WO2022130352A1 - Novel compounds suitable for the treatment of dyslipidemia - Google Patents

Novel compounds suitable for the treatment of dyslipidemia Download PDF

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Publication number
WO2022130352A1
WO2022130352A1 PCT/IB2021/061988 IB2021061988W WO2022130352A1 WO 2022130352 A1 WO2022130352 A1 WO 2022130352A1 IB 2021061988 W IB2021061988 W IB 2021061988W WO 2022130352 A1 WO2022130352 A1 WO 2022130352A1
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Prior art keywords
trifluoromethyl
phenyl
methanone
piperidin
hydroxyoxetan
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PCT/IB2021/061988
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French (fr)
Inventor
Rajiv Sharma
Sanjay Kumar
Harikishore Pingali
Pankaj Makadia
Pandurang Zaware
Suresh POLA
Prashant Deshmukh
Kiran Shah
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Zydus Lifesciences Ltd
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Cadila Healthcare Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.
  • the present invention is directed towards compounds which can be used to treat diseases such as hyperlipidemia and also have a beneficial effect on cholesterol.
  • the compounds of the general formula (I) lower blood glucose, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering of LDL (and/or raising of HDL) is beneficial.
  • LDL low-density lipoproteins
  • HDL high-density lipoproteins
  • the compounds of general formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as artereosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X.
  • the characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance.
  • the glucose intolerance can lead to non- insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance.
  • NIDDM non- insulin dependent diabetes mellitus
  • Diabetes is no longer considered to be associated only with glucose metabolism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state.
  • the compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, like arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.
  • the compounds of the present invention can be useful as aldose reductase inhibitors; for improving cognitive functions in dementia, and in the treatment and/or prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia.
  • disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia.
  • BACKGROUND OF THE INVENTION Higher LDL cholesterol levels in the plasma increase cardiovascular risk and reduction in the levels of LDL would decrease CVD risk by a comparable percentage (PNAS, 2009, 106,
  • LDL receptors in the liver and LDL receptors are cell surface glycoproteins that bind to apoliporpotein B100 (apoB100) on LDL particles with high affinity and mediate their endocytic uptake (Journal of Biological Chemistry, 2009, 284, 10561-10570).
  • apoB100 apoliporpotein B100
  • Defect in hepatic cholesterol clearance and elevated levels of plasma LDL cholesterol that result from the mutations cause familial hypercholesterolemia.
  • Such mutations are identified in the human LDL receptor and later in apolipoprotein-B (Nature Structural and Molecular Biology, 2007, 14, 413-419).
  • the gene asesubtilisin/ gene
  • ADH autosomal dominant hypercholesterolemia
  • Loss-of-function mutations lead to elevated receptor abundance, enhancing clearance of LDL cholesterol from the circulation and reducing cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14, 413-419). Detailed molecular mechanisms explaining the association of LDLR and the particular subtype gene and LDLR degradation is not very clear (Drug News Perspectives, 2008, 21, 323-330). Because of inhibition of LDLR recycling, number of LDL receptors on the cell surface are decreased and this increases plasma LDL levels (PNAS, 2009, 106, 9546- 9547).
  • PCSK9 protein fold change has been found -2.12 and -4.82 at 10 ⁇ M and 30 ⁇ M respectively.
  • Further pharmacokinetic study of same compound (3mg/Kg oral dose) has been carried out in Rat and Dog where AUC(0-t) has been found 4834 ⁇ 1855 and 1117.41 ⁇ 458.60 ng.h/mL respectively.
  • the main objective of the present invention is to provide novel substituted heterocyclic derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
  • a pharmaceutical compositions in combination with additional therapeutic agents is provided.
  • a method of treatment of diseases such as dyslipidemia, hyperlipidemia etc. by providing therapeutically effective amount of the compounds of formula (I) or their pharmaceutically acceptable salts or their suitable pharmaceutical compositions.
  • the present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein ‘A’ represents an optionally substituted single or fused group selected from aryl or heteroaryl groups; ‘Y’ represents either a bond, or may be selected from (C 1 -C 3 )alkyl, -S(O) o -, -C(O)-, -C(O)N(R 5 )-, N(R 5 )C(O)-, -N(R 5 )-, -N(R 5 )S(O) 2 N(R 5 )-, -N(R 5 )C(O)N(R 5 )-, -S(O) 2 N(R 5 ), -N(R 5 )S(O) 2 -; ‘Z’ represents –O-, -S(O) o -
  • ‘X’ at each occurrence independently represents either C or N;
  • R 1 at each occurrence independently represents halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, haloalkylsulfonyl, perhaloalkyls
  • R 2 represents hydrogen, or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, cycloalkyl, aryl, aralkyl, heterocylyl, heterocyclylalkyl, heterocyclylalkoxyacyl, Acyl, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfonyl.
  • R 3 and R 4 at each occurrence independently represents hydrogen, halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, hydroxyl, sulfonic acid and its derivatives.
  • R 5 at each occurrence independently represents H, (C 1 -C 6 )alkyl or (C 3 -C 6 )cycloalkyl;
  • the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxy, heterocyclylalk
  • the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino
  • the substituents on any of A, Cy, R 1 , R 3 or R 4 may be selected from one or more groups described above.
  • A is selected from optionally substituted phenyl, pyridine, thiophene, pyrimidine, benzo[d]thiazole and quinolone groups.
  • A is optionally substituted phenyl and benzo[d]thiazole group.
  • ‘Y’ is selected from –C(O)-, - S(O) o -, -(C 1 -C 3 )alkyl-, -C(O)N(R 5 )-, -N(R 5 )-, -C(O)CH(R 5 ) 2 - .
  • Y is -C(O)- and -C(O)N(R 5 ) 2 -;
  • R 5 is as defined earlier
  • ‘Z’ is selected from –O-, -S(O) o , -C(O)-, -N(R 5 )-, -(C(R 5 ) 2 ) p -, -O(C(R 5 ) 2 ) p -, -O(C(R 5 ) 2 ) p O-, S(O) o (C(R 5 ) 2 ) p -, - S(O) o (C(R 5 ) 2 ) p S(O) o -; -N(R 5 )(C(R 5 ) 2 ) p -, -NHC(O)-, -NHC(O)NH-, or ; R 5 is as defined earlier; In a more preferred embodiment ‘Z’ is selected from –O-,
  • ‘Q’ represents oxygen atom and integers of m and n are independently 1 to form an oxetane ring.
  • the groups, radicals and substituents used anywhere in the specification are described in the following paragraphs.
  • the groups, radicals described above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the “alkenyl” group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-
  • the non-aromatic radicals may be saturated, partially saturated or unsaturated mono, bi, tri or spirocyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4- oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydro
  • N-alkylaminocabonyl and “N,N-dialkylaminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical.
  • N-arylaminocarbonyl and “N-alkyl-N-arylaminocarbonyl” denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical.
  • aminocarbonylalkyl includes alkyl radicals substituted with aminocarbonyl radicals; - the “hydroxyalkyl” group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like; - the “aminoalkyl” group used alone or in combination with other radicals, denotes an amino (-NH 2 ) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl.
  • alkylamino used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di- substituted alkylamino; - the “alkoxyalkyl” group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; - the “alkylthio” group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, - the “thio,
  • the “alkoxycarbonylamino” group used alone or in combination with other radicals is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;
  • the “arylthio” group used either alone or in combination with other radicals denotes a an aryl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like;
  • the “heterocyclylthio” group used either alone or in combination with other radicals denotes an heterocyclyl group as defined above
  • the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, “arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • sulfonyl wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner.
  • the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • treatment of a patient is intended to include prophylaxis.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • Particularly useful compounds of formula (I) may be selected from- (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone; 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzo
  • novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms.
  • Method A Reacting the compounds of general formula II and III wherein all the symbols are defined as earlier using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like to prepare corresponding compounds of general formula IV.
  • the reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; ii.
  • the reaction may be carried in presence of suitable organic bases such as N-ethylmorpholine, triethylamine, diisopropylethylamine, pyridine and the like.
  • the reaction may be carried out in presence of suitable solvent(s) such as N,N-dimethylformamide, N,N- dimethylacetamide, dichloromethane and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Method B i Reacting compounds of general formula II with compounds of general formula V wherein all the symbols are as defined earlier using suitable reaction conditions as provided in step ii of method A to obtain compounds of general formula VI. ii.
  • step ii reacting compounds of general formula VI with compounds of formula III wherein wherein all the symbols are as defined earlier, using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like.
  • the reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours to obtain compounds of general formula (Ia) wherein all the symbols are as defined earlier.
  • the compounds of general formula (Ib) and (Ic) wherein ‘Y’ represents –C(O)NH- and all other symbols are as defined earlier may be prepared by reactions outlined in Scheme 2 below which comprises: Scheme:2 i.
  • the compounds of formula (Ib) wherein all the symbols are as defined earlier may be prepared by reacting aryl amines of general formula VII wherein all the symbols are as defined earlier and corresponding cyclic amines of general formula V wherein all the symbols are as defined earlier under suitable conditions in presence of reagents(s) such as phosgene, triphosgene, Carbonyldiimidazole and the like.
  • the reaction may be carried in presence of organic base(s) such as trimethylamine, diisopropylamine, pyridine and the like using suitable solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane, acetonitrile and the like or mixtures thereof.
  • organic base(s) such as trimethylamine, diisopropylamine, pyridine and the like
  • suitable solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane, acetonitrile and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii.
  • the compounds of formula (Ic) wherein all the symbols are as defined earlier may be prepared by coupling reaction of acids of general formula VIII wherein all the symbols are as defined earlier and amines of general formula VII wherein all the symbols are as defined earlier under suitable conditions in presence of reagents(s) such as N-(3- dimethylaminopropyl)-N’-ethylcarbodimide hydrochloride (EDC) & 1- Hydroxybenzotriazole (HOBT), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N,N′,N′- Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and the like.
  • reagents(s) such as N-(3- dimethylaminopropyl)-N’-ethylcarbod
  • the reaction may be carried in presence of suitable organic bases such as triethyl amine, diisopropylethyl amine, pyridine and the like.
  • the reaction may be carried out in presence of suitable solvent(s) such as N,N-dimethylformamide, N,N- dimethylacetamide, dichloromethane and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • the compounds of general formula (Id) wherein ‘Y’ represents –CH 2 - and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 3 below which comprises: Scheme:3
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii. Reacting Compounds of general formula X wherein all the symbols are as defined earlier and cyclic ketones of general formula III, using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like to prepare corresponding compounds of general formula (Id) wherein the symbols are as defined earlier.
  • the reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (Ie) wherein ‘Y’ represents –NH- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 4 below which comprises: Scheme: 4 i. Reacting the compounds of general formula VII wherein all the symbols are as defined earlier and the cyclic ketones of general formula XI wherein all the symbols are as defined earlier, using suitable methods available in the literature for the reductive amination to prepare compounds of general formula (Ie) wherein the symbols are as defined earlier.
  • the reaction may be carried out using reducing agents such as sodium tricatoxyborohydride, sodium cynoborohydride, sodium brohydride and the like.
  • reducing agents such as sodium tricatoxyborohydride, sodium cynoborohydride, sodium brohydride and the like.
  • the reaction may be carried out in presence of solvent(s) such as dichloromethane, 1,2-dicloroethane, toluene, methanol, ethanol, isopropanol, n-butanol and the like or suitable mixtures thereof.
  • reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (If) wherein ‘Y’ represents –SO2- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 5 below which comprises: Scheme:5 i.
  • the reaction may be carried out neat or in presence of suitable aprotic solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • suitable aprotic solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii.
  • the reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours;
  • suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (Ig) wherein all the symbols are as defined earlier, may be prepared by reactions outlined in Scheme 6 below which comprises: Scheme:6 i.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (Ih), (Ii), (Ij) & (Ik) wherein ‘Q’ represents –NH and NR6 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 7 below which comprises: Scheme:7 i.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; iii. Reacting the compounds of general formula (Ih) and (Ij) wherein all the symbols are as defined earlier and the compounds of general formula XVII wherein ‘L 4 ’ represents suitable leaving group such as and all other symbols are as defined earlier, using suitable inorganic base(s) such as K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, NaH, KH and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like to prepare compounds of general formula (Ii) and (Ik) respectively, wherein the symbols are as defined earlier.
  • suitable inorganic base(s) such as K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, NaH, KH and the like
  • organic base(s) such as pyridine
  • the reaction may be carried out neat or in presence of suitable aprotic solvent(s) such as N,N- dimethyl formamide, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene and the like or suitable mixtures thereof.
  • suitable aprotic solvent(s) such as N,N- dimethyl formamide, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (Il) wherein ‘Q’ represents –S(O) o - wherein ‘o’ represents integers 1 & 2 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 8 below which comprises: Scheme:8 i.
  • the compounds of general formula (Il) wherein all the symbols are as defined earlier may be prepared by the oxidation of the compounds of general formula (Ia) wherein ‘Q’ represents ‘S’ and all other symbols are as defined earlier using suitable oxidizing agents such as H 2 O 2 , m-chloroperbenzoic acid, sodium periodate, potassium peroxymonosulfate and the like.
  • suitable oxidizing agents such as H 2 O 2 , m-chloroperbenzoic acid, sodium periodate, potassium peroxymonosulfate and the like.
  • suitable solvent(s) such as chloroform, dichloromethane, acetone, water, tetrahydrofuran, methanol, ethanol and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -40 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • the compounds of general formula (Im) wherein ‘Z’ represents –S(O) o - wherein ‘o’ represents integers 1 & 2 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 9 below which comprises: Scheme: 9
  • the compounds of general formula (Im) wherein all the symbols are as defined earlier may be prepared by the oxidation of the compounds of general formula (Ia) wherein ‘Z’ represents ‘S’ and all other symbols are as defined earlier using suitable oxidizing agents such as H 2 O 2 , m-chloroperbenzoic acid, sodium periodate, potassium peroxymonosulfate and the like.
  • the reaction may be carried in presence of suitable solvent(s) such as chloroform, dichloromethane, acetone, water, tetrahydrofuran, methanol, ethanol and the like or suitable mixtures thereof.
  • suitable solvent(s) such as chloroform, dichloromethane, acetone, water, tetrahydrofuran, methanol, ethanol and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -40 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • the compounds of general formula (I) wherein ‘Q’ represents ‘O’, ‘m’ and ‘n’ represents integer 1 and all other symbols are as defined earlier may also be prepared by reactions outlined in Scheme 10 below which comprises: Scheme:10 i.
  • Reacting the compounds of general formula XVIII wherein all the symbols are as defined earlier and magnesium metal using suitable methods available in the literature for the preparation of Grignard reagents to prepare compounds of general formula XIX wherein all the symbols are as defined earlier.
  • the reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; ii.
  • reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; iii.
  • the compounds of formula (I) wherein all the symbols are as defined earlier may be prepared from compounds of general formula XXI wherein all the symbols are as defined earlier using the procedure given in literature (Angewandte Chemie, International Edition (2007), 46(15), 2616-2618; US6255540 and Journal of Medicinal Chemistry (1992), 35(14), 2600-2609) with appropriate modifications in the reaction conditions.
  • an intermediate of compound of formula XXI is Wherein symbols are as defined earlier.
  • compound of formula XXI is (4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone.
  • the said compound is an intermediate for the process for the preparion of compounds of formula (I).
  • the invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
  • 1 H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in ⁇ scale.
  • ESI-MS data is recorded using mass spectrometer (waters Xevo G2 QToF).
  • Step 1 Preparation of tert-butyl 4-(4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (92 g, 457 mmol) in dimethylacetamide (750 ml), potassium tert-butoxide (103 g, 914 mmol) was added and stirred at 30 °C for 30 minute.
  • Step 2 Preparation of tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine-1- carboxylate
  • 2-chloro-5-(trifluoromethyl)phenol (0.500 g, 2.544 mmol)
  • tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate 0.782 g, 2.798 mmol
  • cesium carbonate 1.658 g, 5.088 mmol
  • reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic layer was washed with 1M NaOH (1 x 10 ml), water (25 ml) & brine (25 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.7 g, 72% yield) as yellow liquid.
  • Step 3 Preparation of 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine To a stirred solution of tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine- 1-carboxylate (700 mg, 1.843 mmol) in dichloromethane (50 ml), trifluoroacetic acid (1.420 ml, 18.43 mmol) was added and the reaction mixture was stirred at 30 o C for 24 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (2 x 20 ml).
  • Step 1 Preparation of tert-butyl 4-((4-(trifluoromethyl)phenyl)amino)piperidine-1- carboxylate.
  • 4-(trifluoromethyl) aniline 3.90ml, 31.0 mmol
  • tert-butyl 4-oxopiperidine-1-carboxylate 12.37 g, 62.1 mmol
  • acetic acid 50 ml
  • sodium sulfate 44.1g, 310mmol
  • Step 2 Preparation of N-methyl-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine hydrochloride
  • the title product 400 mg 98% yield
  • the reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 15% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((4- (trifluoromethyl)phenyl)thio)piperidine-1-carboxylate (315 mg, 0.872 mmol, 31.1% yield) as off-white solid.
  • Step 1 Preparation of tert-butyl 4-((6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1- carboxylate.
  • 6-(trifluoromethyl)pyridin-3-amine (0.500 g, 3.08 mmol)
  • tert-butyl 4-oxopiperidine-1-carboxylate (0.737 g, 3.70 mmol)
  • 1,2-dichloroethane (20 ml) acetic acid (0.177 ml, 3.08 mmol) was added and stirring was continued at ambient temperature for 3.0 hours.
  • Step 2 Preperation of N-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-2-amine dihydrochloride
  • the title product (737 mg, 100% yield) was prepared from tert-butyl 4-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 2.316 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)thio)piperidine-1-carboxylate (550 mg, 54.4% yield) as a thick liquid.
  • Step 2 Preparation of 2-(piperidin-4-ylthio)-5-(trifluoromethyl)pyridine dihydrochloride
  • the title product (458 mg, 99% yield) was prepared from of tert-butyl 4-((5- (trifluoromethyl)pyridin-2-yl)thio)piperidine-1-carboxylate (500 mg, 1.380 mmol) according to the procedure given in step-2 of Intermediate-1 as white solid.
  • Intermediate-10 5-(methylthio)-2-(piperidin-4-yloxy)pyrimidine dihydrochloride
  • Step 1 Preparation of tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)oxy)piperidine-1- carboxylate.
  • reaction mixture was poured into water (25 ml), separated solid was collected by filtration, washed with water and dried over P 2 O 5 under vacuum to yield tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)oxy)piperidine-1- carboxylate (144 mg, 35.5% yield) as white solid.
  • Step 2 Preparation of 5-(methylthio)-2-(piperidin-4-yloxy)pyrimidine dihydrochloride
  • the title product (132 mg, 100% yield) was prepared from of tert-butyl 4-((5- (methylthio)pyrimidin-2-yl)oxy)piperidine-1-carboxylate (144 mg, 0.442 mmol) according to the procedure given in step-2 of Intermediate-1 as a white solid.
  • Intermediate-11 5-(methylthio)-N-(piperidin-4-yl)pyrimidin-2-amine dihydrochloride
  • Step 1 Preparation of tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)amino)piperidine-1- carboxylate.
  • Step 1 Preparation of tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate.
  • tert-butyl 4-hydroxypiperidine-1-carboxylate 0.93 g, 3.44 mmol
  • quinolin-4-ol 0.5 g, 3.44 mmol
  • triphenyl phosphine 2.2g, 8.61mmol
  • reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extract was washed with water (2 x 50 ml) & brine (75 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate (400 mg, 35% yield) as a thick liquid.
  • Step 3 tert-butyl 4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidine-1- carboxylate.
  • 2-chloro-6-(trifluoromethyl)benzo[d]thiazole 600 mg, 2.52 mmol
  • tert-butyl 4-hydroxypiperidine-1-carboxylate 457 mg, 2.272 mmol
  • potassium tert-butoxide 567 mg, 5.05 mmol
  • the reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 25 ml). The organic layer was washed with water (2 x 50 ml) & brine (25 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 10% ethyl acetate in n-hexane as an eluent to yield pure tert-butyl 4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidine-1-carboxylate (600 mg, 59% yield) as a thick liquid.
  • Step 1 Preparation of tert-butyl 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine-1- carboxylate
  • tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate 750 mg, 2.480 mmol
  • sodium azide 806 mg, 12.40 mmol
  • ammonium chloride 663 mg, 12.40 mmol
  • reaction mixture was cooled, poured into water (25 ml) and neutralized using aqueous hydrochloric acid. Separated solid was collected by filtration, washed with water and dried over P 2 O 5 under vacuum to yield tert-butyl 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine-1- carboxylate (0.650 g, 76% yield) as a white solid.
  • Step 2 Preparation of 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine hydrochloride
  • the title product (255 mg, 99% yield) was prepared from of tert-butyl 4-(4-(2H- tetrazol-5-yl)phenoxy)piperidine-1-carboxylate (300 mg, 0.869 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid.
  • Step 1 Preparation of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate To a stirred solution of tert-butyl piperazine-4-carboxylate (0.98 g, 5.26 mmol), 4- (trifluoromethyl)benzoic acid (1.0 g, 5.26 mmol) and HBTU (2.99 g, 7.89 mmol) in N,N- dimethylformamide (5.0 ml), diisopropylethylamine (2.76 ml, 15.78 mmol) was added and stirred at 30 o C for 16 hours.
  • Step 2 Preparation of piperazin-1-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride
  • the title product (617 mg, 100% yield) was prepared from tert-butyl 4-(4- (trifluoromethyl)benzoyl)piperazine-1-carboxylate (750 mg, 2.093 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid.
  • Step 1 Preparation of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate To a stirred solution of 1-bromo-4-(trifluoromethyl)benzene (0.467 ml, 3.33 mmol) in dry tetrahydrofuran (50 ml), n-butyllithium (1.600 ml, 4.00 mmol) was added dropwise over a period of 15 minutes at -78°C and stirring was continued for 30 minutes at -78°C.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 20% ethyl acetate as eluent in n-hexane to yield tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate (245 mg, 20.57% yield) as a thick liquid.
  • the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water (25 ml) & brine (15 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 10% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carboxylate (400 mg, 62.6% yield) as a white solid.
  • Step 2 Preparation of 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine.
  • the title product (215 mg, 72.8% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenoxy)methyl)piperidine-1-carboxylate (400 mg, 1.113 mmol) according to the procedure described in step-2 of Intermediate-2 as a yellow liquid.
  • Step 1 Preparation of tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate.
  • tert-butyl 4-hydroxypiperidine-1-carboxylate 2 g, 9.94 mmol
  • Tetrahydrofuran 20 ml
  • 50% sodium hydride 0.596 g, 24.84 mmol
  • ethyl bromoacetate 213 ml, 19.87 mmol
  • Reaction mixture was poured in water (10 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1- carboxylate. (1.5 g, 52.5% Yield) as a thick liquid.
  • Step 3 Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethoxy)piperidine-1- carboxylate.
  • tert-butyl 4-(2-hydroxyethoxy) piperidine-1-carboxylate (1.45 g, 6.09 mmol) in dimethylacetamide (10 ml)
  • potassium tert-butoxide (1.36 g, 12.19 mmol) was added and stirred at 30 °C for 30 minutes.
  • 1-fluoro-4-(trifluoromethyl) benzene 1.0g, 6.09 mmol
  • reaction mixture was stirred at 60 °C for 24 hours.
  • Reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (2 x 50 ml) & brine (350 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 5-20% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidine-1-carboxylate. (1.0 g, 42.0% Yield) as a thick liquid.
  • Step 1 Preparation of tert-butyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate.
  • ethyl acrylate (2.98 g, 29.84 mmol) was added at 0-5 oC under nitrogen atmosphere.
  • potassium hydroxide (0.056g, 0.994 mmol) was added and stirring was continued for 24 hours at ambient temperature.
  • Reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate. (1.0 g, 33.4% Yield) as a thick liquid.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate. (0.7g, 71% Yield) as a thick liquid.
  • Step 1 Preparation of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate To a stirred solution of propyl 2-(diethoxyphosphoryl) acetate (6.28 ml, 31.4 mmol) in tetrahydrofuran (50 ml), 50% sodium hydride (1.642 g, 37.64 mmol) was added at 0-5 oC under nitrogen atmosphere atmosphere and stirred for 30 minutes.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 5-20% ethyl acetate in n-hexane as eluent to yield tert-butyl 4- (2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (6.0 g, 89% Yield) as a thick liquid.
  • Step 5 Preparation of 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine hydrochloride.
  • the title product 500 mg 100% yield
  • Step 1 Preparation of 2-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridine hydrochloride.
  • the title product (500 mg, 100% yield) was prepared from tert-butyl 4-(2- hydroxyethyl)piperidine-1-carboxylate (1.54 g, 6.64 mmol) and 2-bromo-5- (trifluoromethyl)pyridine (1.1g, 6.70 mmol) according to the procedures described in Intermediate-22 as a white solid.
  • Step 1 Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazine-1- carboxylate.
  • 1-fluoro-4-(trifluoromethyl)benzene 500 mg, 3.05 mmol
  • tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate 702 mg, 3.05 mmol
  • potassium tert-butoxide (684 mg, 6.09 mmol
  • the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (2 x 15 ml) & brine (15 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 20% ethyl acetate in n- hexane as eluent to yield pure tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylate (700 mg, 61.4% yield) as a thick liquid.
  • Step 2 Preparation of 1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazine dihydrochloride
  • the title product (617 mg 95% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylate (700 mg, 1.870 mmol) according to the procedure described in step-2 of Intermediate-1 as a white solid.
  • Intermediate-25 1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride
  • Step 1 tert-butyl (1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate.
  • Step 2 1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride.
  • the title product (0.140 g, 86% yield) was prepared from tert-butyl (1-(4- (trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate (0.165 g, 0.479 mmol) according to the procedure described in step-2 of Intermediate-1 as an off white solid.
  • Step 1 tert-butyl (1-(2-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate.
  • tert-butyl pyrrolidin-3-ylcarbamate 0.5 g, 2.68 mmol
  • 2-(trifluoromethyl)benzaldehyde 0.514 g, 2.95 mmol
  • Step 1 Diethyl (4-(trifluoromethyl)benzyl)phosphonate.
  • a mixture of 1-(bromomethyl)-4-(trifluoromethyl)benzene (2.0 gm, 8.37 mmol) and triethyl phosphate (2.195 ml, 12.55 mmol) was heated for 16 hours at 150 °C.
  • the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (30 ml), washed with water (3 x 25 ml) & brine (25 ml), dried over sodium sulphate and concentrated on rotavapor under vacuum.
  • Step 2 tert-butyl 4-(4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate.
  • sodium hydride 50%, 292 mg, 6.04 mmol
  • tetrahydrofuran 3 ml
  • diethyl (4-(trifluoromethyl)benzyl)phosphonate 1.2 gm, 4.05 mmol
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 5% ethyl acetate in n-hexane as an eluent to yield pure tert- butyl 4-(4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (1.12 g, 81% yield) as thick liquid.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 5% ethyl acetate in n-hexane as an eluent to yield pure tert-butyl 4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.0 gm, 99% yield) as a thick liquid.
  • the reaction mixture was poured into water (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum.
  • the solid product was triturated with diisopropyl ether (20 ml), filtered through a Buchner Funnel, rinsed with diisopropyl ether (5.0 ml) and dried to yield tert-butyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)piperidine-1- carboxylate (500 mg, 82% yield) as a white solid.
  • Step 2 Preparation of N-(piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide hydrochloride
  • the title product (384 mg, 91% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)sulfonamido)piperidine-1-carboxylate (500 mg, 1.224 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid.
  • Step 2 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine hydrochloride.
  • the title product (750 mg, 100% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazine-1-carboxylate (0.85 gm, 2.155 mmol) according to the procedure described in step-2 of Intermediate-1 as a white solid.
  • Step 1 Preparation of 1-(tert-butyl) 4-ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-1,4- dicarboxylate.
  • n-butyl lithium 5.60 ml, 13.99 mmol was added below 0 °C and stirred for 30 minutes at 0 °C.
  • Step 1 Ethyl 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate.
  • 1-(bromomethyl)-4-(trifluoromethyl)benzene 2.0 gm, 8.37 mmol
  • ethyl piperidine-4-carboxylate 1.315 gm, 8.37 mmol
  • diisopropyl ethyl amine 1.754 ml, 1.298 mmol
  • Step 2 Preparation of 4-bromo-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid.
  • tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1- carboxylate (2.0 g, 5.42 mmol) and sulphamic acid (4.31 g, 44.4 mmol) in water (10 ml) sodium chlorite (1.34 g, 11.92mmol) was added and stirring was continued at ambient temperature for 20 hours.
  • the reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml).
  • Step 3 Preparation of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(3-hydroxyoxetan-3- yl)benzoic acid: To a stirred solution of 4-bromo-2-(4-(isopropoxycarbonyl)piperazin-1-yl)benzoic acid (700mg, 1.817 mmol) in tetrahydrofuran (15 ml), n-butyllithium (25% in hexane) (1.2 ml, 4.54 mmol) was added dropwise under nitrogen atmosphere at -78 o C over a period of 10 minutes.
  • the reaction mixture was poured into saturated ammonium chloride solution (100 mL), acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 500 ml). The combined organic layer was washed with brine (500 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by triturating with diethyl ether to yield 4-(3-hydroxyoxetan-3-yl)benzoic acid (13.8 g, 35% Yield) as an off white solid.
  • Step 3 4-(3-methoxyoxetan-3-yl) benzoic acid.
  • the title product (1.5g 71.6% yield) was prepared from benzyl 4-(3-methoxyoxetan- 3-yl)benzoate (3.0g, 75% yield) as thick liquid according to the procedure described in step-2 of intermediate-22 as a yellow solid.
  • the reaction mixture was poured into ice cold saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (2 x 100 ml) & brine (100 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 2-3% methanol in chloroform as an eluent to yield (4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone (515 mg, 22% yield) as a white solid.
  • Example- 1 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride 114 mg, 0.408 mmol
  • 4-(3-hydroxyoxetan-3-yl)benzoic acid 79 mg, 0.408 mmol
  • HBTU 232 mg, 0.612 mmol
  • N,N-dimethylformamide 3.0 ml
  • diisopropylethylamine 0.214 ml, 1.223 mmol
  • the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with water (2 x 25 ml) & brine (25 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (100 mg, 55% yield) as a white solid.
  • Example- 2 (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • sodium hydride 17.08 mg, 0.356 mmol
  • a solution of (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 100 mg, 0.237 mmol
  • iodomethane 0.018 ml, 0.285 mmol
  • reaction mixture was poured into ice cold water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic extract was washed with water (2 x 20 ml) & brine (25 ml), dried over sodium sulfate and evaporated under reduced pressure to yield (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (60 mg, 56.9% yield) as pale yellow solid.
  • Example- 3 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methyl)phenyl) o xetan-3-ol
  • Step 1 1-(4-bromobenzyl)-4-(4-(trifluoromethyl)phenoxy)piperidine
  • 1-bromo-4-(bromomethyl)benzene 0.359 g, 1.436 mmol
  • 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride 0.337 g, 1.197 mmol
  • dimethyformamide (4 ml) dimethyformamide
  • cesium carbonate 1.170 g, 3.59 mmol
  • the reaction mixture was poured into ice cold water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extract was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 6% ethyl acetate in n-hexane as an eluent to yield 1-(4-bromobenzyl)-4-(4- (trifluoromethyl)phenoxy)piperidine (0.394 g, 79%) as a thick liquid.
  • Step 2 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)phenyl)oxetan-3-ol.
  • 1-(4-bromobenzyl)-4-(4-(trifluoromethyl)phenoxy)piperidine 0.390 g, 0.941 mmol
  • n-buthyllithium 2.5M in hexane
  • stirring was continued for 30 minute at -78 o C.
  • Crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to get pure product (0.1 g, 24.18%) as colorless oil.
  • Example- 4 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone
  • 4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)thio)phenoxy)piperidin-1-yl)methanone 500 mg, 1.103 mmol
  • dichloromethane 50 ml
  • meta-chloroperoxybenzoic acid 951 mg, 5.51 mmol
  • the reaction mixture was poured into saturated sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 230-400 silica gel column and 2-4% methanol in chloroform as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone (150 mg, 28.0% yield) as a white solid.
  • Example- 5 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzoic acid
  • Step 1 Preparation of ethyl 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoate
  • 4-(3-hydroxyoxetan-3-yl)benzoic acid 257 mg, 1.324 mmol
  • ethyl 4-(piperidin-4-yloxy)benzoate 300 mg, 1.203 mmol
  • HBTU 685 mg, 1.805 mmol
  • N,N-dimethylformamide 5.0 ml
  • N,N-diisopropylethylamine 0.631 ml, 3.61 mmol
  • Reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water (3 x 30 ml) & brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure.
  • Step 2 Preparation of 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoic acid
  • ethyl 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoate 330 mg, 0.776 mmol
  • methanol 15 ml
  • tetrahydrofuran 30.0 ml
  • another solution of lithium hydroxide hydrate (65.1 mg, 1.551 mmol) in water (15.0 ml) was added at 30 °C and stirring was continued for 24 hours.
  • Example- 6 N-cyclopropyl-4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzamide
  • 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoic acid 60 mg, 0.151 mmol
  • cyclopropylamine 0.013 ml, 0.181 mmol
  • HBTU 86 mg, 0.226 mmol
  • N-N-dimethylformaamide 5.0 ml
  • N,N- diisopropylethylamine 0.079 ml, 0.453 mmol
  • Example- 7 (4-(3-methoxypyrrolidin-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • tert-butyl 3-methoxy-3-(4-(4-(4- (trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)pyrrolidine-1-carboxylate 0.3 g, 0.547 mmol
  • 1, 2 dichloromethane (4 ml) trifluoroacetic acid (0.421 ml, 5.47 mmol) was added at 0-5 oC and stirring was continued for further 2 hours at ambient temperature.
  • Example- 8 (4-(3-hydroxypyrrolidin-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • the title product (0.490 g, 93% yield) was prepared from tert-butyl 3-hydroxy-3-(4- (4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)pyrrolidine-1-carboxylate (0.6 g, 1.122 mmol) according to the procedure described in Example-7 as light brown solid.
  • Example- 9 (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methanone
  • 4-(3-hydroxythietan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methanone (0.150 g, 0.342 mmol) in a mixture of acetone (4 ml) and water (1 ml), oxone (0.631 g, 1.026 mmol) was added at 0- 5 oC and stirring was continued for 6 hours at ambient temperature.
  • Reaction mixture was concentrated on rotavapor under vacuum. Residue was transferred to a Buckner funnel, washed with water (20 ml) and dried over phosphorous pentaoxide to yield (4-(3-hydroxy- 1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1- yl)methanone (0.134 g, 81% yield) as an off white solid.
  • Example- 10 (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
  • the title product (70 mg, 65% yield) was prepared from (4-(3-hydroxythietan-3- yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1-yl)methanone (0.1 gm, 0.230 mmol) according to the procedure described in Example-9 as a white solid.
  • Example- 11 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)amino)phenyl) o xetan-3-ol
  • Step 1 Preparation of 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-one
  • 4-(Trifluoromethyl)benzenesulfonyl chloride 0.02 g, 3.69 mmol
  • triethylamine 1.542 ml, 11.06 mmol
  • Step 2 Preparation of 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)amino)phenyl)oxetan-3-ol
  • 3-(4-aminophenyl)oxetan-3-ol 50 mg, 0.303 mmol
  • 1- ((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-one 93 mg, 0.303 mmol
  • 2- dichloroethane (10 ml) sodium triacetoxyborohydride (96 mg, 0.454 mmol) was added at 30 °C and stirring was continued for 20 hours.
  • the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layer was washed with water (2 x 15 ml) & brine (15 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield 3-(4-((1- ((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)amino)phenyl)oxetan-3-ol (6.0 mg, 3.97% yield) as a white solid.
  • Example- 12 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)sulfonyl)phenyl) o xetan-3-ol
  • Step 1 Preparation of 1-((4-bromophenyl)sulfonyl)-4-(4- (trifluoromethyl)phenoxy)piperidine.
  • Step 2 Preparation of 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)sulfonyl)phenyl)oxetan-3-ol
  • 1-((4-bromophenyl)sulfonyl)-4-(4- (trifluoromethyl)phenoxy)piperidine (0.700 g, 1.508 mmol) in tetrahydrofuran (10 ml)
  • n- butyllithium 0.784 ml, 1.960 mmol
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 30% ethyl acetate in n-hexane as an eluent to yield 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)sulfonyl)phenyl)oxetan-3-ol (40 mg, 5.45% yield) as a white solid.
  • Example- 13 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfonyl)piperidin-1-yl)methanone O
  • (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)thio)piperidin-1-yl)methanone 200 mg, 0.456 mmol
  • dichloromethane (10 ml) meta-chloroperoxybenzoic acid (315 mg, 0.912 mmol) was added at 30 °C and stirring was continued for 5.0 hours.
  • reaction mixture was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic layer was washed with water (3 x 10 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 6% methanol in ethyl acetate as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)sulfonyl)piperidin-1-yl)methanone (90 mg, 40.7% yield) as a white solid.
  • Example- 14 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfinyl)piperidin-1-yl)methanone
  • the title product (24 mg, 4.21 % yield) was isolated as a polar byproduct during the purification of Example-13 as white solid.
  • Example- 15 (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperidin-1-yl)methanone
  • another solution of oxone (281 mg, 0.457 mmol) in water (1 ml) was added under nitrogen atmosphere at ambient temperature and stirring was continued for 12 hours.
  • Example- 16 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylic acid
  • Step 1 Preparation of ethyl 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylate
  • 4-(3-hydroxyoxetan-3-yl)benzoic acid 254 mg, 1.308 mmol
  • HBTU 6-76 mg, 1.784 mmol
  • N,N-dimethylformamide 5.0 ml
  • N,N- diisopropylethylamine 0.23 ml, 3.57 mmol
  • reaction mixture was concentrated under reduced pressure.
  • the residue was dissolved in water (15 ml), acidified with aqueous hydrochloric acid and extracted with ethyl acetate (2 x 20 ml).
  • the combined organic layer was washed with water (2 x 20 ml) & brine (10 ml), dried over sodium sulfate and evaporated under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 4% methanol in chloroform as an eluent to yield pure 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4- carboxylic acid (40 mg, 15.22% yield) as a white solid.
  • Example- 17 N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4- (trifluoromethyl)phenoxy) piperidine-1-carboxamide
  • Step 1 Preparation of 4-(3-bromo-5-nitrophenyl)morpholine
  • morpholine (2.97 ml, 34.1 mmol)
  • potassium carbonate (6.28 g, 45.5 mmol) were added under nitrogen atmosphere at 27 °C. Then the reaction mixture was stirred at 120 °C for 18 hours under nitrogen atmosphere.
  • Step 2 Preparation of 3-bromo-5-morpholinoaniline
  • 4-(3-bromo-5-nitrophenyl)morpholine 6.0 g, 20.90 mmol
  • tin(II) chloride dihydrate 18.86 g, 84 mmol
  • the reaction mixture was refluxed for 1 hour.
  • the reaction mixture was cooled to room temperature and solvent was evaporated on rotavapor under vacuum.
  • the residue was dissolved in ethyl acetate (100 ml) and the solution was basified by dropwise addition of saturated aqueous ammonia solution.
  • the solid separated was filtered and washed with ethyl acetate (50 ml).
  • Step 3 Preparation of N,N-dibenzyl-3-bromo-5-morpholinoaniline To a solution of 3-bromo-5-morpholinoaniline (5.3 g, 20.61 mmol) in acetonitrile (100 ml), potassium carbonate (8.55 g, 61.8 mmol) was added followed by the addition of benzyl bromide (5.39 ml, 45.3 mmol) under nitrogen atmosphere at 28 o C and refluxed for 18 hrs.
  • Step 4 Preparation of 3-(3-(dibenzylamino)-5-morpholinophenyl)oxetan-3-ol
  • N,N-dibenzyl-3-bromo-5-morpholinoaniline (0.75 g, 1.71 mmol) in THF (10 ml)
  • n-butyllithium 2.5M in hexane
  • the reaction mixture was stirred at the same temperature for 30 minutes.
  • the crude product was purified by column chromatography using 230-400 mesh silica gel column and 20-50% ethyl acetate in n-hexane as an eluent to obtain 3-(3- (dibenzylamino)-5-morpholinophenyl)oxetan-3-ol (500 mg, 68% Yield) as thick liquid.
  • Step 5 Preparation of 3-(3-amino-5-morpholinophenyl)oxetan-3-ol
  • a solution of 3-(3- (dibenzylamino)-5-morpholinophenyl)oxetan-3-ol (0.33 g, 0.76 mmol) in methanol (10 ml) was added and the reaction mixture was stirred under hydrogen at a pressure of 50 psi for 18 hrs.
  • the reaction mixture was filtered through celite and washed with methanol (10 ml).
  • Step 6 N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4- (trifluoromethyl)phenoxy) piperidine-1-carboxamide
  • 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride 90 mg, 0.367 mmol
  • acetonitrile 3 ml
  • N,N-diisopropylethyl amine (0.192 ml, 1.101 mmol) was added under nitrogen atmosphere at ambient temperature and followed by the dropwise addition of another solution of 3-(3-amino-5-morpholinophenyl)oxetan-3-ol (101 mg, 0.404 mmol), triphosgene (35.9 mg, 0.330 mmol) in tetrahydrofuran (3 ml) at 0 °C over the period of 10 minutes.
  • reaction mixture was stirred for 12 hours at ambient temperature, poured into water (25 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic layers was washed with water (2 x 25 ml) & brine (20 ml), dried over sodium sulphate and evaporated in rotavapor under vacuum.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield N-(3-(3-hydroxyoxetan-3-yl)-5- morpholinophenyl)-4-(4-(trifluoromethyl)phenoxy) piperidine-1-carboxamide (17 mg, 9% yield) as white solid.
  • Example-18 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
  • Example-19 (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
  • Example-21 (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 1 H NMR (DMSO-d 6 ) ⁇ : 1.24-1.30 (m, 1H), 1.78-1.94 (m, 3H), 2.67-2.68 (m, 2H), 3.33- 3.37 (m, 1H), 3.54-3.60 (m, 2H), 4.75-4.78 (m, 1H), 4.80-4.85 (m, 2H), 6.45 (s, 1H), 7.01- 7.03 (m, 1H), 7.23-7.28 (m, 1H), 7.33-7.36 (m, 1H), 7.52-7.55 (m, 1H), 7.56-7.59 (m, 1H), 7.60-7.68 (m, 2H), 7.67-7.70 (m, 1H), 7.95-8.05 (m, 1H); ESI-MS: m/z 422.14 (M+
  • Example-22 (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 1 H NMR (DMSO-d 6 ) ⁇ : 1.24-1.30 (m, 1H), 1.78-1.94 (m, 3H), 3.33-3.37 (m, 1H), 3.54- 3.60 (m, 2H), 4.01-4.05 (m, 1H), 4.80-4.85 (m, 5H), 6.45 (s, 1H), 7.01-7.03 (m, 1H), 7.23- 7.28 (m, 3H), 7.33-7.36 (m, 3H), 7.67-7.70 (m, 1H); ESI-MS: m/z 422.14 (M+H) + , 100%.
  • Example-24 (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)pyrrolidin-1-yl)methanone
  • Example-25 (3-(3-methoxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 1H NMR (CDCl 3 ) ⁇ : 1.27-1.30 (m, 1H), 1.89-2.03 (m, 3H), 2.80-2.95 (m, 2H), 3.15-3.18 (m, 1H), 3.35 (s, 3H), 4.12-4.15 (m, 1H), 4.30-4.32 (m, 1H), 4.74-4.76 (m, 2H), 4.83-4.92 (m, 2H), 6.80-6.85 (m, 1H), 7.08-7.10 (m, 1H), 7.24-7.28 (m, 2H), 7.50-7.54 (m, 2H), 7.57- 7.76 (m, 2H); ESI-MS: m/z 436.16 (M+H) + , 100%.
  • Example-26 (4-([1,1'-biphenyl]-4-yloxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone
  • Example-27 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((2'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
  • Example-28 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
  • Example-29 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
  • Example-31 (4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone
  • Example-32 (4-(4-(1H-imidazol-1-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan- 3-yl)phenyl)methanone
  • 1 H NMR (DMSO-d 6 ) ⁇ : 1.65-1.86 (m, 2H), 1.88-2.20 (m, 2H), 3.32-3.80 (m, 3H), 3.94- 4.17 (m, 1H), 4.94-5.03 (m, 5H), 6.44 (s, 1H), 6.09-7.14 (m, 3H), 7.32-7.99 (m, 7H), 8.32- 8.35 (m, 1H);
  • ESI-MS m/z, 420.24 (M+H) + , 100%.
  • Example-34 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzonitrile O 1 H NMR (DMSO-d6) ⁇ : 1.65 (m, 2H), 2.01 (m, 2H), 3.34-3.81 (m, 3H), 4.01 (m, 1H), 4.70- 5.04 (m, 5H), 6.45 (s, 1H), 7.18 (m, 2H), 7.46 (m, 2H), 7.67-7.95 (m, 4H); ESI-MS: m/z, 379.15 (M+H) + , 100%.
  • Example-35 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(2-phenylpropan-2- yl)phenoxy)piperidin-1-yl)methanone
  • Example-36 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-phenoxyphenoxy)piperidin-1- yl)methanone 1 H NMR (DMSO-d 6 ) ⁇ : 1.60 (m, 2H), 1.98-2.14 (m, 2H), 3.38-3.80 (m, 3H), 3.99 (m, 1H), 4.61-5.09 (m, 5H), 6.45 (s, 1H), 6.60-7.35 (m, 7H), 7.46-7.89 (m, 4H), 7.95-8.09 (m, 2H); ESI-MS: m/z, 446.26 (M+H) + , 100%.
  • Example-37 (4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone
  • Example-39 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-41 (4-(4-(2H-tetrazol-5-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone
  • Example-43 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazin-1-yl)methanone
  • Example-46 (4-(3-(methoxy-d3)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-47 (4-(3-((tetrahydro-2H-pyran-4-yl)methoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-48 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone
  • Example-52 (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone
  • Example-53 (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone
  • 1 H NMR (DMSO-d 6 ) ⁇ : 2.25-2.43 (m, 2H), 2.78-2.83 (m, 2H), 4.06 (s, 1H), 4.15 (s, 1H), 4.32 (s, 1H), 4.41 (s, 1H), 4.67-4.79 (m, 5H), 6.49 (s, -OH), 7.02 (d, J 8.0 Hz, 2H), 7.63- 7.68 (m, 6H); ESI-MS: m/z, 434.15 (M+H) + , 100%.
  • Example-54 (4-(3-methoxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone
  • Example-55 (4-(4-hydroxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride
  • Example-56 (4-(4-methoxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride
  • Example-57 tert-butyl 4-hydroxy-4-(4-(5-(4- (trifluoromethyl)phenoxy) o ctahydrocyclopenta[c]pyrrole-2- carbonyl)phenyl)piperidine-1-carboxylate
  • Example-60 (4-(3-methoxyoxetan
  • Example-61 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)amino)piperidin-1-yl)methanone
  • Example-63 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone
  • Example-65 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)amino)piperidin-1-yl)methanone
  • Example-67 (4-(3-hydroxyoxetan-3-yl)-3,5-dimethoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-68 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)amino)piperidin-1-yl)methanone
  • Example-70 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
  • Example-73 (4-(3-hydroxyoxetan-3-yl)
  • Example-74 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone
  • Example-75 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone
  • Example-77 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)azepan-1-yl)methanone 1 H NMR (DMSO-d 6 ) ⁇ : 1.63-2.16 (m, 6H), 3.33-3.57 (m, 2H), 3.64-3.79 (m, 2H), 4.69- 4.89 (m, 5H), 6.43 (s, -OH), 7.09-7.15 (m, 2H), 7.45 (s, 2H), 7.64 (s, 4H); ESI-MS: m/z, 436.22 (M+H) + , 100%.
  • Example-78 (4-(3-hydroxyoxetan-3-yl)-2-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-83 (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
  • Example-87 (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone
  • Example-90 (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
  • Example-95 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)benzyl)amino)piperidin-1-yl)methanone
  • Example-103 (4-(3-methoxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-106 (4-(3-methoxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-107 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
  • Example-108 (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
  • Example-109 (4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-112 (4-(3-methoxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-113 tert-butyl 4-hydroxy-4-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)phenyl)piperidine-1-carboxylate
  • Example-114 (4-(4-hydroxypiperidin-4-yl) phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone hydrochloride
  • Example-115 3-(4-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl) o xetan-3-yl acetate
  • Example-116 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone.
  • Example-117 (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone.
  • Example-120 (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
  • Example-121 (3-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
  • Example-122 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzylidene)piperidin-1-yl)methanone 1 H NMR (DMSO-d 6 ) ⁇ : 2.01 (m, 2H), 2.23 (m, 2H), 3.43 (m, 2H), 3.83 (m, 2H), 4.69 (s, 2H), 4.78 (s, 2H), 6.46 (s, 1H), 6.49 (s, 1H), 7.43-7.48 (m, 4H), 7.665-7.69 (m, 4H); ESI- MS: m/z 418.21 (M+H) + , 100%.
  • Example-130 (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
  • Example-131 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidin-1-yl)methanone
  • Example-132 (4-(3-methoxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidin-1-yl)methanone
  • Example-133 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)methanone
  • Example-139 (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone
  • Example-141 (4-(3-hydroxythietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
  • ESI-MS 4-(3-hydroxythietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
  • Example-143 (4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-144 (4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)(4- (4-(trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-149 (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone
  • Example-150 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone
  • Example-151 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)ethyl)piperidin-1-yl)methanone
  • Example-152 (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone
  • Example-157 4-(2-chloro-4-(trifluoromethyl)phenoxy)-N-(4-(3-hydroxyoxetan-3- yl)phenyl)piperidine-1-carboxamide
  • 1 H NMR (DMSO-d 6 ) ⁇ : 1.53-1.84 (m, 2H), 1.96-2.27 (m, 2H), 3.33-3.62 (m, 2H), 3.73- 3.91 (m, 2H), 4.55-4.67 (m, 2H), 4.73-4.95 (m, 2H), 5.03 (m, 1H), 6.15-6.21 (m, 1H), 7.34 (d, J 6.8 Hz, 1H), 7.47 (m, 4H), 7.61-7.92 (m, 2H), 8.60-8.71 (m, 1H); ESI-MS: m/z, 471.12 (M+H) + , 100%.
  • Example-159 N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxamide
  • Example-160 N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxamide
  • Example-168 tert-butyl 4-(3-(3-hydroxyoxetan-3-yl)-5-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)piperazine-1-carboxylate
  • Example-169 (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • Example-170 (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
  • Example-178 (4-(3-hydroxythietan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
  • BODIPY-LDL uptake assay in HepG2 cells.
  • An established assay for PCSK9 inhibition features uptake of fluorescently labeled LDL nanoparticles (BODIPY-LDL) by hepatocytes and uptake of the BODIPY-containing particles is maximized in the absence of PCSK9.
  • BODIPY-LDL fluorescently labeled LDL nanoparticles
  • HepG2 cells were seeded at a density of 6x104 cells/well in a 96-well plate. After 24 h, the test compounds at various concentrations were pre-incubated with 5 ⁇ g/ml PCSK9 in 0.2% DMSO for 60 min prior to the addition on to the cells.
  • PCSK9 protein was measured using the ELISA kit (R & D System kit DY3888). The procedure was used as per the directions given in the kit. The cells in the wells were washed and lysed with 0.1% Triton® X-100 and total protein was estimated using Bradford method. PCSK9 protein levels were normalized with the total protein concentration from respective wells. The modulation in PCSK9 protein with NCE treatment was represented as the ratio compared to the control DMSO. Table 4 In certain instances, it may be appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent.
  • a combination therapy may be used depending on the need of the patient.
  • one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • combination therapy may be envisaged for all such situations.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • the pharmaceutical composition is prepared by employing conventional techniques.
  • the composition is in unit dosage form containing an effective amount of the active component, i.e. the compounds of formula (I) according to this invention.
  • a pharmaceutical composition comprising compound of formula (I) and pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include those which are commonly used for formulation of such compounds as is known in the art and may be selected from diluents, bulking agents, binders, disintegrants and other necessary excipicients.
  • the quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
  • the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • Specific, non- limiting examples of possible combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta.
  • an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastat

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Abstract

Present invention relates to compounds of general formula (I), their tautomeric forms, stereoisomers, pharmaceutically acceptable salts and pharmaceutical composition containing them. Invention also relates to process for the preparation of compounds of general formula (I) and intermediates thereof. Compounds of present invention can be useful in treating diseases such as hyperlipidemia and other disorders related to hyperlipidemia. Compounds of present invention also have a beneficial effect on lowering cholesterol.

Description

NOVEL COMPOUNDS SUITABLE FOR THE TREATMENT OF DYSLIPIDEMIA FIELD OF INVENTION The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. The present invention is directed towards compounds which can be used to treat diseases such as hyperlipidemia and also have a beneficial effect on cholesterol.
Figure imgf000002_0001
The compounds of the general formula (I) lower blood glucose, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering of LDL (and/or raising of HDL) is beneficial. Thus, it can be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions. The compounds of general formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as artereosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non- insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabolism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, like arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia. The compounds of the present invention can be useful as aldose reductase inhibitors; for improving cognitive functions in dementia, and in the treatment and/or prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia. BACKGROUND OF THE INVENTION Higher LDL cholesterol levels in the plasma increase cardiovascular risk and reduction in the levels of LDL would decrease CVD risk by a comparable percentage (PNAS, 2009, 106, 9546-9547). Clearance of LDL cholesterol from plasma is through the action of LDL receptors in the liver and LDL receptors are cell surface glycoproteins that bind to apoliporpotein B100 (apoB100) on LDL particles with high affinity and mediate their endocytic uptake (Journal of Biological Chemistry, 2009, 284, 10561-10570). Defect in hepatic cholesterol clearance and elevated levels of plasma LDL cholesterol that result from the mutations cause familial hypercholesterolemia. Such mutations are identified in the human LDL receptor and later in apolipoprotein-B (Nature Structural and Molecular Biology, 2007, 14, 413-419). Recently, mutations within certain subtypes of the pro- protein convertasesubtilisin/ gene such as the subtype nine (hereinafter “the gene”) were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). The discovery, etiology and functions of this subtype gene is discussed in details in Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434 etc.. Several missense mutations (S127R, D129G, F216L, D374H, D374Y) are associated with hypercholesterolemia and premature atherosclerosis (J Lipid Res. 2008, 49, 1333-1343). Loss-of-function mutations (R46L, L253F, A433T) lead to elevated receptor abundance, enhancing clearance of LDL cholesterol from the circulation and reducing cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14, 413-419). Detailed molecular mechanisms explaining the association of LDLR and the particular subtype gene and LDLR degradation is not very clear (Drug News Perspectives, 2008, 21, 323-330). Because of inhibition of LDLR recycling, number of LDL receptors on the cell surface are decreased and this increases plasma LDL levels (PNAS, 2009, 106, 9546- 9547). Various approaches for inhibiting this particular subtype gene are reported, including gene silencing by siRNA or antisense oligonucleotides, mAb disrupting protein-protein interactions or by peptides; all the above-mentioned strategies have shown lowering of LDL cholesterol which may be effective therapy for treating hypercholesterolemia (Biochemical Journal, 2009, 419, 577-584; PNAS, 2008, 105, 11915-11920; Journal of Lipid Research, 2007, 48, 763-767; PNAS, 2009, 106, 9820-9825). However, very little success has been reported in trying to inhibit this subtype gene by using small molecules. Such small molecule inhibitors have their obvious clinical and therapeutic benefits over the other known approaches as discussed above. We herein disclose novel small molecules which have shown to inhibit this particular gene in in-vitro studies and therefore provide an alternate beneficial approach for treating patients in need of such therapy. We have disclosed earlier compounds which inhibits this particular gene in patent applications no. WO2015107541, WO2014192023, WO2012090220, WO2014002105 and WO2021130723. Inhibitors of this gene have been disclosed by few companies in application no WO2014150395, WO2014150326, WO2016021706, WO2016055901, WO2017222953, WO2017034990, WO2017034997, WO2017034994, WO2018165718, WO2018053517, WO2018057409. As compounds of present invention are related to PCSK9 protein, we have carried out PCSK9 protein and gene expression of Example 1 of WO2021130723. We have found that PCSK9 protein fold change has been found -2.12 and -4.82 at 10μM and 30μM respectively. Further pharmacokinetic study of same compound (3mg/Kg oral dose) has been carried out in Rat and Dog where AUC(0-t) has been found 4834±1855 and 1117.41±458.60 ng.h/mL respectively. PREFERRED EMBODIMENTS OF THE INVENTION The main objective of the present invention is to provide novel substituted heterocyclic derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof. In an embodiment of the present invention is provided a process for the preparation of novel substituted heterocyclic derivatives represented by the general formula (I), their intermediates, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts. In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. In an embodiment of the present invention is provided a pharmaceutical compositions in combination with additional therapeutic agents. In a further embodiment of the present invention is provided a method of treatment of diseases such as dyslipidemia, hyperlipidemia etc. by providing therapeutically effective amount of the compounds of formula (I) or their pharmaceutically acceptable salts or their suitable pharmaceutical compositions. The above and other embodiments are described in details hereinafter. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the general formula (I),
Figure imgf000006_0001
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein ‘A’ represents an optionally substituted single or fused group selected from aryl or heteroaryl groups; ‘Y’ represents either a bond, or may be selected from (C1-C3)alkyl, -S(O)o-, -C(O)-, -C(O)N(R5)-, N(R5)C(O)-, -N(R5)-, -N(R5)S(O)2N(R5)-, -N(R5)C(O)N(R5)-, -S(O)2N(R5), -N(R5)S(O)2-; ‘Z’ represents –O-, -S(O)o-, -C(O)-, -N(R5)-, -(C(R5)2)p-, -O(C(R5)2)p-, -(C(R5)2)pO-, -O(C(R5)2)pO-, -S(O)o(C(R5)2)p-, -(C(R5)2)pS(O)o-, -S(O)o(C(R5)2)pS(O)o-; - N(R5)(C(R5)2)p-, -(C(R5)2)pN(R5)-, -N(R5)(C(R5)2)pN(R5)-, -NHC(O)-, -C(O)NH-, - NHC(O)NH-, -NHS(O)2NH-, -NHS(O)2-, -S(O)2NH- or ; ‘Q’ represents O, C(R5)2, NR6 or S(O)o; wherein R6 represents H, (C1-C6)alkyl, (C3- C6)cycloalkyl, -C(O)OR5, -C(O)R5,-C(O)NH2; ‘o’ represents integers from 0-2; ‘m, n and p’ independently represent an integers from 0-4; ‘Cy’ represents saturated or partially unsaturated or unsaturated, monocyclic, bicyclic or spirocyclic groups containing 0-4 heteroatoms selected from O, N or S. ‘X’ at each occurrence independently represents either C or N; R1 at each occurrence independently represents halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, haloalkylsulfonyl, perhaloalkylsulfonyl, hydroxyl, sulfonic acid and its derivatives. R2 represents hydrogen, or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, cycloalkyl, aryl, aralkyl, heterocylyl, heterocyclylalkyl, heterocyclylalkoxyacyl, Acyl, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfonyl. Each of R3 and R4 at each occurrence independently represents hydrogen, halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, hydroxyl, sulfonic acid and its derivatives. R5 at each occurrence independently represents H, (C1-C6)alkyl or (C3-C6)cycloalkyl; When either of Cy or A are substituted with one or more groups, the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfinyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives. When one or more of R1, R3 or R4 are substituted, the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfinyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives. When the substituents on any of A, Cy, R1, R3 or R4 are further substituted, the substituents may be selected from one or more groups described above. In one of the preferred embodiment A is selected from optionally substituted phenyl, pyridine, thiophene, pyrimidine, benzo[d]thiazole and quinolone groups. In a more preferred embodiment A is optionally substituted phenyl and benzo[d]thiazole group. In another preferred embodiment of present invention ‘Y’ is selected from –C(O)-, - S(O)o-, -(C1-C3)alkyl-, -C(O)N(R5)-, -N(R5)-, -C(O)CH(R5)2-. In more preferred embodiment Y is -C(O)- and -C(O)N(R5)2-; R5 is as defined earlier In another preferred embodiment of present invention ‘Z’ is selected from –O-, -S(O)o, -C(O)-, -N(R5)-, -(C(R5)2)p-, -O(C(R5)2)p-, -O(C(R5)2)pO-, S(O)o(C(R5)2)p-, - S(O)o(C(R5)2)pS(O)o-; -N(R5)(C(R5)2)p-, -NHC(O)-, -NHC(O)NH-, or
Figure imgf000008_0001
; R5 is as defined earlier; In a more preferred embodiment ‘Z’ is selected from –O-, -S(O)o-, -N(R5)-, - (C(R5)2)p-, -O(C(R5)2)p-, or
Figure imgf000008_0002
In another preferred embodiment of present invention ‘X’ independently represent a carbon atom. In yet another preferred embodiment ‘Q’ represents oxygen atom and integers of m and n are independently 1 to form an oxetane ring.The various groups, radicals and substituents used anywhere in the specification are described in the following paragraphs. In a further preferred embodiment the groups, radicals described above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the “alkenyl” group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the “alkenyl” group includes dienes and trienes of straight and branched chains; - the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to eight carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; - the “cycloalkenyl” group used either alone or in combination with other radicals, are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cylobutenyl, 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl and the like; The terms “bicycloalkenyl” means more than one cycloalkenyl groups fused together; - the “alkoxy” group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like; - the “cycloalkoxy” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyloxy, cyclobutylxoy, cyclopentyloxy, cyclohexyloxy and the like; The terms “bicycloalkyloxy” means more than one cycloalkyl groups fused together; - the “alkenoxy” group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like; - the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(C1-C6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; - the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like; - the “aryloxy” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like; the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable aromatic or non-aromatic radicals containing one or more hetero atoms selected from O, N or S. The non-aromatic radicals may be saturated, partially saturated or unsaturated mono, bi, tri or spirocyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4- oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, hexahydro-1H-furo[3,4-c]pyrrolyl, azaspiro[3.5]nonanyl, azaspiro[3.3]heptanyl, hexahydrocyclopenta[c]pyrrolyl, tetrahydrocyclopenta[c]pyrrolyl, azepanyl, azabicyclo[3.2.1]octanyl, hexahydropyrrolo[3,4-c]pyrrolyl, tetrahydropyrrolo[3,4-c]pyrrolyl, dihydropyrrolo[3,4-c]pyrrolyl, dihydropyrrolo[3,4-c]pyrazolyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydropyrrolo[3,4-c]pyrazolyl and the like; the aromatic radicals, may be selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyrazinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like; - the groups “heterocycloxy”, “heterocylylalkoxy” are selected from suitable heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom; - the “acyl” group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; - the “acyloxy” group used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, iso- butanoyloxy, benzoyloxy and the like; - the “acylamino” group used either alone or in combination with other radicals, is selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted; - the “mono-substituted amino” group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (C1- C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, n-butylamine, n-pentylamine and the like; - the ‘disubstituted amino” group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or different selected from (C1-C6)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; - the “arylamino” used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamino, N-methyl anilino and the like; - the “oxo” or “carbonyl” group used either alone (-C=O-) or in combination with other radicals such as alkyl described above, for e.g. “alkylcarbonyl”, denotes a carbonyl radical (–C=O-) substituted with an alkyl radical described above such as acyl or alkanoyl; - the “carboxylic acid” group, used alone or in combination with other radicals, denotes a –COOH group, and includes derivatives of carboxylic acid such as esters and amides; - the “ester” group used alone or in combination with other radicals, denotes –COO- group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; - the “amide” group used alone or in combination with other radicals, represents an aminocarbonyl radical (H2N-C=O), wherein the amino group is mono- or di-substituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl amide, ethyl amide, diethyl amide, and the like; - the “aminocarbonyl” group used either alone or in combination with other radicals, may be selected from ‘aminocarbonyl’, ‘aminocarbonylalkyl”, “n- alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”, “N- alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and “N-alkyl-N- hydroxyaminocarbonylalkyl”, each of them being optionally substituted. The terms “N-alkylaminocabonyl” and “N,N-dialkylaminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term “aminocarbonylalkyl” includes alkyl radicals substituted with aminocarbonyl radicals; - the “hydroxyalkyl” group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like; - the “aminoalkyl” group used alone or in combination with other radicals, denotes an amino (-NH2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term “alkylamino” used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di- substituted alkylamino; - the “alkoxyalkyl” group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; - the “alkylthio” group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, - the “thioalkyl” group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula –SR’, where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted. - the “alkoxycarbonylamino” group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like; - the “arylthio” group used either alone or in combination with other radicals, denotes a an aryl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like; - the “heterocyclylthio” group used either alone or in combination with other radicals, denotes an heterocyclyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from aziridinylthio, azetidinylthio, pyrrolidinylthio, imidazolidinylthio, piperidinylthio, piperazinylthio, 2-oxopiperidinylthio, 4-oxopiperidinylthio, 2- oxopiperazinylthio, 3-oxopiperazinylthio, morpholinylthio, thiomorpholinylthio, 2- oxomorpholinylthio, azepinylthio, diazepinylthio, oxapinylthio, thiazepinylthio, oxazolidinylthio, thiazolidinylthio, dihydrothiophenethio, dihydropyranthio, dihydrofuranthio, dihydrothiazolethio, benzopyranylthio, benzopyranonylthio, benzodihydrofuranylthio, benzodihydrothienylthio, pyrazolopyrimidonylthio, azaquinazolinoylthio, thienopyrimidonylthio, quinazolonylthio, pyrimidonylthio, benzoxazinylthio, benzoxazinonylthio, benzothiazinylthio, benzothiazinonylthio, thieno piperidinylthio, pyridylthio, thienylthio, furylthio, pyrrolylthio, oxazolylthio, thiazolylthio, isothiazolylthio, imidazolylthio, isoxazolylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, benzofuranylthio, benzothienylthio, indolinylthio, indolylthio, azaindolylthio, azaindolinylthio, pyrazolopyrimidinylthio, azaquinazolinylthio, pyridofuranylthio, pyridothienylthio, thienopyrimidylthio, quinolinylthio, pyrimidinylthio, pyrazolylthio, quinazolinylthio, pyridazinylthio, triazinylthio, benzimidazolylthio, benzotriazolylthio, phthalazynilthio, naphthylidinylthio, purinylthio, carbazolylthio, phenothiazinylthio, phenoxazinylthio, benzoxazolylthio, benzothiazolylthio and the like; - the “alkoxycarbonylamino” group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like; - the “aminocarbonylamino”, “alkylaminocarbonylamino”, “dialkylaminocarbonylamino” groups used alone or in combination with other radicals, is a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above; - the “amidino” group used either alone or in combination with other radicals, represents a –C(=NH)-NH2 radical; the “alkylamidino” group represents an alkyl radical, as described above, attached to an amidino group; - the “alkoxyamino” group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group; - the “hydroxyamino” group used either alone or in combination with other radicals, represents a –NHOH moiety, and may be optionally substituted with suitable groups selected from those described above; - the “sulfenyl” group or “sulfenyl derivatives” used alone or in combination with other radicals, represents a bivalent group, –SO- or RxSO, where Rx is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above; - the “sulfonyl” group or “sulfones derivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical – SO2-, or RxSO2-, where Rx is as defined above. More preferably, the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, “arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like. - The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. - The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder. - The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. - As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Particularly useful compounds of formula (I) may be selected from- (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone; 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzoic acid; N-cyclopropyl-4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzamide; (4-(3-methoxypyrrolidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxypyrrolidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone; 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)amino)phenyl)oxetan-3- ol; 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)sulfonyl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfonyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfinyl)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin- 1-yl)methanone; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4- carboxylic acid; N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4-(trifluoromethyl)phenoxy) piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1- yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-([1,1'-biphenyl]-4-yloxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((2'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-isopropylphenoxy)piperidin-1-yl)methanone; (4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(4-(1H-imidazol-1-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)phenyl)(morpholino)methanone; 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzonitrile; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(2-phenylpropan-2-yl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-phenoxyphenoxy)piperidin-1-yl)methanone; (4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-methoxyphenoxy)piperidin-1-yl)methanone; (4-(4-(2H-tetrazol-5-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenoxy)methyl)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-((trifluoromethyl)thio)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-((trifluoromethyl)thio)phenoxy)piperidin-1- yl)methanone; (4-(3-(methoxy-d3)oxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-((tetrahydro-2H-pyran-4-yl)methoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2-yl)oxy)piperidin-1- yl)methanone; (4-(3-isobutoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)(4- (trifluoromethyl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone; (4-(4-hydroxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride; (4-(4-methoxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride; tert-butyl 4-hydroxy-4-(4-(5-(4- (trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2- carbonyl)phenyl)piperidine-1-carboxylate; (4-(4-(3-methoxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2-yl)amino)piperidin- 1-yl)methanone; N-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-4- (trifluoromethyl)benzenesulfonamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)amino)piperidin-1-yl)methanone; (4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3,5-dimethoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)amino)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3-(trifluoromethyl)phenyl)amino)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((3-(trifluoromethyl)phenyl)amino)piperidin-1- yl)methanone; (2-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(4-(difluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)azepan-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-thiomorpholinophenoxy)piperidin-1- yl)methanone; (4-(3-hydroxytetrahydrofuran-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)azetidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)azetidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; 4-(3-hydroxyoxetan-3-yl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(2-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)benzyl)amino)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)benzyl)amino)piperidin-1-yl)methanone; 2-(4-(3-hydroxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one; 2-(4-(3-methoxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one; (3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (3-fluoro-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)pyrrolidine-1-carboxylate; (4-(3-hydroxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (3-methoxy-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 4-hydroxy-4-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)piperidine-1-carboxylate; (4-(4-hydroxypiperidin-4-yl) phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone hydrochloride; 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)oxetan-3-yl acetate; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)piperidin- 1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)thio)piperidin-1- yl)methanon; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)thio)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzylidene)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin- 1-yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethoxy)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethoxy)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxytetrahydrothiophen-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidine-1-carboxamide; N-(3-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- carboxamide; 4-(2-chloro-4-(trifluoromethyl)phenoxy)-N-(4-(3-hydroxyoxetan-3- yl)phenyl)piperidine-1-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidine-1-carboxamide; N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidine-1-carboxamide; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4-(trifluoromethyl)phenyl)piperidine-4- carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4- carboxamide; 4-(3-hydroxyoxetan-3-yl)-N-(6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)benzamide; N-(4-(3-methoxyoxetan-3-yl)phenyl)-6-(3-(trifluoromethyl)phenoxy)nicotinamide; 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)oxetan-3-ol; 3-(3-morpholino-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)oxetan-3- ol; (4-(3-hydroxyoxetan-3-yl)-2-morpholinophenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 4-(3-(3-hydroxyoxetan-3-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)phenyl)piperazine-1-carboxylate; (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(1-hydroxycyclobutyl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethyl)piperazin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone; (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone; 2-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidine-4-carbonitrile; 2-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)-5- (trifluoromethyl)pyrimidine-4-carbonitrile; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrazin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridazin-3- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((8-(trifluoromethyl)quinolin-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((7-(trifluoromethyl)quinolin-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3-(trifluoromethyl)quinolin-7- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)naphthalen-1- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)-5,6,7,8- tetrahydronaphthalen-1-yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)naphthalen-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(4- (trifluoromethyl)phenoxy)phenyl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-methyl-4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-methyl-4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (3-fluoro-4-(4-;(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone;1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)phenoxy)piperidine-3-carboxylic acid; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-methoxy-4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-3- carbonitrile; (3,3-difluoro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (3-chloro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyazetidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-morpholinophenoxy)piperidin-1- yl)methanone; (4-(4-((2S,6R)-2,6-dimethylmorpholino)phenoxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)phenoxy)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-((4- (trifluoromethyl)phenyl)sulfonyl)piperidine-4-sulfonamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-(4-(trifluoromethyl)benzoyl)piperidine-4- sulfonamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4- yl)benzenesulfonamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)benzenesulfonamide; (4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)piperidin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3,5-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperazin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(3- (trifluoromethyl)benzyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)methyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)methyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)methyl)piperazin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-3,4- dihydroquinolin-1(2H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-6,7- dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)indolin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)-1H-indol-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-2-(4-(trifluoromethyl)phenoxy)pyrimidine-5- carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperazin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperazine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]oxazol-2- yl)oxy)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]oxazol-2- yl)oxy)piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)amino)piperidin1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzofuran-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzofuran-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[b]thiophen-2- yl)oxy)piperidin-1-yl)methanone; (4-fluoro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-methyl-4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-methyl-4-((6-(trifluoromethyl)benzo[d]thiazol- 2-yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)-4-(4- (trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)amino)piperidin-1-yl)methanone (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)oxy)- 4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- sulfonamide; 1-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-3-(4- (trifluoromethyl)phenyl)urea; 1-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-3-(4- (trifluoromethyl)phenyl)sulfonylurea; 1-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4- yl)urea; 1-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4- yl)sulfonylurea; 4-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1- carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(2-methoxyethoxy)-4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-(2-methoxyethoxy)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-(2-(methylsulfonyl)ethoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3,3-difluoro-1-hydroxycyclobutyl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; 3-(3-(morpholinosulfonyl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4-(trifluoromethyl)phenyl)sulfonyl)-3,5- dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4- (trifluoromethyl)phenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)-3,4,5,6- tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(pyrimidin-2-ylamino)piperidin-1- yl)methanone; N-(1-benzylpyrrolidin-3-yl)-4-(3-hydroxyoxetan-3-yl)benzamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(pyridin-4-yloxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(quinolin-4-yloxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(quinolin-4-yloxy)piperidin-1-yl)methanone; (4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone; tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)azetidine-1-carboxylate; tert-butyl 3-methoxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)azetidine-1-carboxylate; (4-(3-methoxyazetidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone hydrochloride; (4-(3-hydroxythietan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)piperidine-1- carboxamide; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; 4-(3-hydroxyoxetan-3-yl)-N-((1r,4r)-4-(4- (trifluoromethyl)phenoxy)cyclohexyl)benzamide and (4-(4-hydroxypiperidin-4-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)amino)piperidin- 1-yl)methanone hydrochloride. The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers and/or diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention. The compounds of general formula (Ia) wherein ‘Y’ represents C=O and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 1 below which comprises: Scheme:1
Figure imgf000034_0001
Compounds of formula (Ia) can be synthesized by two methods differentiated by sequence of addition of reactants. However rection conditions remains same. Method A i. Reacting the compounds of general formula II and III wherein all the symbols are defined as earlier using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like to prepare corresponding compounds of general formula IV. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; ii. The compounds of formula IV further reacted with compounds of general formula V wherein all symbols are defined as earlier for form compounds of formula (Ia). suitable conditions in presence of reagents(s) such as N-(3-dimethylaminopropyl)- N’-ethylcarbodimide hydrochloride (EDC) & 1-Hydroxybenzotriazole (HOBT), 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1- yl)uronium hexafluorophosphate (HBTU) and the like. The reaction may be carried in presence of suitable organic bases such as N-ethylmorpholine, triethylamine, diisopropylethylamine, pyridine and the like. The reaction may be carried out in presence of suitable solvent(s) such as N,N-dimethylformamide, N,N- dimethylacetamide, dichloromethane and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours. Method B i. Reacting compounds of general formula II with compounds of general formula V wherein all the symbols are as defined earlier using suitable reaction conditions as provided in step ii of method A to obtain compounds of general formula VI. ii. Further in step ii, reacting compounds of general formula VI with compounds of formula III wherein wherein all the symbols are as defined earlier, using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours to obtain compounds of general formula (Ia) wherein all the symbols are as defined earlier. The compounds of general formula (Ib) and (Ic) wherein ‘Y’ represents –C(O)NH- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 2 below which comprises: Scheme:2
Figure imgf000035_0001
i. The compounds of formula (Ib) wherein all the symbols are as defined earlier may be prepared by reacting aryl amines of general formula VII wherein all the symbols are as defined earlier and corresponding cyclic amines of general formula V wherein all the symbols are as defined earlier under suitable conditions in presence of reagents(s) such as phosgene, triphosgene, Carbonyldiimidazole and the like. The reaction may be carried in presence of organic base(s) such as trimethylamine, diisopropylamine, pyridine and the like using suitable solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane, acetonitrile and the like or mixtures thereof. The reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii. The compounds of formula (Ic) wherein all the symbols are as defined earlier may be prepared by coupling reaction of acids of general formula VIII wherein all the symbols are as defined earlier and amines of general formula VII wherein all the symbols are as defined earlier under suitable conditions in presence of reagents(s) such as N-(3- dimethylaminopropyl)-N’-ethylcarbodimide hydrochloride (EDC) & 1- Hydroxybenzotriazole (HOBT), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N,N′,N′- Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and the like. The reaction may be carried in presence of suitable organic bases such as triethyl amine, diisopropylethyl amine, pyridine and the like. The reaction may be carried out in presence of suitable solvent(s) such as N,N-dimethylformamide, N,N- dimethylacetamide, dichloromethane and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours. The compounds of general formula (Id) wherein ‘Y’ represents –CH2- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 3 below which comprises: Scheme:3
Figure imgf000037_0001
i. Reacting the compounds of general formula V wherein all the symbols are as defined earlier and the compounds of general formula IX wherein ‘L1’ represents suitable leaving group and all other symbols are as defined earlier, using suitable inorganic base(s) such as K2CO3, Cs2CO3, NaOH, KOH, NaH, KH and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like to prepare compounds of general formula X wherein the symbols are as defined earlier. The reaction may be carried out neat or in presence of suitable aprotic solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii. Reacting Compounds of general formula X wherein all the symbols are as defined earlier and cyclic ketones of general formula III, using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like to prepare corresponding compounds of general formula (Id) wherein the symbols are as defined earlier. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; The compounds of general formula (Ie) wherein ‘Y’ represents –NH- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 4 below which comprises: Scheme: 4
Figure imgf000038_0001
i. Reacting the compounds of general formula VII wherein all the symbols are as defined earlier and the cyclic ketones of general formula XI wherein all the symbols are as defined earlier, using suitable methods available in the literature for the reductive amination to prepare compounds of general formula (Ie) wherein the symbols are as defined earlier. The reaction may be carried out using reducing agents such as sodium tricatoxyborohydride, sodium cynoborohydride, sodium brohydride and the like. The reaction may be carried out in presence of solvent(s) such as dichloromethane, 1,2-dicloroethane, toluene, methanol, ethanol, isopropanol, n-butanol and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; The compounds of general formula (If) wherein ‘Y’ represents –SO2- and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 5 below which comprises: Scheme:5
Figure imgf000038_0002
i. Reacting the compounds of general formula V wherein all the symbols are as defined earlier and the compounds of general formula XII wherein ‘L2’ represents suitable leaving group such as Cl, Br and the like and all other symbols are as defined earlier, using suitable inorganic base(s) such as K2CO3, Cs2CO3, NaOH, KOH, NaH, KH and the like or organic base(s) such as pyridine, 4-(N,N- dimethylamino)pyridine, triethyl amine, diisopropyl ethylamine and the like to prepare compounds of general formula XIII wherein the symbols are as defined earlier. The reaction may be carried out neat or in presence of suitable aprotic solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; ii. Reacting Compounds of general formula XIII wherein all the symbols are as defined earlier and cyclic ketones of general formula III, using suitable metal alkyls such as n-butyllithium, s-butyllithium and the like to prepare corresponding compounds of general formula (If) wherein the symbols are as defined earlier. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; The compounds of general formula (Ig) wherein all the symbols are as defined earlier, may be prepared by reactions outlined in Scheme 6 below which comprises: Scheme:6
Figure imgf000039_0001
i. Reacting the compounds of general formula (Ia-f) wherein all the symbols are as defined earlier and the compounds of general formula XIV wherein ‘L3’ represents suitable leaving group such as and all other symbols are as defined earlier, using suitable inorganic base(s) such as K2CO3, Cs2CO3, NaOH, KOH, NaH, KH and the like to prepare compounds of general formula (Ig) wherein the symbols are as defined earlier. The reaction may be carried out neat or in presence of suitable solvent(s) such as N,N-dimethyl formamide, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane, toluene and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; The compounds of general formula (Ih), (Ii), (Ij) & (Ik) wherein ‘Q’ represents –NH and NR6 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 7 below which comprises: Scheme:7
Figure imgf000040_0001
i. Compounds of general formula (Ih) and (Ij) wherein all the symbols are as defined earlier may be prepared from corresponding compounds of general formula XV and XVI wherein P1 represents suitable protecting groups such as tert- butoxycarbonyl, Fmoc, benzyl and the like and all other symbols are as defined earlier using the suitable methods available in the literature for deprotection of secondary amines. ii. Reacting the compounds of general formula XV wherein all the symbols are as defined earlier and the compounds of general formula XIV wherein all the symbols are as defined earlier, using suitable inorganic base(s) such as K2CO3, Cs2CO3, NaOH, KOH, NaH, KH and the like to prepare compounds of general formula XVI wherein all the symbols are as defined earlier. The reaction may be carried out neat or in presence of suitable solvent(s) such as N,N-dimethyl formamide, tetrahydrofuran, dichloromethane, toluene and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; iii. Reacting the compounds of general formula (Ih) and (Ij) wherein all the symbols are as defined earlier and the compounds of general formula XVII wherein ‘L4’ represents suitable leaving group such as and all other symbols are as defined earlier, using suitable inorganic base(s) such as K2CO3, Cs2CO3, NaOH, KOH, NaH, KH and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like to prepare compounds of general formula (Ii) and (Ik) respectively, wherein the symbols are as defined earlier. The reaction may be carried out neat or in presence of suitable aprotic solvent(s) such as N,N- dimethyl formamide, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; The compounds of general formula (Il) wherein ‘Q’ represents –S(O)o- wherein ‘o’ represents integers 1 & 2 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 8 below which comprises: Scheme:8
Figure imgf000041_0001
i. The compounds of general formula (Il) wherein all the symbols are as defined earlier may be prepared by the oxidation of the compounds of general formula (Ia) wherein ‘Q’ represents ‘S’ and all other symbols are as defined earlier using suitable oxidizing agents such as H2O2, m-chloroperbenzoic acid, sodium periodate, potassium peroxymonosulfate and the like. The reaction may be carried in presence of suitable solvent(s) such as chloroform, dichloromethane, acetone, water, tetrahydrofuran, methanol, ethanol and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -40 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours; The compounds of general formula (Im) wherein ‘Z’ represents –S(O)o- wherein ‘o’ represents integers 1 & 2 and all other symbols are as defined earlier, may be prepared by reactions outlined in Scheme 9 below which comprises: Scheme: 9
Figure imgf000042_0001
The compounds of general formula (Im) wherein all the symbols are as defined earlier may be prepared by the oxidation of the compounds of general formula (Ia) wherein ‘Z’ represents ‘S’ and all other symbols are as defined earlier using suitable oxidizing agents such as H2O2, m-chloroperbenzoic acid, sodium periodate, potassium peroxymonosulfate and the like. The reaction may be carried in presence of suitable solvent(s) such as chloroform, dichloromethane, acetone, water, tetrahydrofuran, methanol, ethanol and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -40 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours. In one of the embodiment the compounds of general formula (I) wherein ‘Q’ represents ‘O’, ‘m’ and ‘n’ represents integer 1 and all other symbols are as defined earlier, may also be prepared by reactions outlined in Scheme 10 below which comprises: Scheme:10
Figure imgf000042_0002
i. Reacting the compounds of general formula XVIII wherein all the symbols are as defined earlier and magnesium metal, using suitable methods available in the literature for the preparation of Grignard reagents to prepare compounds of general formula XIX wherein all the symbols are as defined earlier. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; ii. Reacting the compounds of general formula XIX wherein all the symbols are as defined earlier and 2,2-dimethyl-1,3-dioxan-5-one to prepare compounds of general formula XXI wherein the symbols are as defined earlier. The reaction may be carried out in presence of suitable solvent(s) such as tetrahydrofuran, diethylether and the like or suitable mixtures thereof. The reaction may be carried out at a temperature in the range of -78 °C to 28 °C and the reaction time may range from 1 to 48 hours; iii. The compounds of formula (I) wherein all the symbols are as defined earlier may be prepared from compounds of general formula XXI wherein all the symbols are as defined earlier using the procedure given in literature (Angewandte Chemie, International Edition (2007), 46(15), 2616-2618; US6255540 and Journal of Medicinal Chemistry (1992), 35(14), 2600-2609) with appropriate modifications in the reaction conditions. In an embodiment an intermediate of compound of formula XXI is
Figure imgf000043_0001
Wherein symbols are as defined earlier. In a preferred embodiment of the present invention, wherein compound of formula XXI is (4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone. The said compound is an intermediate for the process for the preparion of compounds of formula (I). The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in ^ scale. ESI-MS data is recorded using mass spectrometer (waters Xevo G2 QToF). Intermediate - 1: 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride
Figure imgf000044_0001
Step 1: Preparation of tert-butyl 4-(4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (92 g, 457 mmol) in dimethylacetamide (750 ml), potassium tert-butoxide (103 g, 914 mmol) was added and stirred at 30 °C for 30 minute. To this 1-fluoro-4-(trifluoromethyl)benzene (58.0 ml, 457 mmol) was added maintaining the temperature of the reaction mixture below 40 °C and stirring was continued for 24 hours. The reaction mixture was poured into water (500 ml) and extracted with tert-butyl methyl ether (2 x 300 ml). The combined organic layer was washed with water (2 x 350 ml) & brine (350 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield crude product as thick liquid. The crude product was triturated with ice-cold hexane (250 ml), resulting solid was filtered, rinsed with ice cold hexane, and dried to yield tert-butyl 4-(4-(trifluoromethyl)phenoxy)piperidine-1- carboxylate (106 g, 67.2% yield) as a white solid.1HNMR (CDCl3) δ : 1.63 (s, 9H), 1.75- 1.82 (m, 2H), 1.92-1.98 (m, 2H), 3.35-3.42 (m, 2H), 3.68-3.74 (m, 2H), 4.54-4.58 (m, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.0 Hz, H z, 2H). Step 2: 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride. To a solution of tert-butyl 4-(4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (2 g, 5.79 mmol) in dichloromethane (10 ml), another solution of dioxane saturated with HCl (25 ml) was added and the reaction mixture was stirred for 5 hours at 30 oC. Solvent was evaporated under reduced pressure and the residue was stirred in diisopropyl ether (50 ml). The solid was filtered, washed with diisopropyl ether (10 ml) and dried to yield 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride (1.307 g, 80% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.85-1.92 (m, 2H), 2.10-2.17 (m, 2H), 3.04-3.09 (m, 2H), 3.19- 3.23 (m, 2H), 4.77-4.83 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H); ESI- MS: m/z: 246.11 (M+H)+, 100%. Intermediate-2: 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine
Figure imgf000045_0001
Step 1: tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7 g, 34.8 mmol) in dichloromethane (50 mL), triethylamine (9.70 mL, 69.6 mmol) was added followed by the addition of methane sulfonyl chloride (2.98 mL, 38.3 mmol) dropwise at 5 °C over the period of 10 minutes under nitrogen atmosphere and the reaction mixture was stirred for 1 hour at ambient temperature. The reaction mixture was poured into with water (40 ml) and extracted with dichloromethane (3 x 30 ml). Organic layer was washed with diluted hydrochloric acid (10%, 50 ml), water (3 x 50 ml) & brine (50 ml), dried over sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 10% ethyl acetate in hexane as an eluent to yield tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (9.5 gm, 98% yield) as yellowish solid. 1H NMR (DMSO-d6) δ: 1.47 (s, 9H), 1.80-1.85 (m, 2H), 1.95-1.98 (m, 2H), 3.05 (s, 3H), 3.28-3.34 (m, 2H), 3.69-3.75 (m, 2H), 4.88-4.90 (m, 1H); ESI-MS: m/z 280.07 (M+H), 70%. Step 2: Preparation of tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine-1- carboxylate To a stirred solution of 2-chloro-5-(trifluoromethyl)phenol (0.500 g, 2.544 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.782 g, 2.798 mmol) in N,N- dimethylformamide (5.0 ml), cesium carbonate (1.658 g, 5.088 mmol) was added at ambient temperature and the reaction mixture was stirred at 80 °C for 48 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic layer was washed with 1M NaOH (1 x 10 ml), water (25 ml) & brine (25 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.7 g, 72% yield) as yellow liquid. 1HNMR (CDCl3) δ : 1.49 (s, 9H), 1.84-1.96 (m, 4H), 3.50-3.54 (m, 2H), 3.63-3.69 (m, 2H), 4.61-4.64 (m, 1H), 7.17 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H). Step 3: Preparation of 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine To a stirred solution of tert-butyl 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine- 1-carboxylate (700 mg, 1.843 mmol) in dichloromethane (50 ml), trifluoroacetic acid (1.420 ml, 18.43 mmol) was added and the reaction mixture was stirred at 30 oC for 24 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layer was washed with water (20 ml) and dried over sodium sulfate and evaporated on rotavapor under vacuum to yield 4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidine (400 mg, 71.0% yield) as brown liquid. 1H NMR (DMSO-d6) δ: 1.50-1.56 (m, 2H), 1.84-1.91 (m, 2H), 2.57-2.68 (m, 2H), 2.92- 2.97 (m, 2H), 4.70-4.76 (m, 1H), 7.29 (dd, J = 8.0 & 1.6 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 8.4 & 0.4 Hz, 1H); ESI-MS: m/z: 280.10 (M+H)+, 100%. Intermediate-3: N-(piperidin-4-yl)-6-(trifluoromethyl)pyridin-3-amine dihydrochloride
Figure imgf000046_0001
Step 1: Preparation of tert-butyl 4-((4-(trifluoromethyl)phenyl)amino)piperidine-1- carboxylate. To a stirred solution of 4-(trifluoromethyl) aniline (3.90ml, 31.0 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (12.37 g, 62.1 mmol) in acetic acid (50 ml) sodium sulfate ( 44.1g, 310mmol) was added and the reaction mixture was stirred at 30 °C for 3.0 hours. To this sodium triacetoxyborohydride (19.73 g, 93 mmol) was added and stirring was continued for 20 hours. The reaction mixture was poured into water (50 ml). White solid separated was collected by filtration and washed with water (50 ml) and dried over phosphrous pentoxide to yield tert-butyl 4-((4-(trifluoromethyl)phenyl)amino)piperidine- 1-carboxylate. (5.0g, 46.8% yield) as an off white solid.1H NMR (CDCl3) δ : 1.30-1.40 (m, 2H), 1.47 (s, 9H), 2.02-2.06 (m, 2H), 2.92-2.97 (m, 2H), 3.45-3.50 (m, 1H), 3.97 (br s , 1H), 4.06-4.10 (m, 2H), 6.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H). Step 2: Preparation of N-(piperidin-4-yl)-6-(trifluoromethyl)pyridin-3-amine dihydrochloride. The title product (400 mg, 98% yield) was prepared from tert-butyl 4-((6- (trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylate (500 mg, 1.452 mmol) according to the procedure given in step-2 of Intermediate-1 as a white solid. 1H NMR (DMSO-d6) δ : 1.58-1.62 (m, 2H), 2.03-2.06 (m, 2H), 3.01-3.06 (m, 2H), 3.18- 3.20 (m, 2H), 3.78-3.88(m, 1H), 6.51 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 8.62 (s, 1H), 8.78 (s, 1H); ESI-MS: m/z: 245.13 (M+H)+, 100%. Intermediate-4 : N-methyl-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine hydrochloride
Figure imgf000047_0001
Step 1: Preparation of tert-butyl 4-(methyl(4-(trifluoromethyl)phenyl)amino)piperidine-1- carboxylate. To a suspension of sodium hydride (87 mg, 2.178 mmol) in tetrahydrofuran (10 ml) tert-butyl 4-((4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (500 mg, 1.452 mmol) in tetrahydrofuran (3 ml) was added followed by addition of iodomethane (309 mg, 2.178 mmol) at 0 °C and stirring was continued at 30 °C for 3 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic extract was washed with water (2 x 20 ml) & brine (25 ml), dried over sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography using 100-200 mesh silica gel column and 15% ethyl acetate in n-hexane as an eluent to yield tert-butyl 4-(methyl(4- (trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (300 mg, 57.7% yield) as a white solid.1H NMR (CDCl3) δ : 1.5 (s, 9H), 1.6-1.76 (m, 5H), 2.76-2.81 (m, 2H), 2.83 (s, 3H), 4.28-4.30 (m, 2H), 6.78 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 359.5 (M+H)+, 100%. Step 2: Preparation of N-methyl-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine hydrochloride The title product (400 mg 98% yield) was prepared from tert-butyl 4-(methyl(4- (trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (500 mg, 1.452 mmol) according to the procedure given in step-2 of Intermediate-1 as white solid.1H NMR (DMSO-d6) δ : 1.73-1.76 (m, 2H), 1.99-2.09 (m, 2H), 2.79 (s, 3H), 2.99-3.08 (m, 2H), 3.31-3.39(m, 2H), 4.11-4.17 (m, 1H), 6.96 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 9.0 (s, 2H); ESI-MS: m/z: 259.16 (M+H)+, 100%. Intermediate-5: 4-((4-(trifluoromethyl)phenyl)thio)piperidine hydrochloride
Figure imgf000048_0001
Step 1: tert-butyl 4-((4-(trifluoromethyl)phenyl)thio)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (678 mg, 3.37 mmol) in N,N-dimethylformamide (5 ml), potassium carbonate (776 mg, 5.61 mmol) was added followed by the addition of 4-(trifluoromethyl)benzenethiol (500 mg, 2.81 mmol) at ambient temperature and stirring was continued for further 16 hours. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 15% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((4- (trifluoromethyl)phenyl)thio)piperidine-1-carboxylate (315 mg, 0.872 mmol, 31.1% yield) as off-white solid. 1H NMR (DMSO-d6) δ: 1.34-1.44 (m, 11H), 1.91-1.95 (m, 2H), 2.98 (m, 2H), 3.63-3.70 (m, 1H), 3.81-3.85 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H). Step 2: 4-((4-(trifluoromethyl)phenyl)thio)piperidine hydrochloride. The title product (235 mg, 93% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)thio)piperidine-1-carboxylate (300 mg, 0.830 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ: 1.68-1.77 (m, 2H), 2.09-2.12 (m, 2H), 2.97-3.02 (m, 2H), 3.25- 3.28 (m, 2H), 3.72-3.77 (m, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 8.82 (br s, 2H); ESI-MS: m/z 262.06 (M+H), 100%. Intermediate-6: 2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine hydrochloride
Figure imgf000048_0002
Step 1: tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.95 g, 9.73 mmol) in N-Methyl-2-pyrrolidone (10 ml), 50% sodium hydride (0.849 g, 17.70 mmol) was added at 0-5 ºC followed by addition of 2-bromo-5-(trifluoromethyl)pyridine (2 g, 8.85 mmol) and stirring was continued for further 1.5 hours at ambient temperature. Reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidine-1-carboxylate. (1.97 g, 64.3% Yield) as a thick liquid.1H NMR (CDCl3) δ: 1.49 (s, 9H), 1.71-1.29 (m, 2H), 1.98-2.03 (m, 2H), 3.28-3.34 (m, 2H), 3.77-3.82 (m, 2H), 5.77-5.33 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.4 Hz, & J = 2.4 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H); ESI-MS: m/z 247.14 (M+H)+, 100%. Step 2: 2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine hydrochloride. The title product (1.36 g, 88.0% yield) was prepared from tert-butyl 4-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (1.90 g, 5.49 mmol) according to the procedure given in step-2 of Intermediate-1 as an off white solid. 1H NMR (DMSO-d6) δ: 1.90-1.98 (m, 2H), 2.14-2.19 (m, 2H), 3.07-3.13 (m, 2H), 3.20- 3.33 (m, 2H), 5.30-5.36 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 8.4 Hz, & J = 2.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 9.14 (brs, 2H); ESI-MS: m/z 247.14 (M+H)+, 100%. Intermediate-7: N-(piperidin-4-yl)-6-(trifluoromethyl)pyridin-3-amine dihydrochloride
Figure imgf000049_0001
Step 1: Preparation of tert-butyl 4-((6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1- carboxylate. To a stirred solution of 6-(trifluoromethyl)pyridin-3-amine (0.500 g, 3.08 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.737 g, 3.70 mmol) in 1,2-dichloroethane (20 ml), acetic acid (0.177 ml, 3.08 mmol) was added and stirring was continued at ambient temperature for 3.0 hours. To this sodium triacetoxyborohydride (0.981 g, 4.63 mmol) was added and stirred at 60 °C for 48 hours. The reaction mixture was poured into water (50 ml). Separated solid was collected by filtration, washed with water (20 ml) and dried over P2O5 to yield crude product as an off white solid. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 10% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((6-(trifluoromethyl)pyridin-3-yl)amino)piperidine-1- carboxylate (175 mg, 16.43% yield) as a white solid.1H NMR (DMSO-d6) δ : 1.21-1.30 (m, 2H), 1.41 (s, 9H), 1.86-1.90 (m, 2H), 2.93 (m, 2H), 3.53-3.55 (m, 1H), 3.85-3.89 (m, 2H), 6.58 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.4 & 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H). Step 2: Preparation of N-(piperidin-4-yl)-6-(trifluoromethyl)pyridin-3-amine dihydrochloride. The title product (138 mg, 100% yield) was prepared from tert-butyl 4-((6- (trifluoromethyl)pyridin-3-yl)amino)piperidine-1-carboxylate (150 mg, 0.434 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. Intermediate-8: N-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-2-amine dihydrochloride
Figure imgf000050_0001
Step 1: Preparation of tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1- carboxylate. To a stirred solution of 2-bromo-5-(trifluoromethyl)pyridine (400 mg, 1.770 mmol) in N,N-dimethylformamide (20 ml), cesium carbonate (807 mg, 2.478 mmol) was added followed by addition of tert-butyl 4-aminopiperidine-1-carboxylate (390 mg, 1.947 mmol) under nitrogen atmosphere at ambient temperature and stirred at 80 °C for 24 hours. Reaction mixture was poured to water (20 ml) and extracted with ethyl acetate (2 x 20 ml). Combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and concentrated under vacuum. Crude product was purified by column chromatography using 230-400 mesh silica gel column and 15% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1- carboxylate (600 mg, 99.0% yield) as a white solid.1H NMR (CDCl3) δ : 1.35-1.46 (m, 2H), 1.49 (s, 9H), 2.04-2.08 (m, 2H), 2.94-2.99 (m, 2H), 3.89-3.92 (m, 1H), 4.08 (m, 2H), 4.71 (d, J = 7.6 Hz, -NH), 6.40 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 8.8 & 2.4 Hz, 1H), 8.34 (s, 1H); ESI-MS: m/z: 344.25 (M-H)+, 75%. Step 2: Preperation of N-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-2-amine dihydrochloride The title product (737 mg, 100% yield) was prepared from tert-butyl 4-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 2.316 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.71-1.80 (m, 2H), 2.05-2.09 (m, 2H), 2.95-3.00 (m, 2H), 3.30- 3.33 (m, 2H), 4.11-4.13 (m, 1H), 6.91 (d, J = 9.2 Hz, 1H), 7.83-7.85 (m, 1H), 8.28 (s, 1H), 8.60 (br s, -NH), 9.09 (br s, 2HCl); ESI-MS: m/z: 246.13 (M+H)+, 100%. Intermediate-9: 2-(piperidin-4-ylthio)-5-(trifluoromethyl)pyridine dihydrochloride
Figure imgf000051_0001
Step 1: Preparation of tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)thio)piperidine-1- carboxylate. To a stirred suspension of sodium hydride (268 mg, 5.58 mmol) in 1,2- dimethoxyethane (2.0 ml), a solution of 5-(trifluoromethyl)pyridine-2-thiol (500 mg, 2.79 mmol) in 1,2-dimethoxyethane (5.0 ml) was added at 0 °C and stirring was continued for 30 minutes. To this another solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1- carboxylate (936 mg, 3.35 mmol) in 1,2-dimethoxyethane (2.0 ml) was added and stirred at 85 °C for 48 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water (25 ml) & brine (15 ml), dried over sodium sulfate and evaporated under vacuum to yield crude product as a yellow liquid. The crude product was purified by column chromatography using 230-400 mesh silica gel and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-((5-(trifluoromethyl)pyridin-2-yl)thio)piperidine-1-carboxylate (550 mg, 54.4% yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.48 (s, 9H), 1.63-1.68 (m, 2H), 2.07-2.11 (m, 2H), 3.09-3.14 (m, 2H), 3.95-3.98 (m, 2H), 4.07-4.13 (m, 1H), 7.24-7.28 (m, 1H), 7.67 (dd, J = 8.4 & 2.0 Hz, 1H), 8.67 (s, 1H); ESI-MS: m/z: 363.08 (M+H)+, 100%. Step 2: Preparation of 2-(piperidin-4-ylthio)-5-(trifluoromethyl)pyridine dihydrochloride The title product (458 mg, 99% yield) was prepared from of tert-butyl 4-((5- (trifluoromethyl)pyridin-2-yl)thio)piperidine-1-carboxylate (500 mg, 1.380 mmol) according to the procedure given in step-2 of Intermediate-1 as white solid. Intermediate-10: 5-(methylthio)-2-(piperidin-4-yloxy)pyrimidine dihydrochloride
Figure imgf000052_0001
Step 1: Preparation of tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)oxy)piperidine-1- carboxylate. To a stirred suspension of sodium hydride (90 mg, 1.868 mmol) in N,N- dimethylacetamide (2.0 ml), a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (251 mg, 1.245 mmol) in N,N-dimethylacetamide (0.5 ml) was added at 0 °C and stirring was continued for 15 minutes. To this another solution of 2-chloro-5- (methylthio)pyrimidine (200 mg, 1.245 mmol) in N,N-dimethylacetamide (1.0 ml) was added and stirred at 30 °C for 20 hours. The reaction mixture was poured into water (25 ml), separated solid was collected by filtration, washed with water and dried over P2O5 under vacuum to yield tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)oxy)piperidine-1- carboxylate (144 mg, 35.5% yield) as white solid. Step 2: Preparation of 5-(methylthio)-2-(piperidin-4-yloxy)pyrimidine dihydrochloride The title product (132 mg, 100% yield) was prepared from of tert-butyl 4-((5- (methylthio)pyrimidin-2-yl)oxy)piperidine-1-carboxylate (144 mg, 0.442 mmol) according to the procedure given in step-2 of Intermediate-1 as a white solid. Intermediate-11: 5-(methylthio)-N-(piperidin-4-yl)pyrimidin-2-amine dihydrochloride
Figure imgf000052_0002
Step 1: Preparation of tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)amino)piperidine-1- carboxylate. To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (343 mg, 1.712 mmol) in N,N-dimethylformamide (20 ml), cesium carbonate (710 mg, 2.179 mmol) was added followed by addition of 2-chloro-5-(methylthio)pyrimidine (250 mg, 1.556 mmol) under nitrogen atmosphere at ambient temperature and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with water (2 x 15 ml) & brine (15 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield crude product as brown thick liquid. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 44% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-((5-(methylthio)pyrimidin-2-yl)amino)piperidine-1- carboxylate (325 mg, 64% yield) as a thick liquid. 1HNMR (CDCl3) δ : 1.36-1.48 (m, 2H), 1.50 (s, 9H), 2.02-2.06 (m, 2H), 2.38 (s, 3H), 2.93.2.99 (m, 2H), 3.94-4.07 (m, 3H), 5.09 (d, J = 7.6 Hz, -NH), 8.36 (s, 2H); ESI-MS: m/z: 325.15 (M+H)+, 20%. Step 2: Preparation of 5-(methylthio)-N-(piperidin-4-yl)pyrimidin-2-amine dihydrochloride. The title product (260 mg, 72.9% yield) was prepared from tert-butyl 4-((5- (methylthio)pyrimidin-2-yl)amino)piperidine-1-carboxylate (325 mg, 1.002 mmol) according to the procedure given in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.66-1.75 (m, 2H), 1.99-2.03 (m, 2H), 2.37 (s, 3H), 2.93.3.01 (m, 2H), 3.25-3.39 (m, 2H), 3.92-3.99 (m, 1H), 7.27 (m NH), 8.38 (s, 2H), 8.79 (br s, HCl), 9.00 (br s, HCl); ESI-MS: m/z: 225.11 (M+H)+, 100%. Intermediate-12: 4-(piperidin-4-yloxy)quinoline hydrochloride
Figure imgf000053_0001
Step 1: Preparation of tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.693 g, 3.44 mmol) and quinolin-4-ol (0.5 g, 3.44 mmol) in tetrahydrofuran (10 ml) triphenyl phosphine (2.2g, 8.61mmol) was added followed by the addition of diisopropyl azodicarboxylate (1.67ml, 8.61mmol) at ambient temperature and stirring was continued for 24 hours. The reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extract was washed with water (2 x 50 ml) & brine (75 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate (400 mg, 35% yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.50 (s, 9H), 2.08-2.10 (m, 2H), 1.89-1.93 (m, 2H), 3.40-3.48 (m, 2H), 3.80-3.85 (m, 2H), 5.0-5.10 (m, 1H), 7.28-7.30 (m, 1H), 7.57-7.61 (m, 2H), 7.84-7.88 (m, 1H), 8.17-8.19 (m, 1H), 8.80 (s, 1H); ESI-MS: m/z: 329.18 (M+H)+, 100%. Step 2: Preparation of 4-(piperidin-4-yloxy)quinoline hydrochloride. The title product (300 mg 93% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate. (400 mg, 1.28 mmol) according to the procedure dexcribed in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 2.13-2.15 (m, 2H), 2.26-2.31 (m, 2H), 3.19-3.22 (m, 2H), 3.38- 3.40 (m, 2H), 5.73-5.76 (m, 1H), 7.80-7.83 (m, 1H), 8.12-8.14 (m, 3H), 8.33-8.35 (m, 1H), 8.38-8.35 (m, 1H), 9.52 (s, 1H), 9.74 (s, 1H); ESI-MS: m/z: 229.17 (M+H)+, 100%. Intermediate-13: 4-((5-(trifluoromethyl)thiophen-3-yl)oxy)piperidine hydrochloride
Figure imgf000054_0001
Step 1: Preparation of tert-butyl 4-((5-(trifluoromethyl)thiophen-3-yl)oxy)piperidine-1- carboxylate. To a stirred solution of 5-(trifluoromethyl)thiophen-3-ol (340 mg, 2.022 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (621 mg, 2.224 mmol) in N,N- dimethylformamide (5.0 ml), cesium carbonate (1.318 gm, 4.04 mmol) was added at ambient temperature and stirred at 100 °C for 3.0 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with 1M NaOH (10 ml), water (25 ml) & brine (20 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 7% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidine-1-carboxylate (450 mg, 63.3% yield) as a brown liquid. 1H NMR (CDCl3) δ : 1.48 (s, 9H), 1.72-1.78 (m, 2H), 1.90-2.02 (m, 2H), 3.35-3.38 (m, 2H), 3.66-3.68 (m, 2H), 4.25-4.33 (m, 1H), 6.47 (s, 1H), 7.11 (d, J =1.6 Hz, 1H). Step 2: Preperation of 4-((5-(trifluoromethyl)thiophen-3-yl)oxy)piperidine hydrochloride. The title product (300 mg, 79% yield) was prepared from tert-butyl 4-((5- (trifluoromethyl)thiophen-3-yl)oxy)piperidine-1-carboxylate (440 mg, 1.252 mmol) according to the procedure given in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.83-1.90 (m, 2H), 2.10-2.15 (m, 2H), 3.01-3.06 (m, 2H), 3.20- 3.23 (m, 2H), 4.53-4.59 (m, 1H), 7.19 (s, 1H), 7.52 (d, J =1.6 Hz, 1H); ESI-MS: m/z: 252.07 (M+H)+, 100%. Intermediate-14: 2-(piperidin-4-yloxy)-6-(trifluoromethyl)benzo[d]thiazole hydrochloride
Figure imgf000055_0001
Step 1: 6-(trifluoromethyl)benzo[d]thiazol-2-amine. To a stirred solution of 4-(trifluoromethyl)aniline (1.0 gm, 6.21 mmol) and ammonium thiocyanate (0.945 gm, 12.41 mmol) in acetic acid (20ml), another solution of bromine (0.416 ml, 8.07 mmol) in acetic acid (3ml) was added under nitrogen atmosphere at 10 °C. The reaction mixture was warmed to ambient temperature and stirring was continued for next 12 hours. The reaction mixture was poured into ice-cold water (50 ml), basified with aqueous solution of ammonium hydroxide (25%, pH = 9) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (2 x 30 ml) & brine (25 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 30% ethyl acetate in n-hexane as an eluent to yield pure 6- (trifluoromethyl)benzo[d]thiazol-2-amine (430 mg, 31.8% yield) as pale yellow solid. 1H NMR (CDCl3) δ: 7.46 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.96 (br s, 2H), 8.13 (d, J = 9.6 Hz, 1H); ESI-MS: m/z 218.90 (M+H)+, 100%. Step 2: 2-chloro-6-(trifluoromethyl)benzo[d]thiazole. To a stirred suspension of copper(II) chloride (1.479 g, 11.00 mmol) in acetonitrile (20 ml), tert-butyl nitrite (1.418 gm, 13.75 mmol) was added followed by the addition of 6-(trifluoromethyl)benzo[d]thiazol-2-amine (2.0 gm, 9.17 mmol) under nitrogen atmosphere at ambient temperature and the reaction mixture was stirred at 65 °C for 30 minutes. The reaction mixture was cooled to ambient temperature, poured into 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with water (2 x 50 ml) & brine (50 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane to yield pure 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (9.6 gm, 73.5% yield) as yellow solid. 1H NMR (CDCl3) δ: 7.76 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H). Step 3: tert-butyl 4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidine-1- carboxylate. To a stirred solution of 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (600 mg, 2.52 mmol) in N,N-dimethyl acetamide (6 ml), tert-butyl 4-hydroxypiperidine-1-carboxylate (457 mg, 2.272 mmol) was added followed by the addition of potassium tert-butoxide (567 mg, 5.05 mmol) under nitrogen atmosphere at ambient temperature and stirring was continued for 12 hours at 80 °C. The reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 25 ml). The organic layer was washed with water (2 x 50 ml) & brine (25 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 10% ethyl acetate in n-hexane as an eluent to yield pure tert-butyl 4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidine-1-carboxylate (600 mg, 59% yield) as a thick liquid.1H NMR (CDCl3) δ: 1.50 (s, 9H), 1.88-1.94 (m, 2H), 2.09-2.14 (m, 2H), 3.35-3.42 (m, 2H), 3.75-3.80 (m, 2H), 5.39-5.43 (m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H). Step 4: 2-(piperidin-4-yloxy)-6-(trifluoromethyl)benzo[d]thiazole hydrochloride. The title product (350 mg, 69% yield) was prepared from tert-butyl 4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidine-1-carboxylate (0.6 gm, 1.491 mmol) according to the procedure described in step-2 of Intermediate-1 as an off-white solid. 1H NMR (DMSO-d6) δ: 2.04-2.12 (m, 2H), 2.21-2.33 (m, 2H), 3.16 (m, 2H), 3.25 (m, 2H), 5.44-5.48 (m, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 9.05 (br s, 2H); ESI-MS: m/z 303.07 (M+H)+, 70%. Intermediate-15: N-(piperidin-4-yl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine hydrochloride
Figure imgf000057_0001
Step 1: tert-butyl 4-((6-(trifluoromethyl) benzo[d]thiazol-2-yl) amino) piperidine-1- carboxylate. To a stirred solution of 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (200 mg, 0.842 mmol) in N,N-dimethylformamide (3 ml), tert-butyl 4-aminopiperidine-1-carboxylate (202 mg, 1.010 mmol) was added followed by the addition of diisopropylethyl amine (0.176 ml, 1.010 mmol) under nitrogen atmosphere at ambient temperature and stirring was continued for 12 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 25 ml). Organic layer was washed with water (2 x 25 ml) & brine (25 ml), dried over sodium sulphate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 20% ethyl acetate in n-hexane as an eluent to yield pure tert-butyl 4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxylate (250 mg, 74% yield) as a thick liquid. 1H NMR (DMSO-d6) δ: 1.38 (s, 9H), 1.88-1.94 (m, 2H), 2.09-2.14 (m, 2H), 3.35-3.42 (m, 2H), 3.75-3.80 (m, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 9.20 (br s, 1H); ESI-MS: m/z 402.14 (M+H)+. Step 2: N-(piperidin-4-yl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine hydrochloride. The title product (150 mg, 71% yield) was prepared from tert-butyl 4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxylate (0.25 gm, 0.623 mmol) according to the procedure described in step-2 of Intermediate-1 as an off-white solid. 1H NMR (DMSO-d6) δ: 1.74-1.77 (m, 2H), 2.14-2.17 (m, 2H), 3.18-3.21 (m, 2H), 3.29- 3.37 (m, 2H), 3.57 (s, 1H), 4.10-4.17 (m, 1H), 7.52 (d, J = 8.4 Hz, 2H), 8.20 (s, 1H), 9.02 (br s, 2H); ESI-MS: m/z 302.09 (M+H)+, 100%. Intermediate-16: 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine hydrochloride
Figure imgf000057_0002
Step 1: Preparation of tert-butyl 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate (750 mg, 2.480 mmol) in N,N-dimethylformamide (5.0 ml), sodium azide (806 mg, 12.40 mmol) was added followed by addition of ammonium chloride (663 mg, 12.40 mmol) under nitrogen atmosphere at ambient temperature and stirred at 140 °C for 8.0 hours. The reaction mixture was cooled, poured into water (25 ml) and neutralized using aqueous hydrochloric acid. Separated solid was collected by filtration, washed with water and dried over P2O5 under vacuum to yield tert-butyl 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine-1- carboxylate (0.650 g, 76% yield) as a white solid.1H NMR (CDCl3) δ : 1.50 (s, 9H), 1.76- 1.84 (m, 2H), 1.94-1.99 (m, 2H), 3.37-3.43 (m, 2H), 3.68-3.74 (m, 2H), 4.57-4.59 (m, 1H), 7.03 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H). Step 2: Preparation of 4-(4-(2H-tetrazol-5-yl)phenoxy)piperidine hydrochloride The title product (255 mg, 99% yield) was prepared from of tert-butyl 4-(4-(2H- tetrazol-5-yl)phenoxy)piperidine-1-carboxylate (300 mg, 0.869 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ: 1.84-1.93 (m, 2H), 2.13-2.18 (m, 2H), 3.07-3.09 (m, 2H), 3.23- 3.39 (m, 2H), 4.78-4.81 (m, 1H), 7.23 (d, J = 9.2 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 9.11 (br s, -2HCl); ESI-MS: m/z: 246.13 (M+H)+, 100%. Intermediate-17: piperazin-1-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride
Figure imgf000058_0001
Step 1: Preparation of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate To a stirred solution of tert-butyl piperazine-4-carboxylate (0.98 g, 5.26 mmol), 4- (trifluoromethyl)benzoic acid (1.0 g, 5.26 mmol) and HBTU (2.99 g, 7.89 mmol) in N,N- dimethylformamide (5.0 ml), diisopropylethylamine (2.76 ml, 15.78 mmol) was added and stirred at 30 oC for 16 hours. The reaction mixture was poured into water (50 ml), separated solid was collected by filtration, washed with water and dried over P2O5 under vaccum to yield tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate (1.7 g, 90% yield) as an off white solid.1H NMR (DMSO-d6) δ : 1.41 (s, 9H), 3.26-3.43 (m, 6H), 3.61 (m, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H). Step 2: Preparation of piperazin-1-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride The title product (617 mg, 100% yield) was prepared from tert-butyl 4-(4- (trifluoromethyl)benzoyl)piperazine-1-carboxylate (750 mg, 2.093 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 3.11-3.17 (m, 4H), 3.57-3.69 (m, 2H), 3.86 (m, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 9.50 (br s, 2HCl); ESI-MS: m/z: 259.10 (M+H)+, 100%. Intermediate-18: Piperidin-4-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride
Figure imgf000059_0001
Step 1: Preparation of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate To a stirred solution of 1-bromo-4-(trifluoromethyl)benzene (0.467 ml, 3.33 mmol) in dry tetrahydrofuran (50 ml), n-butyllithium (1.600 ml, 4.00 mmol) was added dropwise over a period of 15 minutes at -78°C and stirring was continued for 30 minutes at -78°C. To this another solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (0.908 g, 3.33 mmol) in tetrahydrofuran (5.0 ml) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was poured into water (10 ml) and extracted with diethyl ether (2 x 50 ml). The combined organic layer was washed with water (25 ml) & brine (25 ml), dried over sodium sulfate and evaporated on rotavapour under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 20% ethyl acetate as eluent in n-hexane to yield tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate (245 mg, 20.57% yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.49 (s, 9H), 1.70-1.77 (m, 2H), 1.85-1.89 (m, 2H), 2.90-2.96 (m, 2H), 3.39-3.44 (m, 1H), 4.17 (m, 2H), 7.73 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H). Step 2: Preparation of piperidin-4-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride. The title product (205 mg, 100% yield) was prepared from tert-butyl 4-(4- (trifluoromethyl)benzoyl)piperidine-1-carboxylate (250 mg, 0.700 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. Intermediate-19: 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine
Figure imgf000060_0001
Step 1: Preparation of tert-butyl 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine-1- carboxylate To a stirred solution of 1-bromo-4-(trifluoromethyl)benzene (400 mg, 1.778 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (383 mg, 1.778 mmol) in dimethylacetamide (5.0 ml), potassium tert-butoxide (399 mg, 3.56 mmol) was added at ambient temperature and stirred at 90 °C for 6.0 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water (25 ml) & brine (15 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 10% ethyl acetate in n-hexane as eluent to yield pure tert-butyl 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carboxylate (400 mg, 62.6% yield) as a white solid. Step 2: Preparation of 4-((4-(trifluoromethyl)phenoxy)methyl)piperidine. The title product (215 mg, 72.8% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenoxy)methyl)piperidine-1-carboxylate (400 mg, 1.113 mmol) according to the procedure described in step-2 of Intermediate-2 as a yellow liquid. 1H NMR (CDCl3) δ : 1.15-1.34 (m, 2H), 1.67-1.70 (m, 2H), 1.76-1.86 (m, 1H), 2.45-2.51 (m, 2H), 2.94-2.97 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H); ESI-MS: m/z: 260.10 (M+H)+, 100%. Intermediate-20: 4-(2-(4-(trifluoromethyl)phenoxy)ethoxy)piperidine hydrochloride
Figure imgf000060_0002
Step 1: Preparation of tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol) in Tetrahydrofuran (20 ml), 50% sodium hydride (0.596 g, 24.84 mmol) was added at 0-5 ºC under nitrogen atmosphere. After 30 minutes of stirring ethyl bromoacetate (2.213 ml, 19.87 mmol) was added and stirring was continued for 24 hours at ambient temperature. Reaction mixture was poured in water (10 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1- carboxylate. (1.5 g, 52.5% Yield) as a thick liquid.1H NMR (CDCl3) δ: 1.26 (t, J = 8.0 Hz, 3H), 1.47 (s, 9H), 1.57-1.61 (m, 2H), 1.80-1.83 (m, 2H), 3.09-3.15 (m, 2H), 3.47-3.49 (m, 1H), 3.56-3.60 (m, 2H), 4.10 (s, 2H), 4.23 (q, J = 8.0 Hz, 2H). Step 2: Preparation of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate. (1.5 g, 5.22 mmol) in tetrahydrofuran (15 ml), lithium aluminium hydride (0.218g, 5.74mmol) was added in portions at 0-5 ºC under nitrogen atmosphere and stirring was continued for 2 hours. Excess LiAlH4 was quenched by addition of saturated sodium sulfate soltion untill white solid seperated out. The solid was filtered and washed with ethyl acetate (50 ml). The combined filtrate was dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert- butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate. (1.0 g, 78% Yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.50 (s, 9H), 1.51-1.57 (m, 2H), 1.84-1.87 (m, 4H), 2.10 (s, 1H), 3.30- 3.12 (m, 3H), 3.48-3.51 (m, 1H), 3.57-3.59 (m, 1H), 3.73-3.75 (m, 2H). Step 3: Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethoxy)piperidine-1- carboxylate. To a solution of tert-butyl 4-(2-hydroxyethoxy) piperidine-1-carboxylate (1.45 g, 6.09 mmol) in dimethylacetamide (10 ml), potassium tert-butoxide (1.36 g, 12.19 mmol) was added and stirred at 30 °C for 30 minutes. To this 1-fluoro-4-(trifluoromethyl) benzene (1.0g, 6.09 mmol) was added maintaining the temperature of the reaction mixture below 40 °C. Then reaction mixture was stirred at 60 °C for 24 hours. Reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (2 x 50 ml) & brine (350 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5-20% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidine-1-carboxylate. (1.0 g, 42.0% Yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.52 (s, 9H), 1.57-1.63 (m, 2H), 1.86-1.89 (m, 2H), 3.09-3.15 (m, 2H), 3.57-3.59 (m, 1H), 3.77-3.80 (m, 2H), 3.85 (t, J = 8.0 Hz, 2H), 4.17 (t, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H). Step 4. Preparation of 4-(2-(4-(trifluoromethyl)phenoxy)ethoxy)piperidine hydrochloride. The title product (600 mg 81% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl) phenoxy)ethoxy)piperidine-1-carboxylate. (890 mg, 2.28 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.92-1.99 (m, 4H), 2.83-2.92 (m, 2H), 2.93-2.96 (m, 2H), 3.33- 3.35 (m, 3H), 4.17 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 8.82 (s, 2H); ESI-MS: m/z: 304 (M+H)+, 100%. Intermediate-21: 4-(3-(4-(trifluoromethyl)phenoxy)propoxy)piperidine hydrochloride
Figure imgf000062_0001
Step 1: Preparation of tert-butyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 9.94 mmol) in tetrahydrofuran (20 ml), ethyl acrylate (2.98 g, 29.84 mmol) was added at 0-5 ºC under nitrogen atmosphere. After 30 minutes potassium hydroxide (0.056g, 0.994 mmol) was added and stirring was continued for 24 hours at ambient temperature. Reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate. (1.0 g, 33.4% Yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.26 (t, J = 8.0 Hz, 3H), 1.47 (s, 9H), 1.57-1.61 (m, 2H), 1.80-1.83 (m, 2H), 2.56 (t, J = 8.0 Hz, 2H), 3.09-3.15 (m, 2H), 3.47-3.49 (m, 1H), 3.71-3.76 (m, 4H), 4.15 (q, J = 8.0 Hz, 2H). Step 2: Preparation of tert-butyl 4-(3-hydroxypropoxy)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-(3-ethoxy-3-oxopropoxy) piperidine-1- carboxylate (1.0 g, 5.22 mmol) in tetrahydrofuran (15 ml), lithium aluminium hydride (0.139g, 3.65 mmol) was added in portions at 0-5 ºC under nitrogen atmosphere and stirring was continued for 2 hours. Excess LiAlH4 was quenched by addition of saturated sodium sulfate soltion untill white solid seperated out. The solid was filtered and washed with ethyl acetate (50 ml). The combined filtrate was dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate. (0.7g, 71% Yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.43-1.45 (m, 1H), 1.45 (s, 9H), 1.49-1.54 (m, 2H), 1.81-1.87 (m, 3H), 2.50 (s, 1H), 3.07-3.14 (m, 2H), 3.46-3.48 (m, 1H), 3.65-3.67 (m, 2H), 3.72-3.78 (m, 4H). Step 3: Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethoxy)piperidine-1- carboxylate. To a solution of tert-butyl 4-(3-(4-(trifluoromethyl)phenoxy)propoxy)piperidine-1- carboxylate (0.474 g, 1.82 mmol) in dimethylacetamide (8 ml), potassium tert-butoxide (0.4 g, 3.66 mmol) was added and stirred at 30 °C for 30 minutes. To this 1-fluoro-4- (trifluoromethyl) benzene (0.3 g, 1.828 mmol) was added keeping the temperature of the reaction mixture below 40 °C and stirring was continued at 60 °C for 24 hours. Reaction mixture cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5-20% ethyl acetate in n-hexane as eluent to yield tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidine-1-carboxylate. (0.3 g, 40.7% Yield) as a thick liquid. 1HNMR (CDCl3) δ : 1.41-1.47 (m, 2H), 1.54 (s, 9H), 1.58-1.63 (m, 2H), 1.86-1.89 (m, 2H), 3.09-3.15 (m, 2H), 3.57-3.59 (m, 1H), 3.77-3.80 (m, 2H), 3.84-3.87 (m, 2H), 4.17 (t, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H). Step 4: Preparation of 4-(3-(4-(trifluoromethyl)phenoxy)propoxy)piperidine hydrochloride. The title product (400 mg 86% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidine-1-carboxylate. (550 mg, 1.363 mmol) according to the procedure described in step-2 of Intermediate-1 as a white solid. 1H NMR (DMSO-d6) δ : 1.60-1.68 (m, 2H), 1.92-1.99 (m, 4H), 2.89-2.92 (m, 2H), 2.93- 2.96 (m, 2H), 3.33-3.57 (m, 3H), 4.11 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 8.82 (s, 2H); ESI-MS: m/z: 304 (M+H)+, 100%. Intermediate-22: 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine hydrochloride
Figure imgf000064_0001
Step 1: Preparation of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate To a stirred solution of propyl 2-(diethoxyphosphoryl) acetate (6.28 ml, 31.4 mmol) in tetrahydrofuran (50 ml), 50% sodium hydride (1.642 g, 37.64 mmol) was added at 0-5 ºC under nitrogen atmosphere atmosphere and stirred for 30 minutes. To this tert-butyl 4- oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) was added and stirring was continued for 24 hours at ambient temperature. Reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (2 x 50 ml) & brine (50 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 5-20% ethyl acetate in n-hexane as eluent to yield tert-butyl 4- (2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (6.0 g, 89% Yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.24 (t, J = 8.0 Hz, 3H), 1.38 (s, 9H), 2.26 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 8.0 Hz, 2H), 3.45-3.51 (m, 4H), 4.12 (q, J = 8.0 Hz, 2H), 5.70 (s, 1H). Step 2: Preparation of tert-butyl 4-(2-ethoxy-2-oxoethyl) piperidine-1-carboxylate. A solution of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (6.0 g, 22.28 mmol) in methanol (50 ml) was added to a suspension of 10% Pd-C (1.0 g, 0.940 mmol) in methanol (35 ml) and stirred the reaction mixture for 2 hours under hydrogen atmosphere at ambient temperature. Reaction mixture was filtered through celite bed and washed with methanol. Filtrate was concentrated on rotavapor under vacuum to yield tert- butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (6.0 g, 99% yield ) as a thick liquid. 1H NMR (CDCl3) δ : 1.11-1.15 (m, 2H), 1.24-1.29 (m, 3H), 1.46 (s, 9H), 1.68-1.71 (m, 2H), 1.91-1.96 (m, 1H), 2.23-2.24 (m, 2H), 2.69-2.75 (m, 2H), 4.10-4.16 (m, 4H). Step 3: Preparation of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate. The title product (3.0g 59.2% yield) was prepared from tert-butyl 4-(2-ethoxy-2- oxoethyl)piperidine-1-carboxylate. (6.0g, 22.11 mmol) according to the procedure described in step-2 of Intermediate-20 as a thick liquid. 1H NMR (CDCl3) δ: 1.04-1.10 (m, 2H), 1.48 (s, 9H), 1.49-1.55 (m, 3H), 1.60-1.66 (m, 2H), 2.27 (s, 1H), 2.64 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 4.03-4.08 (m, 2H). Step 4: Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine-1- carboxylate. The title product (1.0g 40.0% yield) was prepared from tert-butyl 4-(2- hydroxyethyl)piperidine-1-carboxylate (1.537g, 6.70 mmol) and 1-fluoro-4- (trifluoromethyl)benzene (1.1g, 6.70 mmol) according to the procedure described in step- 1 of Intermediate-1 as a thick liquid. 1HNMR (CDCl3) δ : 1.18-1.24 (m, 2H), 1.44 (s, 9H), 1.68-1.79 (m, 5H), 2.69-2.75 (m, 2H), 4.05-4.14 (m, 4H), 6.95 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H). Step 5: Preparation of 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine hydrochloride. The title product (500 mg 100% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate. (600 mg, 1.607 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.39-1.42 (m, 2H), 1.68-1.72 (m, 2H), 1.75-1.78 (m, 1H), 1.80- 1.87 (m, 2H), 2.78-2.87 (m, 2H), 3.20-3.24 (m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 8.80 (s, 1H), 9.04 (s, 1H); ESI-MS: m/z: 274.13 (M+H)+, 100%. Intermediate-23: 2-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridine hydrochloride
Figure imgf000065_0001
Step 1: Preparation of 2-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridine hydrochloride. The title product (500 mg, 100% yield) was prepared from tert-butyl 4-(2- hydroxyethyl)piperidine-1-carboxylate (1.54 g, 6.64 mmol) and 2-bromo-5- (trifluoromethyl)pyridine (1.1g, 6.70 mmol) according to the procedures described in Intermediate-22 as a white solid. 1H NMR (DMSO-d6) δ : 1.02-1.10 (m, 2H), 1.32-1.37 (m, 3H), 1.43-1.46 (m, 2H), 2.80- 2.86 (m, 2H), 3.12-3.22 (m, 2H), 4.32-4.38 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.57 (s, 1H), 8.91 (s, 1H), 9.11 (s, 1H); ESI-MS: m/z: 275.13 (M+H)+, 100%. Intermediate-24: 1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazine dihydrochloride
Figure imgf000066_0001
Step 1: Preparation of tert-butyl 4-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazine-1- carboxylate. To a stirred solution of 1-fluoro-4-(trifluoromethyl)benzene (500 mg, 3.05 mmol) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (702 mg, 3.05 mmol) in dimethylacetamide (5.0 ml), potassium tert-butoxide (684 mg, 6.09 mmol) was added at ambient temperature and stirred at 60 °C for 24 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (2 x 15 ml) & brine (15 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 20% ethyl acetate in n- hexane as eluent to yield pure tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylate (700 mg, 61.4% yield) as a thick liquid. 1HNMR (CDCl3) δ : 1.48 (s, 9H), 2.53.-2.56 (m, 4H), 2.85 (t, J = 5.6 Hz, 2H), 3.46-3.49 (m, 4H), 4.16 (t, J = 5.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H). Step 2: Preparation of 1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperazine dihydrochloride The title product (617 mg 95% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylate (700 mg, 1.870 mmol) according to the procedure described in step-2 of Intermediate-1 as a white solid. Intermediate-25: 1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride
Figure imgf000067_0001
Step 1: tert-butyl (1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate. To a stirred solution of tert-butyl pyrrolidin-3-ylcarbamate (0.2 g, 1.074 mmol) in N,N-dimethylformamide (3 ml), cesium carbonate (1.050 g, 3.22 mmol) was added followed by the addition of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.257 g, 1.074 mmol) and stirring was continued further for 16 hours at ambient temperature. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as eluent to yield tert-butyl (1-(4-(trifluoromethyl)benzyl)pyrrolidin- 3-yl)carbamate (0.170 g, 46% Yield) as a thick liquid. ESI-MS: m/z 345.17 (M+H)+, 100%. Step 2: 1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride. The title product (0.140 g, 86% yield) was prepared from tert-butyl (1-(4- (trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate (0.165 g, 0.479 mmol) according to the procedure described in step-2 of Intermediate-1 as an off white solid. 1H NMR (DMSO-d6) δ: 2.04-2.08 (m, 1H), 2.18-2.27 (m, 1H), 3.19-3.22 (m, 1H), 3.40- 3.73 (m, 3H), 3.82-4.07 (m, 1H), 4.56-4.63 (m, 2H), 7.86 (s, 4H), 8.45-8.61 (m, 3H), 11.55-11.87 (m, 1H); ESI-MS: m/z 245.12 (M+H)+, 100%. Intermediate-26: 1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride
Figure imgf000067_0002
Step 1: tert-butyl (1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate. To a stirred solution of tert-butyl pyrrolidin-3-ylcarbamate (0.5 g, 2.68 mmol) in 1, 2- dichloromethane (4 ml), 3-(trifluoromethyl)benzaldehyde (0.514 g, 2.95 mmol) was added at ambient temperature followed by addition of sodium triacetoxyborohydride (1.422 g, 6.71 mmol) and stirring was continued further for 24 hours. Reaction mixture was poured into water (15 ml) and extracted with 1, 2-dichloromethane (20 ml). The organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield tert-butyl (1-(3-(trifluoromethyl)benzyl)pyrrolidin-3- yl)carbamate (0.314 g, 34% Yield) as a thick liquid. ESI-MS: m/z 345.18 (M+H)+, 100%. Step 2: 1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride. The title product (0.101 g, 40% yield) was prepared from tert-butyl (1-(3- (trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate (0.310 g, 0.900 mmol) according to the procedure described in step-2 of Intermediate-1 as an off white solid. 1H NMR (DMSO-d6) δ: 2.04-2.08 (m, 1H), 2.25-2.33 (m, 1H), 3.20-3.24 (m, 1H), 3.52- 3.57 (m, 3H), 3.92-4.08 (m, 1H), 4.56-4.64 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.78 (m, 1H), 7.82-7.84 (m, 1H), 7.93-7.99 (m, 1H), 8.55-8.72 (m, 3H), 11.58-11.99 (m, 1H); ESI-MS: m/z 245.12 (M+H)+, 100%. Intermediate-27: 1-(2-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride
Figure imgf000068_0001
Step 1: tert-butyl (1-(2-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate. To a stirred solution of tert-butyl pyrrolidin-3-ylcarbamate (0.5 g, 2.68 mmol) in tetrahydrofuran (5 ml), 2-(trifluoromethyl)benzaldehyde (0.514 g, 2.95 mmol) was added at ambient temperature and the mixture was stirred at 45 ºC for 4 hours. To this sodium triacetoxyborohydride (1.422 g, 6.71 mmol) was added at 0-5 ºC and stirring was continued for further 16 hours at ambient temperature. Reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). Combined organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. Crude product was purified by column chromatography using 100-200 mesh silica gel column and 30% ethyl acetate in n-hexane as eluent to yield tert-butyl (1- (2-(trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate (0.470 g, 51% Yield) as a thick liquid. ESI-MS: m/z 345.18 (M+H)+, 100%. Step 2: 1-(2-(trifluoromethyl)benzyl)pyrrolidin-3-amine dihydrochloride. The title product (0.298 g, 78% yield) was prepared from tert-butyl (1-(2- (trifluoromethyl)benzyl)pyrrolidin-3-yl)carbamate (0.460 g, 1.336 mmol) according to the procedure described in step-2 of Intermediate-1 as an off white solid. 1H NMR (DMSO-d6) δ: 2.13-2.18 (m, 1H), 2.36-2.42 (m, 1H), 3.30-3.38 (m, 1H), 3.42- 3.64 (m, 3H), 3.91-4.08 (m, 1H), 4.64-4.69 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.79-7.91 (m, 3H), 8.72-8.80 (m, 3H), 11.47-12.05 (m, 1H); ESI-MS: m/z 245.12 (M+H)+, 100%. Intermediate-28: tert-butyl (1-benzylpyrrolidin-3-yl)carbamate
Figure imgf000069_0001
The title product (0.890 g, 99% yield) was prepared from tert-butyl (1- benzylpyrrolidin-3-yl)carbamate (1 g, 3.62 mmol) according to the procedure descrbd in step-2 of Intermediate-1 as an off white solid.1H NMR (DMSO-d6) δ: 2.09-2.31 (m, 2H), 3.18-3.25 (m, 1H), 3.50-3.68 (m, 3H), 3.80-3.91 (m, 1H), 4.44-4.51 (m, 2H), 7.45-7.64 (m, 5H), 11.34-11.87 (m, 1H). Intermediate-29: 4-(4-(trifluoromethyl)benzyl)piperidine hydrochloride
Figure imgf000069_0002
Step 1: Diethyl (4-(trifluoromethyl)benzyl)phosphonate. A mixture of 1-(bromomethyl)-4-(trifluoromethyl)benzene (2.0 gm, 8.37 mmol) and triethyl phosphate (2.195 ml, 12.55 mmol) was heated for 16 hours at 150 °C. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (30 ml), washed with water (3 x 25 ml) & brine (25 ml), dried over sodium sulphate and concentrated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 5% ethyl acetate in n-hexane as an eluent to yield pure diethyl (4-(trifluoromethyl)benzyl)phosphonite (1.5 gm, 64% yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.27 (t, J = 7.2 Hz, 6H), 3.19 (s, 2H), 4.01-4.04 (m, 4H), 7.44 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 297.10 (M+H), 100%. Step 2: tert-butyl 4-(4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate. To a stirred suspension of sodium hydride (50%, 292 mg, 6.04 mmol) in tetrahydrofuran (3 ml), a solution of diethyl (4-(trifluoromethyl)benzyl)phosphonate (1.2 gm, 4.05 mmol) in tetrahydrofuran (2 ml) was added dropwise over a period of 3 minutes under nitrogen atmosphere at ambient temperature. To this tert-butyl 4-oxopiperidine-1- carboxylate (686 mg, 3.44 mmol) was added followed by 18-crown-6 (86 mg, 0.324 mmol) and stirring was continued for 6 hours. The reaction mixture was poured into ice-cold water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (3 x 50 ml) & brine (50 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 5% ethyl acetate in n-hexane as an eluent to yield pure tert- butyl 4-(4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (1.12 g, 81% yield) as thick liquid. 1H NMR (CDCl3) δ: 1.50 (s, 9H), 2.36-2.39 (m, 2H), 2.44-2.47 (m, 2H), 3.41-3.44 (m, 2H), 3.53-3.55 (m, 2H), 6.39 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H). Step 3: tert-butyl 4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate. A solution of tert-butyl 4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate ( 1.0 gm, 2.93 mmol) in methanol (20 ml) was added to a suspension of 10% Pd-C (156 mg, 0.146 mmol) in methanol (5 ml) and the reaction mixture was stirred under hydrogen atmosphere at 50 psi pressure for 3 hours at ambient temperature. The reaction mixture was filtered through celite bed, washed with methanol and filtrate was concentrated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 5% ethyl acetate in n-hexane as an eluent to yield pure tert-butyl 4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.0 gm, 99% yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.13-1.22 (m, 2H), 1.49 (s, 9H), 1.66-1.73 (m, 3H), 2.60-2.68 (m, 2H), 4.10 (br s, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H). Step 4: 4-(4-(trifluoromethyl)benzyl)piperidine hydrochloride. The title product (750 mg, 92% yield) was prepared from tert-butyl 4-(4- (trifluoromethyl)benzyl)piperidine-1-carboxylate (1.0 gm, 2.91 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ: 1.29-1.40 (m, 2H), 1.67-1.72 (m, 2H), 1.81-1.86 (m, 1H), 2.63- 2.68 (m, 2H), 2.75-2.82 (m, 2H), 3.20-3.23 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 8.65 (br s, 2H); ESI-MS: m/z 244.10 (M+H), 100%. Intermediate-30: 4-(4-(trifluoromethyl)benzylidene)piperidine hydrochloride The title product (240 mg, 98% yield) was prepared from tert-butyl 4-(4- (trifluoromethyl)benzylidene)piperidine-1-carboxylate (0.3 gm, 0.879 mmol) according to the procedure described in step-2 of Intermediate-1 as an off-white solid. 1H NMR (DMSO-d6) δ: 2.36-2.39 (m, 2H), 2.44-2.47 (m, 2H), 3.41-3.44 (m, 2H), 3.53- 3.55 (m, 2H), 6.39 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 8.93 (s, 1H), 9.02 (s, 1H); ESI-MS: m/z 242.11 (M+H) +, 100%. Intermediate-31: 5-(4-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole hydrochloride
Figure imgf000071_0001
The title product (200 mg, 77% yield) was prepared from tert-butyl 5-(4- (trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.25 gm, 0.667 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ: 0.95 (m, 1H), 1.09 (m, 1H), 1.83 (m, 1H), 1.94 (m, 1H), 2.11-2.15 (m, 1H), 2.56 (m, 2H), 2.73 (d, J = 6.8 Hz, 2H), 3.49-3.63 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 270.18 (M+H)+, 100%. Intermediate-32: N-(piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide hydrochloride
Figure imgf000071_0002
Step 1: Preparation of tert-butyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)piperidine- 1-carboxylate To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.498 mmol) in dichloromethane (20 ml), triethylamine (0.626 ml, 4.49 mmol) was added followed by the addition of 4-(trifluoromethyl)benzenesulfonyl chloride (476 mg, 1.947 mmol) at 0 °C and stirring was continued for 30 minutes. The reaction mixture was poured into water (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The solid product was triturated with diisopropyl ether (20 ml), filtered through a Buchner Funnel, rinsed with diisopropyl ether (5.0 ml) and dried to yield tert-butyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)piperidine-1- carboxylate (500 mg, 82% yield) as a white solid.1H NMR (CDCl3) δ : 1.37-1.46 (m, 2H), 1.47 (s, 9H), 1.77-1.81 (m, 2H), 2.78-2.84 (m, 2H), 3.34-3.38 (m, 1H), 3.94-3.97 (m, 2H), 4.77 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H); ESI-MS: m/z: 407.05 (M-H)+, 100%. Step 2: Preparation of N-(piperidin-4-yl)-4-(trifluoromethyl)benzenesulfonamide hydrochloride The title product (384 mg, 91% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)sulfonamido)piperidine-1-carboxylate (500 mg, 1.224 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.54-1.64 (m, 2H), 1.72-1.80 (m, 2H), 2.82-2.90 (m, 2H), 3.13- 3.16 (m, 2H), 8.00 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 8.34 (d, J = 6.8 Hz, 1H), 8.80 (br s, HCl), 8.91 (br s, HCl); ESI-MS: m/z: 309.10 (M-H)+, 100%. Intermediate-33: 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine hydrochloride
Figure imgf000072_0001
Step 1: tert-butyl 4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine-1-carboxylate. To a stirred solution of 4-(trifluoromethyl)benzenesulfonyl chloride (0.4 gm, 1.635 mmol) in dichloromethane (5 ml), tert-butyl piperazine-1-carboxylate (0.3 gm, 1.635 mmol) was added followed by the addition of triethylamine (0.342 ml, 2.453 mmol) under nitrogen atmosphere at 0 °C and the reaction mixture was warmed to ambient temperature over a period of 1hour. The reaction mixture was poured into ice-cold water (30 ml) and extracted with dichloromethane (2 x 25 ml). The organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over calcium chloride and concentrated under vacuum to yield tert-butyl 4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine-1-carboxylate ( 0.6 gm, 93% yield) as a thick liquid.1H NMR (CDCl3) δ: 1.43 (s, 9H), 3.02-3.04 (m, 4H), 3.53- 3.55 (m, 4H), 7.84 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H). Step 2: 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine hydrochloride. The title product (750 mg, 100% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazine-1-carboxylate (0.85 gm, 2.155 mmol) according to the procedure described in step-2 of Intermediate-1 as a white solid. 1H NMR (DMSO-d6) δ: 3.19 (s, 4H), 3.34 (s, 4H), 8.02 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 9.10 (br s, 2H); ESI-MS: m/z 295.07 (M+H) +, 100%. Intermediate-34: N-(4-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride
Figure imgf000073_0001
Step 1: tert-butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate. To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.5 gm, 2.181 mmol), 4-(trifluoromethyl)aniline ( 0.351 gm, 2.181 mmol), HATU (1.244 gm, 3.27 mmol) in N,N-dimethylformamide (5 ml), diisopropyl ethyl amine (1.143 ml, 6.54 mmol) was added under nitrogen atmosphere at ambient temperature and the reaction mixture was stirred for 16 hours at 70 °C. The reaction mixture was cooled to ambient temperature, poured into ice-cold water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield tert-butyl 4-((4- (trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (550 mg, 68% yield) as a thick liquid. Step 2: N-(4-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride. The title product (240 mg, 96% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (0.3 gm, 0.806 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. Intermediate-35: N-(4-(trifluoromethyl)benzyl)piperidin-4-amine hydrochloride
Figure imgf000073_0002
Step 1: Preparation of tert-butyl 4-(benzylamino)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (2.0 g, 9.99 mmol) and 4-(trifluoromethyl)benzaldehyde (1.74 g, 9.99 mmol) in acetic acid (10 ml), sodium sulfate ( 8.82g, 62.1mmol) was added and the reaction mixture was stirred at 30 °C for 3 hours . To this sodium triacetoxyborohydride (3.95 g, 18.62 mmol) was added and stirring was continued for 20 hours. The reaction mixture was poured into water (50 ml). White solid separated was filtered through Buchner funnel, washed with water (50 ml) and dried over phosphrous pentoxide to yield tert-butyl 4-((4- (trifluoromethyl)phenyl)amino)piperidine-1-carboxylate. (2.0 g, 55.5% yield) as an off white solid. 1H NMR (CDCl3) δ : 1.25-1.28 (m, 2H), 1.46 (s, 9H), 1.85-1.88 (m, 2H), 2.64-2.67 (m, 2H), 2.69-2.84 (m, 2H), 3.89-3.92 (m , 2H), 4.12-4.14 (m, 2H), 5.3 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H). Step 2: Preperation of N-(4-(trifluoromethyl)benzyl)piperidin-4-amine hydrochloride. The title product (350 mg 97% yield) was prepared from tert-butyl 4-(2-(4- (trifluoromethyl) phenoxy)ethyl)piperidine-1-carboxylate. (500 mg, 1.395 mmol) according to the procedure described in step-2 of Intermediate-1 as white solid. 1H NMR (DMSO-d6) δ : 1.92-1.96 (m, 2H), 2.01-2.28 (m, 2H), 2.87-2.96 (m, 2H), 3.3-3.5 (m, 3H), 4.27-4.32 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 9.31 (s, 2H), 9.05 (s, 1H), 9.31 (s, 1H); ESI-MS: m/z: 259.17 (M+H)+, 100%. Intermediate-36: N-methyl-N-(4-(trifluoromethyl)benzyl)piperidin-4-amine hydrochloride
Figure imgf000074_0001
The title product (150 mg, 60.3% yield) was prepared from tert-butyl 4-((4- (trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (0.5g, 1.45 mmol) according to the procedure described in Intermediate-4 as a white solid. 1H NMR (DMSO-d6) δ : 1.09-1.11 (m, 2H), 2.04-2.09 (m, 2H), 2.50 (s, 3H), 2.89-2.96 (m, 2H), 3.36-3.41 (m, 2H), 3.54-3.57 (m, 1H), 4.52-4.54 (m, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 9.06 (s, 1H), 9.21 (s, 1H), 11.52 (s, 1H); ESI-MS: m/z: 27..19 (M+H)+, 100%. Intermediate-37: 1-(tert-butyl) 4-ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-1,4- dicarboxylate
Figure imgf000075_0001
Step 1: Preparation of 1-(tert-butyl) 4-ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-1,4- dicarboxylate. To a solution of diisopropylamine (1.994 ml, 13.99 mmol) in tetrahydrofuran (50 ml), n-butyl lithium (5.60 ml, 13.99 mmol) was added below 0 °C and stirred for 30 minutes at 0 °C. The reaction mixture was cooled to -78 °C and a solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (1.8 g, 6.99 mmol) in tetrahydrofuran (5.0 ml) was added and continued to stir at -78 °C for 1 hour. To this another solution of 1-(bromomethyl)-4- (trifluoromethyl)benzene (1.839 g, 7.69 mmol) in tetrahydrofuran (5.0 ml) was added and continued to stir at -78 °C for further 1 hour and the reaction mixture was slowly warmed to room temperature over period of 2 hours. Reaction mixture was poured into saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (2 x 50 ml) & brine (50 ml), dried over sodium sulfate and evaporated on rotavapor. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 7% ethyl acetate in n-hexane as eluent to yield pure 1-(tert-butyl) 4-ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-1,4- dicarboxylate (2.1 g, 72.3% yield) as a thick liquid. 1HNMR (CDCl3) δ : 1.20 (t, J = 7.2 Hz, 3H), 1.46 - 1.47 (m, 11H), 2.09 – 2.12 (m, 2H), 2.82-2.89 (m, 4H), 3.85-.3.90 (m, 2H), 4.12 (q, J = 7.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H). Step 2: Preparation of ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate. The title product (380 mg, 100% yield) was prepared from 1-(tert-butyl) 4-ethyl 4-(4- (trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (500 mg, 1.204 mmol) according to the procedure described in step-2 of Intermediate-2 as a yellow liquid. 1HNMR (CDCl3) δ : 1.19 (t, J = 6.8 Hz, 3H), 1.74-1.82 (m, 2H), 2.23.-2.26 (m, 2H), 2.76- 2.88 (m, 2H), 2.93 (s, 2H), 3.23-3.26 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H); ESI-MS: m/z: 316.14 (M+H)+, 100%. Intermediate-38: 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid
Figure imgf000076_0001
Step 1: Ethyl 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate. To a stirred solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (2.0 gm, 8.37 mmol) and ethyl piperidine-4-carboxylate (1.315 gm, 8.37 mmol) in acetonitrile (20 ml), diisopropyl ethyl amine (1.754 ml, 1.298 mmol) was added under nitrogen atmosphere at ambient temperature and the reaction mixture was refluxed over the period of 2 hours. The reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 30 ml). The organic layer was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum to yield ethyl 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (2.6 gm, 99% yield) as a thick liquid. 1H NMR (CDCl3) δ: 1.27 (t, J = 7.2 Hz, 3H), 1.74-1.82 (m, 2H), 1.88-1.92 (m, 2H), 2.04- 2.10 (m, 2H), 2.27-2.37 (m, 1H), 2.83-2.85 (m, 2H), 3.55 (s, 2H), 4.16 (q, J = 14.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 316.15 (M+H)+, 100%. Step 2: 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid. To a stirred solution of ethyl 1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (2.6 gm, 8.25 mmol) in ethanol (20 ml), another solution of sodium hydroxide (0.71 gm, 16.49 mmol) in water (10 ml) was added at ambient temperature and stirring was continued for 6 hours. Solvent was removed on rotavapor under vacuum, residue was added to water (50 ml) and acidified with concentrated hydrochloric acid (pH = 2). Off-white solid formed was collected by filtration and dried over Phosphorous pentoxide to yield 1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylic acid (2.0 gm, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.50-1.60 (m, 2H), 1.77-1.80 (m, 2H), 1.98-2.04 (m, 2H), 2.16- 2.28 (m, 1H), 2.60-2.74 (m, 2H), 3.53 (s, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 12.12 (br s, 1H); ESI-MS: m/z 288.12 (M+H)+, 100%. Intermediate-39: 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(3-hydroxyoxetan-3- yl)benzoic acid
Figure imgf000077_0001
Step 1: Preparation of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate. To a stirred solution of 4-bromo-2-fluorobenzaldehyde (1.0g, 4.93 mmol) and tert- butyl piperazine-1-carboxylate (1.376 g, 7.39 mmol) in dimethyl formamide (10 ml) potassium carbonate (2.04 g, 14.78 mmol) was added at 30 °C and stirring was continued at 100 °C for 24 hours . Reaction mixture was cooled to ambient temperature, poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extract was washed with water (2 x 50 ml) & brine (75 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield 4-bromo-2-(4-(tert- butoxycarbonyl)piperazin-1-yl)benzoic acid (1.0 g, 55% yield) as a thick liquid. 1H NMR (CDCl3) δ : 1.48 (s, 9H), 3.04 (t, J = 4.8 Hz, 4H), 3.63 (t, J = 4.8 Hz, 4H), 7.25- 7.31 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 10.26 (s, 1H). Step 2: Preparation of 4-bromo-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid. To a stirred solution of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1- carboxylate (2.0 g, 5.42 mmol) and sulphamic acid (4.31 g, 44.4 mmol) in water (10 ml) sodium chlorite (1.34 g, 11.92mmol) was added and stirring was continued at ambient temperature for 20 hours. The reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extract was washed with water (2 x 50 ml) & brine (75 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield 4-bromo-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (1.8 g, 86% yield) as an off white solid. 1H NMR (DMSO-d6) δ : 1.43 (s, 9H), 3.01-3.06 (t, J = 4.8 Hz, 4H), 3.33-3.40 (t, J = 4.8 Hz, 4H), 7.39-7.42 (m, 1H), 7.6 (s, 1H), 7.73(d, J = 8.4 Hz, 1H), 14.63 (s, 1H). Step 3: Preparation of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(3-hydroxyoxetan-3- yl)benzoic acid: To a stirred solution of 4-bromo-2-(4-(isopropoxycarbonyl)piperazin-1-yl)benzoic acid (700mg, 1.817 mmol) in tetrahydrofuran (15 ml), n-butyllithium (25% in hexane) (1.2 ml, 4.54 mmol) was added dropwise under nitrogen atmosphere at -78 oC over a period of 10 minutes. To this another solution of oxetan-3-one (196 mg, 2.73 mmol) in tetrahydrofuran (3.0 ml) was added dropwise at -78 oC. The reaction mixture was allowed to warm to room temperature over a period of 3 hours with vigorous stirring. The reaction mixture was poured into saturated ammonium chloride solution (10 mL), acidified with saturated solution of citric acid and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate and evapourated on rotavapor under vaccum. The crude product was purified by triturating with diethyl ether to yield 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(3-hydroxyoxetan-3-yl)benzoic acid. (350mg, 50.9% yield) as an off white solid. 1H NMR (DMSO-d6) δ : 1.44 (s, 9H), 3.01-3.06 (m, 4H), 3.33-3.40 (m, 4H), 4.7-4.78 (m, 4H), 6.56 (s, 1H), 7.57-7.60 (m, 1H), 7.72 (s, 1H), 7.98(d, J = 8.0 Hz, 1H), 16.0 (s, 1H). Intermediate-40: 6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine
Figure imgf000078_0001
Step 1: Preparation of 5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine To a stirred solution of 3-(trifluoromethyl) phenol (1.0 g, 6.17 mmol) in N,N- dimethylformamide (10 ml), cesium carbonate (4.02 g, 12.34 mmol) was added followed by the addition of 2-chloro-5-nitropyridine (0.978 g, 6.17 mmol) under nitrogen atmosphere at ambient temperature and continued stirring for 24 hours. The reaction mixture was poured into water (30 ml) and extracted by ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (2 x 25 ml) & brine (50 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 silica gel column and 5-25% ethyl acetate in n- hexane as an eluent to yield 5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine (700 mg, 40% yield) as a thick liquid. 1HNMR (CDCl3) δ : 7.02 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.33-7.36 (m, 1H), 7.57-7.59 (m, 2H), 8.53-8.56 (m, 1H), 9.04 (d, J = 2.8 Hz, 1H); ESI-MS: m/z: 285.04 (M+H)+.100%. Step 2. Preparation of 6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine To a solution of 5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine (2.0 g, 7.04 mmol) in ethanol (20 ml), stannous chloride (6.67g, 35.2 mmol) was added at 30 oC. and stirred at 50 oC for 3 hours. The reaction mixture was concentrated on rotavapor under vacuum and the residue was diluted with ethylacetate (50 ml) and basified with aqeuous ammonia to (pH =10). Solid was filtered and washed with ethyl acetate (3 x 50 ml). The combined filtrate was dried over sodium sulfate and concentrated on rotavapor under vacuum to yield 6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine (1.0 g, 55.9% yield) as a thick liquid. 1H NMR (CDCl3) δ : 6.82 (d, J = 8.0 Hz, 1H), 7.04-7.08 (m, 1H), 7.11-7.14 (m, 1H), 7.24- 7.26 (m, 1H), 7.31-7.34 (m, 1H), 7.36-7.38 (m, 1H), 7.73 (d, J = 2.4 Hz, 1H); ESI-MS: m/z: 255.09 (M+H)+.100%. Intermediate-41: 6-(3-(trifluoromethyl)phenoxy)nicotinic acid
Figure imgf000079_0001
Step 1: Preparation of methyl 6-(3-(trifluoromethyl)phenoxy)nicotinate. To a stirred solution of 3-(trifluoromethyl)phenol (1.0 g, 6.17 mmol) in N,N- dimethylformamide (10 ml), cesium carbonate (4.02 g, 12.34 mmol) was added followed by the addition of methyl 6-chloronicotinate (1.058 g, 6.17 mmol) under nitrogen atmosphere at 30 oC and stirring was continued at 90 oC for 24 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (2 x 25 ml) & brine (50 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 5-25% ethyl acetate in n- hexane as an eluent to yield 5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine (1.0 g, 54.5% yield) as a thick liquid. 1HNMR (CDCl3) δ : 3.96 (s, 3H), 6.85-6.89 (m, 1H), 7.22-7.25 (m, 1H), 7.55-7.65 (m, 3H), 8.10-8.16 (m, 1H), 8.73 (s, 1H); ESI-MS: m/z: 398.04 (M+H)+.100%. Step 2: Preparation of 6-(3-(trifluoromethyl)phenoxy)nicotinic acid. To a stirred solution of methyl 6-(3-(trifluoromethyl)phenoxy)nicotinate (2.0 g, 6.43 mmol) in a mixture of methanol (15 ml), water (15 ml) and tetrahydrofuran (30.0 ml), lithium hydroxide hydrate (0.38g, 12.85 mmol) was added and continued to stir at 30 °C for 24 hours. Reaction mixture was concentrated on rotavapor under vacuum. The residue was dissolved in water (50 ml) and washed with ethyl acetate (25 ml). The aqueous layer was neutralized with citric acid (pH = 7) and extracted with ethyl acetate (3 x 25 ml). Organic layer was washed with water (15 ml) & brine (15 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield 6-(3- (trifluoromethyl)phenoxy)nicotinic acid. (1.0 g, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ: 6.89-6.91 (m, 1H), 7.20-7.222 (m, 1H), 7.62-7.65 (m, 3H), 8.12- 8.15 (m, 1H), 8.73 (s, 1H), 13.13 (s, 1H); ESI-MS: m/z: 284.07 (M+H)+.100%. Intermediate-42: 4-(3-hydroxyoxetan-3-yl)benzoic acid
Figure imgf000080_0001
To a stirred solution of 4-bromobenzoic acid (40 g, 199 mmol) in tetrahydrofuran (900 ml), n-butyllithium (25% in hexane) (185 ml, 497 mmol) was added dropwise under nitrogen atmosphere at -78 oC over a period of 50 minutes. To this another solution of oxetan-3-one (17.21 g, 239 mmol) in tetrahydrofuran (30 ml) was added dropwise at -78 oC. The reaction mixture was allowed to warm to room temperature over a period of 3 hours with vigorous stirring. The reaction mixture was poured into saturated ammonium chloride solution (100 mL), acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 500 ml). The combined organic layer was washed with brine (500 ml), dried over sodium sulfate and evaporated on rotavapor under vacuum. The crude product was purified by triturating with diethyl ether to yield 4-(3-hydroxyoxetan-3-yl)benzoic acid (13.8 g, 35% Yield) as an off white solid. 1H NMR (DMSO-d6) δ: 4.68 (d, J = 6.8 Hz, 2H), 4.80 (d, J = 6.8 Hz, 2H), 6.53 (s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.98 (d, J = 6.8 Hz, 2H), 12.93 (br s, 1H); ESI-MS: m/z 193.04 (M-1), 100%. Intermediate-43: 4-(3-methoxyoxetan-3-yl)benzoic acid
Figure imgf000080_0002
Step 1: benzyl 4-(3-hydroxyoxetan-3-yl) benzoate. To a stirred solution of 4-(3-hydroxyoxetan-3-yl)benzoic acid (3.0 g, 15.45 mmol) in N,N-dimethylformamide (15 ml), cesium carbonate (5.03 g, 16.99 mmol) was added at ambient temperature followed by the addition of benzyl bromide (2.021 ml, 16.99 mmol) and stirring was continued for 16 hours at 100 °C. The reaction mixture was cooled to ambient temperature, poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (2 x 50 ml) & brine (50 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as eluent to yield benzyl 4-(3-hydroxyoxetan-3-yl)benzoate. (4.0 g, 91% Yield) as a thick liquid. 1HNMR (CDCl3) δ : 3.69 (s, 1H), 4.12 (d, J = 6.8 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 5.39 (s, 2H), 7.28-7.38 (m, 5H), 7.74 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H). Step 2: benzyl 4-(3-methoxyoxetan-3-yl) benzoate. To a suspension of sodium hydride (1.35 g, 28.1 mmol) in tetrahydrofuran (20 ml), a solution of benzyl 4-(3-hydroxyoxetan-3-yl)benzoate (4.0 g, 14.07 mmol) in tetrahydrofuran (10 ml) was added followed by the addition of iodomethane (1.759 ml, 28.1 mmol) at 0 °C and stirring was continued at ambient temperature for 3 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extract was washed with water (2 x 50 ml) & brine (75 ml), dried over sodium sulfate and concentrated on rotavapor under vacuum to yield benzyl 4-(3-methoxyoxetan-3-yl)benzoate (3.0g, 75% yield) as thick liquid. 1HNMR (CDCl3) δ : 3.0 (s, 3H), 4.12 (d, J = 6.8 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 5.39 (s, 2H), 7.28-7.38 (m, 5H), 7.74 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H). Step 3: 4-(3-methoxyoxetan-3-yl) benzoic acid. The title product (1.5g 71.6% yield) was prepared from benzyl 4-(3-methoxyoxetan- 3-yl)benzoate (3.0g, 75% yield) as thick liquid according to the procedure described in step-2 of intermediate-22 as a yellow solid. 1H NMR (DMSO-d6) δ : 3.0 (s, 3H), 4.68 (d, J = 6.8 Hz, 2H), 4.80 (d, J = 6.8 Hz, 2H), 7.74 (d, J = 6.8 Hz, 2H), 7.98 (d, J = 6.8 Hz, 2H), 12.93 (br s, 1H); ESI-MS: m/z: 209.05 (M+H)+, 100%. Intermediate-44: 3-(4-aminophenyl)oxetan-3-ol
Figure imgf000081_0001
To a stirred solution of 3-(4-bromophenyl)oxetan-3-ol (100 mg, 0.437 mmol) in ammonium hydroxide Solution (1 ml) in a microwave vial, copper(II) oxide (34.7 mg, 0.437 mmol) was added under nitrogen atmosphere at ambient temperature and the reaction mixture was microwave irradiated at 100 °C and 40 psi pressure for 1 hour in a CEM microwave synthesizer. The reaction mixture was cooled to ambient temperature, added to ethyl acetate (10 ml) and filtered through celite bed. The filtrate was dried over sodium sulfate and evaporated under vacuum to yield 3-(4-aminophenyl)oxetan-3-ol (70 mg, 97% yield) as a pale brown solid. 1H NMR (DMSO-d6) δ: 4.63 (d, J = 6.4 Hz, 2H), 4.68 (d, J = 6.4 Hz, 2H), 5.02 (s, 2H), 5.96 (s, 1H), 6.56 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 166.11 (M+H)+, 100%. Intermediate-45: (4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3- trihydroxypropan-2-yl)phenyl)methanone
Figure imgf000082_0001
To a mixture of magnesium turning (60 mg, 2.45 mmol) in tetrahydrofuran (2 ml), was added catalytic amount of methyl iodide (1 drop) to activate magnesium and stirred vigorously till the solution became clear. After that a solution of (4-bromophenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (1 g, 2.34 mmol) in tetrahydrofuran (10 ml) was added dropwide under nitrogen atmosphere over a period of 10 min at ambient temperature and stirred for 1 hour to obtained clear solution. Then the reaction mixture was cooled to 0 oC and a solution of 2,2-dimethyl-1,3-dioxan-5-one (304 mg, 2.34 mmol) in tetrahydrofuran (2 ml) was added dropwise over a period of 10 min. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into ice cold saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (2 x 100 ml) & brine (100 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 2-3% methanol in chloroform as an eluent to yield (4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone (515 mg, 22% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.64-1.68 (m, 2H), 1.97-2.01 (m, 2H), 3.34-3.37 (m, 2H), 3.54- 3.62 (m, 5H), 3.94-3.99 (m, 1H), 4.61 (t, J = 5.6 Hz, 2H), 4.79-4.82 (m, 1H), 4.83 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 440.16 (M+H)+, 100%. Example- 1 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000083_0001
To a stirred solution of 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride (114 mg, 0.408 mmol), 4-(3-hydroxyoxetan-3-yl)benzoic acid (79 mg, 0.408 mmol) and HBTU (232 mg, 0.612 mmol) in N,N-dimethylformamide (3.0 ml), diisopropylethylamine (0.214 ml, 1.223 mmol) was added under nitrogen atmosphere at ambient temperature and stirred for 18 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with water (2 x 25 ml) & brine (25 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (100 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.66 (m, 2H), 2.02 (m, 2H), 3.37-3.43 (m, 2H), 3.56-3.60 (m, 1H), 4.00 (br s, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78-4.82 (m, 3H), 6.44 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.64-7.68 (m, 4H); ESI-MS: m/z 422 (M+H)+, 100%. Example- 2 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000083_0002
To a stirred suspension of sodium hydride (17.08 mg, 0.356 mmol) in tetrahydrofuran (1 ml), a solution of (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (100 mg, 0.237 mmol) in tetrahydrofuran (3 ml) was added followed by addition of iodomethane (0.018 ml, 0.285 mmol) at 0 °C and stirred at 30 °C for 3 hours. The reaction mixture was poured into ice cold water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic extract was washed with water (2 x 20 ml) & brine (25 ml), dried over sodium sulfate and evaporated under reduced pressure to yield (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (60 mg, 56.9% yield) as pale yellow solid. 1H NMR (DMSO-d6) δ 1.67 (m, 2H), 1.99 (m, 2H), 3.05 (m, 3H), 3.38-3.43 (m, 3H), 4.00 (m, 1H), 4.75-4.83 (m, 5H), 7.18 (d, J = 8.4 Hz, 2H), 7.48-7.54 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 436 (M+H)+, 100%. Example- 3 : 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methyl)phenyl)oxetan-3-ol
Figure imgf000084_0001
Step 1: 1-(4-bromobenzyl)-4-(4-(trifluoromethyl)phenoxy)piperidine To a stirred solution of 1-bromo-4-(bromomethyl)benzene (0.359 g, 1.436 mmol) and 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride (0.337 g, 1.197 mmol) in dimethyformamide (4 ml), cesium carbonate (1.170 g, 3.59 mmol) was added under nitrogen atmosphere at ambient temperature and stirred at 90 oC for 16 hours. The reaction mixture was poured into ice cold water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extract was washed with water (2 x 30 ml) & brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 6% ethyl acetate in n-hexane as an eluent to yield 1-(4-bromobenzyl)-4-(4- (trifluoromethyl)phenoxy)piperidine (0.394 g, 79%) as a thick liquid. 1H NMR (CDCl3) δ : 1.80-1.98 (m, 2H), 1.99-2.03 (m, 2H), 2.31-2.35 (m, 2H), 2.72-2.80 (m, 2H), 3.49 (s, 2H), 4.39-4.67 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 416.05 (M+H)+, 100%. Step 2: 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)phenyl)oxetan-3-ol. To a stirred solution of 1-(4-bromobenzyl)-4-(4-(trifluoromethyl)phenoxy)piperidine (0.390 g, 0.941 mmol) in tetrahydrofuran (5 ml), n-buthyllithium (2.5M in hexane) (0.565 ml, 1.412 mmol) was added dropwise over a period of 10 minute under nitrogen atmosphere at -78 oC and stirring was continued for 30 minute at -78 oC. To this another solution of oxetan-3-one (0.081 g, 1.130 mmol) in tetrahydrofuran (1 ml) was added dropwise at -78 oC and reaction mixture was allowed to warm to -30 oC over a period of 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (5 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic extract was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to get pure product (0.1 g, 24.18%) as colorless oil. 1H NMR (DMSO-d6) δ : 1.61-1.69 (m, 2H), 1.91-1.99 (m, 2H), 2.24-2.28 (m, 2H), 2.66- 2.69 (m, 2H), 3.50 (s, 2H), 4.48-4.54 (m, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 6.30 (s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 408.15 (M+H)+, 100%. Example- 4 :(4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000085_0001
To a stirred solution of (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)thio)phenoxy)piperidin-1-yl)methanone (500 mg, 1.103 mmol) in dichloromethane (50 ml), meta-chloroperoxybenzoic acid (951 mg, 5.51 mmol) was added at 30 °C and stirring was continued for 24 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 silica gel column and 2-4% methanol in chloroform as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone (150 mg, 28.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.70 (m, 2H), 2.00-2.07 (m, 2H), 3.33-3.50 (m, 2H), 3.50-3.61 (m, 1H), 3.95-4.05 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.94-4.97 (m, 2H), 4.97-5.05 (m, 1H), 6.45 (s, -OH), 7.40 (d, J = 9.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H); ESI-MS: m/z, 486.12 (M+H)+, 100%. Example- 5 : 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzoic acid
Figure imgf000086_0001
Step 1: Preparation of ethyl 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoate To a stirred solution of 4-(3-hydroxyoxetan-3-yl)benzoic acid (257 mg, 1.324 mmol), ethyl 4-(piperidin-4-yloxy)benzoate (300 mg, 1.203 mmol) and HBTU (685 mg, 1.805 mmol) in N,N-dimethylformamide (5.0 ml), N,N-diisopropylethylamine (0.631 ml, 3.61 mmol) was added under nitrogen atmosphere at 30 oC and stirring was continued for 16 hours. Reaction mixture was poured into ice cold water (50 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water (3 x 30 ml) & brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. Crude product was purified by column chromatography using 230-400 silica gel column and 60% ethyl acetate in n-hexane as an eluent to yield the product as a thick liquid which was triturated with n-hexane to yield ethyl 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin- 4-yl)oxy)benzoate (500 mg, 98% yield) as a pink solid on drying. 1H NMR (DMSO-d6) δ: 1.30 (t, J = 6.8 Hz, 3H), 1.55-1.66 (m, 2H), 1.90-2.15 (m, 2H), 3.33-3.43 (m, 2H), 3.57-3.64 (m, 1H), 3.90-4.15 (m, 1H), 4.27 (q, J = 7.6 Hz, 2H), 4.69 (d, J = 6.4 Hz, 2H), 4.70-4.80 (m, 3H), 6.44 (s, -OH), 7.10 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 426.20 (M+H)+, 100%. Step 2: Preparation of 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoic acid To a stirred solution of ethyl 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoate (330 mg, 0.776 mmol) in a mixture of methanol (15 ml) and tetrahydrofuran (30.0 ml), another solution of lithium hydroxide hydrate (65.1 mg, 1.551 mmol) in water (15.0 ml) was added at 30 °C and stirring was continued for 24 hours. Reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 ml) and washed with ethyl acetate (15 ml). The aqueous layer was then acidified with citric acid (pH = 7) and extracted with ethyl acetate (3 x 25 ml). Combined organic layer was washed with water (15 ml) & brine (15 ml), dried over sodium sulfate and concentrated under reduced pressure to yield 4-((1-(4-(3-hydroxyoxetan-3- yl)benzoyl)piperidin-4-yl)oxy)benzoic acid (50 mg, 15.96% yield) as a thick liquid. 1H NMR (DMSO-d6) δ: 1.66 (m, 2H), 1.99-2.02 (m, 2H), 3.33-3.58 (m, 3H), 4.00-4.04 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78-4.79 (m, 3H), 6.44 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 12.61 (- COOH); ESI-MS: m/z, 398.16 (M+H) +, 100%. Example- 6 : N-cyclopropyl-4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzamide
Figure imgf000087_0001
To a stirred solution of 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzoic acid (60 mg, 0.151 mmol), cyclopropylamine (0.013 ml, 0.181 mmol) and HBTU (86 mg, 0.226 mmol) in N-N-dimethylformaamide (5.0 ml), N,N- diisopropylethylamine (0.079 ml, 0.453 mmol) was added at 30 °C and stirring was continued for 16 hours. Reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). Combined organic layer was washed with water (3 x 30 ml) & brine (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 90% ethyl acetate in n-hexane as an eluent to yield pure N-cyclopropyl-4-((1- (4-(3-hydroxyoxetan-3-yl) benzoyl)piperidin-4-yl)oxy)benzamide (10 mg, 15.14 % yield) as a white solid. 1H NMR (DMSO-d6) δ: 0.66-0.68 (m, 2H), 0.84-0.85 (m, 2H), 1.64 (m, 2H), 1.91-2.01 (m, 2H), 2.80-2.81 (m, 1H), 3.32-3.70 (m, 3H), 4.00 (br s, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.78-4.79 (m, 3H), 6.43 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 3.2 Hz, 1H); ESI-MS: m/z, 437.25 (M+H) +, 100%. Example- 7 : (4-(3-methoxypyrrolidin-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone To a stirred solution of tert-butyl 3-methoxy-3-(4-(4-(4- (trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)pyrrolidine-1-carboxylate (0.3 g, 0.547 mmol) in 1, 2 dichloromethane (4 ml), trifluoroacetic acid (0.421 ml, 5.47 mmol) was added at 0-5 ºC and stirring was continued for further 2 hours at ambient temperature. Reaction mixture was concentrated on rotavapor under vaccum. Residue was diluted with 1, 2-dichloromethane (10 ml) and saturated sodium bicarbonate solution (10 ml). Organic layer was separated and aqueous layer was extracted again with 1, 2 dichloromethane (20 ml). Combined organic layer was dried over sodium sulfate and concentrated on rotavapour under vacuum. Crude product was triturated with di-isopropyl ether to yield (4-(3- methoxypyrrolidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone (0.210 g, 80% Yield) as a light brown solid. 1H NMR (DMSO-d6) δ: 1.63-1.69 (m, 2H), 2.01-2.09 (m, 3H), 2.20-2.29 (m, 1H), 2.91- 2.95 (m, 4H), 3.02-3.14 (m, 2H), 3.34-3.37 (m, 2H), 3.45-3.48 (m, 1H), 3.95-4.03 (m, 2H), 4.80 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.42-7.46 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H); ESI- MS: m/z 449.27 (M+H)+, 100%. Example- 8 :(4-(3-hydroxypyrrolidin-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone The title product (0.490 g, 93% yield) was prepared from tert-butyl 3-hydroxy-3-(4- (4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)pyrrolidine-1-carboxylate (0.6 g, 1.122 mmol) according to the procedure described in Example-7 as light brown solid. 1H NMR (DMSO-d6) δ: 1.63-1.69 (m, 2H), 2.02-2.13 (m, 3H), 2.98-3.01 (m, 1H), 3.09- 3.15 (m, 4H), 3.18-3.25 (m, 3H), 3.96-4.01 (m, 1H), 4.78-4.82 (m, 1H), 5.43 (br s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 435.26 (M+H)+, 100%. Example- 9 : (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methanone
Figure imgf000089_0001
To a stirred solution of (4-(3-hydroxythietan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methanone (0.150 g, 0.342 mmol) in a mixture of acetone (4 ml) and water (1 ml), oxone (0.631 g, 1.026 mmol) was added at 0- 5 ºC and stirring was continued for 6 hours at ambient temperature. Reaction mixture was concentrated on rotavapor under vacuum. Residue was transferred to a Buckner funnel, washed with water (20 ml) and dried over phosphorous pentaoxide to yield (4-(3-hydroxy- 1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1- yl)methanone (0.134 g, 81% yield) as an off white solid. 1H NMR (DMSO-d6) δ: 1.68-1.73 (m, 2H), 1.91-2.09 (m, 2H), 2.48-2.49 (m, 1H), 3.43- 3.54 (m, 2H), 3.98-4.04 (m, 1H), 4.39 (d, J = 15.2 Hz, 2H), 4.72 (d, J = 15.2 Hz, 2H), 5.32- 5.39 (m, 1H), 6.81 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 8.08 (dd, J = 8.8 Hz & 2.6 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H); ESI-MS: m/z 471.00 (M+H)+, 100%. Example- 10 : (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000089_0002
The title product (70 mg, 65% yield) was prepared from (4-(3-hydroxythietan-3- yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1-yl)methanone (0.1 gm, 0.230 mmol) according to the procedure described in Example-9 as a white solid. 1H NMR (DMSO-d6) δ: 1.16-1.18 (m, 2H), 1.64 (m, 2H), 1.81-1.84 (m, 1H), 2.64 (d, J = 7.2 Hz, 2H), 2.67 (m, 1H), 2.71 (br s, 1H), 3.55 (m,1H), 4.37-4.41 (m, 3H), 4.668-4.72 (m, 2H), 6.81 (s, 1H), 7.41 (d, J = 8.4 Hz, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 466.13 (M+H)+, 100%. Example- 11: 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)amino)phenyl)oxetan-3-ol
Figure imgf000090_0001
Step 1: Preparation of 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-one To a stirred solution of piperidin-4-one hydrochloride (0.500 g, 3.69 mmol) in dichloromethane (10 ml), 4-(Trifluoromethyl)benzenesulfonyl chloride (0.902 g, 3.69 mmol) was added followed by the addition of triethylamine (1.542 ml, 11.06 mmol) at 30 °C and stirring was continued at for 20 hours. Reaction mixture was poured to ice cold water (25 ml) and extracted with dichloromethane (2 x 25 ml). The combined organic layer was washed with water (2 x 15 ml) & brine (10 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was triturated with 10% ethyl acetate in hexane (2 x 10 ml), the resulting solid was collected by filtration, washed with 10% ethyl acetate in hexane and dried to yield 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- one (1.020 g, 90% yield) as yellow solid. 1H NMR (CDCl3) δ: 2.57-2.60 (m, 2H), 3.45-3.48 (m, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H); ESI-MS: m/z, 308.05 (M-H) +, 30%. Step 2: Preparation of 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)amino)phenyl)oxetan-3-ol To a stirred solution of 3-(4-aminophenyl)oxetan-3-ol (50 mg, 0.303 mmol) and 1- ((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-one (93 mg, 0.303 mmol) in 1, 2- dichloroethane (10 ml), sodium triacetoxyborohydride (96 mg, 0.454 mmol) was added at 30 °C and stirring was continued for 20 hours. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layer was washed with water (2 x 15 ml) & brine (15 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield 3-(4-((1- ((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)amino)phenyl)oxetan-3-ol (6.0 mg, 3.97% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.57-1.69 (m, 2H), 2.08-2.16 (m, 2H), 2.54-2.59 (m, 2H), 3.30- 3.33 (m, 1H), 3.77-3.80 (m, 2H), 4.88 (s, 4H), 4.93 (s, -OH), 6.71 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESI-MS: m/z, 457.19 (M+H) +, 100%. Example- 12 : 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)sulfonyl)phenyl)oxetan-3-ol
Figure imgf000091_0001
Step 1: Preparation of 1-((4-bromophenyl)sulfonyl)-4-(4- (trifluoromethyl)phenoxy)piperidine. To a stirred solution of 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride (0.500 g, 1.775 mmol) in dichloromethane (20 ml), triethylamine (0.742 ml, 5.32 mmol) was added followed by the addition of 4-bromobenzenesulfonyl chloride (0.590 g, 2.307 mmol) at 0°C and stirring was continued at 0°C for 30 minute. The reaction mixture was poured into water (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic layers were washed with water (2 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum to yield 1-((4-bromophenyl)sulfonyl)-4-(4- (trifluoromethyl)phenoxy)piperidine (0.700 g, 85% yield) as a white solid. 1H NMR (CDCl3) δ: 1.94-2.10 (m, 4H), 3.12-3.31 (m, 4H), 4.48-4.51 (m, 1H), 6.89 (d, J =8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H). Step 2: Preparation of 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)sulfonyl)phenyl)oxetan-3-ol To a stirred solution of 1-((4-bromophenyl)sulfonyl)-4-(4- (trifluoromethyl)phenoxy)piperidine (0.700 g, 1.508 mmol) in tetrahydrofuran (10 ml), n- butyllithium (0.784 ml, 1.960 mmol) was added dropwise at -78 °C over period of 5.0 minutes and stirring was continued for 1.0 hour at -78 °C. To this another solution of oxetan-3-one (0.326 g, 4.52 mmol) in tetrahydrofuran (1.0 ml) was added and stirring was continued at -78 °C for 1.0 hour. Then the reaction mixture was slowly warmed to ambient temperature over a period of 2.0 hours. The reaction mixture was poured into 0.1M hydrochloric acid (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with water (3 x 20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 30% ethyl acetate in n-hexane as an eluent to yield 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)sulfonyl)phenyl)oxetan-3-ol (40 mg, 5.45% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.68-1.74 (m, 2H), 2.01-2.04 (m, 2H), 2.79-2.85 (m, 2H), 3.31- 3.34 (m, 2H), 4.55-4.59 (m, 1H), 4.70 (d, J = 6.8 Hz, 2H), 4.83 (d, J = 6.8 Hz, 2H), 6.67 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 458.12 (M+H)+, 60%. Example- 13 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfonyl)piperidin-1-yl)methanone
Figure imgf000092_0001
O To a stirred solution of (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)thio)piperidin-1-yl)methanone (200 mg, 0.456 mmol) in dichloromethane (10 ml), meta-chloroperoxybenzoic acid (315 mg, 0.912 mmol) was added at 30 °C and stirring was continued for 5.0 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic layer was washed with water (3 x 10 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 6% methanol in ethyl acetate as an eluent to yield (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5- (trifluoromethyl)pyridin-2-yl)sulfonyl)piperidin-1-yl)methanone (90 mg, 40.7% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.57-1.65 (m, 2H), 1.92-1.99 (m, 2H), 2.86-3.15 (m, 2H), 3.70 (s, 1H), 3.95-4.06 (m, 1H), 4.53 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.45 (s, -OH), 7.42 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 8.28 (d, J = 8.0 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 9.29 (s, 1H); ESI-MS: m/z, 471.12 (M+H)+, 100%. Example- 14 :(4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfinyl)piperidin-1-yl)methanone
Figure imgf000093_0001
The title product (24 mg, 4.21 % yield) was isolated as a polar byproduct during the purification of Example-13 as white solid. 1H NMR (DMSO-d6) δ: 1.25-1.27 (m, 2H), 1.92-2.02 (m, 2H), 2.23-2.35 (m, 2H), 2.71- 2.92 (m, 3H), 3.29-3.35 (m, 1H), 3.78-3.97 (m, 1H), 4.84 (d, J = 6.4 Hz, 2H), 4.94 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.93 (s, 1H); ESI-MS: m/z, 455.15 (M+H)+, 60%. Example- 15 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperidin-1-yl)methanone
Figure imgf000093_0002
To a stirred solution of (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)thio)piperidin-1-yl)methanone (100 mg, 0.229 mmol) in acetone (2 ml), another solution of oxone (281 mg, 0.457 mmol) in water (1 ml) was added under nitrogen atmosphere at ambient temperature and stirring was continued for 12 hours. Solvent was removed on rotavapor under vacuum and the residue was poured into water (25 ml). White solid was filtered, washed with water and dried over phosphorous pentoxide under vacuum to yield (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperidin-1-yl)methanone (78 mg, 66% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.51-1.53 (m, 2H), 1.88-1.91 (m, 2H), 3.02-3.04 (m, 2H), 3.71- 3.77 (m, 2H), 4.02-4.06 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.44 (s, 1H), 7.31 (d, J = 6.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.68 (s.1H), 7.69 (d, J = 6.8 Hz, 1H), 8.06-8.11 (m, 4H); ESI-MS: m/z 470.11 (M+H)+, 100%. Example- 16 : 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylic acid
Figure imgf000094_0001
Step 1: Preparation of ethyl 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylate To a stirred solution of ethyl 4-(4-(trifluoromethyl)benzyl)piperidine-4- carboxylate (375 mg, 1.189 mmol), 4-(3-hydroxyoxetan-3-yl)benzoic acid (254 mg, 1.308 mmol) and HBTU (676 mg, 1.784 mmol) in N,N-dimethylformamide (5.0 ml), N,N- diisopropylethylamine (0.623 ml, 3.57 mmol) was added under nitrogen atmosphere at 30 °C and continued the stirring 16 hours. Reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (10 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield ethyl 1-(4-(3- hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (275 mg, 47.0% yield) as a white solid. ESI-MS: m/z, 492.19 (M+H)+, 100%. Step 2: Preparation of 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylic acid To a stirred solution of ethyl 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4- (trifluoromethyl)benzyl)piperidine-4-carboxylate (275 mg, 0.560 mmol) in methanol (10 ml), another solution of sodium hydroxide (67.1 mg, 1.679 mmol) in water (2.0 ml) was added at 30 °C and stirring was continued for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (15 ml), acidified with aqueous hydrochloric acid and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (2 x 20 ml) & brine (10 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 4% methanol in chloroform as an eluent to yield pure 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4- carboxylic acid (40 mg, 15.22% yield) as a white solid. 1H NMR (DMSO-d6) δ: 1.50-1.67 (m , 2H), 1.84-1.99 (m, 2H), 2.74-2.76 (m, 1H), 3.04- 3.53 (m, 4H), 4.31 (m, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.41 (s,- OH), 7.35 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.53-7.73 (m, 4H); ESI-MS: m/z, 464.19 (M+H)+, 100%. Example- 17 : N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4- (trifluoromethyl)phenoxy) piperidine-1-carboxamide
Figure imgf000095_0001
Step 1: Preparation of 4-(3-bromo-5-nitrophenyl)morpholine To a solution of 1-bromo-3-fluoro-5-nitrobenzene (5 g, 22.73 mmol) in N,N- dimethylacetamide (50 ml), morpholine (2.97 ml, 34.1 mmol) and potassium carbonate (6.28 g, 45.5 mmol) were added under nitrogen atmosphere at 27 °C. Then the reaction mixture was stirred at 120 °C for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and poured into ice cold water (50 ml). The solid separated was filtered, washed with water and dried over P2O5 under vacuum to yield 4- (3-bromo-5-nitrophenyl)morpholine (6.0 g, 92 % yield) as yellow solid. 1H NMR (CDCl3) δ: 3.26-3.28 (m, 4H), 3.88-3.90 (m, 4H), 7.28 (dd, J = 2.4 & 1.6 Hz, 1H), 7.64 (t, J = 2.2 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H); ESI-MS: m/z: 288.9 (M+H)+, 100%. Step 2: Preparation of 3-bromo-5-morpholinoaniline To a solution of 4-(3-bromo-5-nitrophenyl)morpholine (6.0 g, 20.90 mmol) in ethanol (150 ml), tin(II) chloride dihydrate (18.86 g, 84 mmol) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled to room temperature and solvent was evaporated on rotavapor under vacuum. The residue was dissolved in ethyl acetate (100 ml) and the solution was basified by dropwise addition of saturated aqueous ammonia solution. The solid separated was filtered and washed with ethyl acetate (50 ml). The filtrate was dried over sodium sulfate and evaporated under reduced pressure to yield 3- bromo-5-morpholinoaniline (5.3 g, 99 % yield) as a thick liquid. The product was directly used for the next step without purification. Step 3: Preparation of N,N-dibenzyl-3-bromo-5-morpholinoaniline To a solution of 3-bromo-5-morpholinoaniline (5.3 g, 20.61 mmol) in acetonitrile (100 ml), potassium carbonate (8.55 g, 61.8 mmol) was added followed by the addition of benzyl bromide (5.39 ml, 45.3 mmol) under nitrogen atmosphere at 28 oC and refluxed for 18 hrs. The reaction mixture was cooled to room temperature. The solid separated was filtered and washed with ethyl acetate (50 ml). The filtrate was dried over sodium sulfate and evaporated under reduced pressure to yield N,N-dibenzyl-3-bromo-5- morpholinoaniline (7.5 g, 83 % yield) as a thick liquid. 1H NMR (CDCl3) δ: 2.99-3.05 (m, 4H), 3.75-3.78 (m, 4H), 4.72 (s, 4H), 6.13 (t, J = 2.0 Hz, 1H), 6.43 (t, J = 1.8 Hz, 1H), 6.49 (t, J = 1.8 Hz, 1H), 7.23-7.40 (m, 10H); ESI-MS: m/z: 439.19 (M+H)+, 100%. Step 4: Preparation of 3-(3-(dibenzylamino)-5-morpholinophenyl)oxetan-3-ol To a solution of N,N-dibenzyl-3-bromo-5-morpholinoaniline (0.75 g, 1.71 mmol) in THF (10 ml), n-butyllithium (2.5M in hexane) (1.03 ml, 2.57 mmol) was added dropwise under nitrogen atmosphere at -78 oC over a period of 10 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. To this another solution of oxetan-3-one (0.247 g, 3.43 mmol) in THF (1 ml) was added dropwise at -78 oC. The reaction mixture was allowed to warmed to ambient temperature and stirred for 30 minutes. under nitrogen atmosphere. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted by ethyl acetate (3 x 25 ml). The combined organic layer was washed with water (20 ml) & brine (20 ml), dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography using 230-400 mesh silica gel column and 20-50% ethyl acetate in n-hexane as an eluent to obtain 3-(3- (dibenzylamino)-5-morpholinophenyl)oxetan-3-ol (500 mg, 68% Yield) as thick liquid. 1H NMR (DMSO-d6) δ: 3.05-3.07 (m, 4H), 3.78-3.81 (m, 4H), 4.68 (s, 4H), 4.80-4.84 (m, 4H), 6.24 (s, 1H), 6.50 (s, 2H), 7.25-7.36 (m, 10H); ESI-MS: m/z: 431.31 (M+H)+, 100%. Step 5: Preparation of 3-(3-amino-5-morpholinophenyl)oxetan-3-ol To a suspension of Pd/C (10%) (66 mg) in methanol (2 ml), a solution of 3-(3- (dibenzylamino)-5-morpholinophenyl)oxetan-3-ol (0.33 g, 0.76 mmol) in methanol (10 ml) was added and the reaction mixture was stirred under hydrogen at a pressure of 50 psi for 18 hrs. The reaction mixture was filtered through celite and washed with methanol (10 ml). The combined filtrate was evaporated under vacuum to yield 3-(3-amino-5- morpholinophenyl)oxetan-3-ol (170 mg, 89% Yield) as a thick liquid. 1H NMR (DMSO-d6) δ: 3.16-3.19 (m, 4H), 3.85-3.87 (m, 4H), 4.87-4.92 (m, 4H), 6.21 (t, J = 2.2 Hz, 1H), 6.47 (t, J = 1.6 Hz, 1H), 6.56 (t, J = 1.8 Hz, 1H); ESI-MS: m/z: 251.19 (M+H)+, 100%. Step 6: N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4- (trifluoromethyl)phenoxy) piperidine-1-carboxamide To a stirred solution of 4-(4-(trifluoromethyl)phenoxy)piperidine hydrochloride (90 mg, 0.367 mmol) in acetonitrile (3 ml), N,N-diisopropylethyl amine (0.192 ml, 1.101 mmol) was added under nitrogen atmosphere at ambient temperature and followed by the dropwise addition of another solution of 3-(3-amino-5-morpholinophenyl)oxetan-3-ol (101 mg, 0.404 mmol), triphosgene (35.9 mg, 0.330 mmol) in tetrahydrofuran (3 ml) at 0 °C over the period of 10 minutes. The reaction mixture was stirred for 12 hours at ambient temperature, poured into water (25 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic layers was washed with water (2 x 25 ml) & brine (20 ml), dried over sodium sulphate and evaporated in rotavapor under vacuum. The crude product was purified by column chromatography using 100-200 mesh silica gel column and 50% ethyl acetate in n-hexane as an eluent to yield N-(3-(3-hydroxyoxetan-3-yl)-5- morpholinophenyl)-4-(4-(trifluoromethyl)phenoxy) piperidine-1-carboxamide (17 mg, 9% yield) as white solid. 1H NMR (DMSO-d6) δ: 1.59-1.63 (m, 2H), 1.94-2.02 (m, 2H), 3.05-3.08 (m, 4H), 3.26- 3.28 (m, 2H), 3.72-3.75 (m, 4H), 3.81-3.85 (m, 2H), 4.64 (d, J = 6.4 Hz, 2H), 4.71 (d, J = 6.4 Hz, 2H), 4.72-4.75 (m, 1H), 6.75 (s, 1H), 7.14 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H); ESI-MS: m/z: 522.6 (M+H)+, 100%. The following compounds were prepared by procedure similar to that described in Example 1-17 with appropriate variations of reactants, reaction conditions and quantities of reagents. Example-18 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000097_0001
1H NMR (DMSO-d6) δ: 1.16-1.24 (m, 2H), 1.91-1.99 (m, 2H), 3.08-3.12 (m, 2H), 3.60- 3.3.63 (m, 2H), 4.35-4.36 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 6.32 (d, J = 7.6 Hz,1H), 6.45 (s, 1H), 6.70 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 421.4 (M+H)+, 100%. Example-19 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000098_0001
1H NMR (DMSO-d6) δ: 1.23-1.35 (m, 2H), 1.91-1.99 (m, 2H), 3.05 (s, 3H), 3.07 (s, 1H) 3.10-3.11 (m, 1H), 3.61-3.63 (m, 2H), 4.36 (s, 1H), 4.75-4.81 (m, 4H), 6.31 (d, J = 8.0 Hz, 1H), 6.70-6.73 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 435.1 (M)+, 100%. Example-20 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000098_0002
1H NMR (DMSO-d6) δ: 1.16-1.24 (m, 1H), 1.60-1.72 (m, 1H), 1.74-1.82 (m, 3H), 2.81 (s, 3H), 3.27-3.30 (m, 1H), 3.8-4.02 (m, 1H), 4.18-4.20 (m, 1H), 4.50 (br s, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.45-7.49 (m, 4H), 7.67 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 435.4 (M+H)+, 100%. Example-21 : (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000098_0003
1H NMR (DMSO-d6) δ: 1.24-1.30 (m, 1H), 1.78-1.94 (m, 3H), 2.67-2.68 (m, 2H), 3.33- 3.37 (m, 1H), 3.54-3.60 (m, 2H), 4.75-4.78 (m, 1H), 4.80-4.85 (m, 2H), 6.45 (s, 1H), 7.01- 7.03 (m, 1H), 7.23-7.28 (m, 1H), 7.33-7.36 (m, 1H), 7.52-7.55 (m, 1H), 7.56-7.59 (m, 1H), 7.60-7.68 (m, 2H), 7.67-7.70 (m, 1H), 7.95-8.05 (m, 1H); ESI-MS: m/z 422.14 (M+H)+, 100%. Example-22 : (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000099_0001
1H NMR (DMSO-d6) δ: 1.24-1.30 (m, 1H), 1.78-1.94 (m, 3H), 3.33-3.37 (m, 1H), 3.54- 3.60 (m, 2H), 4.01-4.05 (m, 1H), 4.80-4.85 (m, 5H), 6.45 (s, 1H), 7.01-7.03 (m, 1H), 7.23- 7.28 (m, 3H), 7.33-7.36 (m, 3H), 7.67-7.70 (m, 1H); ESI-MS: m/z 422.14 (M+H)+, 100%. Example-23 : (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)pyrrolidin-1-yl)methanone
Figure imgf000099_0002
1H NMR (CDCl3) δ: 2.10-2.15 (m, 1H), 2.16-2.18 (m, 1H), 2.21-2.2.17 (m, 1H), 3.16 (s, 3H), 3.63-3.66 (m, 1H), 3.68-3.72 (m, 1H), 3.85-3.89 (m, 1H), 4.11-4.15 (m, 1H), 4.83 (d, J = 6.4 Hz, 2H), 4.96 (d, J = 6.4 Hz, 2H), 6.99-7.01 (m, 1H), 7.05-7.08 (m, 1H), 7.28-7.33 (m, 3H), 7.54-7.57 (m, 2H), 7.61-7.65 (m, 1H); ESI-MS: m/z 422.15 (M+H)+, 100%. Example-24 : (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)pyrrolidin-1-yl)methanone
Figure imgf000099_0003
1H NMR (CDCl3) δ: 2.10-2.15 (m, 1H), 2.16-2.20 (m, 1H), 2.98-3.0 (m, 1H), 3.38-3.40 (m, 1H), 3.49-3.51 (m, 1H), 3.61-3.68 (m, 1H), 3.69-3.72 (m, 1H), 3.85-3.89 (m, 1H), 4.82- 4.88 (m, 4H), 6.90-6.92 (m, 1H), 7.01-7.08 (m, 1H), 7.28-7.35 (m, 3H), 7.47-7.50 (m, 1H), 7.72-7.75 (m, 1H); ESI-MS: m/z 408.1 (M+H)+, 100%. Example-25 : (3-(3-methoxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000099_0004
1H NMR (CDCl3) δ: 1.27-1.30 (m, 1H), 1.89-2.03 (m, 3H), 2.80-2.95 (m, 2H), 3.15-3.18 (m, 1H), 3.35 (s, 3H), 4.12-4.15 (m, 1H), 4.30-4.32 (m, 1H), 4.74-4.76 (m, 2H), 4.83-4.92 (m, 2H), 6.80-6.85 (m, 1H), 7.08-7.10 (m, 1H), 7.24-7.28 (m, 2H), 7.50-7.54 (m, 2H), 7.57- 7.76 (m, 2H); ESI-MS: m/z 436.16 (M+H)+, 100%. Example-26 : (4-([1,1'-biphenyl]-4-yloxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone
Figure imgf000100_0001
1H NMR (CDCl3) δ: 1.93-2.11 (m, 4H), 3.15 (s, 1H), 3.42 (m, 1H), 3.71 (m, 1H), 3.91- 3.92 (m, 2H), 4.63-4.68 (m, 1H), 4.84 (d, J = 7.2 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 6.8 & 2.0 Hz, 2H), 7.31-7.36 (m, 1H), 7.42-7.46 (m, 4H), 7.53-7.57 (m, 4H), 7.67 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 430.20 (M+H)+, 100%. Example-27 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((2'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
Figure imgf000100_0002
1H NMR (CDCl3) δ: 1.93-2.06 (m, 4H), 3.26 (m, 1H), 3.60-3.83 (m, 3H), 4.66 (m, 1H), 4.85 (d, J = 6.8 Hz, 2H), 4.74 (d, J = 6.0 Hz, 2H), 6.95-7.05 (m, 2H), 7.16-7.28 (m, 3H), 7.32- 7.76 (m, 8H); ESI-MS: m/z, 498.18 (M+H)+, 100%. Example-28 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
Figure imgf000100_0003
1H NMR (CDCl3) δ: 1.88-2.08 (m, 4H), 3.23-3.29 (m, 2H), 3.43-3.70 (m, 1H), 3.79-4.07 (m, 2H), 4.68 (m, 1H), 4.84 (d, J = 6.8 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 7.28 (s, 2H), 7.36-7.59 (m, 4H), 7.65 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H); ESI-MS: m/z, 498.22 (M+H)+, 100%. Example-29 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
Figure imgf000101_0001
F 1H NMR (DMSO-d6) δ: 1.68 (m, 2H), 2.01 (m, 2H), 3.32-3.70 (m, 3H), 4.01 (m, 1H), 4.70 (d, J = 8.4 Hz, 2H), 4.76-4.80 (m, 3H), 6.44 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.68-7.70 (m, 4H), 7.77 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H). ESI- MS: m/z, 498.24 (M+H)+, 100% Example-30 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-isopropylphenoxy)piperidin-1- yl)methanone
Figure imgf000101_0002
1H NMR (DMSO-d6) δ: 1.17 (d, J = 6.8 Hz, 6H), 1.61 (m, 2H), 1.96 (m, 2H), 2.80-2.84 (m, 1H), 3.33-3.43 (m, 2H), 3.45-3.65 (m, 1H), 3.80-3.95 (m, 1H), 4.57-4.61 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.44 (s, 1H), 6.88-6.92 (m, 2H), 7.12- 7.15 (m, 2H), 7.44 (d, J = 6.4 & 1.6 Hz, 2H), 7.67 (dd, J = 6.4 & 2.0 Hz, 2H); ESI-MS: m/z, 396.24 (M+H)+, 100%. Example-31 : (4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone
Figure imgf000101_0003
1H NMR (DMSO-d6) δ: 1.71 (m, 2H), 1.98-2.02 (m, 2H), 3.33-3.59 (m, 1H), 3.74 (m, 2H), 3.86 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 4.99-5.01 (m, 1H), 6.45 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4, 2H), 7.61 (d, J = 1.2 Hz, 1H), 7.66-7.71 (m, 3H); ESI-MS: m/z, 356.11 (M+H)+, 100%. Example-32 : (4-(4-(1H-imidazol-1-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan- 3-yl)phenyl)methanone
Figure imgf000102_0001
1H NMR (DMSO-d6) δ: 1.65-1.86 (m, 2H), 1.88-2.20 (m, 2H), 3.32-3.80 (m, 3H), 3.94- 4.17 (m, 1H), 4.94-5.03 (m, 5H), 6.44 (s, 1H), 6.09-7.14 (m, 3H), 7.32-7.99 (m, 7H), 8.32- 8.35 (m, 1H); ESI-MS: m/z, 420.24 (M+H)+, 100%. Example-33 : (4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)phenyl)(morpholino)methanone
Figure imgf000102_0002
O O 1H NMR (DMSO-d6) δ: 1.64 (m, 2H), 1.99 (m, 2H), 3.32-3.70 (m, 11H), 4.00 (m, 1H), 4.68-4.79 (m, 5H), 6.45 (s, 1H), 7.03 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H); ESI-MS: m/z, 467.28 (M+H)+, 100%. Example-34 : 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000102_0003
O 1H NMR (DMSO-d6) δ: 1.65 (m, 2H), 2.01 (m, 2H), 3.34-3.81 (m, 3H), 4.01 (m, 1H), 4.70- 5.04 (m, 5H), 6.45 (s, 1H), 7.18 (m, 2H), 7.46 (m, 2H), 7.67-7.95 (m, 4H); ESI-MS: m/z, 379.15 (M+H)+, 100%. Example-35 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(2-phenylpropan-2- yl)phenoxy)piperidin-1-yl)methanone
Figure imgf000102_0004
1H NMR (DMSO-d6) δ: 1.60 (m, 8H), 1.99 (m, 2H), 3.28-3.45 (m, 2H), 3.55 (m, 1H), 3.96 (m, 1H), 4.57-4.61 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 6.87-6.90 (m, 2H), 7.10-7.46 (m, 7H), 7.66 (d, J = 4.8 Hz, 2H), 7.95 (s, 2H). ESI-MS: m/z, 372.20 (M+H) +, 100%. Example-36 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-phenoxyphenoxy)piperidin-1- yl)methanone
Figure imgf000103_0001
1H NMR (DMSO-d6) δ: 1.60 (m, 2H), 1.98-2.14 (m, 2H), 3.38-3.80 (m, 3H), 3.99 (m, 1H), 4.61-5.09 (m, 5H), 6.45 (s, 1H), 6.60-7.35 (m, 7H), 7.46-7.89 (m, 4H), 7.95-8.09 (m, 2H); ESI-MS: m/z, 446.26 (M+H)+, 100%. Example-37 : (4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone
Figure imgf000103_0002
1H NMR (DMSO-d6) δ: 1.65 (m, 2H), 1.99 (m, 2H), 3.33-3.56 (m, 3H), 3.99 (s, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 4.86-4.88 (m, 1H), 6.44 (s, 1H), 7.15 (d, J = 8.8 & 1.6 z, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H); ESI-MS: m/z, 456.06 (M+H)+, 100%. Example-38 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000103_0003
1H NMR (DMSO-d6) δ: 1.71 (m, 2H), 1.97 (m, 2H), 3.33 (m, 1H), 3.49 (m, 1H), 3.70 (m, 2H), 4.69 (d, J = 5.6 Hz, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.92 (m, 1H), 6.45 (s, 1H), 7.07-7.10 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.79-7.86 (m, 4H); ESI-MS: m/z 422.15 (M+H) +, 100%. Example-39 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000104_0001
1H NMR (DMSO-d6) δ : 1.65 (m, 2H), 1.99-2.01 (m, 2H), 3.34-3.57 (m, 3H), 3.99 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.80-4.83 (m, 3H), 6.45 (s, 1H), 7.28-7.33 (m, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.51-7.55 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 422.13 (M+H) +, 100%. Example-40 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-methoxyphenoxy)piperidin-1- yl)methanone
Figure imgf000104_0002
1H NMR (DMSO-d6) δ: 1.60 (m, 2H), 1.93-2.05 (m, 2H), 3.40-3.56 (m, 3H), 3.69 (s, 3H), 3.96 (s, 1H), 4.50 (s, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.45 (s, 1H), 6.85(d, J = 8.48 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 384.10 (M+H)+, 100%. Example-41 : (4-(4-(2H-tetrazol-5-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone
Figure imgf000104_0003
1H NMR (DMSO-d6) δ : 1H NMR (DMSO-d6) δ : 1.67 (m, 2H), 2.02 (m, 2H), 3.20-3.53 (m, 2H), 3.72-3.76 (m, 1H), 3.80-4.18 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.78-4.79 (m, 3H), 6.47 (br s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 422.17 (M+H)+, 100%. Example-42 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenoxy)methyl)piperidin-1-yl)methanone 1
Figure imgf000105_0001
H NMR (DMSO-d6) δ : 1.29 (m, 2H), 1.75-1.86 (m, 2H), 2.08 (m, 1H), 2.82 (m, 1H), 3.09 (m, 1H), 3.65 (m, 1H), 3.96 (d, J = 5.2 Hz, 2H), 4.53 (s, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 6.0 Hz, 2H), 6.45 (s, -OH), 7.12 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.63- 7.68 (m, 4H); ESI-MS: m/z, 436.18 (M+H)+, 100%. Example-43 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazin-1-yl)methanone
Figure imgf000105_0002
1H NMR (CDCl3) δ: 2.55-2.69 (m, 4H), 1.90 (t, J = 6.4 Hz, 2H), 3.47 (m, 2H), 3.84 (m, 2H), 4.17 (t, J = 6.8 Hz, 2H), 4.82 (d, J = 6.8 Hz, 2H), 4.94 (d, J =7.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7356 (d, J = 8.8 Hz,2H), 7.63 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 451.20 (M+H)+, 100%. Example-44 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)thio)phenoxy)piperidin-1-yl)methanone
Figure imgf000105_0003
1H NMR (DMSO-d6) δ : 1.66 (m, 2H), 2.02 (m, 2H), 3.27-3.37 (m, 2H), 3.50-3.60 (m, 1H), 3.90-4.10 (m, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.75-5.00 (m, 3H), 6.44 (s, -OH), 7.14 (d, J = 6.8 Hz, 2H), 7.45 (d, J =6.8 Hz, 2H), 7.62-7.68 (m, 4H); ESI-MS: m/z, 454.12 (M+H)+, 100%. Example-45 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)thio)phenoxy)piperidin-1-yl)methanone
Figure imgf000106_0001
1H NMR (DMSO-d6) δ : 1.67 (m, 2H), 1.90-2.10 (m, 2H), 3.05 (s, 3H), 3.27-3.42 (m, 2H), 3.45-3.55 (m, 1H), 3.90-4.10 (m, 1H), 4.75-4.80 (m, 5H), 7.15 (d, J = 8.4 Hz, 2H), 7.48-7.53 (m, 4H), 7.63 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 468.14 (M+H)+, 100%. Example-46 : (4-(3-(methoxy-d3)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000106_0002
1H NMR (CDCl3) δ: 1.95-2.06 (m, 4H), 3.46 (m, 1H), 3.71-3.80 (m, 1H), 3.91 (m, 2H), 4.67-4.71 (m, 1H), 4.82 (d, J = 7.6 Hz, 2H), 4.96 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.49-7.58 (m, 6H); ESI-MS: m/z, 439.19 (M+H)+, 100%. Example-47 : (4-(3-((tetrahydro-2H-pyran-4-yl)methoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000106_0003
1H NMR (CDCl3) δ: 1.23-1.41 (m, 3H), 1.69 (dd, J = 6.6 Hz, 2H), 1.83-2.06 (m, 5H), 3.04 (d, J = 6.4 Hz, 2H), 3.38-3.45 (m, 3H), 3.71 (m, 1H), 3.91-4.01 (m, 3H), 4.68-4.71 (m, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.94 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.49-7.58 (m, 6H); ESI-MS: m/z, 520.23 (M+H)+, 100%. Example-48 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone
Figure imgf000106_0004
1H NMR (DMSO-d6) δ : 1.71 (m, 2H), 2.00-2.06 (m, 2H), 2.50 (s, 3H), 3.31-3.43 (m, 2H), 3.51-3.56 (m, 1H), 4.02 (m, 1H), 4.70 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 5.18-5.22 (m, 1H), 6.44 (s, -OH), 7.46 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 8.61 (s, 2H); ESI-MS: m/z, 402.14 (M+H)+, 100%. Example-49 : (4-(3-isobutoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000107_0001
1H NMR (CDCl3) δ: 0.94 (d, J = 6.8 Hz, 6H), 1.83-2.11 (m, 5H), 2.96 (d, J = 6.4 Hz, 2H), 3.35-3.55 (m, 1H), 3.60-3.99 (m, 3H), 4.68-4.71 (m, 1H), 4.80 (d, J = 7.2 Hz, 2H), 4.97 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.50 (dd, J = 6.8 & 2.0 Hz, 2H), 7.54-7.58 (m, 4H); ESI-MS: m/z, 478.22 (M+H)+, 100%. Example-50: (4-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone
Figure imgf000107_0003
1H NMR (CDCl3) δ: 3.19 (s, -OH), 3.52-4.07 (m, 8H), 4.85 (d, J = 6.0 Hz, 2H), 6.94 (d, J = 6.8 Hz, 2H), 7.45 (d, J =7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.69-7.73 (m, 4H); ESI- MS: m/z, 435.15 (M+H)+, 100%. Example-51 : (1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)(4- (trifluoromethyl)phenyl)methanone
Figure imgf000107_0002
1H NMR (CDCl3) δ: 1.72.-1.89 (m, 4H), 3.05-3.20 (m, 2H), 3.46 (s, 1H), 3.54-3.68 (m, 1H), 3.88 (m, 1H), 4.61-4.70 (m, 1H), 4.84 (d, J = 6.8 Hz, 2H), 4.94 (d, J = 6.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H); ESI-MS: m/z, 434.15 (M+H)+, 100%. Example-52: (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone
Figure imgf000108_0002
1H NMR (CDCl3) δ: 1.78 (m, 2H), 2.04 (m, 2H), 2.50 (m, 2H), 3.32-3.37 (m, 2H), 3.46 (s, 2H), 3.70-3.76 (m, 2H), 4.76 (s, 2H), 4.84 (d, J = 6.8 Hz, 2H), 4.94 (d, J = 6.8 Hz, 2H), 6.86 (d, J =8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H); ESI-MS: m/z, 462.18 (M+H)+, 100%. Example-53 : (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone
Figure imgf000108_0001
1H NMR (DMSO-d6) δ : 2.25-2.43 (m, 2H), 2.78-2.83 (m, 2H), 4.06 (s, 1H), 4.15 (s, 1H), 4.32 (s, 1H), 4.41 (s, 1H), 4.67-4.79 (m, 5H), 6.49 (s, -OH), 7.02 (d, J = 8.0 Hz, 2H), 7.63- 7.68 (m, 6H); ESI-MS: m/z, 434.15 (M+H)+, 100%. Example-54 : (4-(3-methoxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone
Figure imgf000108_0003
1H NMR (DMSO-d6) δ : 2.28-2.33 (m, 2H), 2.78-2.83 (m, 2H), 3.04 (s, 3H), 4.07 (s, 1H), 4.16 (s, 1H), 4.33 (s, 1H), 4.41 (s, 1H), 4.71-4.80 (m, 5H), 7.00-7.039 (m, 2H), 7.51-7.55 (m, 2H), 7.63-7.71 (m, 4H); ESI-MS: m/z, 448.15 (M+H)+, 100%. Example-55 : (4-(4-hydroxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride
Figure imgf000109_0001
1H NMR (CD3OD) δ: 1.18-1.19 (m, 1H), 1.21-1.41 (m, 2H), 1.70-1.81 (m, 1H), 1.93-1.96 (m, 3H), 2.27-2.36 (m, 4H), 3.32-3.35 (m, 2H), 3.47-3.51 (m, 3H), 3.75-3.79 (m, 2H), 3.81- 3.85 (m, 1H), 4.98-5.01 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.57- 7.61 (m, 4H); ESI-MS: m/z 475.4 (M+H)+, 100%. Example-56 : (4-(4-methoxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride
Figure imgf000109_0002
1H NMR (DMSO-d6) δ: 1.58-1.61 (m, 1H), 1.73-1.77 (m, 1H), 2.07-2.10 (m, 4H), 2.29- 2.33 (m, 2H), 2.77-2.80 (m, 2H), 2.91 (s, 3H), 3.20-3.23 (m, 2H), 3.34-3.39 (m, 3H), 3.59- 3.67 (m, 3H), 4.95-4.96 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 8.92 (m, 2H); ESI-MS: m/z 430.8 (M)+, 100%. Example-57 : tert-butyl 4-hydroxy-4-(4-(5-(4- (trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2- carbonyl)phenyl)piperidine-1-carboxylate
Figure imgf000109_0003
1H NMR (CDCl3) δ: 1.49 (s, 9H), 1.65-1.69 (m, 3H), 2.05-2.07 (m, 1H), 2.27-2.31 (m, 3H), 2.33-2.35 (m, 2H), 2.80-2.82 (m, 1H), 3.24 (s, 2H), 3.47-3.51 (m, 2H), 3.67-3.69 (m, 1H), 3.77-3.79 (m, 1H), 3.92-3.94 (m, 1H), 4.12-4.14 (m, 1H), 5.3-5.35 (m, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.44 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 575.2 (M+H)+, 100%. Example-58 : (4-(4-(3-methoxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone
Figure imgf000110_0001
1H NMR (DMSO-d6) δ : 3.04 (s, 3H), 3.29-3.80 (m, 8H), 4.76-4.80 (m, 4H), 7.52 (d, J = 5.6 Hz, 4H), 7.64 (d, J = 7.2 Hz, 2H), 7.84 (d, J = 5.6 Hz, 2H); ESI-MS: m/z, 449.16 (M+H)+, 100%. Example-59 : (4-(3-methoxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone
Figure imgf000110_0002
1H NMR (CDCl3) δ: 1.53-1.61 (m, 4H), 1.97-2.10 (m, 2H), 2.51 (m, 2H), 3.17 (s, 3H), 3.34-3.48 (m, 2H), 3.71-3.77 (m, 2H), 4.77 (s, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.96 (d, J = 6.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.52-7.55 (m, 4H); ESI-MS: m/z, 476.20 (M+H)+, 100% Example-60 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone
Figure imgf000110_0003
1H NMR (CDCl3) δ: 1.84-2.06 (m, 4H), 3.44 (m, 2H), 3.68 (m, 2H), 3.88 (m, 2H), 4.44- 4.49 (m, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.96 (m, 2H), 6.50 (s, 1H), 7.14 (s, 2H), 7.49-7.51 (m, 2H), 7.54 (dd, J =6.4 & 1.6 Hz, 2H); ESI-MS: m/z, 442.10 (M+H)+, 100%. Example-61 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)amino)piperidin-1-yl)methanone
Figure imgf000111_0001
1H NMR (CDCl3) δ: 1.28-1.64 (m, 2H), 2.06-2.21 (m, 2H), 2.38 (s, 3H), 3.10-3.28 (m, 2H), 3.79 (m, 1H), 4.06-4.15 (m, 1H), 4.64 (m, 1H), 4.88 (d, J = 7.2 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 5.20 (s, J = 7.6 Hz, -NH), 7.43 (dd, J = 6.8 & 2.0 Hz, 2H), 7.66 (dd, J = 6.4 & 1.6 Hz, 2H), 8.37 (s, 2H); ESI-MS: m/z, 401.16 (M+H)+, 100%. Example-62 : N-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000111_0002
1H NMR (DMSO-d6) δ: 1.19-1.32 (m, 2H), 1.50-1.63 (m, 2H), 2.89-3.02 (m, 2H), 3.35- 3.36 (m, 1H), 3.50 (m, 1H), 4.20 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 6.43 (s, -OH), 7.36 (dd, J = 6.4 & 1.6 Hz, 2H), 7.64-7.66 (m, 2H), 8.00 (d, J = 8.4 Hz, 2H), 8.51 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 6.8 Hz, -NH); ESI-MS: m/z, 485.13 (M+H)+, 100%. Example-63 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone
Figure imgf000111_0003
1H NMR (CDCl3) δ: 1.80 - 2.20 (m, 4H), 3.02 (s, -OH), 3.41-3.43 (m, 1H), 3.66 (m, 1H), 3.80 (m, 2H), 4.44-4.49 (m, 1H), 4.88 (d, J = 6.8 Hz, 2H), 4.95 (d, J = 6.8 Hz, 2H), 6.49 (s, 1H), 7.14 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 428.12 (M+H)+, 100%. Example-64 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000112_0001
O 1H NMR (CDCl3) δ: 1.83-2.10 (m, 4H), 3.43 (m, 1H), 3.56 (s, -OH), 3.67 (m, 1H), 3.91 (m, 2H), 4.64-4.69 (m, 1H), 4.83 (d, J = 6.8 Hz, 2H), 4.90 (d, J = 6.8 Hz, 2H), 7.10 (dd, J = 8.0 & 2.0 Hz, 1H), 7.16 (s, 1H), 7.23-7.28 (m, 1H), 7.35-7.49 (m, 3H), 7.15 (d, J = 1.2 Hz, 1H), 7.73 (dd, J = 2.8 & 1.6 Hz, 1H); ESI-MS: m/z, 422.16 (M+H)+, 100%. Example-65 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)amino)piperidin-1-yl)methanone 1
Figure imgf000112_0002
H NMR (DMSO-d6) δ: 1.24-1.40 (m, 2H), 1.80-2.05 (m, 2H), 3.00-3.20 (m, 2H), 3.60- 3.70 (m, 2H), 4.40 (m, 1H), 7.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.44 (s, - OH), 6.63 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 8.4 & 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 2.0 Hz, 1H); ESI-MS: m/z, 422.17 (M+H)+, 100%. Example-66 : (4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000112_0003
1H NMR (DMSO-d6) δ: 1.53 (d, J = 12.8 Hz, 2H), 1.65 (m, 2H), 1.94-2.01 (m, 4H), 3.32- 3.42 (m, 2H), 3.55-3.57 (m, 1H), 3.69-3.81(m, 4H), 3.97 (m, 1H), 4.78-4.80 (m, 1H), 5.11 (s, -OH), 7.17 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H); ESI-MS: m/z, 450.19 (M+H)+, 100%. Example-67 : (4-(3-hydroxyoxetan-3-yl)-3,5-dimethoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000113_0001
1H NMR (DMSO-d6) δ: 1.69 (m, 2H), 1.90-2.10 (m, 2H), 3.31-3.33 (m, 1H), 3.44 (m, 1H), 3.57 (m, 1H), 3.75 (s, 6H), 3.95-4.05 (m, 1H), 4.49 (d, J = 8.0 Hz, 2H), 4.79-4.82 (m, 1H), 4.89 (d, J = 8.0 Hz, 2H), 5.74 (s, -OH), 6.66 (s, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z, 482.12 (M+H)+, 100%. Example-68 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)amino)piperidin-1-yl)methanone 1
Figure imgf000113_0002
H NMR (DMSO-d6) δ: 1.34-1.40 (m, 2H), 1.91-2.01 (m, 2H), 3.06 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 4.09 (m, 1H), 4.36 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.44 (s, 1H), 6.59 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 8.8 & 2.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 8.29 (s, 1H); ESI-MS: m/z, 422.17 (M+H)+, 100%. Example-69 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000113_0003
1H NMR (DMSO-d6) δ: 1.24-1.35 (m, 2H), 1.89-2.01 (m, 2H), 3.07-3.21 (m, 2H), 3.61- 3.63 (m, 2H), 4.37 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.33 (d, J = 8.0 Hz, 1H), 6.47 (s, -OH), 6.71 (d, J = 8.4 Hz, 2H), 7.31-7.37 (m, 3H), 7.47-7.51 (m, 1H), 7.59 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H); ESI-MS: m/z, 421.18 (M+H)+, 100%. Example-70 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000114_0001
1H NMR (DMSO-d6) δ: 1.34 (m, 2H), 1.90-1.99 (m, 2H), 3.05-3.20 (m, 2H), 3.61-3.63 (m, 2H), 4.32 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.08 (d, J = 8.0 Hz, 1H), 6.45 (s, -OH), 6.79 (d, J = 7.2 Hz, 2H), 6.86 (d, J = 6.4 Hz, 2H), 7.25-7.29 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H); ESI-MS: m/z, 421.18 (M+H)+, 100%. Example-71 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((3- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone
Figure imgf000114_0002
1H NMR (DMSO-d6) δ: 1.34 (m, 2H), 1.90-1.99 (m, 2H), 3.05-3.20 (m, 2H), 3.61-3.63 (m, 2H), 4.35 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.08 (d, J = 8.0 Hz, 1H), 6.46 (s, -OH), 6.79 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 6.4 Hz, 2H), 7.25-7.29 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.47-7.51 (m, 1H), 7.59 (s, -OH), 7.70 (d, J = 8.0 Hz, 1H); ESI-MS: m/z, 421.18 (M+H)+, 100%. Example-72 : (2-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000114_0003
1H NMR (DMSO-d6) δ: 1.60-1.69 (m, 2H), 1.93 (m, 1H), 2.02-2.04 (m, 1H), 3.26-3.33 (m, 1H), 3.43-3.51 (m, 2H), 4.01-4.02 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.77-4.83 (m, 3H), 6.58 (s, -OH), 7.18 (d, J = 8.4 Hz, 2H), 7.43-7.56 (m, 3H), 7.65( d, J = 8.4 Hz, 2H); ESI-MS: m/z, 440.20 (M+H)+, 100% Example-73 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(pyrimidin-2-ylamino)piperidin- 1-yl)methanone
Figure imgf000115_0001
1H NMR (DMSO-d6) δ: 1.44 (m, 2H), 1.84-1.99 (m, 2H), 2.99 (m, 1H), 3.17 (m, 1H), 3.62 (m, 1H), 3.94-4.04 (m, 1H), 4.39 (m, 1H), 4.70 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.44 (s, -OH), 6.56 (t, J = 4.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.41 ( d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 8.26 (d, J = 4.8 Hz, 2H); ESI-MS: m/z, 355.24 (M+H)+, 100%. Example-74 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone 1
Figure imgf000115_0002
H NMR (DMSO-d6) δ: 1.77 (m, 2H), 1.90-2.05 (m, 2H), 3.37 (m, 1H), 3.54 (m, 2H), 3.97 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 6.0 Hz, 2H), 5.30 (s, 1H), 6.44 (s, - OH), 7.47 (d, J = 8.0 Hz, 2H), 7.63-7.69 (m, 3H), 8.99 ( d, J = 4.4 Hz, 1H);ESI-MS: m/z, 424.14 (M+H)+, 100%. Example-75 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone
Figure imgf000115_0003
1H NMR (DMSO-d6) δ: 1.47 (m, 2H), 1.82-1.99 (m, 2H), 3.09 (m, 1H), 3.18 (m, 1H), 3.49 (m, 1H), 4.05 (m, 1H), 4.40 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.44 (s, -OH), 6.97 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.97 (s, -NH), 8.62 (s, 1H); ESI-MS: m/z, 423.16 (M+H)+, 100%. Example-76 : (4-(4-(difluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone
Figure imgf000116_0001
1H NMR (DMSO-d6) δ: 1.65 (m, 2H), 2.00 (m, 2H), 3.30-3.56 (m, 4H), 3.99 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H),4.75-4.79 (m, 3H), 6.44 (s, -OH), 7.11 (d, J = 8.4 Hz, 2H), 7.45- 7.51 (m, 4H), 7.67 ( d, J = 8.0 Hz, 2H); ESI-MS: m/z, 404.16 (M+H)+, 100%. Example-77 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)azepan-1-yl)methanone
Figure imgf000116_0002
1H NMR (DMSO-d6) δ: 1.63-2.16 (m, 6H), 3.33-3.57 (m, 2H), 3.64-3.79 (m, 2H), 4.69- 4.89 (m, 5H), 6.43 (s, -OH), 7.09-7.15 (m, 2H), 7.45 (s, 2H), 7.64 (s, 4H); ESI-MS: m/z, 436.22 (M+H)+, 100%. Example-78 : (4-(3-hydroxyoxetan-3-yl)-2-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000116_0003
1H NMR (DMSO-d6) δ: 1.52-1.66 (m, 2H), 1.90 (m, 1H), 2.00 (m, 1H), 3.10-3.28 (m, 1H), 3.33-3.45 (m, 2H), 3.84 (s, 3H), 4.02-4.06 (m, 1H) 4.72(d, J = 6.4 Hz, 2H), 4.76- 4.78 (m, 3H), 6.44 (s, -OH), 7.18 (t, J = 6.8 Hz, 2H), 7.25-7.27 (m, 3H), 7.64 ( d, J = 8.8 Hz, 2H); ESI-MS: m/z, 452.22 (M+H)+, 100%. Example-79 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- thiomorpholinophenoxy)piperidin-1-yl)methanone
Figure imgf000116_0004
1H NMR (DMSO-d6) δ: 1.59 (m , 2H), 1.87-2.05 (m, 2H), 2.67-2.69 (m, 4H), 3.30-3.58 (m, 5H), 3.42-3.57 (m, 2H), 3.96 (m, 1H), 4.49-4.51 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.44 (s, -OH), 6.88 (s, 4H), 7.44 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 455.29 (M+H)+, 100%. Example-80 : (4-(3-hydroxytetrahydrofuran-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000117_0001
1H NMR (DMSO-d6) δ: 1.66 (m, 2H), 1.90-2.10 (m, 2H), 2.13-2.16 (m, 1H), 2.23-2.28 (m, 1H), 3.30-3.66 (m, 3H), 3.75 (d, J = 8.8 Hz, 1H), 3.80 (d, J = 8.8 Hz, 1H), 3.99-4.03 (m, 3H), 4.79-4.81 (m, 1H), 5.44 (s, -OH), 7.18 (d, J = 6.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z, 436.27 (M+H)+, 100%. Example-81 (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone
Figure imgf000117_0002
1H NMR (DMSO-d6) δ: 1.47 (m, 2H), 1.86-2.00 (m, 2H), 2.99 (m, 1H), 3.17 (m, 1H), 3.59-3.63 (m, 1H), 4.05-4.15 (m, H), 4.41 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H) 6.44 (s, -OH), 7.42 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 7.6 Hz, 1H), 8.63 (d, J = 9.6 Hz, 2H); ESI-MS: m/z, 423.10 (M+H)+, 100%. Example-82 :(5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000117_0003
1H NMR (DMSO-d6) δ: 1.91-2.11 (m, 4H), 3.47-3.51 (m, 1H), 3.69-3.70 (m, 1H), 3.84- 3.91 (m, 1H), 3.96-4.00 (m, 1H), 4.70-4.73 (m, 1H), 4.86 (d, J = 8.0 Hz, 2H), 4.97 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H); ESI-MS: m/z 423.13 (M+H)+, 100%. Example-83 : (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone 1
Figure imgf000118_0001
H NMR (DMSO-d6) δ: 1.82-2.86 (m, 1H), 2.00-2.04 (m, 1H), 2.29-2.36 (m, 2H), 2.88- 2.94 (m, 2H), 3.48-3.52 (m, 1H), 3.71-3.73 (m, 1H), 3.88-3.93 (m, 2H), 4.84 (d, J = 7.2 Hz, 2H), 4.90-4.94 (m, 1H), 4.95 (d, J = 7.6 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 2.4 Hz, 1H); ESI-MS: m/z 449.15 (M+H)+, 100%. Example-84 : (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)azetidin-1-yl)methanone
Figure imgf000118_0002
1H NMR (DMSO-d6) δ: 4.02-4.05 (m, 1H), 4.36-4.38 (m, 1H), 4.56-4.60 (m, 1H), 4.66 (d, J = 6.8 Hz, 2H), 4.73-4.75 (m, 1H), 4.78 (d, J = 6.8 Hz, 2H), 5.17-5.22 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.67-7.72 (m, 6H); ESI-MS: m/z 394.11 (M+H)+, 100%. Example-85 : (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4- (trifluoromethyl)phenoxy)azetidin-1-yl)methanone
Figure imgf000118_0003
1H NMR (DMSO-d6) δ: 3.17 (s, 3H), 4.31-4.39 (m, 2H), 4.68-4.69 (m, 2H), 4.79 (d, J = 7.6 Hz, 2H), 4.96 (d, J = 7.2 Hz, 2H), 5.06-5.11 (m, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.55- 7.60 (m, 4H), 7.72-7.74 (m, 2H). ESI-MS: m/z 408.14 (M+H)+, 100%. Example-86 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 1
Figure imgf000119_0001
H NMR (DMSO-d6) δ: 1.66-1.68 (m, 2H), 1.96-2.02 (m, 2H), 3.38-3.55 (m, 3H), 3.99- 4.03 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78-4.83 (m, 3H), 6.46 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.62-7.70 (m, 4H); ESI-MS: m/z 422.20 (M+H)+, 100%. Example-87 : (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone
Figure imgf000119_0002
1H NMR (DMSO-d6) δ: 1.88-2.28 (m, 7H), 2.32-2.35 (m, 1H), 3.93-3.96 (m, 1H), 4.60- 4.64 (m, 1H), 4.70 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 4.85-4.89 (m, 1H), 6.55 (br s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.57-7.70 (m, 4H); ESI-MS: m/z 448.14 (M+H)+, 100%. Example-88 : (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone
Figure imgf000119_0003
1H NMR (DMSO-d6) δ: 1.54-1.58 (m, 1H), 1.74-1.78 (m, 1H), 1.93-1.98 (m, 4H), 2.14- 2.18 (m, 1H), 2.20-2.25 (m, 1H), 4.00-4.14 (m, 1H), 4.68-4.69 (m, 3H), 4.79 (d, J = 6.8 Hz, 2H), 4.98-5.03 (m, 1H), 6.47 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.43-7.45 (m, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.70-7.75 (m, 2H); ESI-MS: m/z 448.14 (M+H)+, 100%. Example-89 : N-(1-benzylpyrrolidin-3-yl)-4-(3-hydroxyoxetan-3-yl)benzamide
Figure imgf000120_0001
1H NMR (DMSO-d6) δ: 2.06-2.08 (m, 1H), 2.23-2.25 (m, 1H), 3.10-3.29 (m, 1H), 3.34- 3.37 (m, 1H), 3.47-3.56 (m, 1H), 3.56-3.74 (m, 1H), 4.40-4.44 (m, 2H), 4.49-4.60 (m, 1H), 4.67 (t, J = 6.0 Hz, 2H), 4.79-4.81 (m, 2H), 6.52 (s, 1H), 7.48-7.54 (m, 5H), 7.70-7.74 (m, 2H), 7.87-7.90 (m, 2H), 8.59-8.76 (m, 1H); ESI-MS: m/z 353.19 (M+H)+, 100%. Example-90 : (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
Figure imgf000120_0002
1H NMR (DMSO-d6) δ: 1.33-1.37 (m, 2H), 2.31-2.35 (m, 1H), 2.42-2.46 (m, 1H), 2.73- 2.79 (m, 2H), 3.24-3.29 (m, 1H), 3.53-3.70 (m, 5H), 4.68 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.45 (s, 1H), 7.50-7.54 (m, 4H), 7.65-7.69 (m, 4H); ESI-MS: m/z 447.19 (M+H)+, 100%. Example-91 : 4-(3-hydroxyoxetan-3-yl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin- 3-yl)benzamide
Figure imgf000120_0003
1H NMR (DMSO-d6) δ: 1.80-1.84 (m, 1H), 2.13-2.21 (m, 1H), 2.43-2.48 (m, 1H), 2.58- 2.67 (m, 2H), 2.80-2.86 (m, 1H), 3.70 (s, 2H), 4.40-4.43 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.47 (s, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.62-7.70 (m, 4H), 7.88 (d, J = 8.4 Hz, 2H), 8.48 (d, J = 6.8 Hz, 1H); ESI-MS: m/z 421.17 (M+H)+, 100%. Example-92 : 4-(3-hydroxyoxetan-3-yl)-N-(1-(3-(trifluoromethyl)benzyl)pyrrolidin- 3-yl)benzamide
Figure imgf000120_0004
1H NMR (DMSO-d6) δ: 1.80-1.87 (m, 1H), 2.12-2.21 (m, 1H), 2.42-2.46 (m, 1H), 2.53- 2.55 (m, 1H), 2.62-2.68 (m, 1H), 2.80-2.84 (m, 1H), 3.70 (s, 2H), 4.36-4.45 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.47 (s, 1H), 7.55-7.68 (m, 6H), 7.88 (d, J = 8.4 Hz, 2H), 8.48 (d, J = 7.2 Hz, 1H); ESI-MS: m/z 421.17 (M+H)+, 100%. Example-93 : 4-(3-hydroxyoxetan-3-yl)-N-(1-(2-(trifluoromethyl)benzyl)pyrrolidin- 3-yl)benzamide
Figure imgf000121_0001
1H NMR (DMSO-d6) δ: 1.80-1.87 (m, 1H), 2.14-2.22 (m, 1H), 2.45-2.47 (m, 1H), 2.55- 2.61 (m, 1H), 2.64-2.70 (m, 1H), 2.86-2.90 (m, 1H), 3.78 (s, 2H), 4.40-4.45 (m, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.47 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.64- 7.70 (m, 4H), 7.82 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 8.48 (d, J = 6.8 Hz, 1H); ESI-MS: m/z 421.17 (M+H)+, 100%. Example-94 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)benzyl)amino)piperidin-1-yl)methanone
Figure imgf000121_0002
1H NMR (DMSO-d6) δ: 1.53-1.55 (m, 2H), 1.67-1.76 (m, 2H), 2.84-3.00 (m, 1H), 3.12- 3.20 (m, 1H), 3.23-3.30 (m, 3H), 4.29-4.32 (m, 2H), 4.34-4.40 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.63 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.68-7.86 (m, 4H); ESI-MS: m/z 435.2 (M+H)+, 100%. Example-95 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)benzyl)amino)piperidin-1-yl)methanone
Figure imgf000121_0003
1H NMR (DMSO-d6) δ: 1.50-1.58 (m, 2H), 1.67-1.70 (m, 1H), 1.91-1.95 (m, 2H), 2.26 (s, 3H), 3.23-3.30 (m, 2H),3.67-3.70 (m, 2H), 4.12 (s, 2H), 4.68 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 6.40 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.66- 7.68 (m, 4H); ESI-MS: m/z 449.2 (M+H)+, 100%. Example-96 : 2-(4-(3-hydroxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one
Figure imgf000122_0001
1H NMR (DMSO-d6) δ: 1.18-1.28 (m, 2H), 1.45 (s, 6H), 1.61-1.64 (m, 2H), 2.85-2.95 (m, 2H), 3.23-3.29 (m, 2H), 4.54-4.61 (m, 1H), 4.66 (d, J = 6.8 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 6.33 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.57-7.61 (m, 4H); ESI-MS: m/z 464.21 (M+H)+, 100%. Example-97 : 2-(4-(3-methoxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one
Figure imgf000122_0002
1H NMR (CDCl3) δ: 1.40-1.44 (m, 2H), 1.58 (s, 6H), 1.69-1.79 (m, 2H), 3.13 (s, 3H), 3.14-3.20 (m, 1H), 3.65-3.75 (m, 2H), 4.45-4.48 (m, 1H), 4.83 (d, J = 7.2 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 5.32 (s, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 478.22 (M+H)+, 100%. Example-98: (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(pyridin-4-yloxy)piperidin-1- yl)methanone
Figure imgf000122_0003
1H NMR (DMSO-d6) δ: 1.62-1.68 (m, 2H), 1.97-2.05 (m, 2H), 3.34-3.38 (m, 2H), 3.53- 3.58 (m, 1H), 4.00-4.05 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 4.80- 4.84 (m, 1H), 6.45 (s, 1H), 7.02 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 8.38 (d, J = 6.4 Hz, 2H); ESI-MS: m/z 355.17 (M+H)+, 100%. Example-99 : (3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000123_0001
1H NMR (DMSO-d6) δ: 1.65-1.69 (m, 2H), 1.97-2.04 (m, 2H), 3.29-3.32 (m, 1H), 3.46- 3.50 (m, 2H), 3.97-4.01 (m, 1H), 4.70 (d, J = 7.2 Hz, 2H), 4.79-4.82 (m, 1H), 4.98 (d, J = 7.2 Hz, 2H), 6.45 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.25-7.33 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 440.15 (M+H)+, 100%. Example-100 : (4-(3-hydroxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000123_0002
1H NMR (DMSO-d6) δ: 1.63-1.67 (m, 2H), 1.97-2.02 (m, 2H), 2.21 (s, 3H), 2.99-3.32 (m, 1H), 3.35-3.39 (m, 1H), 3.55-3.59 (m, 1H), 3.98-4.01 (m, 1H), 4.70 (d, J = 6.8 Hz, 2H), 4.78-4.82 (m, 1H), 5.04 (d, J = 6.8 Hz, 2H), 6.17 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.21- 7.24 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 436.17 (M+H)+, 100%. Example-101 :(3-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000123_0003
1H NMR (CDCl3) δ: 1.86-2.14 (m, 4H), 3.18 (s, 3H), 3.42-3.45 (m, 1H), 3.67-3.70 (m, 1H), 3.89-3.93 (m, 2H), 4.67-4.72 (m, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.96 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.41-7.43 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.55-7.58 (m, 4H); ESI-MS: m/z 436.17 (M+H)+, 100%. Example-102 :(3-fluoro-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000124_0001
1H NMR (CDCl3) δ: 1.95-2.14 (m, 4H), 3.17 (s, 3H), 3.42-3.45 (m, 1H), 3.68-3.72 (m, 1H), 3.82-3.89 (m, 2H), 4.68-4.73 (m, 1H), 4.95 (d, J = 6.8 Hz, 2H), 5.05 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.18-7.21 (m, 1H), 7.25-7.31 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 454.20 (M+H)+, 100%. Example-103 :(4-(3-methoxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000124_0002
1H NMR (CDCl3) δ: 1.87-2.09 (m, 4H), 2.24 (s, 3H), 3.03 (s, 3H), 3.41-3.46 (m, 1H), 3.67-3.71 (m, 1H), 3.87-3.93 (m, 2H), 4.67-4.71 (m, 1H), 4.92 (d, J = 7.2 Hz, 2H), 5.00 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.20-7.27 (m, 3H), 7.57 (d, J = 8.8 Hz, 2H); ESI- MS: m/z 450.23 (M+H)+, 100%. Example-104 : tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)phenyl)pyrrolidine-1-carboxylate
Figure imgf000124_0003
1H NMR (DMSO-d6) δ: 1.42 (d, J = 11.2 Hz, 9H), 1.63-1.69 (m, 2H), 1.99-2.05 (m, 3H), 2.21-2.28 (m, 1H), 3.41-3.55 (m, 7H), 3.99-4.03 (m, 1H), 4.78-4.81 (m, 1H), 5.50 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H). Example-105 : (4-(3-hydroxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000125_0001
1H NMR (DMSO-d6) δ: 1.53-1.58 (m, 1H), 1.64-1.72 (m, 1H), 1.87-1.93 (m, 1H), 2.02- 2.07 (m, 1H), 2.26 (s, 3H), 3.14-3.20 (m, 1H), 3.34-3.44 (m, 2H), 3.55-3.63 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 4.77-4.80 (m, 1H), 6.38 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H); ESI- MS: m/z 436.25 (M+H)+, 100%. Example-106 : (4-(3-methoxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000125_0002
1H NMR (CDCl3) δ: 1.77-1.82 (m, 1H), 1.87-1.92 (m, 1H), 1.95-2.00 (m, 1H), 2.06-2.10 (m, 1H), 2.39 (s, 3H), 3.16 (s, 3H), 3.23-3.29 (m, 1H), 3.50-3.57 (m, 1H), 3.87-3.91 (m, 1H), 3.98-4.02 (m, 1H), 4.67-4.71 (m, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.94 (d, J = 6.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.25-7.27 (m, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 450.25 (M+H)+, 100%. Example-107 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
Figure imgf000125_0003
1H NMR (DMSO-d6) δ: 1.64-1.72 (m, 2H), 2.01-2.06 (m, 2H), 2.47-2.49 (m, 2H), 3.56- 3.59 (m, 1H), 4.01-4.05 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 5.35- 5.39 (m, 1H), 6.45 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 8.08 (dd, J = 8.8 Hz & 2.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H); ESI-MS: m/z 423.15 (M+H)+, 100%. Example-108 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
Figure imgf000126_0001
1H NMR (DMSO-d6) δ: 1.69-1.73 (m, 2H), 2.02-2.06 (m, 2H), 2.47-2.49 (m, 1H), 3.05 (s, 3H), 3.35-3.58 (m, 1H), 3.55-3.58 (m, 1H), 3.99-4.03 (m, 1H), 4.76 (d, J = 6.8 Hz, 2H), 4.80 (d, J = 6.8 Hz, 2H), 5.35-5.39 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 8.08 (dd, J = 8.8 Hz & 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H); ESI-MS: m/z 437.05 (M+H)+, 100%. Example-109 : (4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000126_0002
1H NMR (DMSO-d6) δ: 1.66-1.69 (m, 2H), 1.96-2.01 (m, 2H), 2.29-2.33 (m, 1H), 3.36- 3.45 (m, 1H), 3.52-3.62 (m, 1H), 3.80 (s, 3H), 3.96-4.04 (m, 1H), 4.63 (d, J = 6.8 Hz, 2H), 4.79-4.81 (m, 1H), 4.96 (d, J = 6.8 Hz, 2H), 5.93 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 452.22 (M+H)+, 100%. Example-110: (4-(3-hydroxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000126_0003
1H NMR (DMSO-d6) δ: 1.53-1.56 (m, 1H), 1.66-1.69 (m, 1H), 1.89-1.91 (m, 1H), 2.04- 2.09 (m, 1H), 2.20 (s, 3H), 2.22 (s, 3H), 3.15-3.18 (m, 1H), 3.28-3.32 (m, 1H), 3.49-3.54 (m, 1H), 4.08-4.12 (m, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 4.77-4.81 (m, 1H), 6.32 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.30 (s, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI- MS: m/z 450.24 (M+H)+, 100%. Example-111 : (3-methoxy-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000127_0001
1H NMR (DMSO-d6) δ: 1.66-1.69 (m, 2H), 1.97-2.00 (m, 2H), 2.97 (s, 3H), 3.34-3.45 (m, 1H), 3.78 (s, 3H), 3.76-3.79 (m, 1H), 4.71 (d, J = 7.6 Hz, 2H), 4.79-4.82 (m, 1H), 4.88 (d, J = 7.6 Hz, 2H), 7.01 (dd, J = 8.0 Hz & 1.2 Hz, 1H), 6.32 (s, 1H), 7.07 (d, J = 1.2 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 465.8 (M+H)+, 100%. Example-112 : (4-(3-methoxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000127_0002
1H NMR (DMSO-d6) δ: 1.56-1.60 (m, 1H), 1.64-1.71 (m, 1H), 1.89-1.93 (m, 1H), 2.03- 2.08 (m, 1H), 2.21 (s, 3H), 2.23 (s, 3H), 3.02 (s, 3H), 3.12-3.18 (m, 1H), 3.19-3.28 (m, 1H), 3.49-3.55 (m, 1H), 4.08-4.12 (m, 1H), 4.75-4.80 (m, 5H), 7.15-7.19 (m, 4H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 463.8 (M+H)+, 100%. Example-113 : tert-butyl 4-hydroxy-4-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)phenyl)piperidine-1-carboxylate
Figure imgf000127_0003
1H NMR (CDCl3) δ: 1.50 (s, 9H), 1.66-1.71 (m, 2H), 1.74-2.00 (m, 6H), 2.82 (s, 1H), 2.90 (s, 1H), 2.98 (s, 1H), 3.25 (m, 2H), 3.44 (m, 1H), 3.69-3.73 (m, 1H), 3.89 (m, 2H), 4.06 (m, 2H), 4.68 (m, 1H), 5.32 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H). Example-114 : (4-(4-hydroxypiperidin-4-yl) phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone hydrochloride
Figure imgf000128_0001
1H NMR (DMSO-d6) δ: 1.66-1.71 (m, 2H), 1.74-2.00 (m, 6H), 2.82 (s, 1H), 2.90 (s, 1H), 2.98 (s, 1H), 3.25 (m, 2H), 3.44 (m, 1H), 3.69-3.73 (m, 1H), 3.89 (m, 2H), 4.06 (m, 2H), 4.81 (m, 1H), 5.53 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 8.42 (br s, 2H); ESI-MS: m/z 449.12 (M+H)+, 100%. Example-115 : 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)oxetan-3-yl acetate
Figure imgf000128_0002
1H NMR (CDCl3) δ: 1.67 (m, 2H), 1.99 (m, 2H), 2.33 (s, 3H), 3.38-3.43 (m, 2H), 3.99 (m, 2H), 4.82 (d, J = 8.0 Hz, 3H), 4.95 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z, 464.20 (M+H) +, 100%. Example-116 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone.
Figure imgf000128_0003
1H NMR (DMSO-d6) δ: 1.69 (m, 2H), 2.02 (m, 2H), 3.38 (m, 2H), 3.56-3.60 (m, 1H), 4.00-4.06 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 4.89-4.93 (m, 1H), 6.42 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.67-7.72 (m, 3H), 7.85 (d, J = 9.2 Hz, 1H), 8.49 (s, 1H); ESI-MS: m/z 423.01 (M+H)+, 100%. Example-117 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone.
Figure imgf000129_0001
1H NMR (DMSO-d6) δ: 1.70 (m, 2H), 2.02 (m, 2H), 3.40-3.47 (m, 3H), 4.00 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 4.91 (s, 1H), 6.47 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H); ESI-MS: m/z 423.12 (M+H)+, 100%. Example-118 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)thio)piperidin-1-yl)methanon
Figure imgf000129_0002
1H NMR (DMSO-d6) δ: 1.54 (m, 2H), 2.02 (m, 2H), 3.18 (m, 2H), 3.46-3.61 (m, 1H), 3.79 (s, 1H), 4.31 (m, 1H), 4.68 (d, J = 6.0 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 6.44 (s, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.66 (m, 4H); ESI-MS: m/z 438.09 (M+H)+, 100%. Example-119 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)thio)piperidin-1-yl)methanone
Figure imgf000129_0003
1H NMR (DMSO-d6) δ: 1.51-1.55 (m, 2H), 1.99-2.02 (m, 2H), 3.18 (m, 2H), 3.61 (m, 1H), 3.79 (s, 1H), 4.31 (m, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 3H), 7.66- 7.70 (m, 3H); ESI-MS: m/z 438.16 (M+H)+, 100%. Example-120 : (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
Figure imgf000129_0004
1H NMR (DMSO-d6) δ: 1.45-1.49 (m, 2H), 1.91-2.05 (m, 1H), 2.10-2.15 (m, 1H), 2.49- 2.50 (m, 4H), 3.70-3.80 (m, 3H), 4.67 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 6.43 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 6.6 Hz, 2H), 7.63-7.95 (m, 4H); ESI-MS: m/z 448.16 (M+H)+, 100%. Example-121 :(3-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
Figure imgf000130_0001
1H NMR (DMSO-d6) δ: 1.58-1.62 (m, 1H), 1.74-1.78 (m, 1H), 2.23-2.33 (m, 2H), 2.68- 2.69 (m, 2H), 3.32 (d, J = 8.0 Hz, 1H), 3.56-3.68 (m, 4H), 4.65 (d, J = 6.4 Hz, 2H), 4.77 (d, J = 8.0 Hz, 2H), 4.95-4.99 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.13-7.23 (m, 1H), 7.34- 7.36 (m, 1H), 7.62-7.64 (m, 2H), 7.68-7.77(m, 2H); ESI-MS: m/z 448.14 (M+H)+, 80%. Example-122: (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzylidene)piperidin-1-yl)methanone
Figure imgf000130_0002
1H NMR (DMSO-d6) δ: 2.01 (m, 2H), 2.23 (m, 2H), 3.43 (m, 2H), 3.83 (m, 2H), 4.69 (s, 2H), 4.78 (s, 2H), 6.46 (s, 1H), 6.49 (s, 1H), 7.43-7.48 (m, 4H), 7.665-7.69 (m, 4H); ESI- MS: m/z 418.21 (M+H)+, 100%. Example-123 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000130_0003
1H NMR (DMSO-d6) δ: 1.01-1.09 (m, 2H), 1.16-1.26 (m, 2H), 1.81-1.87 (m, 1H), 2.64 (d, J = 7.2 Hz, 2H), 2.67 (m, 1H), 2.97 (m, 1H), 3.57 (m, 1H), 4.45 (m, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.43 (s, 1H), 7.38-7.43 (m, 4H), 7.63-7.67 (m, 4H); ESI- MS: m/z 420.17 (M+H)+, 100%. Example-124 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000131_0001
1H NMR (DMSO-d6) δ: 1.17 (m, 2H), 1.63 (m, 1H), 1.73 (m, 1H), 1.85 (m, 1H), 2.66 (d, J = 7.6 Hz, 2H), 2.71 (m, 1H), 2.98 (m, 1H), 3.56 (m, 1H), 4.46 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 6.45 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.41-7.49 (m, 3H), 7.56 (s, 1H), 7.60-7.69 (m, 3H); ESI-MS: m/z 420.20 (M+H)+, 100%. Example-125 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000131_0002
1H NMR (DMSO-d6) δ: 1.18 (m, 2H), 1.51 (m, 1H), 1.64 (m, 1H), 1.81-1.87 (m, 1H), 2.65 (d, J = 7.2 Hz, 2H), 2.67 (m, 1H), 2.97 (m, 1H), 3.07 (s, 3H), 3.55 (m, 1H), 4.46 (m, 1H), 4.74-4.80 (m, 4H), 7.42 (d, J = 8.0 Hz, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H); ESI-MS: m/z 434.19 (M+H)+, 100%. Example-126 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methanone
Figure imgf000131_0003
1H NMR (DMSO-d6) δ: 3.08 (m, 4H), 3.39 (m, 2H), 3.45 (m, 2H), 4.66 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 6.44 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 471.30 (M+H)+, 100%. Example-127: (3-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000132_0001
1H NMR (DMSO-d6) δ: 1.16-1.26 (m, 2H), 1.81-1.90 (m, 3H), 2.66 (d, J = 7.6 Hz, 2H), 2.71 (m, 1H), 2.98 (m, 1H), 3.16 (s, 3H), 3.56 (m, 1H), 4.46 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.41-7.49 (m, 3H), 7.56 (s, 1H), 7.60-7.69 (m, 3H); ESI-MS: m/z 434.19 (M+H)+, 100%. Example-128 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methanone
Figure imgf000132_0002
1H NMR (DMSO-d6) δ: 3.02 (s, 3H), 3.08 (m, 4H), 3.39 (m, 2H), 3.45 (m, 2H), 4.66 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 485.13 (M+H)+, 100%. Example-129: (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperazin-1-yl)methanone
Figure imgf000132_0003
1H NMR (DMSO-d6) δ: 2.33-2.41 (m, 4H), 3.38 (m, 2H), 3.61 (m, 4H), 4.68 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.65-7.71 (m, 4H); ESI-MS: m/z 421.17 (M+H)+, 100%. Example-130 : (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
Figure imgf000132_0004
1H NMR (DMSO-d6) δ: 0.95 (m, 1H), 1.09 (m, 1H), 1.83 (m, 1H), 1.94 (m, 1H), 2.11- 2.15 (m, 1H), 2.56 (m, 2H), 2.73 (d, J = 6.8 Hz, 2H), 3.49-3.63 (m, 4H), 4.69 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.46-7.50 (m, 2H), 7.61-7.67 (d, J = 8.4 Hz, 4H); ESI-MS: m/z 446.19 (M+H)+, 100%. Example-131 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidin-1-yl)methanone
Figure imgf000133_0001
1H NMR (DMSO-d6) δ: 2.14 (m, 2H), 2.36 (m, 2H), 3.43-3.46 (m, 1H), 3.57 (m, 2H), 3.90 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 5.48 (s, 1H), 6.45 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.42 (s, 1H); ESI-MS: m/z 479.12 (M+H)+, 100%. Example-132 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)oxy)piperidin-1-yl)methanone
Figure imgf000133_0002
1H NMR (DMSO-d6) δ: 2.14 (m, 2H), 2.36 (m, 2H), 3.18 (s, 3H), 3.43-3.46 (m, 1H), 3.57 (m, 2H), 3.90 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 5.48 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.42 (s, 1H); ESI-MS: m/z 493.14 (M+H)+, 100%. Example-133 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)methanone
Figure imgf000133_0003
1H NMR (DMSO-d6) δ: 1.40-1.48 (m, 2H), 1.99-2.08 (m, 2H), 3.17-3.23 (m, 2H), 3.65 (m, 1H), 4.04-4.08 (m, 2H), 4.23 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.44 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.52 (s, 2H), 7.68 (d, J = 8.0 Hz, 2H), 8.48 (s, 1H); ESI-MS: m/z 478.14 (M+H)+, 100%. Example-134 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethoxy)phenoxy)piperidin-1-yl)methanone
Figure imgf000134_0001
1H NMR (DMSO-d6) δ: 1.67 (m, 2H), 1.99 (m, 2H), 3.05 (m, 3H), 3.38-3.43 (m, 3H), 4.00 (m, 1H), 4.75 (m, 1H), 4.77-4.80 (m, 4H), 7.18 (d, J = 6.8 Hz, 2H), 7.43-7.49 (m, 4H), 7.52 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 452.17 (M+H)+, 100%. Example-135 :(4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethoxy)phenoxy)piperidin-1-yl)methanone
Figure imgf000134_0002
1H NMR (DMSO-d6) δ: 1.62 (m, 2H), 1.94-1.96 (m, 2H), 3.38-3.43 (m, 3H), 4.00 (m, 1H), 4.64-4.67 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.44 (s, 1H), 6.97 (d, J = 7.2 Hz, 2H), 7.42-7.46 (m, 4H), 7.67 (d, J = 8.4 Hz, 2H). Example-136 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(quinolin-4-yloxy)piperidin-1- yl)methanone
Figure imgf000134_0003
1H NMR (DMSO-d6) δ: 1.91-1.99 (m, 2H), 2.10-2.15 (m, 2H), 3.61-3.64 (m, 3H), 3.90- 4.05 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 5.67-5.69 (m, 1H), 6.40 (s, 1H), 6.46 (d, J = 5.6 Hz, 2H), 7.47-7.68 (m, 3H), 7.91-7.97 (m, 2H), 8.23 (d, J = 7.6 Hz, 2H), 8.08 (s, 1H); ESI-MS: m/z 405.41 (M+H)+, 100%. Example-137 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(quinolin-4-yloxy)piperidin-1- yl)methanone
Figure imgf000135_0001
1H NMR (DMSO-d6) δ: 1.91-1.99 (m, 3H), 2.10-2.15 (m, 2H), 3.26 (s, 3H), 3.60-3.75 (m, 2H), 3.90-4.05 (m, 1H), 4.76-4.81 (m, 4H), 5.67-5.69 (m, 1H), 7.46-7.55 (m, 4H), 7.68- 7.70 (m, 1H), 7.97-7.99 (m, 2H), 8.23 (d, J = 8.0 Hz, 2H), 8.08 (s, 1H); ESI-MS: m/z 419.4 (M+H)+, 100%. Example-138 : (4-(3-hydroxythietan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000135_0002
1H NMR (CDCl3) δ: 1.85-2.06 (m, 5H), 3.02 (m, 1H), 3.45 (m, 1H), 3.63 (s, 4H), 3.82 (m, 2H), 4.68 (m, 1H), 7.00 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 438.13 (M+H) +, 100%. Example-139 : (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone
Figure imgf000135_0003
1H NMR (DMSO-d6) δ: 1.25 (s, 1H), 1.66 (m, 2H), 2.02 (m, 2H), 3.43-3.46 (m, 2H), 4.01 (m, 1H), 4.38 (d, J = 16.0 Hz, 2H), 4.71 (d, J = 15.2 Hz, 2H), 4.81 (m, 1H), 6.82 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 9.2 Hz, 2H); ESI-MS: m/z, 470.12 (M+H) +, 100%. Example-140 : (4-(3-hydroxythietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000136_0001
1H NMR (DMSO-d6) δ: 1.16-1.21 (m, 2H), 1.51-1.68 (m, 2H), 1.83 (m, 1H), 2.60 (d, J = 8.4 Hz, 2H), 2.64 (m, 1H), 2.98 (m, 1H), 3.38 (d, J = 10.0 Hz, 2H), 3.62-3.35 (m, 3H), 4.41 (m, 1H), 6.47 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 436.20 (M+H)+, 100%. Example-141 : (4-(3-hydroxythietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone
Figure imgf000136_0002
1H NMR (DMSO-d6) δ: 1.70-1.73 (m, 2H), 2.02-2.06 (m, 2H), 2.47-2.49 (m, 1H), 3.39 (d, J = 10.4 Hz, 3H), 3.62 (d, J = 10.4 Hz, 3H), 4.01-4.05 (m, 1H), 5.35-5.39 (m, 1H), 6.48 (s, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 8.08 (dd, J = 8.8 Hz & 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H); ESI-MS: m/z 439.13 (M+H)+, 100%. Example-142 : (4-(3-hydroxytetrahydrothiophen-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000136_0003
O 1H NMR (DMSO-d6) δ: 1.66 (m, 2H), 1.99 (m, 2H), 2.17-2.21 (m, 2H), 2.88-2.93 (m, 2H), 3.04-3.14 (m, 2H), 3.33-3.42 (m, 2H), 3.57 (m, 1H), 3.98-4.02 (m, 1H), 4.78-4.82 (m, 1H), 5.42 (s, -OH), 7.18 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.60-7.66 (m 4H); ESI-MS: m/z, 452.23 (M+H)+, 100%. Example-143 : (4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone 1
Figure imgf000137_0003
H NMR (DMSO-d6) δ: 1.65 (m , 2H), 1.85 (d, J = 12.8 Hz, 2H), 1.96-2.02 (m, 4H), 2.39-2.41 (m, 2H), 3.06-3.13 (m, 2H), 3.33-3.42 (m, 2H), 3.57-3.61 (m, 1H), 3.90-4.04 (m, 1H), 4.80 (m, 1H), 5.10 (s, -OH), 7.18 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 466.22 (M+H)+, 100%. Example-144 : (4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)(4- (4-(trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000137_0002
1H NMR (DMSO-d6) δ: 1.65 (m, 2H), 1.95-2.10 (m, 4H), 2.33-2.45 (m, 2H), 3.04 (d, J = 12.4 Hz, 2H), 3.33-3.41 (m, 4H), 3.54-3.56 (m, 1H), 3.94-4.04 (m, 1H), 4.80 (s, 1H), 5.72 (s, -OH), 7.18 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z, 498.05 (M+H)+, 100%. Example-145 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone
Figure imgf000137_0001
1H NMR (CDCl3) δ: 1.60-1.62 (m, 1H), 1.75-1.79 (m, 2H), 1.92-1.95 (m, 3H), 2.07-2.09 (m, 2H), 2.10-2.14 (m, 3H), 3.16 (s, 3H), 3.60-3.67 (m, 1H), 3.89-3.86 (m, 1H), 4.12-4.15 (m, 2H), 4.80 (d, J = 6.4 Hz, 2H), 4.94 (d, J = 6.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50-7.56 (m, 4H); ESI-MS: m/z 494.5 (M+H)+, 100%. Example-146 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone
Figure imgf000138_0001
1H NMR (CDCl3) δ: 1.17-1.23 (m, 1H), 1.30-1.34 (m, 3H), 1.86-1.92 (m, 1H), 2.06-2.09 (m, 2H), 3.22-3.28 (m, 1H), 3.60-3.67 (m, 5H), 3.81-3.86 (m, 1H), 4.12-4.15 (m, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.92 (d, J = 6.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.40-7.61 (m, 4H); ESI-MS: m/z 480.2 (M+H)+, 100%. Example-147 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone
Figure imgf000138_0002
1H NMR (DMSO-d6) δ: 1.34-1.39 (m, 2H), 1.85-1.88 (m, 2H), 3.27-3.29 (m, 2H), 3.34- 3.39 (m, 1H), 3.40-3.42 (m, 1H), 3.64-3.69 (m, 2H), 3.81-3.86 (m, 1H), 4.18-4.20 (m, 2H), 4.68 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 6.43 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.63-7.67 (m, 4H); ESI-MS: m/z 466.18 (M+H)+, 100%. Example-148 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone
Figure imgf000138_0003
1H NMR (CDCl3) δ: 1.56-1.60 (m, 1H), 1.91-1.96 (m, 2H), 1.99-2.06 (m, 1H), 2.14-2.21 (m, 1H), 3.12 (s, 3H), 3.22-3.27 (m, 1H), 3.71-3.73 (m, 2H), 3.88-3.90 (m, 2H), 4.06-4.10 (m, 1H), 4.18-4.20 (m, 1H), 4.81 (d, J = 6.4 Hz, 2H), 4.95 (d, J = 6.4 Hz, 2H), 6.43 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H) 7.52-7.57 (m, 4H), 7.98 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 464.2 (M+H)+, 100%. Example-149 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone
Figure imgf000139_0001
1H NMR (DMSO-d6) δ: 1.75-1.84 (m, 4H), 2.10-2.16 (m, 3H), 2.82-2.99 (m, 1H), 3.06- 3.11 (m, 1H), 3.17 (s, 3H), 3.80-3.90 (m, 1H), 4.08-4.15 (m, 2H), 4.76-4.80 (m, 1H), 4.81 (d, J = 8.0 Hz, 2H), 4.95 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0z, 2H), 7.51-7.57 (m, 4H); ESI-MS: m/z 464.2 (M+H)+, 100%. Example-150 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone
Figure imgf000139_0002
1H NMR (DMSO-d6) δ: 1.03-1.05 (m, 2H), 1.71-1.73 (m, 4H), 2.51-2.56 (m, 1H), 2.67- 2.69 (m, 1H), 2.77-3.0 (m, 1H), 3.59-3.60 (m, 1H), 4.10-4.13 (m, 2H), 4.47-4.50 (m, 1H), 4.68 (d, J = 8.0 Hz, 2H), 4.78 (d, J = 8.0 Hz, 2H), 6.44 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 6.8 Hz, 2H), 7.63-7.67 (m, 4H); ESI-MS: m/z 450.18 (M+H)+, 100%. Example-151 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)ethyl)piperidin-1-yl)methanone
Figure imgf000139_0003
1H NMR (DMSO-d6) δ: 1.18-1.20 (m, 2H), 1.72-1.75 (m, 5H), 2.76-2.80 (m, 1H), 3.02- 3.09 (m, 1H), 4.30-4.41 (m, 3H), 4.68 (d, J = 8.0 Hz, 2H), 4.77 (d, J = 8.0 Hz, 2H), 6.40 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 8.01- 8.06 (m, 1H), 8.57 (s, 1H); ESI-MS: m/z 451.18 (M+H)+, 100%. Example-152 (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone
Figure imgf000139_0004
1H NMR (CDCl3) δ: 1.15-1.27 (m, 2H), 1.53-1.56 (m, 4H), 1.85-1.91 (m, 1H), 3.05-3.08 (s, 1H), 3.11-3.14 (m, 1H), 3.16 (s, 3H), 3.79-3.81 (m, 1H), 4.42-4.45 (m, 2H), 4.75-4.78 (m, 1H), 4.81 (d, J = 6.4 Hz, 2H), 4.94 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 5.6 Hz, 1H), 7.46- 7.52 (m, 4H), 7.77 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H); ESI-MS: m/z 465.1 (M+H)+, 100%. Example-153 (N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidine-1-carboxamide
Figure imgf000140_0001
1H NMR (DMSO-d6) δ: 1.62-1.64 (m, 2H), 2.01 (m, 2H), 3.28 (m, 2H), 3.83-3.87 (m, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.85 (m, 1H), 6.21 (s, 1H), 7.43- 7.49 (m, 4H), 7.71 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.61 (s, 1H); ESI-MS: m/z 436.12 (M-H), 100%. Example-154 : N-(3-(3-hydroxyoxetan-3-yl)phenyl)-4-(4- (trifluoromethyl)phenoxy)piperidine-1-carboxamide
Figure imgf000140_0002
1H NMR (DMSO-d6) δ: 1.60-164 (m, 2H), 1.99-2.02 (m, 2H), 3.27-3.31 (m, 2H), 3.83- 3.88 (m, 2H), 4.66 (s, 2H), 4.76 (s, 3H), 6.28 (s, 1H), 7.16-7.26 (m, 4H), 7.47 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 8.62 (s, 1H); ESI-MS: m/z 437.13 (M+H)+, 100%. Example-155 :N-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(4-(trifluoromethyl)phenoxy)- 8-azabicyclo[3.2.1]octane-8-carboxamide
Figure imgf000140_0003
1H NMR (DMSO-d6) δ: 1.62-1.67 (m, 2H), 1.89-1.96 (m, 4H), 2.12-2.16 (m, 2H), 4.48 (m, 2H), 4.67 (d, J = 6.4 Hz, 2H), 4.74 (d, J = 6.8 Hz, 2H), 4.96-4.99 (m, 1H), 6.21 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 8.57 (s, 1H); ESI-MS: m/z 463.10 (M+H)+, 100%. Example-156 : N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-(4- (trifluoromethyl)phenoxy)piperidine-1-carboxamide
Figure imgf000141_0001
1H NMR (DMSO-d6) δ: 1.57-1.65 (m, 2H), 1.99-2.03 (m, 2H), 3.27-3.31 (m, 3H), 3.81- 3.86 (m, 2H), 4.65-4.77 (m, 5H), 7.19 (d,J = 8.4 Hz, 2H), 7.43-7.49 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 8.60 (s, 1H); ESI-MS: m/z 437.00 (M+H)+, 100%. Example-157 :4-(2-chloro-4-(trifluoromethyl)phenoxy)-N-(4-(3-hydroxyoxetan-3- yl)phenyl)piperidine-1-carboxamide
Figure imgf000141_0002
1H NMR (DMSO-d6) δ: 1.53-1.84 (m, 2H), 1.96-2.27 (m, 2H), 3.33-3.62 (m, 2H), 3.73- 3.91 (m, 2H), 4.55-4.67 (m, 2H), 4.73-4.95 (m, 2H), 5.03 (m, 1H), 6.15-6.21 (m, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.47 (m, 4H), 7.61-7.92 (m, 2H), 8.60-8.71 (m, 1H); ESI-MS: m/z, 471.12 (M+H) +, 100%. Example-158 : N-(4-(3-hydroxyoxetan-3-yl)phenyl)-5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide
Figure imgf000141_0003
1H NMR (DMSO-d6) δ: 1.66-1.68 (m, 2H), 2.28-2.33 (m, 2H), 2.81-2.90 (m, 2H), 3.39- 3.45 (m, 2H), 3.57-3.62 (m, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.74 (d, J = 6.4Hz, 2H), 4.98- 5.01 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H); ESI-MS: m/z 463.14 (M+H)+, 100%. Example-159 : N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxamide
Figure imgf000142_0001
1H NMR (DMSO-d6) δ: 1.14-1.49 (m, 2H), 2.02-2.05 (m, 2H), 3.02-3.08 (m, 2H), 4.04- 4.08 (m, 3H), 4.67 (d, J = 6.4 Hz, 2H), 4.74 (d, J = 6.4 Hz, 2H), 6.21(s, 1H), 7.43-7.49 (m, 4H), 7.51 (d, J = 13.2 Hz, 2H), 8.14 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.59 (s, 1H); ESI- MS: m/z, 493.22 (M+H) +, 100%. Example-160 : N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-((6- (trifluoromethyl)benzo[d]thiazol-2-yl)amino)piperidine-1-carboxamide
Figure imgf000142_0002
1H NMR (DMSO-d6) δ: 1.40-1.48 (m, 2H), 1.99-2.08 (m, 2H), 2.98 (s, 3H), 3.17-3.23 (m, 2H), 4.04-4.08 (m, 2H), 4.23 (m, 1H), 4.74 (s, 4H), 7.28 (d, J = 8.8 Hz, 2H), 7.52 (s, 4H), 8.14 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.65 (s, 1H); ESI-MS: m/z 507.17 (M+H)+, 100%. Example-161 : 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4- (trifluoromethyl)phenyl)piperidine-4-carboxamide
Figure imgf000142_0003
1H NMR (DMSO-d6) δ: 1.76-1.81 (m, 2H), 1.89-1.99 (m, 2H), 2.73 (m, 1H), 2.95 (m, 1H), 3.05 (m, 1H), 3.68 (m, 1H), 3.50-3.55 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.6 Hz, 4H), 7.82 (d, J = 8.4 Hz, 2H), 10.32 (s, 1H); ESI-MS: m/z 449.16 (M+H)+, 100%. Example-162 : N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxamide
Figure imgf000143_0001
1H NMR (DMSO-d6) δ: 1.24 (s, 2H), 1.82-1.88 (m, 2H), 2.26-2.33 (m, 2H), 2.80-2.87 (m, 2H), 3.57 (m, 2H), 4.53 (m, 1H), 4.65 (d, J = 6.8 Hz, 2H), 4.74 (d, J = 6.8 Hz, 2H), 6.27 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.71-7.82 (m, 4H), 9.89 (br s, 1H); ESI-MS: m/z 435.18 (M+H)+, 100%. Example-163 : 4-(3-hydroxyoxetan-3-yl)-N-(6-(3-(trifluoromethyl)phenoxy)pyridin- 3-yl)benzamide
Figure imgf000143_0002
1H NMR (DMSO-d6) δ: 4.7 (d, J = 8.0 Hz, 2H), 4.81 (d, J = 6.8 Hz, 2H), 6.54 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.64 (m, 1H), 7.77 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 8.28 (t, J = 8.0 Hz, 1H), 8.55 (s, 1H), 10.46 (s, 1H); ESI-MS: m/z 430.8 (M)+, 100%. Example-164 : N-(4-(3-methoxyoxetan-3-yl)phenyl)-6-(3- (trifluoromethyl)phenoxy)nicotinamide
Figure imgf000143_0004
1H NMR (DMSO-d6) δ: 3.0 (s, 3H), 4.7 (s, 4H), 7.27 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.63-7.66 (m, 3H), 7.81 (d, J = 8.0 Hz, 2H), 8.40 (t, J = 8.0 Hz, 1H), 8.73 (s, 1H).10.42 (s, 1H); ESI-MS: m/z 444.7 (M)+, 100%. Example-165 : 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)oxetan-3- ol
Figure imgf000143_0003
1H NMR (DMSO-d6) δ: 1.73-1.76 (m, 2H), 2.06-2.09 (m, 2H), 3.05-3.11 (m, 2H), 3.52- 3.55 (m, 2H), 4.65 (d, J = 6.4 Hz, 2H), 4.72 (d, J = 6.4 Hz, 3H), 6.14 (s, 1H), 6.99 (d, J = 9.2 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 394.14 (M+H)+, 100%. Example-166 : 3-(3-morpholino-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)phenyl)oxetan-3-ol
Figure imgf000144_0001
1H NMR (DMSO-d6) δ: 1.71-1.76 (m, 2H), 1.99-2.06 (m, 2H), 3.04-3.11 (m, 6H), 3.51- 3.54 (m, 2H), 3.72-3.74 (m, 4H), 4.69 (s, 5H), 6.14 (s, 1H), 6.44 (s, 1H), 6.61 (s, 1H), 6.67 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 479.19 (M+H)+, 100%. Example-167 : (4-(3-hydroxyoxetan-3-yl)-2-morpholinophenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000144_0002
1H NMR (DMSO-d6) δ: 1.67-1.72 (m, 2H), 2.02-2.06 (m, 2H), 2.78-2.81 (m, 2H), 3.13- 3.19 (m, 3H), 3.28-3.31 (m, 1H), 3.45-3.51 (m, 1H), 3.71 (m, 4H), 4.09 (m, 1H), 4.684.71 (m, 2H), 4.76-4.79 (m, 3H), 6.42 (s, 1H), 7.16-7.23 (m, 4H), 7.28-7.36 (m, 1H), 7.64 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 507.15 (M+H)+, 100%. Example-168 :tert-butyl 4-(3-(3-hydroxyoxetan-3-yl)-5-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)piperazine-1-carboxylate
Figure imgf000145_0001
1H NMR (CDCl3) δ: 1.57 (s, 9H), 2.00 (m, 2H), 2.14 (m, 2H), 3.15-3.19 (m, 6H), 3.51- 3.53 (m, 3H), 3.59-3.62 (m, 4H), 4.61 (m, 1H), 4.89-4.95 (m, 4H), 6.49 (s, 1H), 6.69 (s, 1H), 6.76 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H); ESI-MS: m/z 578.25 (M+H)+, 100%. Example-169 : (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000145_0002
1H NMR (CDCl3) δ: 1.64-1.73 (m, 2H), 1.85-2.06 (m, 2H), 2.86-2.89 (m, 2H), 3.06-3.09 (m, 4H), 3.18-3.26 (m, 4H), 3.41-3.47 (m, 2H), 4.12 (m, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.77 (d, J = 6.8 Hz, 3H), 6.45 (s, 1H), 7.16-7.29 (m, 4H), 7.35 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H); ESI-MS: m/z, 506.17 (M+H) +, 100%. Example-170 :(4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone
Figure imgf000145_0003
1H NMR (DMSO-d6) δ: 1.45-1.48 (m, 2H), 1.91-1.93 (m, 1H), 2.49-2.50 (m, 4H), 3.70- 3.80 (m, 3H), 3.02-3.06 (m, 4H), 3.33-3.40 (m, 4H), 4.70-4.78 (m, 4H), 4.98-5.01 (m, 1H), 6.43 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.57-7.66 (m, 1H), 7.72 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.92 (s, 1H); ESI-MS: m/z 532.5 (M+H)+, 100%. Example-171 : (4-(1-hydroxycyclobutyl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000146_0001
1H NMR (DMSO-d6) δ: 1.64-1.70 (m ,2H), 1.90-1.99 (m, 4H), 2.24-2.31 (m, 2H), 2.36- 2.43 (m, 2H), 3.33-3.40 (m, 2H), 3.58 (m, 1H), 3.95-4.10 (m, 1H), 4.79-4.81 (m, 1H), 5.58 (s, -OH), 7.18 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 520.17 (M+H)+, 100%. Example-172 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)benzyl)piperazin-1-yl)methanone
Figure imgf000146_0002
1H NMR (CDCl3) δ: 2.34-2.40 (m, 2H), 2.57-2.62 (m, 2H), 3..08 (s, 1H), 3.46-3.54 (m, 2H), 3.60 (s, 2H), 3.81-3.85 (m, 2H), 4.86 (d, J = 7.2 Hz, 2H), 4.94 (d, J = 7.2 Hz, 2H), 7.41-7.48 (m, 3H), 7.52-7.56 (m, 2H), 7.59-7.66 (m, 3H); ESI-MS: m/z, 421.17 (M+H) +, 100%. Example-173 : 1-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-3-(4- (trifluoromethyl)phenyl)urea
Figure imgf000146_0003
1H NMR (DMSO-d6) δ: 1.351.39 (m, 2H), 1.83-1.88 (m, 2H), 3.07-3.18 (m, 2H), 3.55- 3.58 (m, 1H), 3.76-3.78 (m, 1H), 4.284.32 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.44 (d, J = 6.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.55-7.60 (m, 4H), 7.68 (d, J = 8.4 Hz, 2H), 8.91 (s, 1H).; ESI-MS: m/z, 464.16 (M+H) +, 100%. Example-174 : 4-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4- (trifluoromethyl)phenyl)piperazine-1-carboxamide
Figure imgf000147_0001
1H NMR (DMSO-d6) δ: 3.35-3.67 (m, 8H), 4.70 (d, J = 6.8 Hz, 2H), 4.80 (d, J = 6.8 Hz, 2H), 6.47 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.67-7.71 (m, 4H), 9.01 (s, 1H); ESI-MS: m/z, 450.15 (M+H) +, 100%. Example-175 : tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)phenyl)azetidine-1-carboxylate
Figure imgf000147_0002
1H NMR (DMSO-d6) δ: 1.43 (s, 9H), 1.60-1.66 (m, 2H), 1.96-2.02 (m, 2H), 3.40-3.45 (m, 1H), 3.56-3.68 (m, 2H), 4.03-4.09 (m, 5H), 4.78-4.82 (m, 1H), 6.44 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 521.23 (M+H)+, 15%. Example-176 : tert-butyl 3-methoxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)phenyl)azetidine-1-carboxylate
Figure imgf000147_0003
1H NMR (DMSO-d6) δ: 1.39 (s, 9H), 1.64-1.68 (m, 2H), 1.97-2.01 (m, 2H), 3.00 (s, 3H), 3.34-3.45 (m, 3H), 3.95-4.10 (m, 5H), 4.78-4.81 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.46- 7.48 (m, 4H), 7.64 (d, J = 8.8 Hz, 2H). Example-177 : (4-(3-methoxyazetidin-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone hydrochloride
Figure imgf000147_0004
1H NMR (DMSO-d6) δ: 1.64-1.68 (m, 2H), 1.98-2.04 (m, 2H), 3.00 (s, 3H), 3.35-3.42 (m, 3H), 3.95-4.01 (m, 1H), 4.11-4.20 (m, 2H), 4.29-4.33 (m, 2H), 4.79-4.83 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.47-7.55 (m, 4H), 7.64 (d, J = 8.4 Hz, 2H), 9.55 (brs, 1H), 9.77 (brs, 1H); ESI-MS: m/z 435.19 (M+H)+, 50%. Example-178 : (4-(3-hydroxythietan-3-yl)phenyl)(4-(3- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone
Figure imgf000148_0001
1H NMR (DMSO-d6) δ: 1.61-1.65 (m, 2H), 1.97-2.00 (m, 2H), 3.33-3.39 (m, 3H), 3.46- 3.50 (m, 1H), 3.59-3.67 (m, 3H), 3.94-3.98 (m, 1H), 4.76-4.79 (m, 1H), 6.49 (s, 1H), 7.28 (d, J = 6.4 Hz, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.50-7.54 (m, 1H), 7.76 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 438.12 (M+H)+, 100%. Example-179 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperazin-1-yl)methanone
Figure imgf000148_0002
1H NMR (CDCl3) δ: 2.34-2.41 (m, 2H), 2.51-2.57 (m, 2H), 2.82 (s, 1H), 3.45-3.55 (m, 2H), 3.61 (s, 2H), 3.79-3.83 (m, 2H), 4.88 (d, J = 7.2 Hz, 2H), 4.93 (d, J = 7.6 Hz, 2H), 7.31 (s, 1H), 7.35-7.37 (m, 3H), 7.60 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H); ESI- MS: m/z 421.14 (M+H)+, 100%. Example-180 : (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000148_0003
1H NMR (DMSO-d6) δ: 1.16-1.23 (m, 2H), 1.50-1.64 (m, 2H), 1.81-1.86 (m, 1H), 2.65 (d, J = 6.4 Hz, 2H), 2.68-2.72 (m, 1H), 2.96-2.99 (m, 1H), 3.55-3.59 (m, 1H), 4.43-4.47 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 6.44 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.51-7.55 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H); ESI-MS: m/z 420.16 (M+H)+, 100%. Example-181 : (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)benzyl)piperidin-1-yl)methanone
Figure imgf000149_0001
1H NMR (CDCl3) δ: 1.15-1.30 (m, 2H), 1.56-1.59 (m, 1H), 1.80-1.87 (m, 2H), 2.63-2.68 (m, 2H), 2.732.78 (m, 1H), 2.85-3.02 (m, 2H), 3.713.75 (m, 1H), 4.71-4.76 (m, 1H), 4.87 (d, J = 7.2 Hz, 2H), 4.92 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.41-7.50 (m, 4H), 7.65 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H); ESI-MS: m/z 420.14 (M+H)+, 100%. Example-182 : N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-(3- (trifluoromethyl)benzyl)piperidine-1-carboxamide
Figure imgf000149_0002
1H NMR (DMSO-d6) δ: 1.09-1.18 (m, 2H), 1.55-1.58 (m, 2H), 1.74-1.79 (m, 1H), 2.65 (d, J = 7.2 Hz, 2H), 2.73 (t, J = 12.0 Hz, 2H), 2.97 (s, 3H), 4.084.12 (m, 2H), 4.71-4.75 (m, 4H), 7.26 (d, J = 7.2 Hz, 2H), 7.49-7.57 (m, 6H), 8.54 (s, 1H); ESI-MS: m/z 449.19 (M+H)+, 100%. Example-183 : (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3- (trifluoromethyl)benzyl)piperazin-1-yl)methanone
Figure imgf000149_0003
1H NMR (DMSO-d6) δ: 2.34-2.40 (m, 4H), 3.04 (s, 3H), 3.46-3.54 (m, 4H), 3.62 (s, 2H), 4.75 (d, J = 7.2 Hz, 2H), 4.79 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.56-7.66 (m, 4H); ESI-MS: m/z 435.17 (M+H)+, 100%. Example-184 : 4-(3-hydroxyoxetan-3-yl)-N-((1r,4r)-4-(4- (trifluoromethyl)phenoxy)cyclohexyl)benzamide
Figure imgf000150_0001
1H NMR (DMSO-d6) δ: 1.48-1.57 (m, 4H), 1.92-1.95 (m, 2H), 2.13-2.15 (m, 2H), 3.83- 3.86 (m, 1H), 4.39-4.47 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 6.48 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 7.6 Hz, 1H); ESI-MS: m/z 436.15 (M+H)+, 100%. Example-185 : (4-(4-hydroxypiperidin-4-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone hydrochloride
Figure imgf000150_0002
1H NMR (DMSO-d6) δ: 1.35-1.37 (m, 2H), 1.78-1.80 (m, 2H), 1.99-2.01 (m, 2H), 2.22- 2.25 (m, 2H), 3.07-3.19 (m, 6H), 3.37-3.39 (m, 2H), 3.61-3.63 (m, 1H), 5.76 (s, 1H), 6.73 (d, J = 8.4 Hz, 2H), 7.36-7.41 (m, 4H), 7.52 (d, J = 8.0 Hz, 2H), 8.97 (s, 1H), 9.17 (s, 1H); ESI-MS: m/z 448.15 (M+H)+, 100%. The following compounds can be prepared by procedure similar to those described above with appropriate variations of reactions, reaction conditions and quantities of reagents. (4-(3-hydroxyoxetan-3-yl)phenyl)(3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)ethyl)piperazin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone; (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)(4-(3- hydroxyoxetan-3-yl)phenyl)methanone; 2-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidine-4-carbonitrile; 2-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)-5- (trifluoromethyl)pyrimidine-4-carbonitrile; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridazin-3- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((8-(trifluoromethyl)quinolin-4-yl)oxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((7-(trifluoromethyl)quinolin-4-yl)oxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3-(trifluoromethyl)quinolin-7-yl)oxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)naphthalen-1-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen- 1-yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)naphthalen-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(4-(trifluoromethyl)phenyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(4- (trifluoromethyl)phenoxy)phenyl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (3-fluoro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-3- carboxylic acid; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-methoxy-4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-3- carbonitrile; (3,3-difluoro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (3-chloro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyazetidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-morpholinophenoxy)piperidin-1-yl)methanone; (4-(4-((2S,6R)-2,6-dimethylmorpholino)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)phenoxy)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidine- 4-sulfonamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-(4-(trifluoromethyl)benzoyl)piperidine-4- sulfonamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4- yl)benzenesulfonamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)benzenesulfonamide; (4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)piperidin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3,5-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-3,4-dihydroquinolin- 1(2H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-6,7- dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)indolin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)-1H-indol-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-2-(4-(trifluoromethyl)phenoxy)pyrimidine-5- carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperazin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)methyl)piperazine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]oxazol-2- yl)oxy)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]oxazol-2- yl)oxy)piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzofuran-2-yl)oxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzofuran-2- yl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[b]thiophen-2- yl)oxy)piperidin-1-yl)methanone; (4-fluoro-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-methyl-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)-4-(4- (trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)oxy)-4- (4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- sulfonamide; 1-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-3-(4- (trifluoromethyl)phenyl)sulfonylurea; 1-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)urea; 1-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4- yl)sulfonylurea; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(2-methoxyethoxy)-4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-(2-methoxyethoxy)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone (4-(3-(2-(methylsulfonyl)ethoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3,3-difluoro-1-hydroxycyclobutyl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; 3-(3-(morpholinosulfonyl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4-(trifluoromethyl)phenyl)sulfonyl)-3,5- dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4- (trifluoromethyl)phenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4-(trifluoromethyl)phenoxy)-3,4,5,6- tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; The compounds of the present invention are useful in lowering LDL. This was demonstrated by in vitro as well as in vivo animal experiments as provided below: BODIPY-LDL uptake assay in HepG2 cells. An established assay for PCSK9 inhibition features uptake of fluorescently labeled LDL nanoparticles (BODIPY-LDL) by hepatocytes and uptake of the BODIPY-containing particles is maximized in the absence of PCSK9. In the LDL uptake assay, HepG2 cells were seeded at a density of 6x104 cells/well in a 96-well plate. After 24 h, the test compounds at various concentrations were pre-incubated with 5μg/ml PCSK9 in 0.2% DMSO for 60 min prior to the addition on to the cells. After 16h the medium was removed and 1μg/ml BODIPY-LDL (Invitrogen) in serum free media was added and incubated for 5h. Then the cells were washed twice with 0.25% BSA in PBS. Then the fluorescence of the cells in PBS was measured using TECAN multimode reader (Excitation: 485nm and Emission: 520nm). The readings were taken in triplicate and the final values were normalized with the protein concentration from respective wells. The wells without test compound containing external PCSK9 is considered as zero uptake and the one without PCSK9 was considered as 100% uptake. The percentage increase in LDL uptake for the test compounds were calculated using these values. The results are presented in the tabl1 below. Table 1
Figure imgf000157_0001
Figure imgf000158_0001
LDL-C lowering activity- in high fat diet C57 mice The in-vivo LDL-c lowering for test compound was tested in C57 mice which were kept on high fat diet for 4 weeks and the blood was collected by retro-orbital sinus puncture method under light ether anesthesia on day 0 (pretreatment). Animal are grouped based on LDL-c levels, after that 7 days treatment with vehicle or test compound orally at a dose of 30 mpk dose once a day was given. On completion of treatment on day 7 of the treatment the blood was collected for LDL-c and TC levels measurement. The percent change in LDL-c and TC in test compound group Vs Vehicle group was calculated and presented ijn the table2 below Table 2
Figure imgf000159_0001
Pharmacokinetic studies: Pharmacokinetics of the test compounds was evaluated in rats/dogs. Animals were fasted for 16 hours with free access to water and food was supplied after 4 hours of administration of the test compound. Test substance was administered per oral as a homogenous suspension prepared in 1% tween 80 + 99% of 0.5% w/v Methyl cellulose in water at the dose of 3 mg/kg. Blood samples were withdrawn at various time intervals through retro-orbital plexus and collected into heparinized micro centrifuge tubes. Plasma was separated from collected blood by centrifugation at 4500 rpm for 10 min at 4°C and stored at -70oC until analysis using LC-MS/MS method. Pharmacokinetic parameters were calculated using Non-compartmental modelling of Phoenix (Certara) software. Table 3
Figure imgf000160_0001
PCSK9 protein expression Effect of test compounds on secreted PCSK9 protein was analyzed using ELISA. Human hepatocytic cells, HepG2s were plated at 6 X 104 density in multi-well tissue culture plates. After 24h, the culture media was removed and the media containing different concentrations of test compounds or DMSO as control was replaced and incubated at 37 oC with 5% CO2 for 24 h. At the end of the incubation time, the media supernatant was collected and PCSK9 protein was measured using the ELISA kit (R & D System kit DY3888). The procedure was used as per the directions given in the kit. The cells in the wells were washed and lysed with 0.1% Triton® X-100 and total protein was estimated using Bradford method. PCSK9 protein levels were normalized with the total protein concentration from respective wells. The modulation in PCSK9 protein with NCE treatment was represented as the ratio compared to the control DMSO. Table 4
Figure imgf000160_0002
In certain instances, it may be appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent. Several reasons can be attributed for using a combination therapy depending on the need of the patient. As an example, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Several such instances are well known to a skilled person and the use of combination therapy may be envisaged for all such situations. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. The pharmaceutical composition is prepared by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, i.e. the compounds of formula (I) according to this invention. In an embodiment of present invention there is provided a pharmaceutical composition comprising compound of formula (I) and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include those which are commonly used for formulation of such compounds as is known in the art and may be selected from diluents, bulking agents, binders, disintegrants and other necessary excipicients. The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. Specific, non- limiting examples of possible combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical. Specifically for the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta. agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents. For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin and like), cholesterol- lowering drugs (for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as Ezetimibe, eflucimibe etc. In another embodiment of the present invention, use of compound of formula (I), their tautomeric form, their pharmaceutically acceptable salts or their pharmaceutical composition in the medicament for treating hyperlipidemia and related diseases is disclosed. The compounds of the invention also have beneficial effect in cholesterol lowering. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Such different embodiments are also to be considered to be within the scope of the present invention.

Claims

We claim: 1. Compounds of general formula (I)
Figure imgf000163_0001
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein ‘A’ is selected from an optionally substituted single or fused group selected from aryl or heteroaryl groups; ‘Y’ is either a bond, or selected from (C1-C3)alkyl, -S(O)o-, -C(O)-, -C(O)N(R5)-, N(R5)C(O)-, -N(R5)-, -N(R5)S(O)2N(R5)-, -N(R5)C(O)N(R5)-, -S(O)2N(R5)-, -N(R5)S(O)2- ; ‘Z’ is selected from –O-, -S(O)o-, -C(O)-, -N(R5)-, -(C(R5)2)p-, -O(C(R5)2)p-, - (C(R5)2)pO-,-O(C(R5)2)pO-, -S(O)o(C(R5)2)p-, -(C(R5)2)pS(O)o-, -S(O)o(C(R5)2)pS(O)o-; - N(R5)(C(R5)2)p-, -(C(R5)2)pN(R5)-, -N(R5)(C(R5)2)pN(R5)-, -NHC(O)-, -C(O)NH-, - NHC(O)NH-,-NHS(O)2NH-, -NHS(O)2-, -S(O)2NH- or
Figure imgf000163_0002
; ‘Q’ selected form O, C(R5)2, NR6 or S(O)o; wherein R6 is selected from H, (C1- C6)alkyl, (C3-C6)cycloalkyl, -C(O)OR5, -C(O)R5,-C(O)NH2; ‘o’ is an integer selected from 0-2; ‘m, n and p’ independently represent an integer selected from 0-4; ‘Cy’ is a saturated or partially unsaturated or unsaturated, monocyclic, bicyclic or spirocyclic groups containing 0-4 heteroatoms selected from O, N or S; ‘X’ at each occurrence independently selected from either Carbon atom or Nitrogen atom; R1 at each occurance is selected from halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, haloalkylsulfonyl, perhaloalkylsulfonyl, hydroxyl, sulfonic acid and its derivatives; R2 is selected from hydrogen, or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, cycloalkyl, aryl, aralkyl, heterocylyl, heterocyclylalkyl, heterocyclylalkoxyacyl, Acyl, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfonyl; Each of R3 and R4 at each occurance independently selected from hydrogen, halo, cyano, hydroxy or substituted or unsubstituted groups selected from alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfonyl, hydroxyl, sulfonic acid and its derivatives; R5 at each occurrence independently selected from H, (C1-C6)alkyl or (C3- C6)cycloalkyl.
2. The compound as claimed in claim 1 wherein A is optionally substituted phenyl, pyridine, thiophene, pyrimidine, benzo[d]thiazole and quinolone groups, preferably optionally substituted phenyl and benzo[d]thiazole group.
3. The compound as claimed in claim 1 wherein ‘Y’ is selected from –C(O)-, -S(O)o- , -(C1-C3)alkyl-, -C(O)N(R5)-, -N(R5)-, -C(O)CH(R5)2-; preferably ‘Y’ is -C(O)- and -C(O)N(R5)2- wherein R5 is as defined in claim 1.
4. The compound as claimed in claim 1 wherein ‘Z’ is selected from –O-, -S(O)o-, - C(O)-, -N(R5)-, -(C(R5)2)p-, -O(C(R5)2)p-, -O(C(R5)2)pO-, S(O)o(C(R5)2)p-, - S(O)o(C(R5)2)pS(O)o-; -N(R5)(C(R5)2)p-, -NHC(O)-, -NHC(O)NH-, or
Figure imgf000164_0001
, preferably selected from –O-, -S(O)o-, -N(R5)-, -(C(R5)2)p-, -O(C(R5)2)p-, or
Figure imgf000164_0002
, wherein R5 is as defined in claim 1. 5. The compound as claimed in claim 1 wherein compound is selected from: (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- ((trifluoromethyl)sulfonyl)phenoxy)piperidin-1-yl)methanone; 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzoic acid; N-cyclopropyl-4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)benzamide; (4-(3-methoxypyrrolidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxypyrrolidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4- (trifluoromethyl)benzyl)piperidin-1-yl)methanone; 3-(4-((1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4- yl)amino)phenyl)oxetan-3-ol; 3-(4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)sulfonyl)phenyl)oxetan-3-ol; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfonyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)sulfinyl)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperidin-1-yl)methanone; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4- carboxylic acid; N-(3-(3-hydroxyoxetan-3-yl)-5-morpholinophenyl)-4-(4- (trifluoromethyl)phenoxy) piperidine-1-carboxamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1- yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-([1,1'-biphenyl]-4-yloxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((2'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-isopropylphenoxy)piperidin-1- yl)methanone; (4-(2-chloro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(4-(1H-imidazol-1-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4- yl)oxy)phenyl)(morpholino)methanone; 4-((1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)oxy)benzonitrile; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(2-phenylpropan-2-yl)phenoxy)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-phenoxyphenoxy)piperidin-1- yl)methanone; (4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-methoxyphenoxy)piperidin-1- yl)methanone; (4-(4-(2H-tetrazol-5-yl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenoxy)methyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperazin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-((trifluoromethyl)thio)phenoxy)piperidin- 1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-((trifluoromethyl)thio)phenoxy)piperidin- 1-yl)methanone; (4-(3-(methoxy-d3)oxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (4-(3-((tetrahydro-2H-pyran-4-yl)methoxy)oxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-isobutoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)(4- (trifluoromethyl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(6-(4-(trifluoromethyl)phenoxy)-2- azaspiro[3.3]heptan-2-yl)methanone; (4-(4-hydroxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride; (4-(4-methoxypiperidin-4-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone hydrochloride; tert-butyl 4-hydroxy-4-(4-(5-(4- (trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2- carbonyl)phenyl)piperidine-1-carboxylate; (4-(4-(3-methoxyoxetan-3-yl)benzoyl)piperazin-1-yl)(4- (trifluoromethyl)phenyl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(2-(4-(trifluoromethyl)phenoxy)-7- azaspiro[3.5]nonan-7-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(methylthio)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; N-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-4- (trifluoromethyl)benzenesulfonamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)thiophen-3- yl)oxy)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)amino)piperidin-1-yl)methanone; (4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3,
5-dimethoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)amino)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((3- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((3- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone; (2-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (4-(4-(difluoromethyl)phenoxy)piperidin-1-yl)(4-(3-hydroxyoxetan-3- yl)phenyl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)azepan-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-thiomorpholinophenoxy)piperidin-1- yl)methanone; (4-(3-hydroxytetrahydrofuran-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)methanone; (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(4-(4-(trifluoromethyl)phenoxy)piperidin- 1-yl)methanone; (5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)azetidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)azetidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octan-8-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone; 4-(3-hydroxyoxetan-3-yl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; 4-(3-hydroxyoxetan-3-yl)-N-(1-(2-(trifluoromethyl)benzyl)pyrrolidin-3- yl)benzamide; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)benzyl)amino)piperidin- 1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(methyl(4- (trifluoromethyl)benzyl)amino)piperidin-1-yl)methanone; 2-(4-(3-hydroxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one; 2-(4-(3-methoxyoxetan-3-yl)phenyl)-2-methyl-1-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)propan-1-one; (3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (3-fluoro-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-3-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)pyrrolidine-1-carboxylate; (4-(3-hydroxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-2-methylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (3-methoxy-4-(3-methoxyoxetan-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)-2,6-dimethylphenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 4-hydroxy-4-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)piperidine-1-carboxylate; (4-(4-hydroxypiperidin-4-yl) phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin- 1-yl) methanone hydrochloride; 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)phenyl)oxetan-3-yl acetate; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)thio)piperidin-1- yl)methanon; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-((4-(trifluoromethyl)phenyl)thio)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzylidene)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methanone; (3-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(5-(4- (trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethoxy)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethoxy)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxy-1,1-dioxidothietan-3-yl)phenyl)(4-(4-(trifluoromethyl) phenoxy) piperidin-1-yl) methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (4-(3-hydroxythietan-3-yl)phenyl)(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)piperidin-1-yl)methanone; (4-(3-hydroxytetrahydrothiophen-3-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(4- (trifluoromethyl)phenoxy)propoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethoxy)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-(4- (trifluoromethyl)phenoxy)ethyl)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(2-((5-(trifluoromethyl)pyridin-2- yl)oxy)ethyl)piperidin-1-yl)methanone; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)pyridin-3- yl)oxy)piperidine-1-carboxamide; N-(3-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-3-(4-(trifluoromethyl)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-(4-(trifluoromethyl)phenoxy)piperidine-1- carboxamide; 4-(2-chloro-4-(trifluoromethyl)phenoxy)-N-(4-(3-hydroxyoxetan-3- yl)phenyl)piperidine-1-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidine-1-carboxamide; N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-((6-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)piperidine-1-carboxamide; 1-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4-(trifluoromethyl)phenyl)piperidine-4- carboxamide; N-(4-(3-hydroxyoxetan-3-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4- carboxamide; 4-(3-hydroxyoxetan-3-yl)-N-(6-(3-(trifluoromethyl)phenoxy)pyridin-3- yl)benzamide; N-(4-(3-methoxyoxetan-3-yl)phenyl)-6-(3- (trifluoromethyl)phenoxy)nicotinamide; 3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)oxetan-3-ol; 3-(3-morpholino-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)oxetan- 3-ol; (4-(3-hydroxyoxetan-3-yl)-2-morpholinophenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; tert-butyl 4-(3-(3-hydroxyoxetan-3-yl)-5-(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)piperazine-1-carboxylate; (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)methanone; (4-(3-hydroxyoxetan-3-yl)-2-(piperazin-1-yl)phenyl)(5-(4- (trifluoromethyl)phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone; 1-(1-(4-(3-hydroxyoxetan-3-yl)benzoyl)piperidin-4-yl)-3-(4- (trifluoromethyl)phenyl)urea; 4-(4-(3-hydroxyoxetan-3-yl)benzoyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1- carboxamide; tert-butyl 3-hydroxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)azetidine-1-carboxylate; tert-butyl 3-methoxy-3-(4-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)phenyl)azetidine-1-carboxylate; (4-(3-methoxyazetidin-3-yl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone hydrochloride; (4-(3-hydroxythietan-3-yl)phenyl)(4-(3-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(4-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; (3-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperidin-1- yl)methanone; N-(4-(3-methoxyoxetan-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)piperidine-1- carboxamide; (4-(3-methoxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone; 4-(3-hydroxyoxetan-3-yl)-N-((1r,4r)-4-(4- (trifluoromethyl)phenoxy)cyclohexyl)benzamide; (4-(4-hydroxypiperidin-4-yl)phenyl)(4-((4- (trifluoromethyl)phenyl)amino)piperidin-1-yl)methanone hydrochloride; (4-(1-hydroxycyclobutyl)phenyl)(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)methanone; (4-(3-hydroxyoxetan-3-yl)phenyl)(4-(3-(trifluoromethyl)benzyl)piperazin-1- yl)methanone.
6. A process for the preparation of compound of formula (I) as claimed in claim 1 comprising following steps:
Figure imgf000176_0001
Wherein all symbols are as defined in claim 1;wherein reagents for step (i) is a suitable Grignard reagent and for step (ii) 2,2-dimethyl-1,3-dioxan-5-one; suitable solvents for step (i) and step (ii) are selected from as tetrahydrofuran, diethylether or suitable mixtures thereof; suitable temperature for range for reaction is selected from -78 °C to 28 °C.
7. An intermediate of formula XXI
Figure imgf000176_0002
Wherein all symbols are as defined in claim 1.
8. The compound of formula XXI as claimed in claim 7 is (4-(4- (trifluoromethyl)phenoxy)piperidin-1-yl)(4-(1,2,3-trihydroxypropan-2- yl)phenyl)methanone.
9. A pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) as claimed in claim 1 and suitable pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising compounds of formula (I) as claimed in claim 9 in combination with one or more pharmaceutically active agents selected from group comprising insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP- 1 analogs, dipeptidyl peptidase IV(DPP-IV) inhibitors, GPR- 1 19 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta. agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti- platelet agents and anti-obesity agents or pharmaceutically acceptable salts thereof.
11. The use of compounds as claimed in claim 1 or pharmaceutical composition thereof for the treatment of hyperlipidemia, and other disorders related to hyperlipidemia.
12. Method of treating hyperlipidemia and disorders related to hyperlipidemia comprising the administering to a patient in need thereof therapeutically effective amount of a compound as claimed in claim 1 or pharmaceutical composition thereof.
PCT/IB2021/061988 2020-12-19 2021-12-18 Novel compounds suitable for the treatment of dyslipidemia Ceased WO2022130352A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029808A1 (en) * 2009-09-11 2011-03-17 F. Hoffmann-La Roche Ag Hsl inhibitors useful in the treatment of diabetes
WO2011142359A1 (en) * 2010-05-10 2011-11-17 日産化学工業株式会社 Spiro compound and drug for activating adiponectin receptor
WO2014192023A1 (en) * 2013-05-22 2014-12-04 Cadila Healthcare Limited Novel compounds suitable for the treatment of dyslipidemia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029808A1 (en) * 2009-09-11 2011-03-17 F. Hoffmann-La Roche Ag Hsl inhibitors useful in the treatment of diabetes
WO2011142359A1 (en) * 2010-05-10 2011-11-17 日産化学工業株式会社 Spiro compound and drug for activating adiponectin receptor
WO2014192023A1 (en) * 2013-05-22 2014-12-04 Cadila Healthcare Limited Novel compounds suitable for the treatment of dyslipidemia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY CAS; 14 August 2002 (2002-08-14), ANONYMOUS : "Benzoic acid, 3-[[3,4-dihydro-2-methyl-4-(phenylamino)-1(2H)- quinolinyl]carbonyl]- ", XP055951133, retrieved from STN Database accession no. RN 443910-67-6 *

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