4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl) amino)-
piperidine-l-carboxylate (Intermediate 31).
NMR (400 MHz, CDC13) d; 1.19 (t, J = 7.6 Hz, 3H), 1.43-1.53 (m, 2H), 2.17-2.20 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.08 (s, 3H), 3.12-3.19 (m, 2H), 3.60 (bs, 1H), 3.77 (bs, 2H),
4.65-4.70 (m, 2H), 6.79 (dd, J 3.2, 0.8 Hz, 1H), 7.1 1 (dd, J = 8.8, 3.2 Hz, 1H), 7.29 (d, J
=8.4 Hz, 1H), 7.67 (d, J 3.6 Hz, 1H), 7.76 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J = 2.8 Hz,
1H), 8.06 (d, J = 8.8 Hz, 1H), 8.19 (s, 2H), 8.29 (d, J = 1.6 Hz, 1H); MS: 477(M+1).
Example-120: N-(l-(3-Isopropyl-l ,2,4-oxadiazol-5-yl)piperidin-4-yl)-6-(5-(methyl
sulfonyl)- 1H-indol- 1-yl)pyridin-3 -amine
The title compound was prepared by following the similar procedure as described in
Example-4 using t rt-butyl 4-((6-(5 -(methylsulfonyl)- 1H-indol- l-yl)pyridin-3 -yl)amino)-
piperidine-l-carboxylate (intermediate 31).
NMR (400 MHz, CDC13) d; 1.29 (d, J = 6.8 Hz, 6H), 1.53-1.54 (m, 2H), 2.19-2.23 (m,
2H), 2.86-2.93 (m, 1H), 3.09 (s, 3H), 3.25-3.32 (m, 2H), 3.57-3.59 (m, 1H), 3.78 (d, J = 8.0
Hz, 1H), 4.19-4.15 (m, 2H), 6.80 (dd, J = 3.2, 0.4 Hz, 1H), 7.1 1 (dd, J = 8.8, 3.2 Hz, 1H),
7.30 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 1H), 8.00 (d, J = 2.8
Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H); MS: 481 (M+l).
Example-121: N-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-6-(5-(methylsulfonyl)-indolin-lyl)
pyridin-3 -amine
The title compound was prepared by following the similar procedure as described in
Example-2 using r t-butyl 4-((6-(5-(methylsulfonyl)indolin-l-yl)pyridin-3-yl)amino)-
piperidine-1 -carboxylate. (Intermediate 32).
NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.2 Hz, 3H), 1.39-1.45 (m, 2H), 2.15-2.19 (m,
2H), 2.49 (q, J = 7.6 Hz, 2H), 3.04 (s, 3H), 3.10-317(m, 2H), 3.25 (t, J = 8.8 Hz, 2H), 3.40
(bs, 1H), 3.54 (bs, 1H), 4.12 (t, J = 8.8 Hz, 2H), 4.66-4.69 (m, 2H), 6.79 (d, J 8.8 Hz, 1H),
7.07 (dd, J = 8.8, 2.8 Hz, 1H), 7.64 (s, 1H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H), 7.91 (d, J 2.4
Hz, 1H), 8.02 (d, J =8.8 Hz, 1H), 8.20 (s, 2H); MS: 479 (M+l).
Example-122: tert-Butyl-4-(((6-(5 -isobutyramido- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-
methyl)piperidine- 1-c rboxylate
The title compound was prepared by following the similar procedure as described in
Example- using N-(lH-indol-5-yl)isobutyramide (intermediate 10) and rt-butyl 4-(((6-
chloropyridin-3-yl)oxy)methyl)piperidine-l -carboxylate (intermediate 29).
NMR (400 MHz, CDC13) d; 1.28 (d, J = 6.8 Hz, 6H), 1.47 (s, 9H), 1.83-1.86 (m, 2H),
1.96-2.04 (m, 1H), 2.49-2.56 (m, 1H), 2.76 (bs, 2H), 3.89 (d, J = 6Hz, 2H), 4.09-4.18 (m,
2H), 6.63 (d, J =3.2Hz, 1H), 7.23-7.28 (m, 2H), 7.33-7.39 (m, 2H), 7.59 (d, J =3.6 Hz, 1H),
7.94-7.98 (m, 2H), 8.21 (d, J =2.4 Hz, 1H); MS: 448 (M+l).
Example-123: N-(l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5-yl)isobutyramide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 114.
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.29 (d, J = 6.8 Hz, 6H), 1.83-1.90
(m, 2H), 2.04-2.10 (m, 2H), 2.44-2.57 (m, 3H), 3.62-3.68 (m, 2H), 4.19-4.25 (m, 2H), 4.57-
4.60 (m, IH), 6.63 (d, J = 3.2 Hz, IH), 7.21 (s, IH), 7.40 (s, 2H), 7.61 (d, J = 3.2 Hz, IH),
7.96 (d, J = 2 Hz, IH), 8.00 (d, J =8.8 Hz, IH), 8.19 (s, 2H), 8.26 (bs, IH); MS: 485 (M+1).
Example-124: N-(l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-lHindol-
5-yl)isobutyramide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 122.
NMR (400 MHz, CDC13) d; 1.18 (t, J = 7.6 Hz, 3H), 1.28 (d, J = 6.8 Hz, 6H), 1.33-1.43
(m, 2H), 1.94-1.97 (m, 2H), 2.10-2.16 (m, IH), 2.43-2.56 (m, 3H), 2.89-2.96 (m, 2H), 3.92
(d, J =6.4 Hz, 2H), 4.78-4.81 (m, 2H), 6.62 (d, J =3.6 Hz, IH), 7.21 (s, IH), 7.24 - 7.27 (m,
IH), 7.36-7.39 (m, 2H), 7.59 (d, J = 3.6 Hz, IH), 7.95-7.96 (m, IH), 7.98 (s, IH), 8.81 (s,
2H), 8.22 (d, J =2.0 Hz, IH); MS: 499 (M+1).
Example-125: tert-Butyl- 4-((6-(5-isobutyramidoindolin-l-yl)pyridin-3-yl)oxy)-piperidine-
1-carboxylate.
The title compound was prepared by following the similar procedure as described in
Example- 1 using t rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate 6) and N-(indolin-5-yl)isobutyramide (intermediate 50) (0.0 17g, 14%).
NMR (400 MHz, DMSO-d 6) d; 1.07 (d, J = 7.2 Hz, 6H), 1.40 (s, 9H), 1.46-1.55 (m, 2H),
1.85-1.90 (m, 2H), 2.52-2.54 (m, 1H), 3.1 1-3.15 (m, 4H), 3.64-3.69 (m, 2H), 3.91-3.96 (m,
2H), 4.42-4.46 (m, 1H), 6.78 (d, J = 9.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (dd, J =
8.8, 2.8 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 3.2 Hz, 1H),
9.62 (s, 1H); MS: 481 (M+l).
Example-126: Isopropyl 4-(((6-(5-isobutyramido-lH-indol-l-yl)pyridin-3-yl)oxy)
methyl)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-122 (0.023 g, 10%).
1H NMR (400 MHz, CDC13) d; 1.24-1.36 (m, 14H), 1.88-1.84 (m, 2H), 2.01-2.04 (m, 1H),
2.50-2.56 (m, 1H), 2.77-2.83 (m, 2H), 3.90 (d, J = 6.4 Hz, 2H), 4.23 (bs, 2H), 4.90-4.96 (m,
1H), 6.63 (d, J = 3.2 Hz, 1H), 7.22-7.28 (m, 2H), 7.33-7.39 (m, 2H), 7.60 (d, J = 3.2 Hz, 1H)
7.94-7.98 (m, 2H), 8.21 (d, J =2.4 Hz, 1H); MS: 479 (M+l).
Example-127: N-(l-(5-((l-Isobutyrylpiperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-yl)
isobutyramide
To a stirred solution of Example-1 14 (0.135 g, 0.282 mmol) in dichloromethane (5 mL),
trifluoroacetic acid ( 1 mL) was added at 0°C and stirred for 2-3 h. The reaction mixture was
concentrated in vacuo and the resultant residue was dissolved in anhydrous DMF (5 mL),
DIPEA (0.145 mL, 0.846 mmol), 0-Benzotriazole-N,N,N',N'-tetramethyl-uroniumhexafluoro-
phosphate (0.213 g, 0.564 mmol), isobutyric acid (0.026 mL, 0.564 mmol) were
added and stirred at room temperature for 18h. The reaction was quenched with water and the
organic layer was extracted with ethyl acetate, combined organic layers were dried over
Na S0 4, filtered and concentrated in vacuo. The resultant residue was purified by flash
column chromatography to give N-(l-(5-((l-isobutyrylpiperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5-yl)isobutyramide (0.035g, 26.6%).
NMR (400 MHz, CDC13) ; 1.15 (d, J = 6.8 Hz, 6H), 1.29 (d, J = 6.8 Hz, 6H),_1.86 (bs,
2H), 2.0-2.01 (m, 2H), 2.50-2.55 (m, 1H), 2.81-2.87 (m, 1H), 3.49 (bs, 1H), 3.64-3.70 (m,
1H), 3.79-3.86 (m, 2H), 4.58-4.61(m, 1H), 6.64 (d, J = 3.2 Hz, 1H), 7.20 (s, 1H), 7.29 (d, J =
2.0 Hz, 1H), 7.39-7.40 (m, 2H), 7.61 (d, J = 3.2 Hz, 1H), 7.95 (d, J = 2Hz, 1H), 8.01 (d, J =
8.8 Hz, 1H), 8.24-8.25 (m, 1H); MS: 449 (M+l).
ExampIe-128: 2-Chloro-l-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidin- 1-yl)ethanone
To a stirred solution of example-1 (0.375g, 0.212mmol) in dichloromethane (5 mL)
trifluoroacetic acid (0.5 mL) was added at 0°C and stirred at room temperature for 2-3h. The
solvent was removed in vacuo, the resultant residue was dissolved in dichloromethane (3ml),
triethylamine (0.165ml, 1.190mmol) and chloroacetyl chloride (0.063ml, 0.793mmol) were
added and stirred at room temperature for 2h. The reaction mixture was diluted with
dichloromethane (25ml) and washed with water (10ml). The organic layer was separated,
concentrated under reduced pressure and the resultant residue was purified by flash column
chromatography to give 2-chloro-l-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidin-l-yl)ethanone (0.240 g, 67%).
NMR (400 MHz, CDC13) ; 2.00-2.15 (m, 4H), 3.1 1 (s, 3H), 3.56-3.61 (m, 1H), 3.77-3.83
(m, 3H), 4.13-4.16 (m, 2H), 4.69-4.72 (m, 1H), 6.85 (d, J = 3.2 Hz, 1H), 7.43-7.49 (m, 2H),
7.75 (d, J = 3.2 Hz, 1H), 7.82 (dd, J = 7.2, 1.6 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.32 (d, J =
1.6 Hz, 1H); MS: 448 (M+) .
Example-129: N-(l-(5-((l-(2,2,2-Trifluoroacetyl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-
5-yl)isobutyramide
To a stirred solution of Example-1 17 (0.1 5g, 0.313mniol) in dichloromethane (5 mL),
trifluoroacetic acid (2 mL) was added at 0°C and stirred at room temperature for lh. The
reaction mixture was concentrated in vacuo, the resultant residue was dissolved in dry
dichloromethane (5 mL), triethylamine (0.174 mL, 1.252 mmol) and trifluoroacetic
anhydride (0.048 mL, 0.313 mmol) were added at 0°C and stirred for lhr. The reaction was
quenched with water and the organic layer was extracted with dichloromethane. The organic
layer was separated, concentrated in vacuo, and the residue obtained was purified by flash
column chromatography to give N-(l-(5-((l-(2,2,2-trifluoroacetyl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)isobutyramide .
NMR (400 MHz, CDC13) d; 1.28 (d, J = 6.8 Hz, 6H), 1.99-2.02 (m, 4H), 2.50-2.55 (m,
1H), 3.65-3.81 (m, 3H), 3.89-3.94 (m, IH), 4.66-4.68 (m, 1H), 6.64 (d, J - 3.2 Hz, 1H), 7.23
(s, 1H), 7.28 (dd, J 8.8, 2.0 Hz, 1H), 7.37-7.40 (m, 2H), 7.60 (d, J = 3.2 Hz, 1H), 7.95 (d, J
= 2.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H); MS: 475 (M+l).
Example-130: ter t-Butyl-4-((6-(5-(cyclopropanecarboxamido)-lH-indol-l-yl)pyridine-3-
yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example-1 using N-(lH-indol-5-yl)cyclopropanecarboxamide (intermediate-02) and tertbutyl
4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate (intermediate- 06).
NMR (400 MHz, CDC13) d; 0.82-0.85 (m, 2H), 1.08-1.12 (m, 2H), 1.23-1.27 (m, 1H),
1.47 (s, 9H), 1.77-1.82 (m, 2H), 1.95-1.99 (m, 2H), 3.32-3.39 (m, 2H), 3.70-3.77 (m, 2H),
4.50-4.52 (m, 1H), 6.62 (d, J = 3.2 Hz, 1H), 7.28 (s, 1H), 7.38 (s, 2H), 7.44 (s, 1H), 7.59 (d, J
= 3.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 8.23 (bs, 1H); MS: 477
(M+l).
Example-131: t rt-Butyl-4-((6-(5-((isopropoxycarbonyl)amino)-lH-indol-l-yl)- pyridin-3-
yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate- 06) and Isopropyl lH-indol-5-ylcarbamate (intermediate 78).
NMR (400 MHz, CDC13) d; 1.31 (d, J = 6.0 Hz, 6H), 1.57 (s, 9H), 1.77-1.83 (m, 2H),
1.95-2.00 (m, 2H), 3.30-3.39 (m, 2H), 3.71-3.77 (m, 2H), 4.49-4.53 (m, 1H), 5.02-5.05 (m,
1H), 6.55 (bs, 1H), 6.62 (dd, J = 3.6, 0.8 Hz, 1H), 7.17 (dd, J = 8.8, 2.0 Hz, 1H), 7.38-7.38
(m, 2H), 7.60 (d, J =3.2 Hz, 1H), 7.75 (bs, 1H), 7.99 (d, J =8.8 Hz, 1H), 8.22-8.23 (m, 1H);
MS: 495 (M+l).
Example-132: Isopropyl (l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-
lH-indol-5-yl)carb
The title compound was prepared by following the similar procedure as described in
Example- 2 by using Example-131.
NMR (400 MHz, CDC13) d; 1.19 (t, J = 7.6 Hz, 3H), 1.31 (d, J = 6.4 Hz, 6H), 1.83-1.88
(m, 2H), 2.05-2.10 (m, 2H), 2.47 (q, J = 7.6 Hz, 2H), 3.62-3.68 (m, 2H), 4.19-4.25 ( , 2H),
4.58-4.61 (m, 1H), 5.01-5.07 (m, 1H), 6.56 (bs, 1H), 6.62 (d, J =3.2 Hz, 1H), 7.17 (d, J =8.8
Hz, 1H), 7.40 (s, 2H), 7.60 (d, J = 3.6 Hz, 1H), 7.76 (bs, 1H), 7.99 (d, J = 8.8 Hz, 1H), 8.19
(s, 2H), 8.26(s, 1H); MS: 395.48 (M-100).
Example-133 : rt-Butyl- 4-((6-(5 -(N-methylisobutyramido)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)piperidine-l -carboxylate
To a solution of Example-131 (0.05g, 0.104mmol) in anhydrous DMF (10 mL), sodium
hydride (0.006 g, 0.216 mmol) and methyl iodide (0.022 g, 0.156 mmol) were added at 0°C
and stirred at 60°C for 4-5h. The reaction was quenched with water and the organic layer was
extracted with ethyl acetate. The organic layer was separated, concentrated in vacuo and the
resultant residue was purified by flash column chromatography to give tert-butyl 4-((6-(5-(Nmethylisobutyramido)-
1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-carboxylate (0.02 1g,
41%).
Ή NMR (400 MHz, CDC13) d; 1.02 (d, J = 6.8 Hz, 6H), 1.48 (s, 9H), 1.60-1.83 (m, 2H),
1.96-2.02 (m, 2H), 2.56-2.60 (m, 1H), 3.30 (s, 3H), 3.34-3.44 (m, 2H), 3.71-3.77 (m, 2H),
4.53-4.55 (m, 1H), 6.70 (d, J 3.2Hz, 1H), 7.70 (dd, J 8.8, 2.0 Hz, 1H), 7.41 (d, J = 1.6
Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.26-
8.26 (m, 1H); MS: 493 (M+l).
Example-134: Isopropyl (1-(5 -((1-(3 -isopropyl- 1,2,4-oxadiazol-5 -yl)piperidin-4-yl)oxy)
pyridin-2-yl)-lH-indol-5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-131.
NMR (400 MHz, CDC13) d; 1.25-1.30 (m, 12H), 1.93-1.99 (m, 2H), 2.03-2.08 (m, 2H),
2.85-2.92 ( , 1H), 3.60-3.67 (m, 2H), 3.80-3.87 (m, 2H), 4.58-4.60 (m, 1H), 5.00-5.03 (m,
1H), 6.54 (s, 1H), 6.61 (dd, J =3.2, 0.4 Hz, 1H), 7.35-7.38 (m, 2H), 7.58 (d, J =3.2 Hz, 1H),
7.74 (bs, 1H), 7.98 (d, J =8.8 Hz, 1H), 8.22-8.23 (m, 1H); MS: 505 (M+l).
Example-135: N-(l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5-yl)-N-methylisobutyramide
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 133.
NMR (400 MHz, CDC13) ; 1.01 (d, J = 6.8 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.84-1.90
(m, 2H), 2.05-2.1 (m, 2H), 2.47 (q, J = 7.6 Hz, 2H), 2.56-2.59 (m, IH), 3.29 (s, 3H), 3.63-
3.69 (m, 2H), 4.18-4.24 (m, 2H), 4.59-4.63 (m, IH), 6.69 (d, J = 3.6 Hz, IH), 7.06 (dd, J =
8.8, 2.4 Hz, IH), 7.39-7.45 (m, 3H), 7.65 (d, J = 3.2 Hz, IH), 8.09 (d, J = 8.8 Hz, IH), 8.19
(s, 2H), 8.28 (d, J = 2.0 Hz, IH); MS: 499 (M+l).
Example-136: tert-Butyl-4-((6-(5-(isopropylcarbamoyl)indolin-l-yl)pyridin-3-yl)-oxy)
piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate 06) and N-isopropylindoline-5-carboxamide (Intermediate 64).
NMR (400 MHz, CDC13) ; 1.26 (d, J = 6.4 Hz, 6H), 1.48 (s, 9H), 1.71-1.79 (m, 2H),
1.96-1.96 (m, 2H), 3.23 (t, J = 8.8 Hz, 2H), 3.28-3.34 (m, 2H), 3.76-3.77 (m, 2H), 4.07 (t, J =
8.8 Hz, 2H), 4.24-4.31 (m, IH), 4.33-4.36 (m, IH), 5.81 (d, J = 7.6 Hz, IH), 6.78 (d, J = 8.8
Hz, IH), 7.29 (d, J = 3.2 Hz, IH), 7.54 (dd, J = 8.4, 1.6 Hz, IH), 7.62 (s, IH), 8.05 (d, J = 8.4
Hz, IH), 8.01 (d, J = 3.2 Hz, IH); MS: 481 (M+l).
Example-137: Isopropyl (l-(5-((l-(3-methyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)
pyridin-2-yl)- 1H-indol-5-yl)carbamate
Example- 137 was prepared according to procedure described in Example-4 by using
Example-131
NMR (400 MHz, CDC13) ; 1.30 (d, J = 6.4 Hz, 6H), 1.95-2.01 (m, 2H), 2.03-2.09 (m,
2H), 2.22 (s, 3H), 3.62-3.69 (m, 2H), 3.80-3.87 (m, 2H), 4.61-4.62 (m, 1H), 5.01-5.04 ( ,
1H), 6.55 (bs, 1H), 6.62 (d, J = 3.2 Hz, 1H), 7.16 (dd, J = 8.8, 1.6 Hz, 1H), 7.39 (s, 2H), 7.59
(d, J = 3.6 Hz, 1H), 7.74 (bs, 1H), 7.99 (d, J = 8.8 Hz, H), 8.23 (m, 1H); MS: 477 (M+l).
Example-138: t rt-Butyl-4-(((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)methyl)
amino)piperidine-l -carboxylate.
The title compound was prepared by following the similar procedure as described in
example- 1 using 5-(methylsulfonyl)-lH-indole (intermediate 21) and tert-butyl-4-(((6-
chloropyridin-3-yl)methyl)amino)piperidine- 1-carboxylate (intermediate 79).
1H NMR (400 MHz, CDC13) d; 1.31-1.34 (m, 2H), 1.46 (s, 9H), 1.89-1.92 (m, 2H), 2.69-2.74
(m, 1H), 2.80-2.86 (m, 2H), 3.09 (s, 3H), 3.92 (s, 2H), 4.05 (bs, 2H), 6.85 (d, J = 3.2Hz,
1H),7.46 (d, J = 8.4 Hz, 1H), 7.79-7.83 (m, 2H), 7.91 (dd, J = 8.4, 2.0 Hz, 1H), 8.29 (d, J =
1.6 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H); MS: 429 (M-56).
Example-139: l-(5-Ethylpyrimidin-2-yl)-N-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-
3-yl)methyl)piperidin-4-amine
The title compound was prepared by following the similar procedure as described
Example- 2 by using Example-138.
NMR (400 MHz, CDC13) d; 1.16 (t, J = 7.6 Hz, 3H), 1.20-1.28 (m, 2H), 2.02-2.1 1 (m,
2H), 2.43 (q, J = 7.6 Hz, 2H), 2.61-2.66 (m, 2H), 2.81-2.91 (m, 2H), 3.05 (s, 3H), 4.04 (s,
2H), 4.70-4.73 (m, 2H), 6.78 (d, J = 3.2 Hz, IH), 7.43 (d, J = 8.0 Hz, IH), 7.75-7.79 (m, 2H),
8.09-8.14 (m, 2H), 8.21 (s, IH), 8.41-8.45 (m, 2H), 8.63 (s, IH); MS: 491 (M+1).
Example-140: Ethyl (l-(5-((l-(3-methyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy) pyridin-2-
yl)- 1H-indol-5-yl)carb
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example- 8.
NMR (400 MHz, CDC13) d; 1.31 (t, J = 7.2Hz, 3H), 1.95-1.99 (m, 2H), 2.04-2.09 (m,
2H), 2.22 (s, 3H), 3.63-3.69 (m, 2H), 3.80-3.86 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 4.62 (bs,
IH), 6.23-6.63 (m, 2H), 7.16-7.18 (m, IH), 7.39 (s, 2H), 7.59 (d, J = 3.6 Hz, IH), 7.74 (bs,
IH), 7.99 (d, J = 8.8 Hz, IH), 8.23 (s, IH); MS: 463 (M+1).
Example-141: Ethyl (l-(5-((l-(3-isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy) pyridin-
2-yl)-lH-indol-5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example-8
Ή NMR (400 MHz, CDC13) ; 1.30-1.36 (m, 9H), 1.97-2.03 (m, 2H), 2.06-2.13 (m, 2H),
2.90-2.93 (m, IH), 3.64-3.70 (m, 2H), 3.84-3.90 (m, 2H), 4.26 (q, J = 7.2 Hz, 2H), 4.62-4.64
(m, IH), 6.62 (bs, IH), 6.65 (d, J 3.6 Hz, IH), 7.20 (d, J = 7.6 Hz, IH), 7.39-7.44 (m, 2H),
7.62 (d, J = 3.6 Hz, IH), 7.77 (bs, IH), 8.02 (d, J = 8.8 Hz, IH), 8.26 (bs, IH); MS: 491
(M+1).
Example-142: Ethyl (l-(5-((l-(3-ethyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-
yl)-lH-indol-5- yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example- 8.
NMR (400 MHz, CDC13) ; 1.26-1.34 (m, 6H), 1.97-2.00 (m, 2H), 2.05 -2.09 (m, 2H),
2.59 (q, J = 7.6 Hz, 2H), 3.64-3.69 (m, 2H), 3.82-3.85 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H),
4.61-4.63 (m, 1H), 6.60 (bs, 1H), 6.63 (d, J = 3.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.39-7.40
(m, 2H), 7.60 (d, J 3.2 Hz, 1H), 7.75 (bs, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.24-8.25 (m, 1H);
MS: 477 (M+1).
Example-143: Isopropyl (l-(5-((l-(3-ethyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy) pyridin-
2-yl)- 1H-indol-5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 131.
NMR (400 MHz, CDC13) d; 1.23-1.31 (m, 9H), 1.95-1.96 (m, 2H), 1.97-2.01 (m, 2H),
2.03-2.10 (m, 2H), 2.30 (q, J = 7.6 Hz, 2H), 3.62-3.68 (m, 2H), 3.81-3.87 (m, 2H), 4.60-4.63
(m, 1H), 4.99-5.04 (m, 1H), 6.55 (bs, 1H), 6.62 (d, J = 3.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H),
7.39-7.39 (m, 2H), 7.59 (d, J = 3.6 Hz, 1H), 7.74 (bs, 1H), 7.99 (d, J - 8.8 Hz, 1H); MS: 491
(M+l).
Example-144: 3-Ethyl-5 -(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 using Example- 1.
NMR (400 MHz, CDC13) d; 1.32 (t, J = 7.6 Hz, 3H), 1.99-2.05 (m, 2H), 2.08-2.16 (m,
2H), 2.61 (q, J = 7.6 Hz, 2H), 3.10 (s, 3H), 3.67-3.73 (m, 2H), 3.84-3.91 (m, 2H), 4.68-4.71
(m, 1H), 6.85 (d, J = 3.2 Hz, 1H), 7.46-7.46 (m, 2H), 7.74 (d, J = 3.6 Hz, 1H), 7.82 (dd, J =
8.8, 1.6 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.31-8.31 (m, 2H); MS: 468 (M+l).
Example-145: 5-(4-((6-(5-(Ethylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)piperidin-l-yl)-3-
methyl-1 ,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 10.
NMR (400 MHz, CDC13) d; 1.26 (t, J = 7.6 Hz, 3H), 1.96-2.02 (m, 2H), 2.06-2.1 1 (m,
2H), 2.22 (s, 3H), 3.13 (q, J = 7.6 H, 2H), 3.64-3.70 (m, 2H), 3.81-3.87 (m, 2H), 4.64-4.67
(m, 1H), 6.81 (d, J = 3.2 Hz, 1H), 7.40-7.45 (m, 2H), 7.70 (d, J = 3.2 Hz, 1H), 7.74 (dd, J =
8.4, 1.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 1.2 Hz, 1H).
Example-146: 3-Ethyl-5-(4-((6-(5-(ethylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described
Example- 18 by using Example- 10.
Ή NMR (400 MHz, CDC13) d; 1.23-1.29 (m, 6H), 1.99-2.01 (m, 2H), 2.06-2.10 (m, 2H),
2.58 (q, J = 7.6 Hz, 2H), 3.14 (q, J = 7.2 Hz, 2H), 3.64-3.70 (m, 2H), 3.82-3.88 (m, 2H),
4.66-4.67 (m, 1H), 6.82 (d, J = 3.6 Hz, 1H), 7.41-7.46 (m, 2H), 7.70 (d, J = 3.6 Hz, 1H), 7.75
(dd, J = 8.8, 2.0 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.29 (m, 1H);
MS: 467.1 (M+l).
ExampIe-147: l-(5-((l-(3-Ethyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described
Example-4 by using Example-39.
NMR (400 MHz, CDC13) d; 1.28 (t, J = 7.6 Hz, 3H), 2.00-2.02 (m, 2H), 2.05-2.12 (m,
2H), 2.59 (q, J = 7.6 Hz, 2H), 3.09 (bs, 6H), 3.64-3.70 (m, 2H), 3.82-3.89 (m, 2H), 4.63-4.65
(m, 1H), 6.72 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 8.4, 1.2Hz, 1H), 7.42-7.43 (m, 2H), 7.65 (d, J
= 3.2 Hz, 1H), 7.75 (d, J 1.2 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.27-8.28 (m, 1H); MS: 461
(M+l).
Example-148: l-(5-((l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-pyridin-2-yl)-
N,N-dimethyl- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described
Example-4 by using Example-39.
Ή NMR (400 MHz, DMSO-d 6) d; 1.19 (d, J = 6.8 Hz, 6H), 1.73-1.80 (m, 2H), 2.06-2.1 1 (m,
2H), 2.08-2.84 (m, 1H), 2.99 (s, 6H), 3.47-3.54 (m, 2H), 3.79-3.85 (m, 2H), 4.78-4.80 (m,
1H), 6.78 (d, J = 3.2 Hz, 1H), 7.29 (dd, J = 8.8, 1.6 Hz, 1H), 7.70-7.73 (m, 3H), 8.00 (d, J =
3.6 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.36-8.36 (m, 1H); MS: 475 (M+l).
Example-149: Ethyl (l-(5-((l-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)
pyridin-2-yl)-lH-indol-5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example- 4 by using Example-8.
•H NMR (400 MHz, CDC13) d; 0.93-0.97 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H), 1.86-1.89 (m,
1H), 1.95-1.97 (m, 2H), 2.02-2.06 (m, 2H), 3.59-3.65 (m, 2H), 3.79-3.84 (m, 2H), 4.24 (q, J
= 7.2 Hz, 2H), 4.60-4.61(m, 1H), 6.59 (bs, 1H), 6.63 (d, J = 3.6 Hz, 1H), 7.17-7.20 (m, 1H),
7.37-7.42 (m, 2H), 7.60 (d, J = 3.6 Hz, 1H), 7.74 (bs, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.24 (m,
1H); MS: 489 (M+l).
Example-150: 7V-(2-Hydroxyethyl)-l -(5-((l -(3-isopropyl-l ,2,4-oxadiazol-5-yl)piperidin-4-
yl)oxy)pyridin-2-yl)-lH-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-76.
NMR (400 MHz, CDC13) d; 1.31 (d, J = 6.8 Hz, 6H), 1.98-2.04 (m, 2H), 2.07-2.14 (m,
2H), 2.88-2.93 (m, 1H), 3.65-3.71 (m, 4H), 3.84-3.90 (m, 4H), 4.65-4.67 (m, 1H), 6.71-6.73
(m, 1H), 6.77 (d, J = 3.2 Hz, 1H), 7.45 (s, 2H), 7.68 (d, J = 3.6 Hz, 1H), 7.73 (dd, J = 8.8, 1.6
Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.29-8.30 (m, 1H); MS: 491
(M+l).
Example-151: (±)-l-(5-((l-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-N-(2-
hydroxyethyl)- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example-2 using (±)-tert-butyl 3-((6-(5-((2-hydroxyethyl)carbamoyl)-lH-indol-l-yl)pyridin-
3-yl)oxy)pyrrolidine- 1-carboxylate (intermediate-33).
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 2.32-2.38 (m, 2H), 2.49 (q, J = 7.6
Hz, 2H), 2.96 (bs, 1H), 3.66-3.70 (m, 2H), 3.74-3.81 (m, 1H), 3.86-3.99 (m, 5H), 5.13-5.14
(m, 1H), 6.70-6.75 (m, 2H), 7.38-7.43 (m, 2H), 7.66 (d, J = 3.2 Hz, 1H), 7.72 (dd, J = 8.4,
1.6 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 8.22-8.26 (m, 3H); MS: 473.1 (M+l).
Example-152: (±)-3-Ethyl-5-(3-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
pyrrolidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described
Example-4 by using Example-24.
H NMR (400 MHz, CDC13) d; 1.30 (t, J = 7.6 Hz, 3H), 2.34-2.38 (m, 1H), 2.45-2.46 (m,
1H), 2.62 (q, J = 7.6 Hz, 2H), 3.1 1 (s, 3H), 3.82-3.90 (m, 2H), 3.93-3.94 (m, 2H), 5.15-5.17
(m, 1H), 6.85-6.86 (m, 1H), 7.41-7.47 (m, 2H), 7.74 (d, J = 3.6 Hz, 1H), 7.82 (dd, J = 8.8, 1.6
Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.28 (dd, J = 2.8, 0.8 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H);
MS: 454.23 (M+l).
(±)-3 -ethyl-5 -(3 -((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)pyrrolidin- 1-yl)-
1,2,4-oxadiazole was purified into its enantiomers via preparatory HPLC utilizing a
CHIRAL CEL OJ-H 250 X 30 mm, with mobile phase (MeOH: 85% CH3CN: 15 %) at a
Flow rate of 50mL/min wavelength for monitoring the separation was 210nm.
Isomer 1 RT = 8.85 min. and isomer 2 RT = 9.96 min.
Example-153: 5-(Methylsulfonyl)- 1-(5 -((l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)
oxy)pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example- 82 by using Example- 1 and 4-(trifluoromethyl)benzaldehyde.
NMR (400 MHz, CDC13) d 1.93-1.94 ( m, 2H), 2.03-2.08 ( m, 2H), 2.33-2.38 ( m, 2H),
2.76 ( bs, 2H), 3.08 (s, 3H), 3.60 (s, 2H), 4.41-4.44 ( , 1H), 6.82 (d, J = 3.6 Hz, 1H), 7.38-
7.48 (m, 4H), 7.58 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 3.2 Hz, 1H), 7.79 (dd, J = 8.8, 1.6
Hz,IH), 8.16-8.19 (m, 1H), 8.26-8.29 (m, 2H); MS: 529 (M+l).
Example-154: rt-Butyl-4-((6-(5-methoxy-l H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidine-lcarboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine- 1-carboxylate
(intermediate-06) and 5-methoxy-l H-indole (0.085g, 20 %).
NMR (400 MHz, CDC13) ; 1.49 (s, 9H), 1.79-1.84 (m, 2H), 1.96-2.02 (m, 2H), 3.35-
3.41 (m, 2H), 3.71-3.78 (m, 2H), 3.89 (s, 3H), 4.51-4.53 (m, 1H),6.63 (d, J = 3.2Hz, 1H),
6.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.13 (d J = 2.4 Hz, 1H), 7.37-7.42 (m, 2H),7.60-7.6 (d, J
3.2 Hz,IH) 7.99 (d, J = 9.2 Hz, 1H), 8.24-8.25 (m, 1H); MS: 424 (M+l).
Example-155: (±)-3 -Isopropyl-5 -(3 -((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)pyrrolidin-l-yl)-l,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example-24.
NMR (400 MHz, CDC13) d; 1.31 (d, J = 6.8 Hz, 6H), 2.34-2.38 (m, 1H), 2.44-2.45 (m,
1H), 2.90-2.97 ( , 1H), 3.1 1 (s, 3H), 3.81-3.90 (m, 2H), 3.91-3.94 (m, 2H), 5.15-5.16 (m,
1H), 6.85 (d, J = 3.6 Hz, 1H), 7.41-7.47 ( , 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.83 (dd, J = 8.8,
1.6 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H); MS:
468.1 (M+l).
Example- 155 was purified into its enantiomers via preparatory HPLC utilizing a CHIRAL IA
250 x 30 mm, with mobile phase (MeOH: 90% CH3CN: 10 %) at a Flow rate of 60mL/min
wavelength for monitoring the separation was 210nm. isomer 1 RT = 8.99 min. and isomer 2
RT = 11.20 min.
Example-156: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-methoxylH-
indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 154 (0.03 lg, 20%).
1H NMR (400 MHz, CDC13) ; 1.21 (t, J =7.6 Hz, 3H), 1.85-1.92 ( m, 2H), 2.06-2.12 ( m,
2H), 2.50 (q, J = 7.6 Hz, 2H), 3.64-3.71 ( , 2H), 3.89 (s, 3H), 4.21-4.27 (m, 2H), 4.60-4.62
(m, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.93 (dd, J =2.4, 9.2 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H),
7.42 ( bs, 2H), 7.61 (d, J = 3.2 Hz, 1H), 8.0 (d, J = 8.8 Hz, 1H), 8.21 ( bs, 2H), 8.28 (d, J =
2.0 Hz, 1H); MS: 430 (M+l).
Example-157: 1-(5-((l -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-methoxy-
1H-pyrrolo[2,3-b]pyridine
The title compound was prepared by following the similar procedure as described in
Example- 2 using t rt-Butyl-4-((6-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-3-
yl)oxy)-piperidine-l-carboxylate (intermediate-76) (0.03 lg, 20%).
NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.86-1.92 (m, 2H), 2.05-2.1 1 ( ,
2H), 2.50 (q, J = 7.6 Hz, 2H), 3.71 ( bs, 2H), 3.92 (s, 3H), 4.18-4.25 (m, 2H), 4.57 - 4.60 (m,
1H), 6.57 (d, J = 4.0 Hz, 1H), 7.45 (d, J =2.8 Hz, 1H), 7.47 (d, J = 2.8 Hz, 1H), 8.15 (d, J =
2.8 Hz, 1H), 8.20 (d, J = 3.2 Hz, 1H), 8.22 (d, J = 3.2 Hz, 3H), 8.69 (d, J = 8.8 Hz, 1H); MS:
431 (M+l).
Example-158: (±)-3-Ethyl-5-((3-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)
oxy)pyrrolidin-l-yl)methyl)-l,2,4-oxadiazole
The title compound was prepared according to procedure described in Example-79 by using
Example-24.
Ή NMR (400 MHz, CDC13) d; 1.37 (t, J = 7.6 Hz, 3H), 2.12-2.15 (m, 1H), 2.39-2.48 (m,
1H), 2.80 (q, J = 7.6 Hz, 2H), 2.84 (bs, 1H), 3.02-3.08 (m, 2H), 3.10 (s, 3H), 3.24-3.26 (m,
1H), 3.28 (s, 2H), 4.97 (m, 1H), 6.84 (d, J = 3.6Hz, 1H), 7.37-7.44 (m, 2H), 7.73 (d, J = 3.6
Hz, 1H), 7.80-7.82 (m, 1H), 8.19-8.23 (m, 2H), 8.31 (s, 1H); MS: 468.1 (M+l).
Example-159: (±)-3 -Isopropyl-5 -((3 -((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)pyrrolidin- 1-yl)methyl)- 1,2,4-oxadiazole
The title compound was prepared according to procedure described in Example-79 by using
Example-24.
Ή NMR (400 MHz, CDC13) d; 1.36 (d, J = 6.8 Hz, 6H), 2.1 1-2.15 (m, IH), 2.41-2.46 (m,
IH), 2.83-2.87 (m, IH), 3.02-3.07 (m, 2H), 3.10-3.16 (m, 4H), 3.21-3.25 (m, IH), 4.04 (s,
2H), 4.95-4.99 (m, IH), 6.83-6.84 (m, IH), 7.37-7.43 (m, 2H), 7.73 (d, J = 3.6 Hz, IH), 7.81
(dd, J = 8.8, 2.0 Hz, IH), 8.20 (d, J = 8.8 Hz, IH), 8.23 (d, J = 2.4 Hz, IH), 8.31 (d, J = 1.6
Hz, IH); MS: 481.9 (M+l).
Example-160: 3-Isopropyl-5 -((3 -((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)azetidin- 1-yl)methyl)- 1,2,4-oxadiazole
The title compound was prepared according to procedure described in Example-79 by using
Example-27.
NMR (400 MHz, CDC13) d; 1.36 (d, J = 6.8 Hz, 6H), 3.10 (s, 3H), 3.1 1-3.16 (m, IH),
3.45-3.52 (m, 2H), 3.99 (s, 2H), 4.07-4.10 (m, 2H), 4.93-4.99 (m, IH), 6.84-6.85 (m, IH),
7.32 (dd, J = 8.8, 2.8 Hz, IH), 7.73 (d, J = 3.6 Hz, IH), 7.81 (dd, J = 8.8, 1.6 Hz, IH),
8.16(d, J = 2.8 Hz, IH), 8.1 1 (d, J = 8.8 Hz, IH), 8.12 (d, J 8.8 Hz, IH), 8.31 (d, J = 1.6
Hz, IH); MS: 467.48 (M+l).
Example-161: 3-Ethyl-5-((3-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
azetidin- 1-yl)methyl)- 1,2,4-oxadiazole
The title compound was prepared according to procedure described in Example-79 by using
Example-27.
NMR (400 MHz, CDC13) d 1.35 (t, J = 7.6 Hz, 3H), 2.79 (q, J = 7.6 Hz, 2H), 3.10 (s,
3H), 3.45-3.49 (m, 2H), 3.99 (s, 2H), 4.07-4.10 (m, 2H), 4.95-4.98 (m, 1H), 6.84 (d, J = 3.2
Hz, 1H), 7.32 (dd, J = 8.8, 3.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 3.6 Hz, 1H),
7.81 (dd, J = 8.8, 2.0 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.31 (d, J=
1.6 Hz, 1H); MS: 454.23 (M+l).
Example-162: l-(5-((l-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2-
hydroxyethyl)- 1H-indole-5-carboxamide
The title compound was prepared by following the similar procedure as described in
Example- 1 using N-(2-hydroxyethyl)-lH-indole-5-carboxamide (intermediate- 19) and 2-
Chloro-5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridine (intermediate-54).
NMR (400 MHz, CDC13) d; 1.40 (d, J = 21.2 Hz, 6H), 1.90.(bs, 2H), 2.05 (bs, 2H), 2.47-
2.53 (m, 3H), 2.90-2.97 (m, 3H), 3.66-3.70 (m, 2H), 3.87-3.88 ( , 2H), 4.38 (bs, 1H), 6.71-
6.72 ( , 1H), 6.75 (d, J = 3.2 Hz, 1H), 7.41-4.41 (m, 2H),7.67 (d, J = 3.2 Hz, 1H), 7.72 (dd,
J = 8.8, 1.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.26-8.27 (m, 1H);
MS: 454.5 (M+l).
ExampIe-163: cis (±)-tert-Butyl-3-fluoro-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)-pyridin-
3-yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate 21) and cis(±)-tert-bu\y\-4-
((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-l-carboxylate (intermediate 7).
NMR (400 MHz, CDC13) d; 1.49 (s, 9H), 1.92 (bs, IH), 2.1 1-2.17 (m, IH), 3.09 (s, 3H),
3.41-3.50 (m, 2H), 3.73 (bs, 3H), 3.96-3.99 (m, IH), 6.83 (d, J = 3.6 Hz, IH), 7.43 (d, J = 8.8
Hz, IH), 7.51 (dd, J = 8.8, 2.8 Hz, IH), 7.73 (d, J = 3.2 Hz, IH), 7.80 (dd, J = 8.8, 1.6 Hz,
IH), 8.21 (d, J = 8.8 Hz, IH), 8.30 (d, J = 1.2 Hz, IH), 8.34 (d, J = 2.8 Hz, IH); MS: 490.2
(M+l).
Example-164: cis (±) (l-(5-(-l-(5-Ethylpyrimidin-2-yl)-3-fluoropiperidin-4-yl)oxy)
pyridin-2-yl)-5-(methylsulfonyl)-lH-indole.
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 163 (0.71 g, 46%);
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.97-2.01 (m, IH), 2.18-2.23 (m,
IH), 2.49 (q, J = 7.6 Hz, 2H), 3.09 (s, 3H), 3.82-3.85 (m, IH), 4.03-4.14 (m, 2H), 4.36-4.41
(m, IH), 4.69-4.75 (m, IH), 4.83-4.84 (m, 0.5H), 4.94-4.96 (m, 0.5H), 6.83 (d, J = 3.6 Hz,
IH), 7.44 (d, J = 8.8 Hz, IH), 7.55 (dd, J = 8.8, 3.2 Hz, IH), 7.73 (d, J = 3.6 Hz, IH), 7.81
(dd, J = 8.8, 1.6 Hz, IH), 8.21 (s, 2H), 8.23 (s, IH), 8.30 (d, J = 1.6 Hz, IH), 8.37 (s, IH);
MS: 496.2 (M+l).
C (±)(l-(5-(-l-(5-ethylpyrimidin-2-yl)-3-fluoropiperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)-lH-indole was purified into its enantiomers via preparatory HPLC utilizing
a Cellulose-1 250mmX21mm, Column No- CRL-023 with mobile phase (MeOH:85%
CH3CN 15 %) at a Flow rate of 21mL/min wavelength for monitoring the separation was
210nm. isomer 1 RT = 8.75 min. and isomer 2 RT = 9.89 min.
Example-165: t rt-Butyl-4-((6-(5-(2-oxooxazolidin-3-yl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar .procedure as described in
Example- 1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l-carboxylate
(intermediate-06) and 3-(lH-indol-5-yl)oxazolidin-2-one (intermediate-59) (0.390g, 63%).
NMR (400 MHz, CDC13) ; 1.49 (s, 9H), 1.83( bs, 2H), 1.99 ( bs, 2H), 3.35-3.41 (m,
2H), 3.74-3.78 (m, 2H), 4.13-4.18 (m, 2H), 4.50-4.54 (m, 3H), 6.68-6.71 (m, 1H), 7.42 (
bs, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.73 (bs, 1H), 8.07 (d, J = 9.2
Hz, 1H), 8.26 ( bs, 1H); MS: 423 (M-56).
Example-166: Isopropyl 4-((6-(5-(2-oxooxazolidin-3-yl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example- 165 (0.01 lg, 08%).
NMR (400 MHz, CDC13) d; 1.28 (d, J = 3.6 Hz, 6H), 1.84-1.86 (m, 2H), 2.00-2.02 (m,
2H), 3.41-3.47 (m, 2H), 3.77-3.81 (m, 2H), 4.14-4.18 (m, 2H), 4.51-4.57 (m, 3H), 4.94-4.97
(m, 1H), 6.68 (d, J = 3.6 Hz, 1H), 7.42 (bs, 2H), 7.52-7.55 (m, 1H), 7.66 (d, J = 3.6 Hz,
1H), 7.73 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.26 (bs, 1H); MS: 465 (M+l).
Example-167: tert-Butyl- 4-((6-(3 -methyl-5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example-1 by using t rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and 3-methyl-5 -(methylsulfonyl)- lH-indole (intermediate-23).
Ή NMR (400 MHz, CDC13) d; 1.47 (s, 9H), 1.77-1.85 (m, 2H), 1.96-2.01 (m, 2H), 2.41 (s,
3H), 3.09 (s, 3H), 3.34-3.40 (m, 2H), 3.71-3.77 (m, 2H), 4.51-4.55 (m, 1H), 7.35-7.43 (m,
2H), 7.50 (d, J = 0.8 Hz, 1H), 7.79 (dd, J = 8.8, 1.6 Hz, 1H), 8.18-8.25 (m, 3H); MS: 508.2
(M+23).
Example-168: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-3-methyl-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 167.
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.85-1.91 (m, 2H), 2.06-2.1 1 ( ,
2H), 2.41 (s, 3H), 2.48 (q, J = 7.6 Hz, 2H), 3.10 (s, 3H), 3.63-3.70 (m, 2H), 4.19-4.25 (m,
2H), 4.61-4.63 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.8, 2.8 Hz, 1H), 7.51 (d, J =
0.8 Hz, 1H), 7.79 (dd, J = 8.8, 2.0 Hz, 1H), 8.20 (d, J 8.0 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H),
8.28 (s, 1H); MS: 492.2 (M+l).
Example-169: Isopropyl 4-((6-(5-(methylsulfonyl)- 1H-indol- -yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example- 1 (0.01 1 g, 9%).
NMR (400 MHz, CDC13) d; 1.26 (d, J = 6.0 Hz, 6H), 1.80-1.84 (m, 2H), 1.98-2.02 (m,
2H), 3.09 (s , 3H), 3.40-3.48 (m, 2H), 3.74-3.80 (m, 2H), 4.54-4.60 (m, 1H), 4.91-4.97 (m,
1H), 6.68 (d, J = 3.2 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 2H), 7.72 (d, J = 3.6 Hz, 1H), 7.80
(dd, J = 8.8, 1.6 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.28 (dd, J = 3.6, 2.8 Hz, 2H); MS: 458
(M+l).
ExampIe-170: Isopropyl 4-((6-(7-fluoro-5-(methylsulfonyl)-l H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-91.
NMR (400MHz, CDC13) d; 1.28 (d, J = 6.4 Hz, 6H), 1.82-1.88 (m, 2H), 2.00-2.03 (m,
2H), 3.1 1 (s, 3H), 3.42-3.50 (m, 2H), 3.75-3.81 (m, 2H), 4.58-4.62 (m, IH), 4.92-4.98 (m,
IH), 6.86-6.88 (m, IH), 7.39-7.41 (m. 2H), 7.51 (dd, J = 11.6, 1.6 Hz, IH), 7.68 (d, J = 3.2
Hz, IH), 8.12 (d, J = 1.6 Hz, IH), 8.25 (s, IH); MS: 476.1 (M+l).
Example-171: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-7-fluoro -5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example- 2 by using Example-91 (0.01 lg, 22 %).
NMR (400 MHz, CDC13) d; 1.22 (t, J = 7.6 Hz, 3H), 1.93 (bs, 2H), 2.10-2.14 ( m, 2H),
2.51 (q, J = 8.0 Hz, 2H), 3.1 1 (s , 3H), 3.74 (bs , 2H), 4.22-4.25 ( m, 2H), 4.68 (bs, IH), 6.87
(d, J = 3.2 Hz, IH), 7.39-7.45 (m, 2H), 7.52 (dd, J = 11.6, 1.2 Hz, IH), 7.69 (d, J = 3.6 Hz,
IH), 8.13 (d, J =1.2 Hz, IH), 8.23 (bs, 2H), 8.27 (d, J = 2.8 Hz, IH); MS: 496 (M+l).
Example-1 2: 2,2,2-Trifluoro- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)
oxy)piperidin- -yl)ethanone
The title compound was prepared by following the similar procedure as described in
Example- 129 by using Example-1 .
NMR (400 MHz, CDC13) d; 2.01-2.1 1 (m, 4H), 3.1 1 (s, 3H), 3.70-3.79 (m, 2H), 3.81-3.93
(m, IH), 3.94-3.99 (m, IH), 4.72-4.77 (m, IH), 6.86 (dd, J = 3.2, 0.4 Hz, IH), 7.46-7.47 (m,
2H), 7.74 (d, J 3.6 Hz, IH), 7.83 (dd, J = 8.8, 2.0 Hz, IH), 8.23 (d, J = 8.8 Hz, IH), 8.32
(d, J = 1.6 Hz, 2H); MS: 467 (M+)
Example-173: tert-Butyl-4-((5-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-2-yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using 5-(methylsulfonyl)-lH-indole (intermediate 21) and ter t-butyl-4-((5-
bromopyridin-2-yl)oxy)piperidine-l -carboxylate ( intermediate 65) (0.610g, 46%).
1H NMR (400 MHz, CDC13) d; 1.51 ( s, 9H), 1.78-1.85 (m, 2H), 1.98-2.07 (m, 2H), 3.12 (s,
3H), 3.27-3.38 (m, 2H), 3.71-3.84 (m, 2H), 5.29-5.33 (m, IH), 6.87 (d, J =3.2 Hz, IH), 6.93
(d, J =8.4 Hz, IH), 7.41 (d, J =3.2 Hz, IH), 7.50 (d, J = 8.8 Hz, IH), 7.70 (dd, J = 8.8, 2.8
Hz, IH), 7.78 (dd, J = 8.8, 1.6 Hz, IH), 8.29 (d, J = 2.4 Hz, IH), 8.36 (d, J = 1.6 Hz, IH);
MS: 416 (M-56).
Example-174: l-(6-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-3-yl)-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-173 (0.0 11g, 21%).
NMR (400 MHz, CDC13) d; 1.19 (d, J = 7.6 Hz, 3H), 1.82-1.89 (m, 2H), 2.1 1-2.17 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.09 (s, 3H), 3.58-3.64 (m, 2H), 4.27-4.33 (m, 2H), 5.37-5.38
(m, IH), 6.84 (d, J = 3.2 Hz, IH), 6.91 (d, J =8.8 Hz, IH), 7.39 (d, J = 3.2 Hz, IH), 7.45 (d,
J = 8.4 Hz, IH), 7.68 (dd, J = 8.8, 2.8 Hz, IH), 7.76 (dd, J = 8.8, 2.0 Hz, IH), 8.19 (s, 2H),
8.28 (d, J = 2.8 Hz, IH), 8.34 (s, IH); MS: 478 (M+l).
Example-175: (4-((6-(5 -(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl) (1-
(trifluoromethyl)cyclopropyl)methanone
The title compound was prepared by following the similar procedure as described in
Example-23 by using Example- and l-(trifluoromethyl)cyclopropanecarboxylic acid
HNMR (400MHz, CDC13) d: 1.20-1.28 (m, 2H), 1.36-1.39 (m, 2H), 1.93-2.05 (m, 4H), 3.1 1
(s, 3H), 3.80-3.81 (m, 4H), 4.68-4.71 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 7.46 (d, J = 2.4 Hz,
2H), 7.74 (d, J =3.6 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.30-
8.32 (m, 2H); MS: 507.5 (M+l).
Example-176: 3-Isopropyl-5-(4-((5-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-2-yl)oxy)
piperidin- 1-yl)- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 173 (0.0 17g, 9%).
Ή NMR (400 MHz, CDC13) d; 1.29 (d, J = 6.8 Hz, 6H), 2.10-2.16 (m, 2H), 2.86-2.93 (m,
2H), 3.08 (s, 3H), 3.58-3.64 (m, 2H), 3.87-3.94 (m, 2H), 4.66 (bs, 1H), 5.37-5.39 (m, 1H),
6.84 (d, J = 0.8 Hz, 1H), 6.92 (dd, J = 8.8, 0.4 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 7.48 (d, J
= 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.8 Hz, 1H), 7.75 (dd, J = 8.0, 2.8 Hz, 1H), 8.27 (d, J = 2.0
Hz, 1H), 8.33 (s, 1H); MS: 482 (M+l).
Example-177: 5-(4-((6-(7-Fluoro-5-(methylsulfonyl)-l H-indol- l-yl)pyridin-3-yl)oxy)
piperidin- 1-yl)-3-isopropyl- ,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example-4 by using Example- 90 (0.0 18g, 1%).
NMR (400 MHz, CDC13) ; 1.28 (d, J = 7.2 Hz, 6H), 1.96-2.02 (m, 2H), 2.05-2.12 (m,
2H), 2.87-2.90 (m, 1H), 3.08 (s, 3H), 3.63-3.69 (m, 2H), 3.81-3.88 (m, 2H), 4.66-4.67 (m,
1H), 6.84 (dd, J =3.2, 2.4 Hz, 1H), 7.39 (bs, 2H), 7.49 (dd, J = 11.6, 1.6 Hz, 1H), 7.66 (d, J
= 3.6 Hz, 1H), 8.09 ( bs, 1H), 8.23 (d, J = 1.2 Hz, 1H); MS: 500 (M+l).
Example-178: tert-Butyl-4-((6-(5-(2-oxopyrrolidin-l-yl)-lH-indol-l-yl)pyridin-3-yl)
oxy)piperidine- 1-carbox late
The title compound was prepared by following the similar procedure as described in
Example- 1 using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and tert-butyl 5-(2-oxopyrrolidin-l-yl)-lH-indole-l -carboxylate
(intermediate-27) (0.01 1 g, 6 %).
NMR (400 MHz, CDC13) ; 1.48 (s, 9H), 1.78-1.83 (m, 2H), 1.95-2.00 (m, 2H), 2.17-
2.23 (m, 2H), 2.64 (t, J =7.6 Hz, 2H), 3.34-3.40 (m, 2H), 3.71-3.76 (m, 2H), 3.94 (t, J =6.8
Hz, 2H), 4.51-4.53 (m, 1H), 6.67 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 2.8, 0.8 Hz, 2H), 7.52
(dd, J = 9.2, 2.4 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.8
Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H); MS: 477 (M+l).
Example-179: l-(l-(5-((l-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)pyrrolidin-2-one
The title compound was prepared by following the similar procedure as described in
Example- 2 by using Example-178 (0.022g, 29%).
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.85-1.89 ( , 2H), 2.06-2.08 ( ,
2H), 2.17-2.21 (m, 2H), 2.44-2.51 (m, 2H), 2.64 (t, J =8.0 Hz, 2H), 3.63-3.69 (m, 2H), 3.94
(t, J = 6.8 Hz, 2H), 4.20-4.22 (m, 2H), 4.60 (bs, IH), 6.66 (d, J = 3.6 Hz, IH), 7.42 (d, J =
2.0 Hz, 2H), 7.52 (dd, J = 8.8, 2.0 Hz, IH), 7.64 (d, J = 3.6 Hz, IH), 7.77 (d, J = 2.0 Hz,
IH), 8.04 (d, J = 9.2 Hz, IH), 8.19 (bs, 2H), 8.26 (d, J = 2.0 Hz, IH); MS: 483(M+1).
Example-180: rt-Butyl-4-((6-(5 -cyano-7-fluoro- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using rt-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and 7-fluoro-lH-indole-5-carbonitrile (0.085g, 44%) ,
Ή NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.78-1.81 (m, 2H), 1.97-2.05 (m, 2H), 3.35-3.42
(m, 2H), 3.71-3.77 (m, 2H), 4.54-4.58 (m, IH), 6.78-6.80 (m, IH), 7.17-7.20 (m, IH), 7.36-
7.38 (m, 2H), 7.64 (d, J = 3.2 Hz, IH), 7.82 (d, J = 1.2 Hz, IH), 8.22 (bs, IH); MS: 459
(M+23).
Example-181: 1-(5 -(( 1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-7-fluoro -
lH-indole-5-carbonitrile
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 180 (0.022g, 29%).
Ή NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.85-1.89 (m, 2H), 2.06-2.09 (m,
2H), 2.47 (q, J =7.6 Hz, 2H), 3.64-3.71 (m, 2H), 4.18-4.23 (m, 2H), 4.63-4.64 (m, IH) 6.78
(dd, J = 3.2, 2.4 Hz, IH), 7.19 (dd, J = 11.6, 1.2 Hz, IH), 7.35-7.42 (m, 2H), 7.64 (d, J = 3.2
Hz, IH), 7.82 (d, J = 1.6 Hz, IH), 8.19 (s, 2H), 8.24 (bs, IH); MS: 443 (M+l).
Example-182: Ethyl 4-((6-(5-(2-oxopyrrolidin- 1-yl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-181 (0.031 g, 27%).
Ή NMR (400 MHz, CDC13) ; 1.27 (t, J = 7.2 Hz, 3H), 1.81-1.84 (m, 2H), 1.95-1.98 (m,
2H), 2.16-2.20 (m, 2H), 2.63 (t, J = 8.0 Hz, 2H), 3.41-3.46 (m, 2H), 3.74-3.76 (m, 2H), 3.93
(t, J = 7.2 Hz, 2H) 4.15 (q, J = 7.2 Hz, 2H), 4.52-4.54 (m, 1H), 6.66 (d, J =3.2 Hz, 1H),
7.36-7.42 (m, 2H), 7.51 (dd, J = 9.2, 2.4 Hz, 1H), 7.62 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 2.0
Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H); MS: 449 (M+1).
Example-183: tert-Butyl-4-((6-(5-(cyclopropylsulfonyl)-l H-indol- l-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate-6) and 5-(Cyclopropylsulfonyl)-lH-indole (intermediate 24).
H NMR (400 MHz, CDC13) d; 0.98-1.01 (m, 2H), 1.36-1.37 (m, 2H), 1.48 (s, 9H), 1.80-1.84
(m, 2H), 1.97-2.04 (m, 2H), 2.48-2.52 (m, 1H), 3.35-3.41 (m, 2H), 3.71 -3.74 (m, 2H), 4.55-
4.57 (m, 1H), 6.82 (dd, J = 3.6, 0.4 Hz, 1H), 7.42-7.43 (m, 2H), 7.71 (d, J = 3.6 Hz, 1H),
7.76 (dd, J = 8.8, 2.0 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.27-8.28
(m, 1H); MS: 498.09 (M+l).
Example-184: 5-(Cyclopropylsulfonyl)-l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)
oxy)pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 183.
NMR (400 MHz, CDC13) d; 0.99-1.00 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.37 (bs, 2H),
1.89 (bs, 2H), 2.09 (bs, 2H), 2.47-2.49 (m, 3H), 3.68 (bs, 2H), 4.23 (bs, 2H), 4.64 (bs, 1H),
6.83 (bs, 1H), 7.44 (bs, 2H), 7.72-7.78 (m, 2H), 8.20-8.31 (m, 5H); MS: 504.2 (M+1).
Example-185: Ethyl-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)pxy)-piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-1 (0.03 lg, 22%).
H NMR (400 MHz, CDC13) d; 1.27 (t, J = 7.2 Hz, 3H), 1.. 82-1.85 (m, 2H), 1.97-2.01 (m,
2H), 3.08 (s, 3H), 3.41-3.48 (m, 2H), 3.73-3.80 m, 2H), 4.15 (q, J = 6.8 Hz, 2H), 4.56-4.58
(m, 2H), 6.82 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.71 (d, J =3.2 Hz, 1H), 7.79
(dd, J = 8.8, 2.0 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.27 (bs, 1H), 8.28 (d, J = 1.6 Hz, 1H);
MS: 444 (M+1).
ExampIe-186: t rt-Butyl-4-((6-(5-(lH-tetrazol-l-yl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate 06) and 5-(lH-tetrazol-l-yl)-lH-indole (intermediate 57) (0.1 10 g, 24%).
H NMR (400 MHz, CDC13) d; 1.49 (s, 9H), 1.80-1.86 (m, 2H), 1.98-2.03 (m, 2H), 3.36-3.49
(m, 2H), 3.71-3.78 (m, 2H), 4.54-4.58 (m, 1H), 6.81 (dd, J = 3.4, 0.4 Hz,IH), 7.44 (bs, 2H),
7.55 (dd, J = 8.8, 2.4 Hz, 1H), 7.73 (d, J =3.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 8.27 (s,
1H), 8.29 (d, J =2.0 Hz, 1H), 9.03 (s, 1H); MS: 462 (M+l).
Example-187: Ethyl-4-((6-(5-( 1H-tetrazol-1 -yl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 70 by using Example-186 (0.01 8g, 19%).
NMR (400 MHz, CDC13) ; 1.30 (t, J = 7.2 Hz, 3H), 1.82-1.89 (m, 2H), 1.99-2.05 (m,
2H), 3.44-3.50 (m, 2H), 3.76-3.82 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.57-4.62 (m, 1H), 6.82
(dd, J = 3.6, 0.4 Hz, IH), 7.45 (dd, J = 2.0, 0.8 Hz, 2H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.74
(d, J = 3.2 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 9.03 (s,
1H); MS: 434 (M+l).
Example-188: Ethyl (l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5-yl)(methyl)carbamate
To a stirred solution of Example-9 (0.10 g, 0.20mmol) in anhydrous DMF (10 mL), NaH
(0.012g, 0.514 mmol) and methyl iodide (0.035g, 0.0.246 mmol) were added at 0°C and
stirred at 60°C for 4-5h. The reaction was quenched with water. The organic layer was
extracted with ethyl acetate. The organic layer was separated, concentrated in vacuo and the
resultant crude was purified by flash column chromatography to give ethyl (l-(5-((l-(5-
ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)(methyl)carbamate
(0.020 g, 19 %).
NMR (400 MHz, CDC13) d; 1.21 (t, J =7.6 Hz, 6H), 1.90-1.93 (m, 2H), 2.05-2.1 1 (m,
2H), 2.48 (q, J = 7.6 Hz, 2H), 3.34 (s, 3H), 3.63-3.70 (m, 2H), 4.14-4.25 (m, 4H), 4.59-4.62
( , 1H), 6.66 (d, J = 3.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 1.6 Hz, 2H), 7.48
(bs, 1H), 7.64 (d, J =3.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.20 (bs, 2H), 8.27 (d, J = 2.0
Hz, 1H); MS: 501(M+1) .
Example-189: r t-Butyl 4-((6-(5-(lH-l,2,4-triazol-l-yl)-lH-indol-l-yl)pyridin-3-yl)
oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using r t-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate
(intermediate -6) and 5-(lH-l,2,4-triazol-l-yl)-lH-indole (intermediate 58) (0.440g, 29%).
NMR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.78-1.85 (m, 2H), 1.97 -2.02 (m, 2H), 3.34-
3.41 (m, 2H), 3.72-3.78 (m, 2H), 4.53-4.56 (m, 1H), 6.76 (d, J = 3.6 Hz, 1H), 7.43 (d, J =
1.6 Hz, 2H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.70 (d, J = 3.2 Hz, 1H), 7.91 (d, J = 2.0 Hz,
1H), 8.13 (s, 1H), 8.20 (d, J= 9.2 Hz, 1H), 8.28 (t, J = 1.6 Hz, 1H), 8.58 (s, 1H); MS:
461(M+1).
Example-190: l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(lH-
1,2,4-triazol- 1-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-189 (0.022g, 14%).
NMR (400 MHz, CDC13) d; 1.22 (t, J =7.6 Hz, 3H), 1.86-1.94 ( , 2H), 2.09-2.14 ( m,
2H), 2.51 (q, J = 7.6 Hz, 2H), 3.67-3.73 (m, 2H), 4.21-4.27 (m, 2H), 4.63-4.68 (m, 1H), 6.78
(d, J =3.6 Hz, 1H), 7.41 ( m, 2H), 7.57 (dd, J = 8.8, 2.4 Hz, 1H), 7.72 (d, J = 3.2 Hz, 1H),
7.93 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 8.22 (bs, 2H), 8.23 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H),
8.58 (bs, 1H); MS: 466 (M+) .
Example-191 : Isopropyl 4-((6-(5-(l H-1,2,4-triazol- 1-yl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example- 189 (0.05 lg, 26%).
NMR (400 MHz, CDC13) d; 1.26 (d, J = 6.4 Hz, 6H), 1.79-1.87 (m, 2H), 1.97-2.03 ( ,
2H), 3.40-3.46 (m, 2H), 3.71-3.81 ( , 2H), 4.54-4.58 (m, 1H), 4.91-4.94 (m, 1H), 6.77 (d, J
= 3.2 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 2H), 7.70 (d, J =3.2 Hz,
1H), 7.91 (d, J =2.4 Hz, 1H), 8.13 ( s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.27 (t, J = 3.6, 1.6 Hz,
1H), 8.56 (s, 1H); MS: 447 (M+l).
Example-192: Ethyl-4-((6-(5-( 1H- ,2,4-triazol- 1-yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidine-l-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-189 (0.041g, 22%).
1H NMR (400 MHz, CDC13) d; 1.30 (t, J =7.2 Hz, 3H), 1.84-1.90 (m, 2H), 1.99-2.05 (m,
2H), 3.44-3.52 (m, 2H), 3.77-3.83 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.56-4.58 (m, 1H), 6.78
(d, J = 3.6 Hz, lH) , 7.44 (d, J = 1.6 Hz, 2H), 7.56 (dd, J = 9.2, 2.0 Hz, 1H), 7.72 (d, J = 3.6
Hz, 1H), 7.93 (d, J =1.6 Hz, 1H), 8.14 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.29 (t, J = 3.2 Hz,
1H), 8.66 (s, 1H); MS: 433(M+1).
Example-193 : 5-(Methylsulfonyl)- 1-(5 -(( 1-(( 1-(trifluoromethyl)cyclopropyl)methyl)-
piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-30 by using Example-175.
NMR (400 MHz, CDC13) d; 0.67 (m, 2H), 1.01-1.04 (m, 2H), 1.85-1.93 (m, 2H), 2.03-
2.08 (m, 2H), 2.37-2.41 (m, 2H), 2.59 (s, 2H), 2.79 (bs, 2H), 3.10 (s, 3H), 4.40-4.44 (m,
1H), 6.83-6.84 (m, 1H), 7.40-7.45 (m, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.81 (dd, J = 8.8, 2.0
Hz, 1H). 8.19 (d, J = 8.8 Hz, 1H), 8.27-8.31 ( , 2H); MS: 494.2 (M+l).
ExampIe-194: 3-(l-(5-((l -(4-Ethylphenyl)piperidin-4-yl)oxy)pyridin-2 -yl)-1H-indol- 5-
yl)oxazolidin-2-one
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example- 165 (0.03 lg, 20%).
1H NMR (400 MHz, CDC13) d; 1.19 (t, J =7.2 Hz, 3H), 1.85-1.88 (m, 2H), 2.05-2.09 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.64-3.69 (m, 2H), 4.14 (q, J = 8.0 Hz, 2H), 4.18-4.24 (m,
2H), 4.50 (q, J =7.6 Hz, 2H), 4.60-4.66 (m, 1H), 6.66 (d, J =3.2 Hz, 1H), 7.41 (bs, 2H),
7.51(dd, J = 8.8, 2.0 Hz, 1H), 7.64 (d, J = 3.6 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 8.06 (d, J =
9.2 Hz, 1H), 8.19 (bs, 2H), 8.26 (d, J = 1.6 Hz, 1H); MS: 485 (M+l).
Example-195: 5-(Methylsulfonyl)-l-(5-((l-(4-(trifluoromethyl)phenyl)piperidin-4-yl)
oxy)pyridin-2-yl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-81 using Example-1 and l-bromo-4-(trifluoromethyl)benzene (0.074g, 0.424mmol)
(0.041 g, 23%).
NMR (400 MHz, CDC13) d; 2.00-2.03 (m, 2H), 2.12-2.19 (m, 2H), 3.08 (s, 3H), 3.24-
3.30 (m, 2H), 3.59-3.65 (m, 2H), 4.58-4.61 (m, 1H), 6.82 (d, J = 3.2 Hz, 1H), 6.96 (d, J =
8.8 Hz, 2H), 7.40-7.50 (m, 4H), 7.72 (d, J = 3.2 Hz, 1H), 7.80 (d, J =2.0 Hz, 1H), 8.19 (d, J
= 8.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 2H); MS: 516 (M+l).
Example-196: l-(4-((6-(5-(Methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)-piperidin-l-yl)-
2-(pyrrolidin-l-yl)ethanone
To a solution of 2-chloro-l-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidin-l-yl)ethanone (0.080 g, 0.179 mmol) in DMF (2 mL), potassium iodide
(0.009 g, 0.054 mmol), pyrrolidine (0.044 mL, 0.536 mmol), potassium carbonate (0.025 g,
0.179 mmol) were added and stirred at 80°C for 45 minutes. The reaction was quenched by
adding water (20 mL), the mixture was extracted with ethyl acetate, organic layer was
concentrated under reduced pressure. The resulting crude was purified by flash column
chromatography to give l-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidin-l-yl)-2-(pyrrolidin-l-yl)ethanon (0.045 g, 52.32%).
NMR (400 MHz, CDC13) d; 1.77-1.91 (m, 6H), 2.00-2.05 (m, 2H), 2.64 (s, 4H), 3.1 1 (s,
3H), 3.39 (s, 2H), 3.56-3.68 (m, 2H), 3.86-3.90 (m, 2H), 4.63-4.67 (m, 1H), 6.85 (d, J = 3.2
Hz, 1H), 7.43-7.48 (m, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.82 (dd, J= 8.8, 1.6 Hz, 1H), 8.21(d, J
= 8.8 Hz, 1H), 8.30 -8.32 (m, 2H); MS: 483 (M+l).
Exampale-197:l-(4-((6-(5-(Methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)-piperidin-lyl)-
2-(piperidin-l -yl)ethanone
The title compound was prepared by following the similar procedure as described in
Example- 196 using 2-chloro- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidin-l-yl)ethanone and piperidine (0.045 g, 50.56%).
NMR (400 MHz, CDC13) ; 1.46 -1.47 (m, 2H), 1.58-1.64 (m, 4H), 1.85-2.07 (m, 4H),
2.47(bs, 4H), 3.1 1 (s, 3H), 3.20 (s, 2H), 3.60-3.67 (m, 2H), 3.85-3.93 (m, 2H), 4.64-4.67 (m,
1H), 6.85 (d, J= 3.6 Hz, 1H), 7.43-7.48 (m, 2H), 7.74 (d, J = 3.6 Hz, 1H), 7.82 (dd, J = 8.8,
1.6 Hz, 1H), 8.21(d, J = 8.8 Hz 1H), 8.31 -8.32 (m, 2H); MS: 497(M+1).
ExampIe-198: 1-(4-((6-(5-(Methylsulfonyl)-l H-indol- 1-yl)pyridin-3-yl)oxy)-piperidin- 1-yl)-
2-morpholinoethanone
The title compound was prepared by following the similar procedure as described in
Example- 196 using 2-chloro- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidin-l-yl)ethanone and morpholine. (0.050g, 56.18%).
1H NMR (400 MHz, CDC13) d; 1.87-2.07 (m, 4H), 2.56 (bs, 4H), 3.1 1 (s, 3H), 3.25 (s, 2H),
3.58-3.71 (m, 2H), 3.75-3.77 (m, 4H), 3.83-3.91 (m, 2H), 4.65-4.68 (m, lH), 6.85 (d, J = 3.2
Hz ,1H), 7.43-7.48 (m, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 8.21 (d,
J = 8.8 Hz, 1H), 8.31-8.32 (m, 2H); MS: 499 (M+l ) .
Example-199: l-(4-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)-5-(methyl
sulfonyl)-lH-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-3 (0.049 g, 48%).
NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.87-1.89 (m, 2H), 2.06-2.10 ( ,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.09 (s, 3H), 3.65-3.72 (m, 2H), 4.18-4.24 (m, 2H), 4.62-4.63
(m, 1H), 6.80 (dd, J = 3.2, 0.8 Hz, 1H), 7.10 (dd, J = 6.8, 2.4 Hz, 2H), 7.38 (dd, J = 6.8, 2.4
Hz, 2H), 7.42 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.73(dd, J = 8.8, 2.0 Hz, 1H),
8.20 (s , 2H), 8.32 (d, J =1.6 Hz, 1H); MS: 477 (M+l).
Example-200: 1-(4-((l -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)-5-(methyl
sulfonyl)indoline
The title compound was prepared by following the similar procedure as described in
Example-2 using rt-Butyl-4-(4-(5 -(methylsulfonyl)indolin- 1-yl)phenoxy)piperidine- 1-
carboxylate (intermediate 80) (0.035g, 34%).
NMR (400 MHz, CDC13) d; 1.19 (t, J = 7.6 Hz, 3H), 1.80-1.86 ( , 2H), 2.00-2.06 (m,
2H), 2.47 (q, J =7.6 Hz, 2H), 3.10 (s, 3H), 3.19 (t, J = 8.4 Hz, 2H), 3.60-3.67 (m, 2H), 4.03
(t, J = 8.4 Hz, 2H), 4.16-4.22 (m, 2H), 4.50-4.53 (m, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.97 (dd,
J = 6.4, 2.0 Hz, 2H), 7.19 (dd, J = 6.8, 2.4 Hz, 2H), 7.57 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H),
8.18 (s, 1H); MS: 479 (M+l).
Example-201 : tert-Butyl 4-((2-(5-(methylsulfonyl)- 1H-indol-1 -yl)pyridin-4-yl)methoxy)
piperidine-1 -carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate 21) and tert-Butyl 4-((2-
chloropyridin-4-yl)methoxy)piperidine- 1-carboxylate (intermediate 44).
1H NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.62-1.66 (m, 2H), 1.91 (m, 2H), 3.08 (s, 3H),
3.12-3.18 (m, 2H), 3.62-3.66 (m, 1H), 3.79-3.82 (m, 2H), 4.68 (s, 2H), 6.85-6.86 (m, 1H),
7.21 (d, J = 5.2, 1H), 7.49 (s, 1H), 7.81-7.84 (m, 2H), 8.29 (d, J = 1.6, 1H), 8.39 (d, J = 9.2,
1H), 8.54-8.55 (m, 1H); MS: 484.3 (M+l).
Example-202: 1-(4-(((l -(5-Ethylpyrimidin-2-yl)piperidin-4 yl)oxy)methyl)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-20 1.
Ή NMR (400MHz, CDC13) ; 1.20 (t, J = 7.6 Hz, 3H), 1.66-1.74 (m, 2H), 1.99-2.04 (m,
2H), 2.46 (q, J = 7.6 Hz, 2H), 3.08 (s, 3H), 3.37-3.43 ( , 2H), 3.71-3.76 (m, 1H), 4.29-4.39
(m, 2H), 4.71 (s, 2H), 6.84 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 7.51 (s, 1H), 7.80-
7.82 (m, 2H), 8.17 (s, 2H), 8.28 (d, J 1.6 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 4.8
Hz, 1H); MS: 492.2 (M+l).
Example-203 : 5-(Methylsulfonyl)- 1-(5-(( 1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy) pyridin-
2-yl)-l H-indole
To a stirred solution of example 172 (0.10 g, 0.214 mmol) in dry THF (10 mL) boranemethyl
sulfide complex (0.041 mL, 0.428 mmol) was added at 0°C and heated at 65 °C for 3
h. Reaction was quenched with 10% HCl at 0°C and extracted with ethyl acetate. Organic
layer was concentrated in vacuo and residue was purified by flash column chromatography to
give 5-(methylsulfonyl)- 1-(5-((l -(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindole
(0.014 g, 14%)
NMR (400MHz, CDC13) d; 1.95 (bs, 2H), 2.08 (bs, 2H), 2.67-2.69 (m, 2H), 2.97-3.1 1 (m,
7H), 4.46 (bs, 1H), 6.84 (d, J = 2.4 Hz, 1H), 7.43 (bs, 2H), 7.74 (d, J = 1.2 Hz, 1H), 7.81 (d, J
= 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 9.6 Hz, 2H)
MS: 453.48 (M+) .
Example-204: 2-(4-((6-(5-(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3yl)oxy)piperidin- 1-yl)-
1-(pyrrolidin- 1-yl)eth
To a stirred solution of 2-chloro-l -(pyrrolidin- 1-yl)ethanone (Intermediate 71) (0.055 g,
0.366 mmol) in DMF (2 mL), potassium iodide (0.023 g, 0.137 mmol), 5-(methylsulfonyl)-l-
(5-(piperidin-4-yloxy)pyridin-2-yl)-lH-indole (0.170 g, 0.458 mmol) and potassium
carbonate (0.064 g, 0.458 mmol) were added. The resulting mixture was heated at 80°C for
45 minutes. Reaction was quenched with water and extracted with ethyl acetate. The organic
extract was concentrated in vacuo and resultant residue was purified by column
chromatography to yield title compound (0.075 g, 33.3%).
H NMR (400MHz, CDC13) d; 1.85-1.91 (m, 6H), 1.95-2.1 1 (m, 2H), 2.55 (bs, 2H), 2.89 (bs,
2H), 3.00 (s, 3H), 3.10 (s, 2H), 3.51(t , J = 6.4 Hz, 4H), 4.44 (bs, 1H), 6.83 (d, J = 2.4 Hz,
1H), 7.42 (bs, 2H), 7.73 (d, J = 3.2 Hz, 1H), 7.81 (d, J - 8.0 Hz, 1H), 8.19 (d, J = 8.8 Hz,
1H), 8.30 (d, J = 9.6 Hz, 2H); MS: 482.98 (M+) .
Example-205: 2-Cyclopentyl- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)ethanone
The title compound was prepared by following the similar procedure as described in
Example- 127 by using Example- 1 and 2-cyclopentylacetic acid.
H NMR (400 MHz, CDC13) d; 1.20-1.28 (m, 4H), 1.58-1.66 (m, 4H), 1.88-1.89 (m, 2H),
2.02-2.04 (m, 2H), 2.23-2.31 (m, 1H), 2.40-2.42 (m, 2H), 3.1 1 (s, 3H), 3.48-3.50 ( , 1H),
3.67-3.68 (m, 1H), 3.78-3.80 (m, 1H), 3.85-3.87 (m, 1H), 4.65 (m, 1H), 6.85 (d, J = 2.8 Hz,
1H), 7.45 (s, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.81-7.83 (m, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.31
(d, J =2.4 Hz, 2H); MS: 481.9 (M+) .
Example-206: t rt-Butyl-4-((4-(5-(methylsulfonyl)-lH-indol-l-yl)thiazol-2-yl)oxy)-
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate 21) and -butyl 4-((4-
bromothiazol-2-yl)oxy)piperidine-l -carboxylate (intermediate 46) (0.007g, 5%).
NMR (400 MHz, CDC13) d; 1.47 (s, 9H), 1.87-1.91 ( , 2H), 2.04-2.09(m, 2H), 3.08 (s,
3H), 3.35-3.42 (m, 2H), 3.70-3.74 (m, 2H), 5.21-5.23 (m, 1H), 6.49 (s, 1H), 6.77 (d, J =
3.2Hz, 1H), 7.64 (d, J = 3.6 Hz, 1H), 7.80 (dd, J = 8.8, 1.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H),
8.27 (d, J = 1.6 Hz, 1H); MS: 477 (M+l).
Example-207: t rt-Butyl-4-(((4-(5-(methylsulfonyl)-lH-indol-l-yl)thiazol-2-yl)oxy)
methyl)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 by using 5-(methylsulfonyl)-lH-indole (intermediate-21) and tert-Butyl 4-(((4-
bromothiazol-2-yl)oxy)methyl)piperidine-l -carboxylate (intermediate 47) (0.013g, 10%).
H NMR (400 MHZ, CDCI3) d; 1.29-1.33 (m, 2H), 1.47 (s, 9H), 1.81-1.83 (m, 2H), 2.02-2.05
(m, 1H), 2.75 (bs, 2H), 3.10 (s, 3H), 4.18 (bs, 2H), 4.36 (d, J = 6.4 Hz, 2H), 6.51 (s, 1H),
6.77 (d, J 3.2 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.79-7.82 (m, 1H), 8.02 (d, J = 8.8 Hz,
1H), 8.28 (bs, 1H); MS: 491.6 (M+l).
Example-208: 2-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-4-(5-(methyl-sulfonyl)-lHindol-
l-yl)thiazole
The title compound was prepared by following the similar procedure as described in
Example-2 by using Example-206 (0.0 15g, 29%).
NMR (400 MHz, CDC13) d; 1.90 (d, J = 7.6 Hz, 3H), 1.92-1.98 (m, 2H), 2.13-2.18 (m,
2H), 2.47 (q, J = 7.6 Hz, 2H), 3.08 (s, 3H), 3.67-3.73 (m, 2H), 4.15-4.21 ( , 2H), 5.28-5.32
(m, 1H), 6.50 (s, 1H), 6.77 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 3.6 Hz, 1H), 7.78-7.81 (m, 1H),
8.0 (d, J = 8.8 Hz, 1Ή ), 8.18 (bs, 2H), 8.28 (s, 1H); MS: 484 (M+l).
Example-209: 4-(5-(l H-Tetrazol-1 -yl)- 1H-indol- 1-yl)-2-((l -(5-ethylpyrimidin-2-yl)
piperidin-4-yl)oxy)thiazole
To a stirred solution of l-(2-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)-lHindol-
5-amine (0.090 g, 0.214 mmol) in acetic acid (3 mL), triethylorthoformate (0.047 g,
0.324 mmol) and NaN3 (0.020 g. 324 mmol) were added and stirred at 100°C for 1 h. The
reaction was quenched with water and the mixture was extracted with ethyl acetate. The
organic layer was concentrated in vacuo and the residue was purified by flash column
chromatography to give 4-(5-(lH-tetrazol-l-yl)-lH-indol-l-yl)-2-((4-(5-ethylpyrazin-2-
yl)cyclohexyl)oxy)thiazole (0.012 g, 11%)
1H NMR (400 MHz, CDC13) d; 1.20 (t, J = 7.6 Hz, 3H), 1.94-2.01 (m, 2H), 2.16-2.21 (m,
2H), 2.48 (q, J 7.6 Hz, 2H), 3.69-3.76 (m, 2H), 4.22-4.16 (m, 2H), 5.32-5.35 (m, 1H), 6.50
(s, 1H), 6.76 (m, 1H), 7.54 (dd, J =8.8, 2.0 Hz, 1H), 7.68 (d, J =3.6 Hz, 1H), 7.94 (d, J =2.0
Hz, 1H), 8.06 (d, J =3.6 Hz, 1H), 8.20 (s, 2H), 9.01 (s, 1H); MS: 474.1 (M+l).
Example-210: tert-Butyl-4-((4-(5-(lH-tetrazol-l-yl)-lH-indol-l-yl)thiazol-2-yl)oxy)
piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-209 using tert-butyl 4-((4-(5 -amino- lH-indol-1 -yl)thiazol-2-yl)oxy)-piperidine-lcarboxylate
(intermediate-35).
NMR (400 MHz, CDC13) d; 1.47 (s, 9H), 1.90-1.95 (m, 2H), 2.07-2.12 (m, 2H), 3.39-3.46
(m, 2H), 3.71-3.77 (m, 2H), 5.24-5.28 (m, 1H), 6.51 (s, 1H), 6.76-6.77 (m, 1H), 7.56 (dd, J =
8.8, 2.0 Hz, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.94 (d, J = 2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H),
9.01 (s, 1H); MS: 468.1 (M+l).
Example-211: tert-Butyl-4-((4-(5 -((ethoxycarbonyl)amino)- 1H-indol- 1-yl)thiazol-2-yl)
oxy)piperidine- 1-carboxylate
To a stirred solution of rt-butyl 4-((4-(5-amino- 1H-indol- l-yl)thiazol-2-yl)oxy)piperidine-
1-carboxylate (intermediate-35) (0.100 g, 0.214 mmol) in dichloromethane (4 mL),
triethylamine (0.036 g, 0.362 mmol), and chloroethylformate (0.026 g, 0.214 mmol) were
added at 0 °C and stirred at room temperature for 10 minutes. The reaction was quenched
with water and the mixture was extracted with dichloromethane. The organic layer was
concentrated in vacuo and the residue was purified by flash column chromatography to give
tert-butyl 4-((4-(5-((ethoxycarbonyl)amino)- 1H-indol- 1-yl)thiazol-2-yl)oxy)piperidine- 1-
carboxylate (0.010 g, 8.5%)
1H NMR (400 MHz, CDC13) d; 1.32 (t, J = 6.8 Hz, 3H), 1.47 (s, 9H), 1.86-1.90 (m, 2H),
2.03-2.09 (m, 2H), 3.34-3.41 (m, 2H), 3.69-3.74 (m, 2H), 4.23 (q, J 7.2 Hz, 2H), 5.21-5.23
(m, 1H), 6.36 (s, 1H), 6.56 (d, J = 3.2 Hz, 2H), 7.19 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 3.6 Hz,
1H), 7.70 (bs, 1H), 7.76 (d, J = 8.8 Hz, 1H); MS: 487.1 (M+l).
Example-212: tert-Butyl-4-((4-(5-((isopropoxycarbonyl)amino)-l H-indol- l-yl)thiazol-2-
yl)oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-21 1 using tert-butyl 4-((4-(5-amino-l H-indol- l-yl)thiazol-2-yl)oxy)-piperidine-lcarboxylate
(intermediate-35).
NMR (400MHz, CDC13) d; 1.33 (d, J 6.4 Hz, 6H), 1.49 (s, 9H), 1.89-1.92 (m, 2H),
2.06-2.1 1 (m, 2H), 3.36-3.43 (m, 2H), 3.72-3.76 ( , 2H), 5.02-5.08 ( , 1H), 5.22-5.26 (m,
1H), 6.38 (s, 1H), 6.57 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.77 ( ,
2H); MS: 400.1 (M-100).
Example-213 : Ethyl (1-(2-(( 1-(5-ethylpyrimidin-2-yl)piperidin-4-y l)oxy)thiazol-4-yl)- 1Hindol-
5-yl)carbamate
The title compound was prepared by following the similar procedure as described in
Example-21 using l-(2-((l-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)-lH-indol-
5-amine (intermediate-34) (0.0 lOg, 22%).
NMR (400 MHz, CDC13) ; 1.19 (t, J = 7.6 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.92-1.97
(m, 2H), 2.13-2.17 (m, 2H), 2.47 (q, J = 7.2 Hz, 2H), 3.70-3.72 (m, 2H), 4.16-4.26 (m, 4H),
5.29-5.32 (m, 2H), 6.37 (s, 1H), 6.57 (d, J 3.2 Hz, 2H), 7.18 (d, J 9.6 Hz, 1H), 7.51-7.55
(m, 1H), 7.72 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H); MS: 493.1 (M+l).
Example-214: Isopropy 1 (1-(2-(( 1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)-
lH-indol-5-yl)carb
The title compound was prepared by following the similar procedure as described in
Example-2 12 using 1-(2-(( 1-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)- 1H-indol-
5-amine (intermediate 34).
NMR (400 MHz, CDCI3) d; 1.20 (t, J = 7.6 Hz, 3H), 1.32 (d, J = 2.8 Hz, 6H), 1.93-1.98
(m, 2H), 2.14-2.19 (m, 2H), 2.48 (q, J = 7.6 Hz, 2H), 3.68-3.73 (m, 2H), 4.15-4.21 (m, 2H),
5.02-5.05 ( , 2H), 5.31-5.32 (m, 1H), 6.37 (s, 1H), 6.57 (d, J = 3.6 Hz, 2H), 7.13-7.21 (m,
1H), 7.52-7.55 (m, 1H), 7.69-7.73 ( , 1H), 7.79 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H); MS: 507.1
(M+l).
Example-215: 5-(4-((4-(5-(l H-Tetrazol- -yl)- 1H-indol- 1-yl)thiazol-2-yl)oxy)-piperidin- 1-
yl)-3 -isopropyl- 1,2,4-oxadiazole
The title compound was prepared by following the similar procedure as described in
Example- 209 using l-(2-((l-(3-isopropyl-l, 2, 4-oxadiazol-5-yl)piperidin-4-yl)oxy)thiazol-
4-yl)-lH-indol-5-amine (intermediate 70).
NMR (400 MHz, CDC13) d; 1.30 (d, J = 7.2 Hz, 6H), 2.09-2.23 (m, 4H), 2.88-2.95 (m,
1H), 3.68-3.74 (m, 2H), 3.83-3.89 (m, 2H). 5.35-3.39 (m, 1H), 6.54 (s, 1H), 6.77 (d, J = 3.2
Hz, 1H), 7.57 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.95 (d, J = 2.0 Hz,
1H), 8.03 (d, J = 8.8 Hz, 1H). 9.02 (s, 1H); MS: 478.1(M+1).
Example-216: t rt-Butyl 4-((4-(7-fluoro-5-(methylsulfonyl)-lH-indol-l-yl)thiazol-2-yl)
oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using 7-Fluoro-5-(methylsulfonyl)-lH-indole (intermediate 22) and rt-butyl 4-
((4-bromothiazol-2-yl)oxy)piperidine-l -carboxylate ( intermediate 46).
NMR (400 MHz, CDC13) d; 1.46 (s, 9H), 1.82-1.87 (m, 2H), 2.00-2.06 (m, 2H), 3.09 (s,
3H), 3.30-3.37 (m, 2H), 3.70-3.73 (m, 2H), 5.14-5.19 (m, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.78-
6.80 (m, 1H), 7.47-7.51 (m, 1H), 7.55 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H); MS:
518.1(M+23).
Example-217: tert -Butyl-4-((4-(5-(methylsulfonyl)indolin-l-yl)thiazol-2-yl)oxy)-piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example- 1 using 5-(methylsulfonyl)indoline (intermediate 26) and t r/-Butyl 4-((4-
bromothiazol-2-yl)oxy)piperidine- 1-carboxylate ( intermediate 46).
NMR (400 MHz, CDC13) d; 1.47 (s, 9H), 1.88-1.92 (m, 2H), 2.04-2.10 (m, 2H), 3.03 (s,
3H), 3.25 (t, J = 8.8 Hz, 2H), 3.39-3.45 (m, 2H), 3.69-3.75 ( , 2H), 4.00 (t, J 8.8 Hz, 2H),
5.15.518 (m, IH), 5.58 (s, IH), 7.63 (s, IH), 7.70-7.74 (m, 2H); MS: 480.0 (M+l).
Example-218: 2-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-4-(5-(methylsulfonyl)
indolin- 1-yl)thiazole
The title compound was prepared by following the similar procedure as described in
Example- 2 by using Example-217.
1H NMR (400 MHz, CDC13) d; 1.21 (t, J = 7.6 Hz, 3H), 1.95-1.98 (m, 2H), 2.12-2.18 (m,
2H), 2.48 (q, J 7.6 Hz, 2H), 3.03 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H), 3.74 (m, 2H), 4.00 (t, J =
8.4 Hz, 2H), 4.09-4.19 (m, 2H), 5.22-5.25 (m, IH), 5.28 (s, IH), 7.62 (bs, IH), 7.65-8.20 (m,
2H), 8.70 (s, 2H); MS: 486.0(M+1).
Example-219: Isopropyl 4-((4-(5-(methylsulfonyl)indolin-l-yl)thiazol-2-yl)oxy) piperidine-
1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-70 by using Example-217.
Ή NMR (400 MHz, CDC13) d; 1.26 (d, J = 6.4 Hz, 6H), 1.89-1.93 (m, 2H), 2.03-2.09 (m,
2H), 3.02 (s, 3H), 3.23 (t, J = 8.8 Hz, 2H), 3.43-3.48 ( , 2H), 3.70-3.75 (m, 2H), 3.99 (t, J =
8.8 Hz, 2H), 4.90-4.97 (m, 1H), 5.15-5.19 (m, 1H), 5.58 (s, 1H), 7.61 (s, 1H), 7.61-7.72 (m,
2H); MS: 466.0 (M+l).
Example-220: tert-Butyl- 4-((4-(5 -(1H-1,2,4-triazol- 1-yl)- 1H-indol- 1-yl)thiazol-2-yl)
oxy)piperidine- 1-carboxylate
The title compound was prepared by following the similar procedure as described in
Example-1 using -Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-l -carboxylate
(intermediate 46) and 5-(lH-l,2,4-triazol-l-yl)-lH-indole (intermediate 58).
H MR (400 MHz, CDC13) d; 1.48 (s, 9H), 1.89-1.93 (m, 2H), 2.06-2.1 1 (m, 2H), 3.37-3.43
(m, 2H), 3.70-3.76 (m, 2H), 5.25-5.30 (m, 1H), 6.47 (s, 1H), 6.71 (d, J = 3.2 Hz, 1H), 7.56
(dd, J = 8.8, 2.0 Hz, 1H), 7.63 (d, J = 3.6 Hz, 1H), 7.90 (d, J =2.0 Hz, 1H), 7.97 (d, J = 8.8
Hz, 1H), 8.13 (s, 1H), 8.56 (s, 1H); MS: 367.0 (M-100).
Example-221 : Cyclobutyl(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl) oxy)
piperidin- 1-yl)methanone
The title compound was prepared by following the similar procedure as described in
Example-127 by using Example-1 and cyclobutanecarboxylic acid (0.035 g, 18%); MS:
453.98 (M+) .
Example-222: Cyclopentyl(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)
piperidin- l-yl)methanone
The title compound was prepared by following the similar procedure as described in
Example-127 by using Example-1 and cyclopentanecarboxylic acid (0.020 g, 10%)); MS:
468.1 (M+l).
Example-223: Cyclohexyl(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)
piperidin-l-yl)methanone
The title compound was prepared by following the similar procedure as described in
Example-127 by using Example-1 and cyclohexanecarboxylic acid (0.068 g, 33%)); MS:
481.9 (M+) .
Following examples given Table- 1 may be prepared by following one or more procedure as
described herein above
Table- :

Following examples in Table-2 may be prepared by following one or more procedure as
described herein above
Table-2:
Example z Example 2 z
433 0 459 0
1 1
434 0 460 0
- N -
1 F /
435 0 461 0
1 1
436 0 462 0
1
1 /
437 0 463 0
/ 1 0
438 0 464 0
1 /

Biological Example-1
Cyclic AMP assay in Stable cell line:
Chinese Hamster Ovary (CHO-K1) cells were stably transfected with human GPR1 19
and were maintained in Ham's F-12 complete medium containing 10% heat inactivated FBS
(Sigma, UK). The cells were maintained under a selection pressure with 500 mg/ml G418
(GENETICIN). Stable clones were analyzed for functional cAMP response to OEA
(oleoylethanolamide).
To estimate activation of GPR1 19 and induction of cAMP levels by GPR1 19
agonists, cells were serum starvation for 18-24 h, trypsinized and seeded in 96 well plates at
a density of 7500 cells/well. The cells were then treated with test compounds diluted in
serum free Ham's F12 for 1 h at 37 °C. The cAMP levels were measured by using the cAMP
femto kit (CisBio) by following the manufacturer's instructions. Following treatment with a
test compound, the cells were lysed and cAMP levels were estimated by adding D2-labelled
cAMP and europium-cryptate conjugated anti-cAMP antibody. Close proximity of D2 and
cryptate results in FRET and the subsequent fluorescence that is measured at 665 and 620
nm. The FRET response is calculated as the ratio of fluorescence at 665 to fluorescence at
620 nm. The unlabelled cAMP produced as a result of GPR1 19 activation/agonism competes
with the D2-cAMP leading to a decrease in the FRET signal. Thus the FRET signal is
inversely proportional to the amount of cAMP produced by the treated cells. In a separate set
of wells, known concentrations of cAMP were added in order to get a standard linear curve
for extrapolation of the cAMP values in the unknown/test samples. Fluorescence was
measured on BMG Labtech PHERAstar machine.
The concentration of compound required to stimulate a half-maximal response (EC 0) was
determined using the GraphPad Prism software.
The compounds prepared were tested using the above assay procedure and the results
obtained are given below. The EC50 (nM) values of the compounds are set forth in Table-3
wherein "A" refers to an EC ovalue of less than 50 nM, "B" refers to an EC50 value in range
of 50.01 to 250 nM and "C" refers to an EC 0 value in range of 250.01 to 1000 nM.
Activity data has been given in Table-3 for representative compounds.
Table-3:
Compound EC 0 Range
(Example number)
1, 2, 4, 5, 6, 8, 9, 11, 14, 22, 30, 35, 39, 40, 45, 46, 49, 51,
54, 56, 57, 63, 71, 74, 77, 80, 91, 98, 118, 120, 123, 126, A
127, 132, 136, 141, 143, 168, 169, 171, 187, 190, 193
13, 18, 30, 42, 45, 48, 62, 66, 67, 70, 72, 76, 82, 92, 103,
B
108, 119, 126, 147, 153, 157, 182, 185
58,72, 84, 88, 94, 99, 100, 107, 112, 113, 166, 192 C
Thus, certain compounds of the present invention are shown to have functional activity as
agonists of GPR 119.
Biological Example-2
Oral Glucose Tolerance Test:
9-10 weeks old male C57 BL/6J mice were maintained on a regular chow diet. The day of the
experiment mice were fasted for 16 h and then randomized in to groups (n=7-8) based on
blood glucose and bodyweight to receive vehicle (80% PEG400, 10% Tween80, 10%
Ethanol) or test compounds (at 10 mg/kg). Vehicle or test compounds were delivered via oral
gavage at lOml/kg volume. Thirty minutes later, the mice were dosed orally with a glucose
bolus (3 g/kg) at 10 ml/kg volume. Blood glucose measurements were taken at 20, 40, 60 and
120 minutes after glucose administration by glucometer (CONTOUR TS, Bayer). Total AUC
and Delta AUC were calculated by using graph pad prism (5.0).
Table-4:
Thus, the compound of the present invention has been shown to decrease plasma glucose
levels in vivo, indicating potential for use of the compounds of the present invention in the
treatment of diabetes.
All patents, patent applications and publications cited in this application are hereby
incorporated by reference in their entirety for all purposes to the same extent as if each
individual patent, patent application or publication were so individually denoted.
Although certain embodiments and examples have been described in detail above,
those having ordinary skill in the art will clearly understand that many modifications are
possible in the embodiments and examples without departing from the teachings thereof. All
such modifications are intended to be encompassed within the below claims of the invention.
CLAIMS
. A compound of formula I):
(I)
wherein,
is a single or double bond; provided that
when is a double bond, W is selected from group A and group B and
when is a single bond, W is selected from group A;
group A is selected from the group consisting of a 6-membered aromatic ring,
wherein the 6-membered aromatic ring is selected from the group consisting of
a 5-membered heteroaryl, a cycloalkyl, a heterocyclyl, a bicyclic aryl and a bicyclic
heteroaryl, and a member of group A may be optionally substituted with one or more
group B is selected from the group consisting of
wherein, R at each occurrence is selected from the group consisting of haloalkyl, alkoxy,
cycloalkyl and NRaRb;
Ri, R2 are each independently selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, halo, hydroxyalkyl, haloalkyl, -ORa, -NRaRb, -C(0)OR a and -
C(0)NR aRb;
or when 'b' is a single bond, Ri may be oxo (=0);
R3 is selected from the group consisting of -S(0) pRa, -C(0)OR , -(CH2)qC(0)NR aRb, -
(CH )qN(Ra)C(0)R b, -N(Ra)C(0)OR b, -N(Ra)C(0)NR aRb, -S(0) NRaR , -N(R )S(0) 2R , -
CN, alkoxy, hydroxyalkyl, heterocyclyl and heteroaryl;
Y is N or C;
Ra and R are each independently selected from the group consisting of hydrogen,
alkyl, halo, haloalkyl, hydroxy, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryl,
heteroaryl, arylalkyl, and heterocyclyl; or Ra and Rb may join together with the nitrogen atom
to which they are attached to form a heterocyclic ring;
R4 is selected from the group consisting of hydrogen, alkyl, halo, haloalkyl, cyano
and -ORa;
Z is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl,
arylalkyl, haloalkyl, hydroxyalkyl, -(CH2)qC(0)OR a,
(CH2) C(0)OR cRdRe, -(CH ) C(0)R a, -C(0)(CH 2) NRaR , -(CH ) C(0)NR aR , -S(0) 2Ra, -
S(0) 2NRaRb, -C(0)CR RdRe and -(CH )qCRcR Re;
Rc, R and Re are each independently selected from the group consisting of hydrogen,
halogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,
and heterocyclyl; or Rc and R may join together with the carbon atom to which they are
attached to form a 3 to 7 membered carbocyclic or heterocyclic ring;
R , R R , R8 are each independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cylcoalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, haloalkyl,
alkoxy, -C(0)OR a, -OC(0)R a, -C(0)NR aRb, -N(Ra)C(0)R , -S(0) pRa, -S(0) 2NRaR , and -
N(Ra)S(0) Rb; wherein R5, R6, R , and Rg may be present on same or different carbon atom;
or any two of R4, R5, R R , R8 and Z may join together to form a cycloalkyl or heterocyclyl
ring; or any two of R5, R , R and R8, when they are attached to the same carbon, may
together form oxo (=0);
X is selected from the group consisting of -(CRi 0Rn)qO(CRioRn) t-,
(CR,oRii) S(0) p(CRi 0R )t- and -(CR,oRii) q (CRioR )t-;
R is hydrogen or alkyl;
Rio and R are each independently selected from the group consisting of hydrogen,
halogen, alkyl and haloalkyl; or R10 and R may join together with the carbon atom to which
they are attached to form a 3 to 7 membered carbocyclic ring;
Ri2 at each occurrence is independently selected from hydrogen, alkyl, halogen,
haloalkyl, alkoxy, cycloalkyl and NRaR| ;
'm', 'n' and 'p' are each independently selected from 0, 1 or 2;
'q' is an integer ranging from 0 to 4, both inclusive;
't' is an integer ranging from 0 to 4, both inclusive;
with the proviso that when i is double bond and
W is
then X is not -NH- or -NHCH(Ri 1);
and
wherein, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
heterocyclic ring, alkoxy, hydroxyalkyl, haloalkyl, arylalkyl, heterocyclylalkyl,
heteroarylalkyl and carbocyclic ring wherever they occur may optionally be substituted with
one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=0),
thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(0)OR , -
C(0)R , -C(S)RX, -C(0)NR xRy, -NRxC(0)NR yR , -N(R )S(0)R , -N(R )S(0) 2Ry, -NRxR , -
NRxC(0)R , -NR C(S)R , -NRxC(S)NR R , -S(0)NR xR , -S(0) 2NRxR , -ORx, -OC(0)R x, -
OC(0)NR xRy, -RxC(0)OR y, -RxC(0)NR Rz, -R C(0)R y, -SRX, -S(0)R x, and -S(0) 2Rx
wherein each occurrence of R , R and Rz are independently selected from hydrogen, alkyl,
haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic
ring, heterocyclylalkyl ring and heteroarylalkyl;
or pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein is a double bond; and
Wis selected from 6-membered aromatic ring selected from the group consisting of
The compound of claim 1, having the Formula (II):
or pharmaceutically acceptable salt thereof;
wherein,
is a single or double bond; and X, Z, R2, R3, R , R R , R , 'n' and 'm' are as
defined herein above.
4. The compound of claim 1, having the Formula (III):
or pharmaceutically acceptable salt thereof;
wherein,
is a single or double bond;
R3 is selected from the group consisting of -S(0) pRa, -C(0)OR a, -(CH2) C(0)NR aRb, -
(CH2)qN(Ra)C(0)R , -N(Ra)C(0)OR , -N(Ra)C(0)NR aRb, -S(0) NRaR , -N(Ra)S(0) R ,
hydroxyalkyl and heterocyclyl; and
X, Z, R2, R , R6, R , R8, 'n' and 'm' are as defined herein in claim 1.
5. The
wherein,
is a single or double bond; X, Z, R2, R3, R5, R6, R7, R , 'n' and 'm' are as
defined herein in claim 1.
6. The compound of claim 1, having the Formula (V):
or pharmaceutically acceptable salt thereof;
wherein,
is a single or double bond; X, Z, R2 and R3 are as defined herein in
7. The compound of claim 1, wherein is double bond.
8. The compound of claim 1, wherein W is a 5-membered heteroaryl, or a
membered aromatic ring selected from the group consisting of:
9. The compound of claim 1, wherein i is hydrogen, alkyl, cyano, halo,
cycloalkyl, heterocyclyl, aryl or heteroaryl.
10. The compound of claim 1, wherein R2 is hydrogen, halogen or alkyl.
11. The compound of claim 1, wherein R3 is hydroxyalkyl, -C(0)OR a,
-S(0)pRa, -C(0)NR aRb, -N(Ra)C(0)R b, -CH N(Ra)C(0)R , -N(Ra)C(0)OR b,
N(Ra)C(0)NR Rb, -S(0) 2NRaR , -N(R )S(0) 2Rb, heterocyclyl; wherein Ra and Rb are
each independently a hydrogen, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, aryl,
heteroaryl or heterocyclyl; or Ra and Rb may join together with the nitrogen atom to
which they are attached to form a heterocyclic ring.
12. The compound of claim 1, wherein R3 is substituted or unsubstituted heteroaryl or
heterocyclyl.
13. The compound of claim 12, wherein heteroaryl is oxazole, oxadiazole, triazole or
tetrazole.
14. The compound of claim 12, wherein heterocyclyl is pyrrolidine, pyrrolidine-2-one or
oxazolidin-2-one.
15. The compound of claim 12, 13 or 14, wherein substituent(s) is alkyl.
16. The compound of claim 1, wherein X is -(CR oRi q CRioRi or
-(CR10Rii )qNR9(CRioRn)t-; 'q' is 0 or 1; 't' is 0 or 1; and each of Rio and R are
hydrogen.
17. The compound of claim 1, wherein Z is hydrogen, alkyl, haloalkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl,
hydroxyalkyl, -C(0)OR a, -C(0)R a, -C(0)CRcRdRe, -(CH 2) CRcRdRe, -S(0 )2Ra or -
S(0 )2NR Rb wherein Ra, Rb, Rc, R and e are each independently a hydrogen, alkyl,
haloalkyl, cycloalkyl, hydroxyalkyl, aryl, heteroaryl, arylalkyl, and heterocyclyl; or Ra
and Rb may join together with the nitrogen atom to which they are attached to form a
heterocyclic ring; or Rc and R may join together with the carbon atom to which they
are attached to form a 3 to 7 membered carbocyclic or heterocyclic ring; 'm' is 0 or 1;
and 'n' is 0 or 1.
18. The compound of claim 17, wherein the heteroaryl is pyrimidine, oxadiazole,
19. The compound of claim 17, wherein the heteroarylalkyl is oxadiazole-methyl,
20. The compound of claim 17, 18, or 19, wherein the aryl, heteroaryl, heterocyclyl,
arylalkyl or heteroarylalkyl are substituted or unsubstituted, and the substituents are
selected from the group consisting of halogen, alkyl, haloalkyl and cycloalkyl.
21. The compound of claim 1, wherein is hydrogen.
22. The compound of claim 1, wherein R5, R6 R7 and R are each
independently hydrogen or halogen.
23. The compound of claim 1, wherein any two of R4, R5, R R7, R8 and Z are
joined together to form a cycloalkyl or heterocyclyl ring.
24. The compound of claim 1, wherein = is a single or double bond; W is selected from
group A as defined in claim 1, or a 5-membered heteroaryl; R2 is
hydrogen or halogen; R3 is -S(0 ) Ra, -C(0)NR aR , -N(R a)C(0)R b, -N(R a)C(0)OR b,
heterocyclyl or heteroaryl, wherein Ra and R are each independently a hydrogen, alkyl;
X is -O, or -NH-; Z is alkyl, haloalkyl, heteroaryl, heterocyclyl, -C(0)Oalkyl, -
C(0)CR cRdRe, or -(CH2) qCRcR Re; R5, R6, R7 and R are hydrogen or halogen, or any
two of R4, R5, R R7, R8 and Z may join together to form a cycloalkyl or heterocyclyl
ring; Rc, Rd, and Re are as defined in claim 1; 'm' is 1; and 'n' is 1.
25. The compound of claim 1, which is selected from:
tert-Butyl-4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy) piperidine- 1-
carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-
lH-indole;
t rt-Butyl-4-(4-(5-(methylsulfonyl)- 1H-indol- 1-yl)phenoxy)-piperidine- 1-carboxylate;
3-Isopropyl-5-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)-l ,2,4-oxadiazole;
rt-Butyl-4-(((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)methyl)piperidine- 1-carboxylate;
l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-5-
(methylsulfonyl)-lH-indole;
3-Isopropyl-5-(4-(((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)methyl)piperidin- 1-yl)- 1,2,4-oxadiazole;
tert-Butyl-4-((6-(5-((ethoxycarbonyl)amino)-l H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Ethyl (l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-
yl)carbamate;
r/-Butyl-4-((6-(5 -(ethylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
1-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(ethylsulfonyl)-
lH-indole;
2-Methyl- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)propan-2-ol;
1-(4-((6-(5 -(Ethylsulfonyl)- 1H-indol-1 -yl)pyridin-3-yl)oxy)piperidin- 1-yl)-2-
methylpropan-2-ol;
l-(5-((l-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- H-indole;
5-(Ethylsulfonyl)-l-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-
lH-indole;
rt-Butyl 4-((6-(5 -(isopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-
carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(isopropylsulfonyl)- 1H-indole;
5-(4-((6-(5-(Isopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-3-
methyl- 1,2,4-oxadiazole;
tert-Butyl-4-((6-(5-((2-hydroxyethyl)carbamoyl)- 1H-indol- 1-yl)pyridin-3 -
yl)amino)piperidine- 1-carboxylate;
1-(5 -((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N-(2-
hydroxyethyl)- 1H-indole-5-carboxamide;
t rt-Butyl 4-((6-(5-(dimethylcarbamoyl)-lH-indol-l-yl)pyridin-3-yl)amino)piperidine
1-carboxylate;
1-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lH
indole-5-carboxamide;
2-Methyl- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)propan-l-one;
(±)-tert-Butyl-3 -((6-(5-(methylsulfonyl)- 1H-indol- -yl)pyridin-3-yl)oxypyrrolidine- 1
carboxylate;
(±)- 1-(5 -((1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3 -yl)oxy)pyridin-2-yl)-5 -
(methylsulfonyl)-l H-indole;
(±)-5-(methylsulfonyl)- 1-(5 -((1-(4-(trifluoromethyl)benzyl)pyrrolidin-3 -
yl)oxy)pyridin-2-yl)- 1H-indole;
t rt-Butyl-3-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-azetidine- 1-
carboxylate;
1-(5 -((1-(5-Ethylpyrimidin-2-yl)azetidin-3 -yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)-
1H-indole;
5-(Methylsulfonyl)- 1-(5 -((1-(4-(trifluoromethyl)benzyl)azetidin-3 -yl)oxy)pyridin-2-
yl)-lH-indole;
1-(5-((1-Isobutylpiperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)- 1H-indole;
-Butyl-4-((6-(5-(methylsulfonyl)- 1H-pyrrolo [2,3 -b]pyridin- 1-yl)-pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
1-(5-(( 1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-
lH-pyrrolo[2,3-b]pyridine;
1-(5 -((1-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -
(methylsulfonyl)- lH-pyrrolo[2,3-b]pyridine;
2, 2-Dimethyl- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin
l-yl)propan-l-one;
5-(Methylsulfonyl)- 1-(5 -((1-neopentylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole;
/ert-Butyl-4-((6-(5 -(methylsulfonyl)indolin- 1-yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
1-(5 -((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -
(methylsulfonyl)indoline;
3-Isopropyl-5-(4-((6-(5 -(methylsulfonyl)indolin- 1-yl)pyridin-3-yl)oxy)-piperidin- 1-
yl)-l,2,4-oxadiazole;
rt-Butyl-4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1
carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
tert-Butyl-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)-methoxy)piperidine-
1-carboxylate;
1-(5 -((( -(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-5 -
(methylsulfonyl)- 1H-indole;
t rt-Butyl-4-((6-(5-(dimethylcarbamoyl)indolin-l-yl)pyridin-3-yl)oxy)-piperidine-lcarboxylate;
t rt-Butyl-4-(((6-(5-(methylsulfonyl)indolin- 1-yl)pyridin-3 -yl)oxy)-methyl)piperidine-
1-carboxylate;
t rt-butyl 4-(((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)methyl)piperidine- 1-carboxylate;
t rt-Butyl-4-((6-(5-(methylsulfonyl)indolin- -yl)pyridin-3-yl) methoxy) piperidine- -
carboxylate;
1-(5 -(((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-N,Ndimethyl-
H-indole-5-carboxamide;
(syn)-tert-Butyl-9-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-3 -oxa-7-
azabicyclo[3 .3 .1]nonane-7-carboxylate;
(anti) rt-Butyl- 9-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)-3-oxa-7-
azabicyclo[3.3.1]nonane-7-carboxylate;
syn 7-(5-Ethylpyrimidin-2-yl)-9-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)-3-oxa-7-azabicyclo[3.3.1]nonane;
anti 7-(5-Ethylpyrimidin-2-yl)-9-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)-3-oxa-7-azabicyclo[3 .3.1 ]nonane;
t rt-Butyl-4-((6-(5 -cyano- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-carboxylate;
rt-Butyl-4-((6-(5 -(cyclopropylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
N-cyclopropyl- 1-(5 -((1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindole-
5-carboxamide;
t rt-Butyl-4-((6-(5 -(oxazol-2-yl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine- -
carboxylate;
t rt-Butyl-4-((6-(5 -isobutyramido- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
N-(1-(5 -((1-(3 -isopropyl- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)- Hindol-
5-yl)isobutyramide;
l-(5-((l-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-5-
carbonitrile;
2-( 1-(5 -(( 1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)oxazole;
rt-Butyl-4-((6-(5 -(methylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)-oxy)piperidine- 1-
carboxylate;
rt-Butyl-4-((6-(5 -(ethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidine- 1-
carboxylate;
rt-Butyl-4-((6-(5 -(isopropylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1
carboxylate;
1-(5 -(( -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-methyl- 1H-indole
5-carboxamide;
N-ethyl- 1-(5-((l -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-5-
carboxamide;
1-(5 -((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-isopropyl- 1Hindole-
5-carboxamide ;
tert-Butyl-4-(((6-(5-(methylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)-
oxy)methyl)piperidine- 1-carboxylate;
1-(5 -((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-N-methyl- 1Hindole-
5-carboxamide;
l-(5-((l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-metliyl-
1H-indole-5-carboxamide;
ter/-Butyl- 4-((6-(5 -(pyrrolidine- 1-carbonyl)-l H-indol-1 -yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Isopropyl 4-((6-(5 -(pyrrolidine- 1-carbonyl)- H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
(1-(5-((1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)(pyrrolidin- 1-yl)methanone;
Isopropyl 4-((6-(5 -(isopropylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy) piperidine-
1-carboxylate;
Ethyl-4-((6-(5-(isopropylcarbamoyl)- 1H-indol-1-yl)pyridin-3 -yl)oxy)-piperidine- 1-
carboxylate;
Isopropyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy) piperidine- 1
carboxylate;
Ethyl-4-((6-(5-(dimethylcarbamoyl)- 1H-indol-1-yl)pyridin-3 -yl)oxy)-piperidine- 1-
carboxylate;
tert-Butyl-4-((6-(5-((2-hydroxyethyl)carbamoyl)- 1H-indol- 1-yl)-pyridin-3 -
yl)oxy)piperidine-l -carboxylate;
1-(5-(( 1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2-hydroxyethyl)-
1H-indole-5-carboxamide;
tr ra (±)-tert-Butyl-3-fluoro-4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
3-Ethyl-5-((4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidin- 1-
yl)methyl)- 1,2,4-oxadiazole;
3-Isopropyl-5-((4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1
yl)methyl)- 1,2,4-oxadiazole;
l-(5-((l-(4-Fluorophenyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole;
1-(5 -((1-(4-Fluorobenzyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1Hindole;
1-(5 -((1-((4-Ethyloxazol-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-
1H-indole-5-carboxamide;
1-(5 -((1-((4-Isopropyloxazol-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
1H-indole-5-carboxamide;
3-Cyclopropyl-5-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin
1-yl)- 1,2,4-oxadiazole;
4-Cyclopropyl-2-((4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)methyl)oxazole;
terr-Butyl-4-((6-(5-((2,2,2-trifluoroethyl)carbamoyl)-lH-indol-l-yl)-pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2,2,2-
trifluoroethyl)-lH-indole-5-carboxamide;
Isopropyl 4-((6-(5-((2-hydroxyethyl)carbamoyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Ethyl 4-((6-(5-((2-hydroxyethyl)carbamoyl)- 1H-indol- -yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
tert-Butyl-4-((6-(7-fluoro-5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
3-Methyl-5-(4-((6-(5-(methylsulfonyl)-l H-indol- 1-yl) pyridin-3-yl) oxy) piperidin-1-
yl)-l, 2, 4-oxadiazole;
Methyl- l-(5-((l-(tert-butoxycarbonyl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indole-5-
carboxylate;
tert-Butyl-4-((6-(5-(hydroxymethyl)-lH-indol-l-yl) pyridin-3-yl) oxy) piperidine -1-
carboxylate;
Methyl-l-(5-((l-(5-ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indole-
5-carboxylate;
(l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indol-5-yl)
methanol;
rt-Butyl-4-((6-(5-(isobutyramido methyl)- 1H-indol- 1-yl) pyridin-3-yl) oxy)
piperidine- 1-carboxylate;
N-((l-(5-((l-(5-ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indol-5-yl)
methyl) isobutyramide;
fer/-Butyl-4-((6-(5-(3-isopropyl-l, 2, 4-oxadiazol-5-yl)-l H-indol- 1-yl) pyridin-3-yl)
oxy) piperidine- 1-carboxylate;
5-(l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indol-5-yl)-
3-isopropyl-l, 2, 4-oxadiazole;
Isopropyl 4-((6-(5-(3-isopropyl-l, 2, 4-oxadiazol-5-yl)-lH-indol-l-yl) pyridin-3-yl)
oxy) piperidine-l-carboxylate;
rt-Butyl-4-((6-(5 -(3 -methyl- 1, 2, 4-oxadiazol-5-yl)-lH-indol-l-yl) pyridin-3-yl) oxy)
piperidine- 1-carboxylate;
5-(l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-lH-indol-5-yl)-
3-methyl-l, 2, 4-oxadiazole;
rt-Butyl- 4-((6-(5-(pyrrolidin-l-yl)-lH-indol-l-yl) pyridin-3-yl) oxy) piperidine-lcarboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) pyridin-2-yl)-5-(pyrrolidin-l-yl)-
lH-indole;
1-(5-(((l-(5-Ethylpyrimidin-2-yl) piperidin-4-yl) oxy) methyl) pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
Ethyl 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy) piperidine-lcarboxylate;
Isopropyl 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl) pyridin-3-yl) methoxy) piperidine
- 1-carboxylate;
2-Methyl- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl) pyridin-3-yl) methoxy)
piperidin-l-yl) propan-2-ol;
l-(5-(((l-(2-Fluoro-2-methylpropyl) piperidin-4-yl) oxy) methyl) pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
3-Isopropyl-5-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl) pyridin-3-yl) methoxy)
piperidin-l-yl)-l, 2, 4-oxadiazole;
3-Methyl-5-(4-((6-(5-(methylsulfonyl)- lH-indol- 1-yl) pyridin-3-yl) methoxy)
piperidin-l-yl)-l, 2, 4-oxadiazole;
l-(5-(((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2-yl)-5-
(methylsulfonyl)indoline;
rt-Butyl-4-((6-(5-isobutyramido- 1H-indol-1 -yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
3-Isopropyl-5-(4-((6-(5-(methylsulfonyl) indolin-l-yl) pyridin-3-yl) methoxy)
piperidin-l-yl)-l, 2, 4-oxadiazole;
t rt-Butyl-4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-2-yl)oxy)-piperidine- 1-
carboxylate;
1-(6-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)-
lH-indole;
N-(1-(5-((1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- H-indol-5-
yl)pivalamide;
N-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-6-(5-(methylsulfonyl)- 1H-indol- 1-
yl)pyridin-3 -amine;
N-(l -(3-isopropyl- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)-6-(5-(methylsulfonyl)- 1Hindol-
l-yl)pyridin-3-amine;
N-( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-6-(5-(methylsulfonyl)-indolin- 1-
yl)pyridin-3-amine;
t rt-Butyl-4-(((6-(5-isobutyramido- 1H-indol- 1-yl)pyridin-3-yl)oxy)-
methyl)piperidine- 1-carboxylate;
N-(1-(5 -((1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)isobutyramide;
N-(l -(5-(( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)- 1H-indol-5-
yl)isobutyramide;
tert-Butyl- 4-((6-(5-isobutyramidoindolin- 1-yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
Isopropyl 4-(((6-(5-isobutyramido-1H-indol- 1-yl)pyridin-3 -yl)oxy)methyl) piperidine-
1-carboxylate;
N-(l-(5-((l-isobutyrylpiperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-yl)isobutyramide;
2-Chloro- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)ethanone;
N-(l-(5-((l-(2,2,2-trifluoroacetyl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-
yl)isobutyramide;
fe rt-Butyl-4-((6-(5-(cyclopropanecarboxamido)-l H-indol- l-yl)pyridine-3 -
yl)oxy)piperidine- 1-carboxylate;
tert-Butyl-4-((6-(5-((isopropoxycarbonyl)amino)-l H-indol- 1-yl)- pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Isopropyl (1-(5 -((1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)carbamate;
t rt-Butyl- 4-((6-(5-(N-methylisobutyramido)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
Isopropyl (l-(5-((l-(3-isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-
yl)- 1H-indol-5-yl)carbamate;
N-(l-(5-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-yl)-Nmethylisobutyramide;
rt-Butyl-4-((6-(5 -(isopropylcarbamoyl)indolin- 1-yl)pyridin-3 -yl)-oxy)piperidine- 1-
carboxylate;
Isopropyl (l-(5-((l-(3-methyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5-yl)carbamate;
rt-Butyl-4-(((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)methyl)amino)piperidine- 1-carboxylate;
l-(5-Ethylpyrimidin-2-yl)-N-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)methyl)piperidin-4-amine ;
Ethyl (l-(5-((l -(3-methyl- 1,2,4-oxadiazol-5 -yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)carbamate;
Ethyl (1-(5-(( 1-(3 -isopropyl- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)carbamate;
Ethyl (l-(5-((l-(3-ethyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5- yl)carbamate;
Isopropyl (1-(5 -(( 1-(3 -ethyl- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)carbamate;
3-Ethyl-5-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-
1,2,4-oxadiazole;
5-(4-((6-(5 -(ethylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-3-methyl-
1,2,4-oxadiazole;
3-ethyl-5-(4-((6-(5-(ethylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)piperidin-l-yl)-
1,2,4-oxadiazole;
l-(5-((l-(3-Ethyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyllH-
indole-5-carboxamide;
l-(5-((l-(3-Isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-pyridin-2-yl)-N,Ndimethyl-
lH-indole-5-carboxamide;
Ethyl (l-(5-((l-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5-yl)carbamate;
N-(2-hydroxyethyl)- 1-(5-(( 1-(3 -isopropyl- 1,2,4-oxadiazol-5-yl)piperidin-4-
yl)oxy)pyridin-2-yl)-lH-indole-5-carboxamide;
(±)- 1-(5 -((1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3 -yl)oxy)pyridin-2-yl)-N-(2-
hydroxyethyl)- 1H-indole-5-carboxamide;
(±)-3-Ethyl-5-(3-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)pyrrolidin-lyl)-
1,2,4-oxadiazole;
5-(Methylsulfonyl)- 1-(5-(( 1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)pyridin-2-
yl)-lH-indole;
tert-Butyl-4-((6-(5-methoxy- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
(±)-3-Isopropyl-5-(3 -((6-(5-(methylsulfonyl)- 1H-indol- -yl)pyridin-3-
yl)oxy)pyrrolidin- 1-yl)-1,2,4-oxadiazole;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-methoxy-lHindole;
1-(5 -(( -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -methoxy- 1Hpyrrolo
[2,3-b]pyridine ;
(±)-3-Ethyl-5-((3 -((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)pyrrolidin-
1-yl)methyl)- 1,2,4-oxadiazole;
(±)-3-Isopropyl-5-((3 -((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)pyrrolidin-l-yl)methyl)-l,2,4-oxadiazole;
3-Isopropyl-5-((3-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)azetidin- 1-
yl)methyl)- 1,2,4-oxadiazole;
3-Ethyl-5-((3 -((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)azetidin- 1-
yl)methyl)- 1,2,4-oxadiazole;
1-(5-(( 1-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-N-(2-
hydroxyethyl)-lH-indole-5-carboxamide;
cis (±)-tert-Butyl-3-fluoro-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)-pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
cis (±) (l-(5-(-l-(5-Ethylpyrimidin-2-yl)-3-fluoropiperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
rt-Butyl-4-((6-(5-(2-oxooxazolidin-3 -yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine-
1-carboxylate;
Isopropyl 4-((6-(5-(2-oxooxazolidin-3-yl)-lH-indol-l-yl)pyridin-3-yl)oxy)piperidine-
1-carboxylate;
t rt-Butyl- 4-((6-(3 -methyl-5-(methylsulfonyl)- H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-3-methyl-5-
(methylsulfonyl)- 1H-indole;
Isopropyl 4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
Isopropyl 4-((6-(7-fluoro-5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-
yl)oxy)piperidine-l -carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-7-fluoro-5-
(methylsulfonyl)- 1H-indole;
2,2,2-Trifluoro- 1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidinl-
yl)ethanone;
tert-Butyl-4-((5-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-2-yl)oxy)-piperidine- -
carboxylate;
l-(6-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-3-yl)-5-(methylsulfonyl)-
lH-indole;
(4-((6-(5-(Methylsulfony 1)- 1H-indol- -yl)pyridin-3 -yl)oxy)piperidin- 1-yl)( 1-
(trifluoromethyl)cyclopropyl)methanone;
3-Isopropyl-5-(4-((5-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-2-yl)oxy) piperidin-1-
yl)- 1,2,4-oxadiazole;
5-(4-((6-(7-Fluoro-5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
3-isopropyl-l ,2,4-oxadiazole;
teri-Butyl-4-((6-(5 -(2-oxopyrrolidin- 1-yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy) piperidine-
1-carboxylate;
l-(l-(5-((l-(5-Ethylpyrirnidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-
yl)pyrrolidin-2-one;
rt-Butyl-4-((6-(5 -cyano-7-fluoro- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidine- 1-
carboxylate;
1-(5 -((1-(5 -Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-7-fluoro- 1H-indole-
5-carbonitrile;
Ethyl 4-((6-(5-(2-oxopyrrolidin- 1-yl)-1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
tert-Butyl-4-((6-(5 -(cyclopropylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine-
1-carboxylate;
5-(Cyclopropylsulfonyl)- 1-(5-((1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-
yl)-lH-indole;
Ethyl-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidine- 1-
carboxylate;
tert-Butyl-4-((6-(5 -(1H-tetrazol- 1-yl)-1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
Ethyl-4-((6-(5 -(1 H-tetrazol- 1-yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidine- 1-
carboxylate;
Ethyl (1-(5 -(( 1-(5 -ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(methyl)carbamate;
rt-Butyl 4-((6-(5 -(1H-1,2,4-triazol- 1-yl)-1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine-
1-carboxylate;
l-(5-((l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(lH-l,2,4-triazoll-
yl)-lH-indole;
Isopropyl 4-((6-(5 -(1H-1,2,4-triazol- 1-yl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine-
1-carboxylate;
Ethyl-4-((6-(5-( 1H-1,2,4-triazol- 1-yl)-1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
5-(methylsulfonyl)- 1-(5 -((1-((1-(trifluoromethyl)cyclopropyl)methyl)-piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indole;
3-(1-(5 -((1-(4-Ethylphenyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)oxazolidin-
2-one;
5-(Methylsulfonyl)- 1-(5 -((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)pyridin-2-
yl)-l H-indole;
1-(4-((6-(5-(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)-piperidin- 1-yl)-2-
(pyrrolidin- 1-yl)ethanone;
1-(4-((6-(5-(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidin- 1-yl)-2-
(piperidin- 1-yl)ethanone;
1-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-piperidin- 1-yl)-2-
morpholinoethanone;
1-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)-5 -(methylsulfonyl)- 1Hindole;
1-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)-5 -
(methylsulfonyl)indoline;
tert-buty14-((2-(5-(methylsulfonyl)- 1H-indol-1-yl)pyridin-4-yl)methoxy)piperidine- 1
carboxylate;
1-(4-(((1-(5 -ethylpyrimidin-2-yl)piperidin-4 yl)oxy)methyl)pyridin-2-yl)-5 -
(methylsulfonyl)- 1H-indole;
5-(methylsulfonyl)- 1-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H -
indole;
2-(4-((6-(5-(methylsulfonyl)- 1H-indol-1-yl)pyridin-3yl)oxy)piperidin- 1-yl)- 1-
(pyrrolidin- 1-yl)ethanone;
2-Cyclopentyl- 1-(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin
1-yl)ethanone;
½rt-Butyl-4-((4-(5-(methylsulfonyl)- 1H-indol- 1-yl)thiazol-2-yl)oxy)-piperi dine-1-
carboxylate;
tert-Butyl-4-(((4-(5-(methylsulfonyl)-lH-indol-l-yl)thiazol-2-
yl)oxy)methyl)piperidine- 1-carboxylate;
2-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-4-(5-(methyl-sulfonyl)- 1H-indol- -
yl)thiazole;
4-(5 -(1H-tetrazol- 1-yl)-1H-indol-1-yl)-2-((1-(5 -ethylpyrimidin-2-yl)piperidin-4-
yl)oxy)thiazole;
rt-Butyl-4-((4-(5 -(1H-tetrazol- 1-yl)- 1H-indol-1-yl)thiazol-2-yl)oxy)piperidine- 1-
carboxylate;
rt-Butyl-4-((4-(5-((ethoxycarbonyl)amino)-lH-indol-l-yl)thiazol-2-
yl)oxy)piperidine- 1-carboxylate;
rt-Butyl-4-((4-(5-((isopropoxycarbonyl)amino)-l H-indol- 1-yl)thiazol-2-
yl)oxy)piperidine- 1-carboxylate;
Ethyl (1-(2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)- 1H-indol-5-
yl)carbamate;
Isopropyl ( -(2-(( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)thiazol-4-yl)- 1H-indol-
5-yl)carbamate;
5-(4-((4-(5-( 1H-tetrazol- 1-yl)- 1H-indol- 1-yl)thiazol-2-yl)oxy)-piperidin- 1-yl)-3 -
isopropyl- 1,2,4-oxadiazole;
tert-Butyl 4-((4-(7-fluoro-5-(methylsulfonyl)- 1H-indol- 1-yl)thiazol-2-
yl)oxy)piperidine- 1-carboxylate;
tert -Butyl-4-((4-(5 -(methylsulfonyl)indolin- 1-yl)thiazol-2-yl)oxy)-piperidine- 1-
carboxylate;
2-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-4-(5-(methylsulfonyl)indolin-lyl)
thiazole;
Isopropyl 4-((4-(5 -(methylsulfonyl)indolin- 1-yl)thiazol-2-yl)oxy)piperidine- 1-
carboxylate;
ter t-Butyl- 4-((4-(5-( 1H-1,2,4-triazol- 1-yl)- 1H-indol- 1-yl)thiazol-2-yl)oxy)piperidine-
1-carboxylate;
Cyclobutyl(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl) oxy) piperidin- 1-
yl)methanone;
Cyclopentyl(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy) piperidin- 1-
yl)methanone;
Cyclohexyl(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy) piperidin- 1-
yl)methanone;
l-(5-((l-(2,2-Difluoropropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole;
l-(5-((l-((l-Fluorocyclopentyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
1-(5-((l -((1 -Fluorocyclobutyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)-l H-indole;
l-(5-((l-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
1-(5 -((1-((5-Fluoropyridin-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -
(methylsulfonyl)- lH-indole;
1-(Furan-2-yl)-2-(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidinl-
yl)ethanone;
3-((6-(5-(Methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)-6-((l-
(trifluoromethyl)cyclopropyl)methyl)-6-azabicyclo[3.1.1]heptanes;
5-(Methylsulfonyl)-l-(5-((8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-
yl)oxy)pyridin-2-yl)- 1H-indole;
(4-((6-(5-(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)(pyrrolidinl-
yl)methanone;
N,N-Diethyl-4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-
carboxamide;
5-(Methylsulfonyl)-l-(5-((l-(4,4,4-trifluoro-2-methylbutan-2-yl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indole;
1-(5-(( 1-(1,1-Difluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-
(methylsulfonyl)- 1H-indole;
1,3-Difluoropropan-2-yl 4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine-l-carboxylate;
3-Fluoro-3 -methyl- -(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)butan- 1-one;
3-Fluoro- 1-(5-((1-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1Hindole;
l-(5-((l-Isobutyl-2,6-dimethylpiperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-
1H-indole;
5-(Methylsulfonyl)- 1-(5-((1-(2-(pyrrolidin- 1-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indole;
1-(5 -((1-Isopropylpiperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1H-indole;
l-(5-((l-(2-Methoxyethyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole;
5-(Methylsulfonyl)- 1-(5-(( 1-propylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole;
3-(4-((6-(5-(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)butan-2-
one;
1-(5-(( 1-Cyclobutylpiperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)- 1H-indole;
1,1,1 -Trifluoro-3 -(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin-
1-yl)propan-2-one;
5-(Methylsulfonyl)-l-(5-((l-(pentan-3-yl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indole;
Isobutyl 4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
2-Methoxyethyl4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine-
1-carboxylate;
Neopentyl4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
Cyclohexyl4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
Cyclobutyl(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- -
yl)methanone;
2-(Dimethylamino)-l -(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)ethanone;
Cyclopentyl(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-
yl)methanone;
Furan-2-yl(4-((6-(5 -(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1- .
yl)methanone;
1-(5-((l-(5-Ethylpyrazin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole;
3-(1-(4-((6-(5 -(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)ethyl)-
6-oxa-3-azabicyclo[3. 1.1]heptanes;
6-( 1-(4-((6-(5 -(Methylsulfonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)ethyl)-
2-oxa-6-azaspiro [3 .3]heptanes;
4-(2-(4-((6-(5-(Methylsulfonyl)- 1H-indol- -yl)pyridin-3-yl)oxy)piperidin- 1-
yl)ethyl)morpholine;
N,N-Dimethyl-2-(4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyridin-3-yl)oxy)piperidinl-
yl)acetamide;
Cyclohexyl(4-((6-(5-(methylsulfonyl)- 1H-indol-1-yl)pyridin-3-yl)oxy)piperidin- 1-
yl)methanone;
Cyclopropyl(4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-
yl)methanone;
1-(5 -((1-Cyclopentylpiperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1H-indole;
1-(5-((1-Cyclohexylpiperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)- 1H-indole;
1-(5 -(( -(Cyclopropylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1Hindole;
l-(5-((l-(Cyclohexylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)-5-(methylsulfonyl)-lHindole;
1-(5-((l-(Cyclobutylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1Hindole;
1-(5 -((1-(4-Chlorobenzyl)piperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1Hindole;
1-(5 -((1-Benzylpiperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1H-indole;
1-(5 -((1-Cyclopropylpiperidin-4-yl)oxy)pyridin-2-yl)-5 -(methylsulfonyl)- 1H-indole;
Cyclopropyl 4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- -
carboxylate;
2-Fluoroethyl 4-((6-(5-(methylsulfonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine- 1-
carboxylate;
Azetidin- 1-yl(1-(5 -((1-(cyclobutylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- l-yl(l-(5-((l-(l,l -difluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl(1-(5 -((1-((1-fluorocyclopentyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5-yl)methanone;
Azetidin- 1-yl(1-(5 -((1-((1-fluorocyclobutyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-
lH-indol-5-yl)methanone;
Azetidin- 1-yl(1-(5-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H -
indol-5-yl)methanone;
Azetidin- 1-yl(l -(5-((l -((5-fluoropyridin-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)
lH-indol-5-yl)methanone;
1-(4-((6-(5 -(Azetidine- 1-carbonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-2-
(furan-2-yl)ethanone;
1,3-Difluoropropan-2-yl 4-((6-(5-(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine-l-carboxylate;
Azetidin- l-yl(l-(5-((l -(pyrrolidine- 1-carbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
4-((6-(5-(Azetidine- 1-carbonyl)- 1H-indol-1-yl)pyridin-3-yl)oxy)-N,Ndiethylpiperidine-
1-carboxamide;
Azetidin- 1-yl(1-(5 -((1-(4,4,4-trifluoro-2-methylbutan-2-yl)piperidin-4-yl)oxy)pyridin
2-yl)-lH-indol-5-yl)methanone;
Azetidin- 1-yl(1-(5 -((1-(1,1-difluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5-yl)methanone;
1-(4-((6-(5 -(Azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
3,3-difluorobutan-l-one;
Azetidin- 1-yl(1-(5-((l -isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl(1-(5 -((1-(2-(pyrrolidin- 1-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone ;
Azetidin- 1-yl(1-(5-(( 1-isopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-propylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-cyclopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-cyclobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-cyclopentylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Azetidin- 1-yl( 1-(5-(( 1-cyclohexylpiperidin-4-yl)oxy)pyridin-2-yl)- H-indol-5-
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-(cyclohexylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-(2-methoxyethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
2-Methoxy ethyl 4-((6-(5 -(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
3-(4-((6-(5 -(Azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)butan-2-one;
3-(4-((6-(5 -(Azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
1,1,1 -trifluoropropan-2-one
Azetidin- 1-yl( 1-(5 -(( 1-(cyclopropylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
Azetidin- 1-yl( 1-(5-(( 1-(cyclobutylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl( 1-(5 -(( 1-(pentan-3 -yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Neopentyl 4-((6-(5 -(azetidine- 1-carbonyl)- H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine-
1-carboxylate;
Cyclohexyl 4-((6-(5 -(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
Cyclopropyl 4-((6-(5 -(azetidine- -carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- -carboxylate;
2-Fluoroethyl 4-((6-(5 -(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
Azetidin- 1-yl( 1-(5 -((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Azetidin- -yl( 1-(5 -((1-(cyclobutanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Azetidin- 1-yl( 1-(5 -((1-(cyclopentanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- Hindol-
5-yl)methanone;
Azetidin- 1-yl( 1-(5 -(( -(5 -ethylpyrazin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
Azetidin- 1-yl(l -(5-(( 1-(2-morpholinoethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
2-(4-((6-(5-(Azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
N,N-dimethylacetamide;
Azetidin- 1-yl( 1-(5-((l -(morpholinomethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
(l-(5-((l-(l -(6-Oxa-3 -azabicyclo [3.1.1 ]heptan-3 -yl)ethyl)piperidin-4-yl)oxy)pyridin-
2-yl)- 1H-indol-5-yl)(azetidin- 1-yl)methanone;
( 1-(5-(( 1-(1-(2-Oxa-6-azaspiro[3 .3]heptan-6-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5 -yl)(azetidin- 1-yl)methanone;
Azetidin-l-yl(l-(5-((l-((lS,4R)-bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)oxy)pyridin-
2-yl)-lH-indol-5-yl)methanone;
Azetidin- 1-yl( 1-(5 -((1-(isopropylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)methanone;
Azetidin- l-yl(l-(5-((l -(cyclopropylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Azetidin-l-yl(l-(5-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-
yl)methanone;
Azetidin- 1-yl(1-(5-((1-(ethylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl(1-(5-((1-(3,3,3 -trifluoro-2,2-dimethylpropyl)piperidin-4-yl)oxy)pyridin-
2-yl)-lH-indol-5-yl)methanone;
Azetidin- 1-yl(1-(5-((1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-
yl)oxy)pyridin-2-yl)-lH-indol-5-yl)methanone;
Azetidin- l-yl(l-(5-((l-((l -(triiluoromethyl)cyclobutyl)methyl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)methanone;
Azetidin- 1-yl(1-(5-((1-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Azetidin- 1-yl(1-(5-((1-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
(1-(5 -((1-(1,1-Difluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
(l-(5-((l-((l -Fluorocyclopentyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
(l-(5-((l-((l -Fluorocyclobutyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)- H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
(1-(5-((1-(2-Fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
( 1-(5-((l -((5-Fluoropyrimidin-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-
5-yl)(pyrrolidin-l-yl)methanone;
2-(Furan-2-yl)- -(4-((6-(5-(pyrrolidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)ethanone;
1,3-Difluoropropan-2-yl 4-((6-(5-(pyrrolidine- 1-carbonyl)- H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Pyrrolidin- 1-yl(4-((6-(5 -(pyrrolidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidin- 1-yl)methanone;
N,N-Diethyl-4-((6-(5-(pyrrolidine- 1-carbonyl)-1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxamide;
Pyrrolidin- 1-yl(1-(5 -((1-(4,4,4-trifluoro-2-methylbutan-2-yl)piperidin-4-
yl)oxy)pyridin-2-yl)-lH-indol-5-yl)methanone;
(1-(5-((1-(1,1-Difluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
3,3-Difluoro- 1-(4-((6-(5 -(pyrrolidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidin- 1-yl)butan- 1-one;
( 1-(5-((l -Isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)(pyrrolidin- 1-
yl)methanone;
Pyrrolidin- 1-yl(l -(5-((l -(2-(pyrrolidin- 1-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone ;
(1-(5 -((1-Isopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)(pyrrolidin- 1-
yl)methanone;
(1-(5 -((1-Cyclopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)(pyrrolidin- 1-
yl)methanone;
( 1-(5-((1-Cyclobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)(pyrrolidin- 1-
yl)methanone;
( 1-(5-((1-Cyclopentylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)(pyrrolidin- 1-
yl)methanone;
( 1-(5-((l -Cyclohexylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)(pyrrolidin-l -
yl)methanone;
(l-(5-((l -(Cyclohexylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)(pyrrolidin- 1-yl)methanone;
(l-(5-((l-(2-Methoxyethyl)piperidin-4-yl)oxy)pyridin-2-yl)-lH-indol-5-yl)(pyrrolidin
l-yl)methanone;
Pyrrolidin -1-yl(1-(5 -((1-(cyclobutylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- Hindol-
5-yl)methanone;
Pyrrolidin -1-yl(1-(5 -((1-(1,1-difluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol
5-yl)methanone;
Pyrrolidin -1-yl(1-(5 -((1-((1-fluorocyclopentyl)methyl)piperidin-4-yl)oxy)pyridin-2-
yl)- 1H-indol-5-yl)methanone;
Pyrrolidin -1-yl(1-(5-((1-((1-fluorocyclobutyl)methyl)piperidin-4-yl)oxy)pyridin-2-
yl)-lH-indol-5-yl)methanone;
Pyrrolidin -l-yl(l-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indol-5-yl)methanone;
Pyrrolidin -1-yl(1-(5-((1-((5-fluoropyridin-2-yl)methyl)piperidin-4-yl)oxy)pyridin-2-
yl)-l H-indol-5-yl)methanone;
1-(4-((6-(5 -(Azetidine- 1-carbonyl)-1H-indol-1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-2-
(furan-2-yl)ethanone;
1,3-Difluoropropan-2-yl 4-((6-(5 -(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
Pyrrolidin - -yl(1-(5 -((1-(pyrrolidine-1-carbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H
indol-5-yl)methanone;
4-((6-(5-(Azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)-N,Ndiethylpiperidine-
-carboxamide;
Pyrrolidin - 1-yl(l -(5-((l -(4,4,4-trifluoro-2-methylbutan-2-yl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)methanone;
Pyrrolidin -1-yl(1-(5-((1-(1,1-difluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridin-2-
yl)-lH-indol-5-yl)methanone;
1-(4-((6-(5 -(Azetidine- 1-carbonyl)- 1H-indol-1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
3,3-difluorobutan- 1-one;
Pyrrolidin -1-yl( 1-(5-(( 1-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-(2-(pyrrolidin- 1-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)-
lH-indol-5-yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-isopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-propylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-cyclopropylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-cyclobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Pyrrolidin -1-yl( 1-(5 -(( 1-cyclopentylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5-
yl)methanone;
Pyrrolidin -1-yl( 1-(5 -(( 1-cyclohexylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Pyrrolidin -1-yl( 1-(5 -(( 1-(cyclohexylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone ;
Pyrrolidin -1-yl( 1-(5-(( 1-(2-methoxyethyl)piperidin-4-yl)oxy)pyridin-2-yl)- H-indol-
5-yl)methanone;
2-Methoxyethyl 4-((6-(5-(azetidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine-l-carboxylate;
3-(4-((6-(5 -(Pyrrolidin -1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-
yl)butan-2-one;
3-(4-((6-(5 -(Pyrrolidin -1-carbonyl)- H-indol- 1-yl)pyridin-3 -yl)oxy)piperidin- 1-yl)-
1,1,1 -trifluoropropan-2-one;
Pyrrolidin -1-yl( 1-(5 -(( 1-(cyclopropylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5 -yl)methanone ;
Pyrrolidin -1-yl( 1-(5-((l -(cyclobutylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-(pentan-3-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Neopentyl 4-((6-(5-( pyrrolidin - 1-carbonyl)- 1H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Cyclohexyl 4-((6-(5-( pyrrolidin - 1-carbonyl)- 1H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- -carboxylate;
Cyclopropyl 4-((6-(5-( pyrrolidin - 1-carbonyl)- 1H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
2-Fluoroethyl 4-((6-(5-( pyrrolidin - 1-carbonyl)- 1H-indol- l-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Pyrrolidin -1-yl(1-(5 -((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Pyrrolidin -l-yl(l-(5-((l-(cyclobutanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-lHindol-
5-yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-(cyclopentanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-(5 -ethylpyrazin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hmdol-
5-yl)methanone;
Pyrrolidin -1-yl(l -(5-((l -(2-mo holinoethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
2-(4-((6-(5-( Pyrrolidin -1-carbonyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidin- 1-yl)-
N,N-dimethylacetamide;
Pyrrolidin -1-yl(1-(5-((l -(morpholinomethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
(1-(5-(( 1-(1-(6-Oxa-3 -azabicyclo [3.1.1 ]heptan-3-yl)ethyl)piperidin-4-yl)oxy)pyridin-
2-yl)-lH-indol-5-yl)( pyrrolidin -l-yl)methanone;
(l-(5-((l-(l-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)
1H-indol- 5-yl)( pyrrolidin -1-yl)methanone ;
Pyrrolidin -1-yl( 1-(5 -((1-((1S,4R)-bicyclo [2.2.1 ]heptan-2-yl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-(isopropylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5 -yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-(cyclopropylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindol-
5-yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-(methylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-(ethylsulfonyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
Pyrrolidin -1-yl( 1-(5-(( 1-(3 ,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5-yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-
yl)oxy)pyridin-2-yl)- 1H-indol-5 -yl)methanone;
Pyrrolidin -1-yl( 1-(5 -((1-isobutylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indol-5 -
yl)methanone;
2-Methoxyethyl 4-((6-(5 -(pyrrolidine- 1-carbonyl)- 1H-indol- 1-yl)pyridin-3 -
yl)oxy)piperidine- 1-carboxylate;
1-(5 -((1-(1-(2-Oxa-6-azaspiro [3.3]heptan-6-yl)ethyl)piperidin-4-yl)oxy)pyridin-2-yl)-
N,N-dimethyl- 1H-indole-5-carboxamide;
1-(5 -((1-(1-(6-Oxa-3 -azabicyclo [3.1.1 ]heptan-3 -yl)ethyl)piperidin-4-yl)oxy)pyridin-2-
yl)-N,N-dimethyl-lH-indole-5-carboxamide;
1-(5 -((1-(2-(Dimethylamino)-2-oxoethyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
lH-indole-5-carboxamide;
N,N-Dimethyl- 1-(5 -((1-(2-morpholinoethyl)piperidin-4-yl)oxy)pyridin-2-yl)- 1Hindole-
5-carboxamide;
1-(5-((l -(5-Ethylpyridin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
1-(5 -((1-(5-Ethylpyridin-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide ;
l-(5-((l-(Cyclopropanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
1-(5 -((1-(Cyclobutanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
l-(5-((l-(Cyclohexanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
1-(5-((l -(Cyclopentanecarbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
1-(5-((1-(2-(Dimethylamino)acetyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-
1H-indole-5-carboxamide;
1-(5-((l-(Furan-2-carbonyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lH-indole
5-carboxamide;
Isobutyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3 -yl)oxy)piperidine- 1-
carboxylate;
2-Methoxyethyl 4-((6-(5-(dimethylcarbamoyl)- H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
2-Fluoroethyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-
yl)oxy)piperidine- 1-carboxylate;
Neopentyl 4-((6-(5-(dimethylcarbarnoyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidinecarboxylate;
Cyclopropyl 4-((6-(5-(dimethylcarbamoyl)-lH-indol-l-yl)pyridin-3-yl)oxy)piperidine
1-carboxylate;
Cyclohexyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-yl)oxy)piperidine-
1-carboxylate;
l-(5-((l-(2-Methoxyethyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lH-indole-
5-carboxamide;
N,N-Dimethyl- 1-(5-((l -propylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-5-
carboxamide;
l-(5-((l-Cyclobutylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lH-indole-5-
carboxamide;
l-(5-((l-Isopropylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl-lH-indole-5-
carboxamide;
N,N-Dimethyl- 1-(5 -((1-(3-oxobutan-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-
5-carboxamide;
1-(5 -((1-Cyclopentylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
N,N-Dimethyl- 1-(5-((1-(3 ,3,3-trifluoro-2-oxopropyl)piperidin-4-yl)oxy)pyridin-2-yl)-
1H-indole-5-carboxamide;
1-(5-((1-Cyclohexylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
N,N-Dimethyl- 1-(5 -((1-phenethylpiperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-5-
carboxamide;
l-(5-((l -(Cyclopropylmethyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
1-(5-((l -(4-Chlorobenzyl)piperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
1-(5 -((1-Benzylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
1-(5-((l -Cyclopropylpiperidin-4-yl)oxy)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
1-(5-((l-((lS,4R)-Bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)oxy)pyridin-2-yl)-N,Ndimethyl-
1H-indole-5-carboxamide;
N,N-Dimethyl- 1-(5 -((1-(pentan-3-yl)piperidin-4-yl)oxy)pyridin-2-yl)- 1H-indole-5-
carboxamide;
1-(5-((l -(1 -(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)piperidin-4-yl)amino)pyridin-2-
yl)-N,N-dimethyl-lH-indole-5-carboxamide;
1-(5-((l -(1 -(6-Oxa-3-azabicyclo[3 .1.1 ]heptan-3-yl)ethyl)piperidin-4-yl)amino)pyridin-
2-yl)-N,N-dimethyl- 1H-indole-5-carboxamide;
1-(5 -(( -(2-(Dimethylamino)-2-oxoethyl)piperidin-4-yl)amino)pyridin-2-yl)-N,Ndimethyl-
lH-indole-5-carboxamide;
N,N-Dimethyl- 1-(5 -(( 1-(2-morpholinoethyl)piperidin-4-yl)amino)pyridin-2-yl)- 1Hindole-
5-carboxamide;
l-(5-((l-(5-Ethylpyridin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
l-(5-((l-(5-Ethylpyridin-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
1-(5 -(( -(Cyclopropanecarbonyl)piperidin-4-yl)amino)pyridin-2-y l)-N,N-dimethyl-
1H-indole-5-carboxamide;
1-(5-((l -(Cyclobutanecarbonyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
l-(5-((l-(Cyclohexanecarbonyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
l-(5-((l-(Cyclopentanecarbonyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
l-(5-((l-(2-(Dimethylamino)acetyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimeth^
1H-indole-5-carboxamide;
l-(5-((l-(Furan-2-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lHindole-
5-carboxamide;
Isobutyl 4-((6-(5-(dimethylcarbamoyl)-l H-indol-1-yl)pyridin-3-yl)amino)piperidine-
1-carbaminolate;
2-Methaminoethyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-
yl)amino)piperidine- 1-carbaminolate;
2-Fluoroethyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-
yl)amino)piperidine- 1-carbaminolate;
Neopentyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-
yl)amino)piperidine- 1-carbaminolate;
Cyclopropyl 4-((6-(5-(dimethylcarbamoyl)- 1H-indol- 1-yl)pyridin-3-
yl)amino)piperidine- 1-carbaminolate;
Cyclohexyl 4-((6-(5-(dimethylcarbamoyl)-1H-indol-1-yl)pyridin-3-
yl)amino)piperidine- 1-carbaminolate;
1-(5 -((1-(2-Methaminoethyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
N,N-Dimethyl- -(5-((l -propylpiperidin-4-yl)amino)pyridin-2-yl)- 1H-indole-5-
carboxamide;
l-(5-((l-Cyclobutylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl-lH-indole-5-
carboxamide;
1-(5-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
N,N-Dimethyl- 1-(5 -((1-(3-oxobutan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)- 1Hindole-
5-carboxamide;
1-(5 -((1-Cyclopentylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- H-indole-5-
carboxamide;
N,N-Dimethyl-l-(5-((l-(3,3,3-trifluoro-2-oxopropyl)piperidin-4-yl)amino)pyridin-2-
yl)-lH-indole-5-carboxamide;
1-(5-((1-Cyclohexylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5-
carboxamide;
N,N-Dimethyl- 1-(5-((l -phenethylpiperidin-4-yl)amino)pyridin-2-yl)- 1H-indole-5 -
carboxamide;
1-(5-(( 1-(Cyclopropylmethyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
1-(5-(( 1-(4-Chlorobenzyl)piperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1Hindole-
5-carboxamide;
1-(5 -(( 1-Benzylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5 -
carboxamide;
1-(5-(( 1-Cyclopropylpiperidin-4-yl)amino)pyridin-2-yl)-N,N-dimethyl- 1H-indole-5 -
carboxamide;
l-(5-((l-((lS,4R)-Bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-N,Ndimethyl-
1 H-indole-5 -carboxamide and
N,N-Dimethyl- 1-(5 -(( 1-(pentan-3 -yl)piperidin-4-yl)amino)pyridin-2-yl)- H-indole-5-
carboxamide
or pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising one or more compounds of Formula (I)
according to Claim 1, and one or more pharmaceutically acceptable excipients; wherein
the pharmaceutically acceptable exipient is a carrier or a diluent.
27. The pharmaceutical composition of claim 26, further comprising at least
one additional pharmaceutical agent selected from the group consisting of an antiobesity
agent, anti diabetic agent, anti-hyperglycemic agents, anti-hyperinsulinemic
agents, anti-retinopathicc agents, anti-neuropathic agents, anti-nephropathic agents,
anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, antidyslipidemic
agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, antihypercholesterolemic
agents, anti-restenotic agents, anti-pancreatic agents, antimetabolic
syndrome agents, lipid lowering agents, anti-lipodystrophy agents, anti¬
inflammatory agents, appetite suppressants, treatments for heart failure agents and
treatment for peripheral arterial disease agents.
28. The pharmaceutical composition of claim 27, wherein said at least one additional
pharmaceutical agent is an anti diabetic agent selected from the group consisting of
insulin and insulin analogs, insulin secretagogues, insulin sensitizers, glucagon-like
peptide- 1 (GLP-1) receptor agonists including glucagon-like peptides and its analogues,
SGLT2 inhibitors, insulin signaling agonists, RXR agonists, fatty acid oxidation
inhibitors, beta-agonists, phosphodiesterase inhibitors, lipoxygenase inhibitors,
dipeptidyl peptidase-IV (DPP4) inhibitors, PTP1B inhibitors, gluconeogenesis
inhibitors, somatostatin and its analogs, antilipolytic agents; glucose transport
stimulating agents, glucose synthase kinase inhibitors, galanin receptor agonists,
chemokine receptor antagonist, glucokinase activators, GDIR agonists, GPR40
modulators and GPR1 9 modulators.
29. The pharmaceutical composition of claim 27, wherein said additional pharmaceutical
agent is dipeptidyl peptidase-IV (DPP4) inhibitor.
30. The pharmaceutical composition of claim 27, wherein said at least one additional
pharmaceutical agent is Metformin.
31. A method of treating and/or managing diseases or disorders, syndromes or conditions
associated with the modulation of GPR1 19 receptor function comprising administering
to a subject in need thereof, a therapeutically effective amount of a compound of claim
1 or a pharmaceutically acceptable salt thereof.
32. The method of claim 31, wherein the symptoms of a disease, disorder, syndrome or
condition associated with the modulation of GPR1 19 receptor function is selected from
the group consisting of type 2 diabetes, type 1 diabetes, hyperglycemia, impaired
glucose tolerance, insulin resistance, hyperinsulinemia, wound healing, retinopathy,
neuropathy, nephropathy, obesity, Metabolic Syndrome, lipodystrophy including HIV
protease associated lipodystrophy, lipid disorders, hypertension, dyslipidemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,
vascular restenosis, peripheral arterial disease, and its sequela selected from the group
consisting of acute coronary syndrome, myocardial infarction, angina pectoris,
peripheral vascular disease, intermittent claudication, myocardial ischemia, stroke and
heart failure, inflammatory diseases, inflammatory bowel diseases, atherosclerosis and
bone diseases.
A method for the treatment of metabolic or metabolic related diseases, disorders,
syndromes or conditions comprising administering to a subject in need thereof, a
therapeutically effective amount of the compound of Claim 1.
A process for the preparation of a compound of Formula (I):
(I)
comprising,
reacting a compound of formula (2) where L is a leaving group, with a compound of
formula (7), where L' is a leaving group PG is protecting group, in the presence of
suitable base to give a com ound of formula (8),
treating the compound of formula (8) with a compound of formula (5) in the presence
of palladium cataly t to give a compound of formula (9),
ent to give a compound
of formula (10), and
(10)
h) coupling the compound of formula (10) with Z-L where L is a leaving group, to obtain
the compound of formula (I).
36. The compound of claim 16, wherein X is -(CRioRn)qO(CRioRii)t; 'q' is 0 or 1; 't' is 0
or 1; and each of Ri0 and R are hydrogen.
37. The compound of claim 36, wherein X is -0-.
38. The compound of any of the claims 2, 3 or 6, wherein W is selected from