WO2014002106A1 - Novel compounds for the treatment of dyslipidemia and related diseases - Google Patents

Novel compounds for the treatment of dyslipidemia and related diseases Download PDF

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Publication number
WO2014002106A1
WO2014002106A1 PCT/IN2012/000641 IN2012000641W WO2014002106A1 WO 2014002106 A1 WO2014002106 A1 WO 2014002106A1 IN 2012000641 W IN2012000641 W IN 2012000641W WO 2014002106 A1 WO2014002106 A1 WO 2014002106A1
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Prior art keywords
phenoxy
ethanone
methyl
phenyl
oxadiazol
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PCT/IN2012/000641
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French (fr)
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Harikishore Pingali
Vrajesh PANDYA
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Cadila Healthcare Limited
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Publication of WO2014002106A1 publication Critical patent/WO2014002106A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
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    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
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    • 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
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    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

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 to compounds suitable for the treatment of Disease conditions such as hyperlipidemia.
  • the compounds of the present invention also lower LDL-c.
  • the compounds of the general formula (I) lower or modulate cholesterol levels and/or low-density lipoproteins (LDL) and/or triglyceride levels and raises the high- density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) 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.
  • 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.
  • NIDDM non- insulin dependent diabetes mellitus
  • 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.
  • 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.
  • disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing
  • 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 (apoB lOO) 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 the pro-protein convertase subtilisin/kexin of the subtype 9 (PCSK 9) gene were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). Abifadel et al in 2003 discovered pro-protein convertase subtilisin/kexin of the subtype 9 as the third gene involved in autosomal dominant hypercholesterolaemia (ADH) (Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434).
  • ADH autosomal dominant hypercholesterolaemia
  • Pro-protein convertase subtilisin/kexin of the subtype 9 belongs to the subtilisin family of serine proteases and its protein structure consists of a pro-domain, catalytic domain, and cysteine/histidine rich C-terminal domain (Structure, 2007, 15, 545-552). Unlike other pro-protein convertases, wherein the pro-domain is further proteolytically processed to activate the serine protease, the pro-domain of secreted subtype remains intact and tightly bound.
  • this enzyme undergoes autocatalytic process which results in release of -14 kDa prodomain that remains associated with the catalytic/C -terminal domains, wherein the pro-domain serves as both a folding chaperon and as an inhibitor of enzymatic activity (Journal of Biological Chemistry, 2009, 284, 10561 -10570).
  • EGF-A epidermal growth factor-like repeat A
  • This EGF- A interaction site is located >20 A from the catalytic site of this pro-protein subtype.
  • EGF-A and this pro-protein subtype interacts they form a complex with the LDLR that enters endosomal pathway and hence LDLR recycling is prevented leading to LDLR degradation.
  • Detailed molecular mechanisms explaining the association of LDLR and this pro-protein subtype 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).
  • Small molecule inhibitors of this pro-protein subtype has its obvious clinical and therapeutic benefit over the other approaches as discussed above for the inhibition of pro-protein convertase subtilisin/kexin of the subtype 9.
  • Small molecule inhibitors of this subtype have been disclosed by us in our application nos. 3556 MUM/2010 & 2292/MUM/2009.
  • It is an important object of the present invention is to provide novel compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
  • 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.
  • process for treatment of diseases mediated by the pro-protein convertase subtilisin/kexin of the subtype 9 enzyme by providing therapeutically effective amount of the compounds of formula (I) or their pharmaceutically acceptable salts or their suitable pharmaceutical compositions.
  • ' ⁇ ', 'Z' and ' ⁇ ⁇ ' at each occurrence independently represent an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups;
  • each of 'X' or 'Z' or ' ⁇ ⁇ ' is independently selected from optionally substituted aryl or heterocyclyl groups;
  • aryl group may be selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups
  • the aryl group is an optionally substituted phenyl group.
  • the heterocyclyl group may be selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S;
  • the heterocyclyl group may be 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, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, nap
  • Ri, R 2j and R 3 at each occurrence independently represents H, (Ci-C 6 ) linear or branched alkyl, (C ! -C 6 ) linear or branched alkenyl, (Ci-C 6 ) linear or branched alkynyl, hydroxy, (Ci-C 6 ) alkoxy, (Ci-C 6 ) alkenoxy, hydroxy(Ci-C 6 )alkyl, alkoxyalkyl, haloalkyl, (C3-C6) cycloalkyl, thio(Cj-C6)alkyl, (Ci-C 6 )alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Ci-C 6 )alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, hetero
  • ⁇ ' independently represents integers from 0 to 5;
  • Z-U-X-Z A may together form tricyclic 8-15 membered fused ring system optionally containing from 1-4 hetero atoms selected from N, O or S(0) q ;
  • 'A' represents -NR4R5 or the group - ⁇ )( ⁇ 2 ) ⁇ ⁇ 7 ;
  • R4, R5, Re and R 7 at each occurrence independently represents H, (C1-C6) linear or branched alkyl, (Ci-C 6 ) linear or branched alkenyl, (Ci-C 6 ) linear or branched alkynyl, hydroxy, (Ci-C 6 ) alkoxy, (Ci-C 6 ) alkenoxy, hydroxy(Ci-C6)alkyl, alkoxyalkyl, haloalkyl, (C3-C 6 ) cycloalkyl, thio(Ci-C6)alkyl, (Ci-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Ci-C6)alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocycly
  • R4 and R 5 may form optionally substituted 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(0) q ;
  • 'q' represents integers from 0 to 2;
  • ⁇ ' represents either a bond, or O, S(0) q or NR 8 wherein R 8 represents H, (Ci- C 6 ) linear or branched alkyl, (C3-C 6 ) cycloalkyl, aryl, heterocyclyl groups;
  • 'W represents (Ci-Ce) linear or branched alkyl or (C3-C6) linear or branched cycloalkyl;
  • 'V represents O or S
  • 'U' represents either a bond, or O, S(0) q or NR 8 wherein R 8 represents H, (C C 6 ) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, heterocyclyl and 'p' represents integers from 0 to 2;
  • substituents may be selected from hydrogen, 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
  • radicals described above may be selected from:
  • alkyl used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, M-propyl, wo-propyl, w-butyl, ⁇ ec-butyl, tert-butyl, amyl, i-amyl, n-pentyl, n- hexyl, and the like;
  • alkenyl 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,
  • alkenyl includes dienes and trienes of straight and branched chains
  • cycloalkyl or "alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
  • cycloalkenyl 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,
  • bicycloalkenyl means more than one cycloalkenyl groups fused together;
  • alkoxy 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, wo-propoxy, «-butoxy, t-butoxy, «o-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;
  • haloalkyl is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, peril uoro(Ci-C6)alkyl such as fluoromethyl, difiuoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • perhaloalkyl more preferably, peril uoro(Ci-C6)alkyl such as fluoromethyl, difiuoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups
  • haloalkoxy 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;
  • 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;
  • 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 or tricyclic 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, thi
  • heterocycloxy is 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, wo-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
  • acyloxy 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, wo-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 CH 3 CONH, C 2 H 5 CONH, C3H 7 CONH, C 4 H 9 CONH, C 6 H 5 CONH 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 Ci- C 6 )alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, «-butylamine, «-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 (Ci-C 6 )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;
  • carboxylic acid used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides;
  • ester 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 "aminocarbonyl” group used either alone or in combination with other radicals may be selected from 'aminocarbonyl', 'aminocarbonylalkyl", "n- alkylaminocarbonyl", “N-arylaminocarbonyl”, “ ⁇ , ⁇ -dialkylaminocarbonyl”, “N- alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and "N-alkyl- N-hydroxyaminocarbonylalkyl", each of them being optionally substituted.
  • 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;
  • 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;
  • aminoalkyl 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;
  • alkoxyalkyl 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;
  • 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.
  • alkoxycarbonylamino 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 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;
  • heterocyclylthio denotes a 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-oxomorpholinyIthio, azepinylthio, diazepinylthio, oxapinylthio, thiazepinylthio, oxazolidinylthio, thiazolidiny
  • alkoxycarbonylamino 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;
  • dialkylaminocarbonylamino used alone or in combination with other radicals, is a carbonylamino (-CONH 2 ) group, attached to amino(NH 2 ), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above;
  • the "alkylamidino” group represents an alkyl radical, as described above, attached to an amidino group;
  • alkoxyamino used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group;
  • hydroxyamino 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 R x SO, where R x 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 -S0 2 -, or R x S0 2 -, where R x is 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 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.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in
  • administration encompasses coadministration 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. 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.
  • 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.
  • 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 may be selected from:
  • 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 The compounds of formula IV wherein R9 represents Ci-C 6 linear or branched alkyl or aralkyl groups and all other symbols are as defined earlier may be prepared by the nucleophilic substitution reaction of compound of general formula II and compounds of general formula III wherein 'L' represents suitable leaving group and all other symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K 2 C0 3 , Cs 2 C0 3 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • suitable inorganic base(s) such as NaOH, KOH, K 2 C0 3 , Cs 2 C0 3 and the like
  • organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • the reaction may be carried out neat or in presence of suitable protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • suitable protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • suitable protic solvent(s) such as methanol, ethanol, butanol and the like
  • 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 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Method B The compounds of formula IV wherein all the symbols are as defined earlier may be hydrolyzed to compound of formula V wherein all the symbols are as defined earlier using suitable base(s) e.g., NaOH, LiOH, KOH and the like.
  • Reaction may be conducted in suitable solvents e.g., alcohols like methanol, ethanol and the like, THF, water or the mixtures thereof.
  • suitable solvents e.g., alcohols like methanol, ethanol and the like, THF, water or the mixtures thereof.
  • the reaction may be carried out at a temperature in the range 20 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 24 hours.
  • Method C The compounds of formula (I) wherein all the symbols are as defined earlier may be prepared by coupling reaction ' of corresponding acids of general formula V wherein all the symbols are as defined earlier and amine of general formula VI wherein all the symbols are as defined earlier as described in scheme 1 under suitable conditions such as those generally described in Tetrahedron, 2005, 61(46), 10827- , 10852 ' with suitable modifications and alterations as are well known to a skilled person, The reaction may be carried out in presence of reagents(s) such as N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDCl) & 1- Hydroxybenzotriazole (HOBT), and the like.
  • reagents(s) such as N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDCl) & 1- Hydroxybenzotriazole (HOBT), and the like.
  • the reaction may be carried in suitable solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane and the like or mixtures thereof.
  • suitable solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane 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.
  • Method D The compounds of the formula la wherein 'V represents 'S' and all other symbols are as defined earlier may be prepared by reacting compounds of the formula I with reagents with elemental sulfur donating capacity or sulfur itself. The reactions may be carried out using suitable solvents and conditions as reported in literature. Preferred method for sulfur insertion is to treat compounds of formula I with Phosphorous pentasulfide or Lawesson's reagent( 2,4-bis(4-methoxyphenyl)- 1,3,2,4- dithiadiphosphetane-2,4-disulfide) in a solvents such as THF, toluene or pyridine etc. 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.
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
  • 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.
  • the compounds of the present invention can be used either alone or in combination with one or more therapeutic agents selected from insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, a pha- glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP- 1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 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.
  • therapeutic agents selected from insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, bigu
  • Step 1 ethyl 2-(4-(4-methyl-5-phenylisoxazol-3-yl)phenoxy)acetate
  • step 1 To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of methanol (10 ml), THF (30 ml) and H 2 0 (10 ml), lithium hydroxide (0.35 gm, 8.30 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with IN HC1. The solid seperated which was filtered, washed with water & dried over P 2 0 5 under vacuum to give 1.25 g of title product as pale brown solid.
  • Step 3 2-(4-(4-Methyl-5-phenylisoxazo!-3 -vDphenoxy)- 1 -morpholinoethanone
  • Step 1 Ethyl 2-(2-(4-(4-methyl-5-phenylisoxazol-S-yl)phenox )acetamido)acetate
  • step 2 To a solution of the product of step 1 (900 mg, 2.37 mmoles) in ethariol (10 ml), a solution of sodium hydroxide (189 mg, 4.74 mmoles) in water (5 ml) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with IN HC1. White solid seperated which was filtered and washed with water & dried over P 2 0 5 under vacuum to give 730 mg of title product
  • Step 3 2-( " 4-(4-Methyl-5-phenylisoxazol-3-yl ' )phenoxy ' )-N-(2-(4-methylpiperazin-l-yl ' )- 2-oxoethyl)acetamide
  • step 2 To a solution of the product of step 2 (300 mg, 0.81 mmoles) in DMF (2 mL), N-methylpiperizine (98 mg, 0.98 mmoles), HOBT (164 mg, 1.21 mmoles), EDCI (185 mg, 0.97 mmoles) and N-ethyl morpholine (306 ⁇ , 2.43 mmoles) were added and reaction mixture was srirred at 25 °C for 3 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted by ethyl acetate (20 ml x 3). The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by recrystalisation in 50 Ethyl acetate: Hexane (1:1) (20 ml) to yield 200 mg product as white solid.
  • the PCSK9-LDLR in vitro Binding Assay is a quantitative solid phase binding assay between PCSK9 and recombinant LDLR. Plates were pre-coated with a recombinant LDLR-AB domain, which binds PCSK9. Test compound at different concentration was added to the PCSK9 and added to LDLR immobilized on the wells.
  • the amount of bound PCSK9 is measured by binding it with biotinylated anti-His-tag monoclonal antibody, followed by binding with horseradish peroxidase conjugated streptavidin substrate. The colour was quantified by ELISA reader at 450 nM which reflects the relative amount of PCSK9 that binds to LDLR in presence and absence of the inhibitor.
  • the compounds of the present invention are suitable for the treatment and/or mitigation of obesity, hyperlipidaemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions in humans and animals.
  • the pharmaceutical compositions containing the compounds of the present invention optionally with another suitable pharmaceutical agent can comprise of one or more pharmaceutically acceptable excipients as is known in the art.
  • the formulation can be prepared by suitable techniques well known.
  • the formulation may be in the form of a tablet, capsule, caplet, satches etc. which are well known to a skilled person.
  • the doses may vary depending on the disease, gravity of the disease, risk profile of the user etc.

Abstract

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 to compounds suitable for the treatment of Disease conditions such as hyperlipidemia. The compounds of the present invention also lower LDL-c.

Description

NOVEL COMPOUNDS FOR THE TREATMENT OF DYSLIPIDEMIA AND RELATED DISEASES
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 to compounds suitable for the treatment of Disease conditions such as hyperlipidemia. The compounds of the present invention also lower LDL-c.
Figure imgf000002_0001
(R3)o
The compounds of the general formula (I) lower or modulate cholesterol levels and/or low-density lipoproteins (LDL) and/or triglyceride levels and raises the high- density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidaemia, 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 (apoB lOO) 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 the pro-protein convertase subtilisin/kexin of the subtype 9 (PCSK 9) gene were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). Abifadel et al in 2003 discovered pro-protein convertase subtilisin/kexin of the subtype 9 as the third gene involved in autosomal dominant hypercholesterolaemia (ADH) (Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434). Several mis sense 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).
Pro-protein convertase subtilisin/kexin of the subtype 9 belongs to the subtilisin family of serine proteases and its protein structure consists of a pro-domain, catalytic domain, and cysteine/histidine rich C-terminal domain (Structure, 2007, 15, 545-552). Unlike other pro-protein convertases, wherein the pro-domain is further proteolytically processed to activate the serine protease, the pro-domain of secreted subtype remains intact and tightly bound. Within endoplasmic reticulum this enzyme undergoes autocatalytic process which results in release of -14 kDa prodomain that remains associated with the catalytic/C -terminal domains, wherein the pro-domain serves as both a folding chaperon and as an inhibitor of enzymatic activity (Journal of Biological Chemistry, 2009, 284, 10561 -10570).
It is well documented that epidermal growth factor-like repeat A (EGF-A) of LDLR interacts with this pro-protein subtype mainly with residues 367-381. This EGF- A interaction site is located >20 A from the catalytic site of this pro-protein subtype. Once EGF-A and this pro-protein subtype interacts they form a complex with the LDLR that enters endosomal pathway and hence LDLR recycling is prevented leading to LDLR degradation. Detailed molecular mechanisms explaining the association of LDLR and this pro-protein subtype 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 pro-protein subtype 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 beeri reported in trying to inhibit this pro- protein subtype by using small molecules. Small molecule inhibitors of this pro-protein subtype has its obvious clinical and therapeutic benefit over the other approaches as discussed above for the inhibition of pro-protein convertase subtilisin/kexin of the subtype 9. Small molecule inhibitors of this subtype have been disclosed by us in our application nos. 3556 MUM/2010 & 2292/MUM/2009. We herein disclose novel small molecules which have shown to inhibit the pro-protein convertase subtilisin/kexin of the subtype 9 in in-vitro studies and therefore provides an alternate beneficial approach for treating patients in need of such therapy.
PREFERRED EMBODIMENTS OF THE INVENTION
It is an important object of the present invention is to provide novel compounds 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 compounds represented by the general formula (I), 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 a still further embodiment of the present invention is provided process for treatment of diseases mediated by the pro-protein convertase subtilisin/kexin of the subtype 9 enzyme 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 hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general formula (I),
Figure imgf000005_0001
'Χ', 'Z' and 'ΖΑ' at each occurrence independently represent an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups;
In a preferred embodiment, each of 'X' or 'Z' or 'ΖΑ' is independently selected from optionally substituted aryl or heterocyclyl groups;
In a further preferred embodiment when any of 'X' or 'Z' or 'ZA' represents an aryl group, the aryl group may be selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups;
In a still further preferred embodiment, the aryl group is an optionally substituted phenyl group.
In an embodiment, when any of 'X,' 'Z' 'ZA' represents a heterocyclyl group, the heterocyclyl group may be selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S;
In a preferred embodiment, the heterocyclyl group may be 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, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl and the like;
Ri, R2j and R3 at each occurrence independently represents H, (Ci-C6) linear or branched alkyl, (C!-C6) linear or branched alkenyl, (Ci-C6) linear or branched alkynyl, hydroxy, (Ci-C6) alkoxy, (Ci-C6) alkenoxy, hydroxy(Ci-C6)alkyl, alkoxyalkyl, haloalkyl, (C3-C6) cycloalkyl, thio(Cj-C6)alkyl, (Ci-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Ci-C6)alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted;
'm' 'n' and Ό' independently represents integers from 0 to 5;
In another embodiment, Z-U-X-ZA may together form tricyclic 8-15 membered fused ring system optionally containing from 1-4 hetero atoms selected from N, O or S(0)q;
'A' represents -NR4R5 or the group -Ν^)(ΟΗ2)ρΟΟΝ^7;
R4, R5, Re and R7 at each occurrence independently represents H, (C1-C6) linear or branched alkyl, (Ci-C6) linear or branched alkenyl, (Ci-C6) linear or branched alkynyl, hydroxy, (Ci-C6) alkoxy, (Ci-C6) alkenoxy, hydroxy(Ci-C6)alkyl, alkoxyalkyl, haloalkyl, (C3-C6) cycloalkyl, thio(Ci-C6)alkyl, (Ci-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Ci-C6)alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted with a provisio that — NR4R5 and either of R4 or R5 is H the other one does not represe
Figure imgf000007_0001
Alternatively R4 and R5 wherever possible, together may form optionally substituted 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(0)q;
'q' represents integers from 0 to 2;
Ύ' represents either a bond, or O, S(0)q or NR8 wherein R8 represents H, (Ci- C6) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, heterocyclyl groups;
'W represents (Ci-Ce) linear or branched alkyl or (C3-C6) linear or branched cycloalkyl;
'V represents O or S;
'U' represents either a bond, or O, S(0)q or NR8 wherein R8 represents H, (C C6) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, heterocyclyl and 'p' represents integers from 0 to 2;
When any of Ri, R2, R3> R4, R5, e, R7 or U are substituted, such substituents may be selected from hydrogen, 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, aminoalkyi, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, alkylsulfmyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfmyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfonic acid and its derivatives;
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, M-propyl, wo-propyl, w-butyl, ^ec-butyl, tert-butyl, amyl, i-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 six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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, wo-propoxy, «-butoxy, t-butoxy, «o-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, peril uoro(Ci-C6)alkyl such as fluoromethyl, difiuoromethyl, 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 or tricyclic 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, benzodihydrothiehyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, 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, 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, wo-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, wo-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 Ci- C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, «-butylamine, «-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 (Ci-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=0-) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=0-) 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=0), 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", "Ν,Ν-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 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 a 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-oxomorpholinyIthio, 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 -S02-, or RxS02-, 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 coadministration 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 may be selected from
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)-l-morpholinoethanone;
2-(4-(4-Methyl-5-phenyl isoxazol-3 -yl)phenoxy)-N-(2-(4-methylpiperazin- 1 -y l)-2- oxoethy l)acetam ide;
2-(4-(5-Methyl-4-phenylisoxazol-3-yl)phenoxy)-l-mp holinoethanone; 2-(4-(5-Methyl-4-phenylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; 2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; 1 -(4-Hydroxypiperidin- 1 -yl)-2-(4-(4-methyl-5-phenylisoxazol-3-yl)phenoxy)ethanone; 2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)-N-moφholinoacetamide;
2-(4-(4-Methyl-5-phenylisoxazoI-3-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone;
2-(4-(5-(4-Fluoro henyl)-4-methylisoxazol-3-yl)pheno y)-l-moφholinoethanone; 2-(4-(5-(4-Fluorophenyl)-4-methylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(5-(4-Chlorophenyl)-4-methylisoxazol-3-yl)phenoxy)- 1 -morpholinoethanone;
2-(4-(5-(4-Chlorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phertyl)isoxazol-3-yl)phenoxy)-l- mo holinoethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanone;
2-(4-(4-Methyl-5-(p-tolyl)iso azol-3-yl)phenoxy)-l-mo holinoethanone;
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; 2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-l-(piperidin-l-yl)ethanone;
2-(4-(4-Methyl-5-(p-tolyI)iso azol-3-yl)pheno y)-N-mo holinoacetamide;
2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -
Figure imgf000016_0001
2-(4-(5-Methoxy-l-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3-yl)phenoxy)-N-(4- methylpyrimidin-2-yl)acetamide;
N-( 1 ,3-Dimethyl- lH-pyrazol-5-yl)-2-(4-(5-methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H- pyrazol-3-yl)phenoxy)acetamide;
2-(4-( 1 -(4-Fluorophenyl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 - mo holinoethanone;
2-(4-( 1 -(4-Fluorophenyl)-5-methoxy- 1 H-pyrazol-3 -y l)phenoxy)- 1 -(4-methylpiperazin-
1- yl)ethanone;
Figure imgf000016_0002
2-(4-(5-Methoxy- 1 -phenyl- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(4-Methyl-2-phenylthiazoI-5-yl)phenoxy)- 1 -morphoHnoethanone;
2-(4-(4-Methyl-2-phenylthiazol-5-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; 2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l- mo hol inoethanone;
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l-(piperidin-l- yl)ethanone;
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-morpholinoethanone; 2-(4-(2-(4-Fluoropheny l)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-(piperidin-l-yl)ethanone;
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)-l-mo holinoethanone·,
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone;
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)-l-(4-methylpiperazin-l-yl)ethanone;
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l- moφholinoethanone;
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l-(piperidin-l- yl)ethanone;
2-(4-(5-Methyl-2-(pyridin-3-yl)oxazol-4-yl)phenoxy)-l -morphoHnoethanone;
1 -Mo holino-2-(4-(5-(4-(trifluorometh l)phenyl)- 1 ,2,4-oxadiazol-3- yl)phenoxy)ethanone;
2- (4-(5-(4-Fluorophenyl)-l,2,4-oxadiazol-3-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone;
3- (4-Fluorophenyl)-5-(4-(2-(4-methylpiperazin-l-yl)-2-oxoethoxy)phenyl)oxazolidin- 2-one;
2-(4-(3-(4-Fluorophenyl)-2-oxooxazolidin-5-yl)phenoxy)-N (4-methylpyrimidin-2- yl)acetamide; 3-(4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin-l-yl)-2- oxoethoxy)phenyl)oxazolidin-2-one;
3-(4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2- oxoethoxy)phenyl)oxazolidin-2-one;
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)ethanethioamide;
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)acetamide;
2-(4-(3-([l,l,-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N- (cyclohexylmethyl)acetamide;
N-(Byclohexylmethyl)-2-(4-(3-(2'-methyl-[ 1 , 1 '-biphenyl]-3-yl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide;
N-((3,6-Dihydro-2H-pyran-4-y Omethy l)-2-(4-(3-(4-(trifluoromethyl)phenyl)- 1,2,4- oxadiazol-5-yl)phenoxy)ethanethioamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3<p-tolyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide;
N-((3,4-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(p-tolyl)-l ,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide;
2-((4-(3-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenyl)thio)- 1 -(piperidin- 1 - yl)ethanethione;
2-(4-(3-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanethione;
2-(4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenoxy)-l-moφholinoethanethione; 1 -(4-Ethylpiperazin- 1 -yl)-2-(4-(3 -(4-fluorophenyl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)ethanethione;
l-(4-Benzylpiperazin-l-yl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethione;
8-(2-(4-(3-(4-(Trifluoromethyl)phenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)acetyl)- 1 -oxa- 3,8-diazaspiro[4.5]decan-2-one;
8-(2-(4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one; 8-(2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)-3-methyl-l-oxa- 3,8-diazaspiro[4.5]decan-2-one;
8-(2-(4-(3-([l,l'-Biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-(4-(3-([l, -Biphenyl]-4-yl)-2-oxooxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-(4-(2-Oxo-3- p-tolyl)oxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-(4-(2-Oxo-3-(4-(trifluoromethyl)phenyl)oxazolidin-5-yl)phenoxy)acetyl)-l-oxa- 3,8-diazaspiro[4.5]decan-2-one;
2-(4-(3-(2',4'-Dimethyl-[l,r-biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l- ηιο 1ιο1ίηοεΛ3ηοηε;
2-(4-(3 -(2',4'-Dimethyl-[ 1 , 1 '-biphenyl] -4-yl)-2-iminooxazolidin-5 -yl)phenoxy)- 1 -(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(3-([l, -Biphenyl]-4-yl)-2-iminooxazoIidin-5-yl)phenoxy)-l-(4-methylpiperazin-
1- yl)ethanone;
2- (4-(3-([l,r-Biphenyl]-4-yl)-?,-iminooxazolidin-5-yl)phenoxy)-l-(4-ethylpiperazin-l- yl)ethanone;
3- ([ 1 , 1 '-Biphenyl]-4-yl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2- oxoethoxy)phenyl)oxazoiidin-2-one;
3-([l,r-Biphenyl]-4-yl)-5-(4-(2-morpholino-2-oxoethoxy)phenyl)oxazolidin-2-one;
3-(2'-Methyl-[l, -bipheriyl]-4-yl)-5-(4-(2-morpholino-2-oxoethoxy)phenyl)oxazolidin-
2-one;
3^4^Dimethyl-[l , 1 '-biphenyl]-4-yl)-5-(4-(2-morpholino-2- oxoethoxy)phenyl)oxazolidin-2-one;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy-l-(4-methoxyphenyl)-lH- pyrazol-3-yl)phenyl)amino)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenyl)thio)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3-(4-(5-ethoxy-l-(4-methoxyphenyl)-lH- pyrazol-3-yl)phenyl)propanamide; N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3-(4-(5-ethoxy-l-(4-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)phenyl)propanamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-methoxy- 1 -(4- (trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy-l-(4-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy-l-(4-fluorophenyl)-lH- pyrazol-3-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenoxy)acetamide;
2-(4-(5-([ 1 , 1 '-Biphenyl]-4-yl)-4-methylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(l-([l,l'-Biphenyl]-4-yl)-5-methoxy-lH-pyrazol-3-yl)phenoxy)-l- morpholinoethanone;
2-(4-(l-(4'-Fluoro-[l, -biphenyl]-4-yl)-5-methoxy-lH-pyrazol-3-yl)phenoxy)-l- morpholinoethanone;
2-(4-(5 -Methoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol- - yl)phenoxy)-l-morpholinoethanone;
2-(4-(5 -Methoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- yl)phenoxy)- 1 -(4-methy Ipiperazin- 1 -y l)ethanone;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-(trifIuoromethyl)phenyl)-l,2,4- oxadiazol-5-yl)phenoxy)acetaimide;
N- iS^-Dihydro^H-pyran^-y methy ^^-iS^-fluoropheny -l^^-oxadiazol-S- yl)phenoxy)acetam ide ;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-methoxyphenyl)-l,2,4-oxadiazol-5- yl)phenoxy)acetam ide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-nitrophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)acetamide;
2-(4-(3-(4-Bromophenyl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,6-dihydro-2H-pyran-4- yl)methyl)acetamide;
l-(4-Methylpiperazin-l-yl)-2-(4-(3-(4'-(trifluoromethyl)-[l,l'-biphenyl]-4-yl)-l,2,4- oxadiazol-5-yl)phenoxy)ethanone; 1 -(4-(2-Hydroxyethyl)piperazin- 1 -y l)-2-(4-(3 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4- yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)ethanone;
2-(4-(3 -(4-Ethylphenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(4-(2- hydroxyethyl)piperazin-l-yl)ethanone;
2-(4-(3-(4-Ethylphenyl)-l,2,4-oxadiazol-5-yl)phenoxy)-l-(4-phenethylpiperazin-l- yl)ethanone;
2-(4-(2-([l,r-Biphenyl]-4-yI)-4-methylthiazol-5-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone;
2-(4-(2-([l, -Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)-l-mo holinoethanone; 2-(4-(2-([ 1 , Γ-Β iphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-ethylpiperazin- 1 - yl)ethanone;
2-(4-(2-([l, -Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)-l-(4-benzylpiperazin-l- yl)ethanone;
1 -(4-Benzylpiperazin- 1 -yl)-2-(4-(2-(4'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-4-methy lthiazol-5- yi)
phenoxy)ethanone;
1 -(4-Benzylpipefazin- 1 -yl)-2-((4-(2-(4'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-4-methylthiazol-5- y l)phenyl)am ino)ethanone ;
2-(4-(3-(Dibenzo[b,d]thiophen-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-l-(6- azaspiro[2.5 ] octan-6-yl)ethanone;
2-(4-(3 -([1,1 '-Biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5-y l)phenoxy)- 1 -(6-azaspiro[2.5]octan- 6-yl)ethanone;
2-(4-(3 -([1,1 '-Biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanone;
1- (Piperidin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)ethanone;
2- (4-(5-Ethoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5 ]octan-6-yl)ethanone;
2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyI)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(l -([1 , 1 '-Biphenyl]-4-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone; 2-(4-(l-(Dibenzo[b,d]thiophen-3-yl)-5-methoxy-lH-pyrazol-3-yl)phenoxy)-l-(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(5-Methoxy- 1 -(2'-methyl-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(5-Ethoxy-l-(4,-(trifluoromethyl)-[l, r-biphenyl]-4-yl)-l H-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -y l)ethanone;
2-(4-(5 -Ethoxy- 1 -(p-toly 1)- 1 H-pyrazol-3 -yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(5-Ethoxy- 1 -(p-tolyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-propylpiperazin-l - yl)ethanone;
2-(4-(5-Ethoxy-l-(p-tolyl)-lH-pyrazol-3-yl)phenoxy)-l-(4-(2-hydroxyethyl)piperazin-
1- yl)ethanone;
2- (4-(5 -Ethoxy- 1 -(4-(trifluoromethyl)pheny 1)- 1 H-pyrazol-3 -y l)phenoxy) - 1 -(4-(2- hydroxyethyl)piperazin- 1 -yl)ethanone.
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. Scheme: 1 The compounds of general formula (I) wherein all the symbols: are as defined earlier, may be prepared by reactions outlined in Scheme 1 below^ which comprises:
Figure imgf000023_0001
Compounds of general formula IV wherein R9 represents Ci-C6 linear or branched alkyl or aralkyl and all other symbols are as defined earlier may be prepared by coupling of compounds of general formula II wherein all the symbols are as defined earlier and compounds of general formula III whereas 'L' represents a suitable leaving group and R9 represents Q-C6 linear or branched alkyl or aralkyl, and all other symbols are as defined earlier using suitable base and suitable reaction medium by means of the methods available in the literature for standard nucleophilic substitution reaction;
Compounds of general formula V wherein all the symbols are as defined earlier may be prepared by the hydrolysis of compounds of general formula IV wherein all the symbols are as defined earlier under suitable condition;
m. Compounds of formula (I) wherein all the symbols are as defined earlier may be prepared by coupling of compounds of formula V wherein all symbols are as defined earlier and compounds of formula VI wherein all symbols are as defined using suitable methods available in the literature for standard peptide coupling; iv. Compounds of formula (la) wherein V represents S and all the symbols are as defined earlier may be prepared by thionation of compounds of formula (I) V represents O wherein all symbols are as defined earlier using suitable methods available in the literature for sulfur insertion;
Method A: The compounds of formula IV wherein R9 represents Ci-C6 linear or branched alkyl or aralkyl groups and all other symbols are as defined earlier may be prepared by the nucleophilic substitution reaction of compound of general formula II and compounds of general formula III wherein 'L' represents suitable leaving group and all other symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out neat or in presence of suitable protic solvent(s) such as methanol, ethanol, butanol and the like or 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 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
Method B: The compounds of formula IV wherein all the symbols are as defined earlier may be hydrolyzed to compound of formula V wherein all the symbols are as defined earlier using suitable base(s) e.g., NaOH, LiOH, KOH and the like. Reaction may be conducted in suitable solvents e.g., alcohols like methanol, ethanol and the like, THF, water or the mixtures thereof. The reaction may be carried out at a temperature in the range 20 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 24 hours.
Method C: The compounds of formula (I) wherein all the symbols are as defined earlier may be prepared by coupling reaction'of corresponding acids of general formula V wherein all the symbols are as defined earlier and amine of general formula VI wherein all the symbols are as defined earlier as described in scheme 1 under suitable conditions such as those generally described in Tetrahedron, 2005, 61(46), 10827- , 10852 ' with suitable modifications and alterations as are well known to a skilled person, The reaction may be carried out in presence of reagents(s) such as N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDCl) & 1- Hydroxybenzotriazole (HOBT), and the like. The reaction may be carried in suitable solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane 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.
Method D: The compounds of the formula la wherein 'V represents 'S' and all other symbols are as defined earlier may be prepared by reacting compounds of the formula I with reagents with elemental sulfur donating capacity or sulfur itself. The reactions may be carried out using suitable solvents and conditions as reported in literature. Preferred method for sulfur insertion is to treat compounds of formula I with Phosphorous pentasulfide or Lawesson's reagent( 2,4-bis(4-methoxyphenyl)- 1,3,2,4- dithiadiphosphetane-2,4-disulfide) in a solvents such as THF, toluene or pyridine etc. 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 pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
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.
The compounds of the present invention can be used either alone or in combination with one or more therapeutic agents selected from insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, a pha- glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP- 1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 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. The invention is explained in greater detail by the following working 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 A VANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCI3 using tetramethyl silane as the internal standard.
Example 1
2-(4-(.4-MethyI-5-phenylisoxazol-3-yl)phenoxy)-l -morpholinoethanone
Step 1: ethyl 2-(4-(4-methyl-5-phenylisoxazol-3-yl)phenoxy)acetate
To a solution of 4-(4-methyl-5-phenylisoxazol-3-yl)phenol (1.1 gm, 4.38 mmoles) in DMF (10 ml), K2C03 (1.2 gm, 5.26 mmoles) was added followed by the addition of ethyl chloro acetate (0.64 gm, 5.26 mmoles) at room temperature and the reaction mixture was stirred at room temperaturefor 18 hours. The reaction mixture was poured into ice cold water, solid seperated was filtered, washed with water and dried over P205 under vacuum to yield 1.4 gm of title product as off white solid.
'H NMR: 1.31 (t, J = 5.6 Hz, 3H), 2.31 (s, 3H), 4.27 (q, J= 7.1 Hz, 2H), 4.68 (s, 2H), 7.01-7.05 (m, 2H), 7.42-7.53 (m, 3H), 7.61-7.65 (m, 2H), 7.73-7.76 (m, 2H).
Yield: 94%
Step 2: 2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)acetic acid
To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of methanol (10 ml), THF (30 ml) and H20 (10 ml), lithium hydroxide (0.35 gm, 8.30 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with IN HC1. The solid seperated which was filtered, washed with water & dried over P205 under vacuum to give 1.25 g of title product as pale brown solid.
Ή NMR: 2.31 (s, 3H), 4.75 (s, 2H), 7.05-7.07 (m, 2H), 7.45-7.53 (m, 3H), 7.65 (dd, J = 7.0 & 2.2 Hz, 2H), 7.74-7.76 (m, 2H).
Yield: 97%
Step 3 : 2-(4-(4-Methyl-5-phenylisoxazo!-3 -vDphenoxy)- 1 -morpholinoethanone
To a solution of product of step 2 (500 mg, 1.62 mmoles) in DMF (3 mL), morpholine (147 mg, 1.70 mmoles), HOBT (328 mg, 2.43 mmoles), EDC.HC1 (335 mg, 1.94 mmoles) and N-ethyl morpholine (345 mg, 3.00 mmoles) were added and reaction mixture was srirred at room temperature for 20 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water, solid seperated was filtered, washed with water and dried over P2Os under vacuum to yield 428 mg of title product as pale yellow solid.
Ή NMR: 2.31 (s, 3H), 3.64-3.70 (m, 8H), 4.76 (s, 2H), 7.05-7.09 (m, 2H), 7.43-7.53 (m, 3H), 7;62-7.66 (m, 2H), 7.73-7.76 (m, 2H).
Yield: 70%
Example 2
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)-N-(2-(4-methylpiperazin-l-yl)-2- oxoethyl)acetamide
Step 1: Ethyl 2-(2-(4-(4-methyl-5-phenylisoxazol-S-yl)phenox )acetamido)acetate
To a solution of product of step 4 of example 1 (1.0 gm, 3.23 mmoles) in DMF (10 mL), glycine ethyl ester hydrochloride (473 mg, 3.39 mmoles), HOBT (654 mg, 4.84 mmoles), EDCI (668 mg, 3.87 mmoles) and N-ethyl morpholine (1.23 ml, 9.69 mmoles) were added and reaction mixture was srirred at 25 °C for 18 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted by ethyl acetate (20 ml x 3). The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure to yield 950 mg product as thick liquid.
Ή NMR: 2.31 (s, 3H), 3.79 (s, 3H), 4.16 (d, J= 5.2 Hz, 2H), 4.61 (s, 2H), 7.05-709 (m, 2H), 7.43-7.54 (m, 3H), 7.65-7.68 (m, 2H), 7.74-7.77 (m, 2H).
Yield: 75%
Step 2: 2-(2-(4-(4-methyl-5-phenylisoxazol-3-yl)phenoxy)acetamido)acetic acid
To a solution of the product of step 1 (900 mg, 2.37 mmoles) in ethariol (10 ml), a solution of sodium hydroxide (189 mg, 4.74 mmoles) in water (5 ml) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with IN HC1. White solid seperated which was filtered and washed with water & dried over P205 under vacuum to give 730 mg of title product
Ή NMR (DMSO- 5): 2.27 (s, 3H), 3.83 (d, J = 6.0 Hz, 2H), 4.63 (s, 2H), 7.14-7.18 (m, 2H), 7.52-7.62 (m, 3H), 7.64-7.67 (m, 2H), 7.76-7.78 (m, 2H), 7.44 (d, J = 5.8 Hz, NH). Yield: 84%
Step 3: 2-("4-(4-Methyl-5-phenylisoxazol-3-yl')phenoxy')-N-(2-(4-methylpiperazin-l-yl')- 2-oxoethyl)acetamide
To a solution of the product of step 2 (300 mg, 0.81 mmoles) in DMF (2 mL), N-methylpiperizine (98 mg, 0.98 mmoles), HOBT (164 mg, 1.21 mmoles), EDCI (185 mg, 0.97 mmoles) and N-ethyl morpholine (306 ί, 2.43 mmoles) were added and reaction mixture was srirred at 25 °C for 3 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted by ethyl acetate (20 ml x 3). The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by recrystalisation in 50 Ethyl acetate: Hexane (1:1) (20 ml) to yield 200 mg product as white solid.
Ή NMR (DMSO-flk): 2.21 (s, 3H), 2.27 (s, 3H), 2.30-2.35 (m, 4H), 3.43-3.46 (m, 4H), 4.03 (d, J= 5.2 Hz, 2H), 4.65 (s, 2H), 7.14-7.18 (m, 2H), 7.52-7.62 (m, 3H), 7.64-7.67 (m, 2H), 7.76-7.78 (m, 2H), 8.15 (t, J= 5.4 Hz, NH).
Yield: 55%
Example 3
2-(4-(5-Methyl-4-pheny 1 isoxazol-3 -yl)phenoxy)- 1 -morpholinoethanone
Ή NMR (DMSO-ik): 2.42 (s, 3H), 3.58-3.65 (m, 8H), 4.86 (s, 2H), 6.85-6.89 (m, 2H), 7.16-7.18 (m, 2H), 7.34-7.40 (m, 5H).
Example 4
2-(4-(5-Methyl-4-phenylisoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l-yl)ethanone Ή NMR (DMSO-ik): 2.16 (s, 3H), 2.23 (t, J= 4.4 Hz, 2H), 2.30 (t, J= 4.6 Hz, 2H), 2.39 (s, 3H), 3.40-3.41 (m, 4H), 4.82 (s, 2H), 6.88-6.91 (m, 2H), 7.19-7,27 (m, 4H), 7.34-7.43 (m, 3H).
Example s
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l-yl)ethanonel 'H NMR: 2.30 (s, 3H), 2.31 (s, 3H), 2.37-2.43 (m, 4H), 3.60-3.67 (m, 4H), 4.75 (s, 2H), 7.05-7.09 (m, 2H), 7.43-7.53 (m, 3H), 7.61-7.65 (m, 2H), 7.74-7.76 (m, 2H).
Example 6
1 -(4-Hydroxypiperidin- 1 -yl)-2-(4-(4-methyl-5-phenylisoxazol-3-yl)phenoxy)ethanone 'H NMR: 1.48-1.55 (m, 2H), 1.86-1.94 (m, 2H), 2.30 (s, 3H), 3.28-3.38 (m, 2H), 3.83- 3.88 (m, 1H), 3.94-4.06 (m, 2H), 4.76 (s, 2H), 7.05-7.09 (m, 2H), 7.43-7.53 (m, 3H), 7.61 -7.65 (m, 2H) , 7.73-7.76 (m, 2H).
Example 7
2-(4-(4- ethyl-5-phenylisoxazol-3-yl)pheno y)-N-mo holinoacetamide
!H NMR: 2.31 (s, 3H), 2.88-2.90 (m, 4H), 3.84-3.86 (m, 4H), 4.60 (s, 2H), 7.04-7.07 (rt, 2H), 7.29 (s, NH), 7.44-7.54 (m, 3H), 7.66-7.69 (m, 2H), 7.74-7.77 (m, 2H).
Example 8
2-(4-(4-Methyl-5-phenyl isoxazol-3 -yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone
Ή NMR: 1.60-1.68 (m, 6H), 2.31 (s, 3H), 3.50 (t, J= 5.2 Hz, 2H), 3.56 (t, J= 5.4 Hz,
2H), 4.75 (s, 2H), 7.06-7.10 (m, 2H), 7.43-7.53 (m, 3H), 7.61-7.64 (m, 2H), 7.74-7.76
(m, 2H).
Example 9
2-(4-(5-(4-FluoΓophenyl)-4-methyliso azol-3-yl)phenoxy)-l-mo holinoethanone Ή NMR: 2.28 (s, 3.H), 3.62-3.70 (m, 8H), 4.76 (s, 2H), 7.05-7.09 (m, 2H), 7.18-7.23 (m, 2H), 7.61-7.64 (m, 2H), 7.71-7.76 (m, 2H).
Example 10
2-(4-(5-(4-Fluorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone
lH NMR: 2.28 (s, 3H), 2.30 (s, 3H), 2.38-2.43 (m, 4H), 3.60-3.63 (m, 2H), 3.65-3.67 (m, 2H), 4.76 (s, 2H), 7.05-7.09 (m, 2H), 7.18-7.23 (m, 2H), 7.60-7.64 (m, 2H), 7.71- 7.76 (m, 2H).
Example 11
2-(4-(5-(4-Chlorophenyl)-4-methyliso azol-3-yl)pheno y)-l-mo holinoethanone Ή NMR (DMSO-<¾: 2.26 (s, 3H), 3.47 (br s, 4H), 3.58-3.63 (m, 4H), 4.94 (s, 2H), 7.09 (d, J= 6.8 Hz, 2H), 7.60-7.68 (m, 4H), 7.79 (d, J= 6.8 Hz, 2H).
Example 12
2-(4-(5-(4-Chlorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone
Ή NMR (DMSO-i/6): 2.19 (s, 3H), 2.26 (s, 4H), 2.31-2.35 (m, 3H), 3.46 (t, J= 5.0 Hz, 4H), 4.92 (s, 2H), 7.09 (d, J= 7.2 Hz, 2H), 7.60-7.67 (m, 4H), 7.80 (d, J= 6.8 Hz, 2H).
Example 13 2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l- morpholinoethanone
Ή NMR: 2.33 (s, 3H), 3.63-3.70 (m, 8H), 4.77 (s, 2H), 7.07-7.10 (m, 2H), 7.61-7.65 (m, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.0 Hz, 2H).
Example 14
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxaz l-3-yI)phenoxy)-l-(4- methy lpiperazin- 1 -yl)ethanone
Ή NMR: 2.30 (s, 3H), 2.33 (s, 3H), 2.38-2.43 (m, 4H), 3.60 (t, J= 5.0 Hz, 2H), 3.65 (t, J= 5.0 Hz, 2H), 4.76 (s, 2H), 7.07-7.11 (m, 2H), 7.60-7.64 (m, 2H), 7.76 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 8.0 Hz, 2H).
Example 15
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l-(piperidin-l- yl)ethanone
'H NMR: 1.57-1.68 (m, 6H), 2.33 (s, 3H), 3.50 (t, J= 5.2 Hz, 2H), 3.57 (t, J= 5.4 Hz, 2H), 4.76 (s, 2H), 7.07-7.11 (m, 2H), 7.60-7.63 (m, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.0 Hz, 2H).
Example 16
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)- 1 -morpholinoethanone
'.H NMR: 2.29 (s, 3H), 2.42 (s, 3H), 3.63-3.70 (m, 8H), 4.76 (s, 2H), 7.06-7.09 (m, 2H),
7.30 (d, J = 8.4 Hz, 2H), 7.61-7.65 (m, 4H).
Example 17
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-l-(4-methylpiperazin-l-yl)ethanone Ή NMR: 2.29 (s, 3H), 2.30 (s, 3H), 2.38-2.42 (m, 7H), 3.60 (t, J= 5.0 Hz, 2H), 3.65 (t, J= 5.2 Hz, 2H), 4.75 (s, 2H), 7.05-7.08 (m, 2H), 7.30 (d, J= 8.0 Hz, 2H), 7.61-7.65 (m, 4H).
Example 18
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone
Ή NMR: 1.53-1.67 (m, 6H), 2.29 (s, 3H), 2.42 (s, 3H), 3.49-3.59 (m, 4H), 4.74 (s, 2H),
7.05-7.09 (m, 2H), 7.30 (d, J= 8.0 Hz, 2H), 7.60-7.65 (m, 4H).
Example 19
2-(4-(4-Methyl-5-(p-tolyl)isoxazo^-3-yl) henoxy)-N-mo holinoacetamide
Ή NMR: 2.29 (s, 3H), 2.43 (s, 3H), 2.88 (t, J= 4.6 Hz, 4H), 3.84 (t, J= 4.6 Hz, 4H),
4.60 (s, 2H), 7.03-7.07 (m, 2H), 7.30-7.33 (m, 3H), 7.61-7.68 (m, 4H). Example 20
2-(4-(5 -Methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-y l)phenoxy)- 1 - morpholinoethanone
!H NMR (DMSO-i¾: 3.47 (bd, J= 5.2 Hz, 4H), 3.61 (bd, J = 4 Hz, 4H), 4.05 (s, 3H), 4.88 (s, 2H), 6.45 (s, IH), 7.00 (d, J = 9.2 Hz, 2H), 7.79 (dd, J= 7.2 & 2 Hz, 2H), 7.84 (d, J= 8.8 Hz, 2H), 8.01 (d, J= 8.8 Hz, 2H).
: Example 21
2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)-N-(4- methylpyrimidin-2-yl)acetamide
lH NMR (DMSO-i¾: 2.42 (s, 3H), 4.05 (s, 3H), 5.04 (s, 2H), 6.45 (s, IH), 7.00 (dd, J = 6.8 & 2 Hz, 2H), 7.08 (d, J= 5.2 Hz, IH), 7.79-7.83 (m, 2H), 7.84 (d, J= 8.8 Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H), 8.51 (d, J= 5.2 Hz, IH), 10.66 (s, IH)
Example 22
N-(l,3-Dimethyl-lH-pyrazol-5-yl)-2-(4-(5-methoxy-l-(4-(trifluoromethyl)phenyl)-lH- pyrazol-3 -y l)phenoxy)acetam ide
Ή NMR (DMSO-<¾): 2.09 (s, 3H), 3.55 (s, 3H), 4.06 (s, 3H), 4.80 (s, 2H), 5.98 (s, IH), 6.47 (s, IH), 7.07 (d, J= 8.8 Hz, 2H), 7.84 (dd, J= 8.8 & 3.6 Hz, 4H), 8.01 (d, J= 8.4 Hz, 2H), 10.09 (s, IH)
, Example 23
2-(4-(l -(4-Fluorophenyl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -morpholinoethanone 'H NMR (DMSO-i¾: 3.48 (d, J= 5.6 Hz, 4H), 3.61 (d, J= 18.0 Hz, 4H), 4.00 (s, 3H), 4.87 (s, 2H), 6.37 (s, IH), 7.00 (d, J= 8.8 Hz, 2H), 7.33 (t, J= 8.8 Hz, 2H), 7.72-7.77 (m, 4H),
Example 24
2-(4-(l -(4-Fluorophenyl)-5-methoxy- lH-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin-
1- yl)ethanone
'H NMR (DMSO-i¾: 2.19 (s, 3H), 2.34 (d, J= 4.4 Hz, 2H), 2.49-2.51 (m, 2H), 3.46 (s, 4H ), 4.00 (s, 3H ), 4.85 (s, 2H), 6.37 (s, IH), 6.95-6.99 (m, 2H), 7.30-7.35 (m, 2H), 7.72-7.77 (m, 4H),
Example 25
2- (4-(5 -Methoxy- 1 -phenyl- 1 H-pyrazol-3-yl)phenoxy)- 1 -morpholinoethanone Ή NMR (DMSC s):.3.47 (t, J= 5.2 Hz, 4H), 3,62 (d, J= 4.0 Hz, 4H), 4.00 (s, 3Η), 4.87 (s, 2H), 6.37 (s; 1H), 7.00 (d, J= 8.0 Hz, 2H), 7.31 (t, J= 7.4Hz, 1H), 7.48 (t, J= 7.8 Hz, 2H), 7.73 (d, J= 7.6 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H).
Example 26
2-(4-(5-Methoxy- 1 -phenyl- lH-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)cthanone
Ή NMR
Figure imgf000032_0001
2.19 (s, 3H), 2.33 (s, 2H), 2.34 (d, J= 4.4 Hz, 2H), 3.46 (s, 4H), 4.00 (s, 3H ), 4.85 (s, 2H ), 6.37 (s, 1H), 6.99 (d, J= 8.8 Hz, 2H), 7.31 (t, J= 7.2 Hz, 1H), 7.46-7.50 (m, 2H), 7.72 (d, J= 1.2 Hz, 2H), 7.73-7.77 (m, 2H).
Example 27
2-(4-(4-Methyl-2-phenylthiazol-5 -yl)phenoxy)- 1 -morpholinoethanone
Ή NMR (DMSO-i¼): 2.58 (s, 3H), 3.47-3.49 (m, 4H), 3.57-3.63 (m, 4H), 4.90 (s, 2H), 7.04 (d, J= 6.8 Hz, 2H), 7.46-7.52 (m, 3H), 7.66 (d, J= 6.8 Hz, 2H), 7.91 (d, J= 5.6 Hz, 2H).
Example 28
2-(4-(4-Methyl-2-phenylthiazol-5-yl)phenoxy)-l -(4-methylpiperazin^ l-yl)ethanone Ή NMR (DMSO-i¾: 2.20 (s, 3H), 2.28 (bs, 2H), 2.33 (bs, 2H), 2.58 (s, 3H), 3.47 (bs, 4H), 4.88 (s, 2H), 7.02 (d, J= 6.8 z, 2H), 7.46-7.52 (m, 3H), 7.66 (d, J= 6.8 Hz, 2H), 7.91 (d, J = 6.0 Hz, 2H).
Example 29
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l- morpholinoethanone
Ή NMR: 2.61 (s, 3H), 3.65-3.69 (m, 8H), 4.76 (s, 2H), 7.03-7.07 (m, 2H), 7.65-7.69 (m, 4H), 8.04 (d, J= 8.4 Hz, 2H).
Example 30
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanone
'i l NMR: 1.53-1.67 (m, 6H), 2.61 (s, 3H), 3.52 (t, J= 5.2 Hz, 2H), 2.58 (t, J= 5.4 Hz, 2H), 4.74 (s, 2H), 7.04-7.08 (m, 2H), 7.64-7.67 (m, 4H), 8.04 (d, J= 8.0 Hz, 2H).
Example 31
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l-(4- methy lpiperazin- 1 -y l)ethanone Ή NMR (DMSO-ak): 2.21 (s, 3H), 2.31 (bs, 2H), 2.38 (bs, 2H), 2.61 (s, 3H), 3.47 (bs, 4H), 4.89 (s, 2H), 7.03 (d, J= 8.8 z, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.86 (d, J= 8.0 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H).
Example 32
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-morpholinoethanone 'H NMR (DMSO-<¾: 2.54 (s, 3H), 3.46-3.49 (m, 4H), 3.58-3.62 (m, 4H), 4.90 (s, 2H), 7.03 (d, J= 8.8 z, 2H), 7.31-7.37 (m, 2H), 7.66 (d, J= 6.8 Hz, 2H), 7.94-7.99 (m, 2H).
Example 33
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-(4-methylpiperazin-l- yl)ethanone
'HNMR (DMSO-<¾): 2.21 (s, 3H), 2.30 (br s, 2H), 2.37 (br s, 2H), 2.54 (s,. 3H), 3.47 (br s, 4H), 4.88 (s, 2H), 7.02 (d, J= 6.8 z, 2H), 7.31-7.36 (m, 2H), 7.66 (d, J= 7.2 Hz, 2H), 7.94-7.98 (m, 2H).
Example 34
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-(piperidin-l-yl)ethanone 'HNMR (DMSO-<¾: 1.45 (br s, 2H), 1.56-1.59 (m, 4H), 2.57 (s, 3H), 3.43 (br s, 4H),
4.85 (s, 2H), 7.02 (d, J = 8.8 z, 2H), 7.33 (t, J= 8.8 Hz, 2H), 7.66 (d, J= 8.4 Hz, 2H), 7.95 (d, /= 8.0 Hz, 2H).
Example 35
2-(4-(5-MethyI-2-phenyloxazol-4-yl)phenoxy)- 1 -morpholinoethanone
Ή NMR (DMSO-< 6): 2.59 (s, 3H), 3.46-3.49 (m, 4H), 3.57-3.62 (m, 4H), 4.88 (s, 2H),
7.03 (d, J= 6.8 z, 2H), 7.51-7.56 (m, 3H), 7.65 (d, J= 6.8 Hz, 2H), 7.99 (d, J= 7.6 Hz,
2H).
Example 36
2-(4-(5-Methy l-2-phenyloxazol-4-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone
Ή NMR (DMSO-i¾: 1.44 (br s, 2H), 1.54-1.60 (m, 4H), 2.59 (s, 3H), 3.43 (m, 4H), 4.84 (s, 2H), 7.02 (d, J= 6.8 z, 2H), 7.51-7.56 (m, 3H), 7.65 (d, J= 6.8 Hz, 2H), 7.99 (d, J= 8.4 Hz, 2H).
Example 37
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)-l-(4-methylpiperazin-l-yl)ethanone 'H NMR (DMSO-flk): 2.21 (s, 3H), 2.29-2.37 (m, 4H), 2.59 (s, 3H), 3.47 (br s, 4H),
4.86 (s, 2H), 7.02 (d, J= 6.8 z, 2H), 7.49-7.56 (m, 3H), 7.65 (d, J= 6.8 Hz, 2H), 7.99 (d, J= 7.6 Hz, 2H). Example 38
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)- 1 - morpholinoethanone
Ή NMR (DMSO-<¾: 2.62 (s, 3H), 3.46-3.49 (m, 4H), 3.58-3.62 (m, 4H), 4.89 (s, 2H), 7.04 (d, J= 6.8 z, 2H), 7.67 (d, J= 6.8 Hz, 2H), 7.91 (d, J= 8.4 Hz, 2H), 8.19 (d, J= 8.0 Hz, 2H).
Example 39
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone
Ή NMR (DMSO-i¾: 2.20 (s, 3H), 2.28-2.36 (m, 4H), 2.62 (s, 3H), 3.47 (br s, 4H), 4.87 (s, 2H), 7.03 (d, J= 6.8 z, 2H), 7.66 (d, J= 7.2 Hz, 2H), 7.91 (d, J= 8.4 Hz, 2H), 8.19 (d, J= 8.4 Hz, 2H)
Example 40
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanone
Ή NMR (DMSO-i 6): 1.44 (br s, 4H), 1.54-1.60 (m, 2H), 2.62 (s, 3H), 3.42 (br s, 4H), 4.85 (s, 2H), 7.03 (d, J= 6.8 z, 2H), 7.66 (d, J= 6.8 Hz, 2H), 7.91 (d, J= 8.4 Hz, 2H), 8.19 (d, J= 8.0 Hz, 2H).
Example 41
2-(4-(5-Methyl-2-(pyridin-3-yl)o azol-4-yl)pheno y)-l-mo holinoethano e
'H NMR: 2.61 (s, 3H), 3.46-3.49 (m, 4H), 3.56-3.62 (m, 4H), 4.89 (s, 2H), 7.03 (dd, J = 6.8 & 2.0 Hz, 2H), 7.56-7.59 (m, 1H), 7.65 (dd, J= 6.8 & 2.0 Hz, 2H), 8.31-8.34 (m, 1H), 8.69-8.70 (m, IH), 9.16 (d, J= 1.6 Hz, 1H).
Example 42
1 -Mo holino-2-(4-(5-(4-(trifluoromethyl)phenyl)- 1 ,2,4-oxadiazol-3- yl)phenoxy)ethanone
Ή NMR (OMSO-d6): 3.47 (s, 4H), 3.56-3.62 (m, 4H), 4.98 (s, 2H), 7.13 (d, J= 8.8 Hz, 2H), 8.02-8.05 (m, 4H), 8.38 (d, J= 8.8 Hz, 2H).
Example 43
2-(4-(5-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone lH NMR (DMSO-tfc): 2.19 (s, 3H), 2.27 (s, 2H), 2.32 (t, J= 1.8 Hz, 2Η), 3.46 (t, J = 5.0 Hz, 4H), 4.95 (s, 2Η), 7.10-7.13 (m, 2H), 7.49-7.54 (m, 2H), 7.99-8.03 (m, 2H), 8.23-8.27 (m, 2H).
Example 44
3-(4-Fluorophenyl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2-oxoethoxy)phenyl)oxazolidin- 2-one
Ή NMR (DMSO-cfe): 2.18 (s, 3H), 2.25 (s, 2H), 2.33 (s, 2H), 3.44 (t, J= 4.8 Hz, 4H), 4.02 (t, J = 8.6 Hz, 1H), 4.39 (t, J= 9.0 Hz, 1H), 4.85 (s, 2H), 5.67 (t, J= 8.2 Hz, 1H), 6.96 (d, J= 8.8 Hz, 2H), 7.22-7.27 (m, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.60-7.63 (m, 2H).
Example 45
2- (4-(3-(4-Fluorophenyl)-2-oxooxazolidin-5-yl)phenoxy)-N-(4-methylpyrimidin-2- yl)acetamide
1H NMR (DMSO-i/6): 2.41 (s, 3H), 4.02 (t, J = 8.6 Hz, 1H), 4.39 (t, J= 8.2 Hz, IH), 5.03 (s, 2H), 5.68 (t, J= 8.4 Hz, IH), 6.98 (d, j= 8.8 Hz, 2H), 7.07 (d, J= 4.8 Hz, IH), 7.22-7.27 (m, 2H), 7.44 (d, J= 8.8 Hz, 2H), 7.60-7.63 (m, 2H), 8.50 (d, J= 5.2 Hz, IH), 10.67 (s, IH).
Example 46
3- (4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin-l-yl)-2- oxoethoxy)phenyl)oxazolidin-2-one
Ή NMR (DMSO- : 2.18 (s, 3H), 2.26 (s, 2H), 2.33 (s, 2H), 3.44 (t, J= 4.8 Hz, 4H), 3.74 (s, 3H), 3.97 (t, J= 8.6 Hz, I H), 4.36 (t, J= 9.0 Hz, IH), 4.84 (s, 2H), 5.65 (t, J = 8.2 Hz, IH), 6.95-9.98 (m, 4H), 7.42 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.8 Hz, 2H).
Example 47
3-(4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2- oxoethoxy)pheny l)oxazo 1 idin-2-one
Ή NMR (DMSO-c ): 2 1.10-1.17 (m, 2H), 1.51-1.54 (m, 2H), 1.61-1.65 (m, IH), 2.27 (s, 3H), 3.95 (t, J= 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.75 (t, J = 6.0 Hz, 2H), 3.80-3.83 (m, 2H), 4.63 (s, 2H), 7.14-7.17 (m, 2H), 7.52-7.62 (m, 3H), 7.64-7.67 (m, 2H), 7.76- 7.78 (m, 2H), 7.87 (t, J= 5.8 Hz, NH), 8.31 (t, J= 6.2 Hz, NH).
The following compounds can be prepared following the processes described above along with suitable modifications and alterations well within the scope of a skilled person. Example 48
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)ethanethioamide
Example 49
2-(4-(3-([ 1 , 1 '-Biphenyl]-3-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)acetamide
Example 50
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N- (cyc lohexy Imethy l)acetam ide
Example 51
N-(Byclohexylmethyl)-2-(4-(3-(2'-methyl-[ 1 , 1 '-biphenyl]-3-yl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)acetam ide
Example 52
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide
Example 53
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-5-yl)phenoxy)ethanethioamide
Example 54
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(p-tolyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide
Example 55
N-((3,4-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(p-tolyl)-l,2,4-oxadiazol-5- y l)phenoxy)ethanethioam ide
Example 56
2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)-l-(piperidin-l- yl)ethanethione
Example 57
2-(4-(3 -(4-Fluoropheny 1)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanethione
Example 58
2-(4-(3 -(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -morpholinoethanethione
Example 59 l-(4-Ethylpiperazin-l-yl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethione
Example 60
1 - (4-Benzylpiperazin- 1 -yl)-2-(4-(3-(4-fluorophenyl)-l ,2,4-oxadiazol-5- yl)phenoxy)ethanethione
Example 61
8-(2-(4-(3-(4-(Trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)phenoxy)acetyl)-l-oxa- 3,8-diazaspiro[4.5]decan-2-one
Example 62
8-(2-(4-(3-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)acetyl)- 1 -oxa-3,8- diazaspiro[4.5]decan-2-one
Example 63
8-(2-((4-(3-(4-FIuorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)- 1 -oxa-3,8- diazaspiro[4.5]decan-2-one
Example 64
8-(2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)-3-methyl-l-oxa 3,8-diazaspiro[4.5]decan-2-one
Example 65
8-(2-(4-(3 -([ 1 , 1 '-Bipheny 1] -4-y l)-2-im inooxazol idin-5 -y l)phenoxy)acety 1)- 1 -oxa-3 , 8- diazaspiro[4.5]decan-2-one
Example 66
8-(2-(4-(3-([l,r-Biphenyl]r4-yl)-2-oxooxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one
Example 67
8-(2-(4-(2-Oxo-3-(p-tolyl)oxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one
Example 68
8-(2-(4-(2-Oxo-3-(4-(trifluoromethyl)phenyl)oxazolidin-5-yl)phenoxy)acetyl)-l-oxa- 3,8-diazaspiro[4.5]decan-2-one
Example 69
2- (4-(3-(2',4'-Dimethyl-[l,l'-biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l-
Figure imgf000037_0001
Example 70 2-(4-(3-(2',4'-Dimethyl-[l,r-biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone
Example 71
2-(4-(3-([ 1 , 1 '-B iphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)- 1 -(4-methylpiperazin-
1- yl)ethanone
Example 72
2- (4-(3-([ 1 , 1 '-Biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)- 1 -(4-ethylpiperazin- 1 - yl)ethanone
Example 73
3- ([ 1 ,1 '-Biphenyl]-4-yl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2- oxoethoxy)phenyl)oxazolidin-2-one
Example 74
3-([l, -Biphenyl]-4-yl)-5-(4-(2-morpholino-2-oxoethoxy)phenyl)oxazolidin-2-one
Example 75
3-(2'-Methyl-[ 1 , 1 '-biphenyl]-4-yl)-5-(4-(2-morpholino-2-oxoethoxy)phenyl)oxazolidin-
2- one
Example 76
3- (2',4'-DimethyH 1 , 1 ,-biphenyl]-4-yl)-5-(4-(2-morpholino-2- oxoethoxy)phenyI)oxazolidin-2-one
Example 77
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenyl)amino)acetamide ;
Example 78
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenyl)thio)acetamide
Example 79
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3-(4-(5-ethoxy-l-(4-methoxyphenyl)-lH- pyrazol-3-yl)phenyl)propanamide
Example 80
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3-(4-(5-ethoxy-l-(4-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)phenyl)propanamide
Example 81 N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-methoxy-l -(4- (trifluoromethyJ)phenyl)-lH-pyrazol-3-yl)phenoxy)acetamide
Example 82
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy-l-(4-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)phenoxy)acetamide
Example 83
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy-l-(4-fluorophenyl)-lH- pyrazol-3-yl)phenoxy)acetamide
Example 84
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenoxy)acetamide
Example 85
2-(4-(5-([ 1 , Γ-Β ipheny l]-4-yl)-4-methylisoxazol-3-yl)phenoxy)- 1 -(4-methy Ipiperazin- 1 - yl)ethanone
Example 86
2-(4-(l-([ 1 , l'-BiphenyI]-4-yl)-5-methoxy-lH-pyrazol-3-yl)phenoxy)-l - ηιθ Ηο 1 inoethanone
Example 87
2-(4-( 1 -(4'-Fluoro-[ 1 , 1 '-biphenyl]-4-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 - morpholinoethanone
Example 88
2-(4-(5-Methoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- yI)phenoxy)-l-morpholinoethanone
Example 89
2-(4-(5-Methoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone
Example 90
N-((3 ,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-(trifluoromethyl)phenyl)- 1 ,2,4- oxadiazol-5-yl)phenoxy)acetamide
Example 91
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- y l)phenoxy)acetam ide
Example 92 N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-methoxyphenyl)-l,2,4-oxadiazol-5- y l)phenoxy)acetam ide
Example 93
N-((3,6-Dihydro-2H-pyran-4-yl)methyI)-2-(4^(3-(4-nitrophenyl)-l,2,4-oxadiazol-5- yl)phenoxy)acetamide
Example 94
2-(4-(3-(4-Bromophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)-N-((3,6-dihydro-2H-pyran-4- yl)methyl)acetamide
Example 95
1 -(4-Methylpiperazin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 ,2,4- oxadiazol-5-yl)phenoxy)ethanone
Example 96
1- (4-(2-Hydroxyethyl)piperazin-l-yl)-2-(4-(3-(4'-(trifluoromethyl)-[l,l*-biphenyl]-4- yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)ethanone
Example 97
2- (4-(3 -(4-Ethylpheny 1)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(4-(2- hydroxyethy l)piperazin- 1 -yl)ethanone
Example 98
2-(4-(3 -(4-Ethylpheny 1)- 1 ,2,4-oxadiazol-5 -yl)phenoxy)- 1 -(4-phenethylpiperazin- 1 - yl)ethanone
Example 99
2-(4-(2-([ 1 , 1 -Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone
Example 100
2-(4-(2-([ 1 , 1 '-Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 -mo holinoethanone
Example 101
2-(4-(2-([ 1 , 1 '-Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)-l -(4-ethylpiperazin- 1 - yl)ethanone
Example 102
2-(4-(2-([ 1 , 1 '-Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)-l -(4-benzylpiperazin- 1 - yl)ethanone Example 103
1 -(4-Benzylpiperazin- 1 -yI)-2-(4-(2-(4'-fluoro-[l , 1 '-biphenyl]-4-yl)-4-methylthiazol-5- yi)
phenoxy)ethanone
Example 104
1 -(4-Benzylpiperazin- 1 -yl)-2-((4-(2-(4'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-4-methylthiazol-5- y l)pheny l)am ino)ethanone
Example 105
2-(4-(3-(Dibenzo[b,d]thiophen-3-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(6- azaspiro[2.5 ] octan-6-y l)ethanone
Example 106
2-(4-(3-([ 1 , 1 -Biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)-l -(6-azaspiro[2.5]oetan- 6-yl)ethanone
Example 107
2-(4-(3 -([1,1 '-Biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5-y l)phenoxy)- 1 -(piperidin- 1 - yl)ethanone
Example 108
1 -(Piperidin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)ethanone
Example 109
2-(4-(5-Ethoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3 -yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone
Example 110
2-(4-(5-Methoxy- 1 -(4-(trifluoromethy l)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone
Example 111
2-(4-(l -([ 1 , 1 '-Biphenyl]-4-yl)-5-methoxy- 1 H-pyrazol-3-yI)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone
Example 112
2-(4-(l -(Dibenzo[b,d]thiophen-3-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone Example 113
2-(4-(5-Methoxy- 1 -(2'-methyl-[l , 1 *-biphenyl]-4-yl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone
Example 114
2-(4-(5-Ethoxy-l-(4'-(trifluoromethyl)-[l,l'-biphenyl]-4-yl)-lH-pyrazol-3-yl)phenoxy)-
1 - (4-methylpiperazin- 1 -yl)ethanone
Example 115
2- (4-(5-Ethoxy- 1 -(p-tolyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone
Example 116
2-(4-(5-Ethoxy- 1 -(p-tolyl)- 1 H-pyrazol-3 -yl)phenoxy)- 1 -(4-propy Ipiperazin- 1 - yl)ethanone
Example 117
2-(4-(5-Ethoxy- 1 -(/?-tolyl)- 1 H-pyrazol-3 -yl)phenoxy)- 1 -(4-(2-hydroxyethyl)piperazin- l-yl)ethanone
Example 118
2-(4-(5-Ethoxy-l-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3-yl)phenoxy)-l-(4-(2- hydroxyethyl)piperazin- 1 -yl)ethanone
Demonstration of in vitro potency of compounds
The PCSK9-LDLR in vitro Binding Assay is a quantitative solid phase binding assay between PCSK9 and recombinant LDLR. Plates were pre-coated with a recombinant LDLR-AB domain, which binds PCSK9. Test compound at different concentration was added to the PCSK9 and added to LDLR immobilized on the wells.
The amount of bound PCSK9 is measured by binding it with biotinylated anti-His-tag monoclonal antibody, followed by binding with horseradish peroxidase conjugated streptavidin substrate. The colour was quantified by ELISA reader at 450 nM which reflects the relative amount of PCSK9 that binds to LDLR in presence and absence of the inhibitor.
Figure imgf000042_0001
10 30
1
100 61
10 23
2
100 51
10
3 17
100
34
10 8
4 -
100 50
10 44
5
100 59
10 44
7
100 88
10 52
8
100 71
10 32
9
100 49
10 39
10
100 56
10 63
1
100 66
10 57
15
100 69
10 50
16
100 75
10 46
17
100 65
10 77
21
100 58
10 49
22
100 71 10 41
23
100 60
10 44
24
100 71
10 47
25 :
100 60
10 37
26
100 60
10 44
27
100 70
10 56
28
100 62
10 70
31
100 25
10 45
34
100 61
40 10 54
10 58
43
100 59
The compounds of the present invention are suitable for the treatment and/or mitigation of obesity, hyperlipidaemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions in humans and animals. The pharmaceutical compositions containing the compounds of the present invention optionally with another suitable pharmaceutical agent can comprise of one or more pharmaceutically acceptable excipients as is known in the art. The formulation can be prepared by suitable techniques well known. The formulation may be in the form of a tablet, capsule, caplet, satches etc. which are well known to a skilled person. The doses may vary depending on the disease, gravity of the disease, risk profile of the user etc.

Claims

We claim
1. Compounds of formula (I) including their stereoisomers and tautomers wherein
Figure imgf000045_0001
'X', 'Z' and 'ΖΑ' at each occurrence independently represent an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Ri, R2> and R3 at each occurrence independently represents H, (Ci-Ce) linear or branched alkyl, (Ci-C6) linear or branched alkenyl, (Ci-C6) linear or branched alkynyl, hydroxy, (Ci-C6) alkoxy, (C Ce) alkenoxy, hydroxy(Ci- C6)alkyl, alkoxyalkyl, haloalkyl, (C3-C6) cycloalkyl, thioCQ-Ceialkyl, (d- C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Ci-C6)alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted; 'm' 'n' and V independently represents integers from 0 to 5; Alternatively, Z-U-X-ZA together forms tricyclic 8-15 membered fused ring system optionally containing from 1-4 hetero atoms selected from N, O or S(0)q; ;
'A' represents— NR4R5 or the group -N(R6)(CH2)pCONR«R7 wherein R4, R5, R6 and R7 at each occurrence independently represents H, (Ci-C6) linear or branched alkyl, (Ci-C6) linear or branched alkenyl, (Ci-C6) linear or branched alkynyl, hydroxy, (C C6) alkoxy, (Ci-C6) alkenoxy, hydroxy(Ci-C6)alkyl, alkoxyalkyl, haloalkyl, (C3-C6) cycloalkyl, thio(d-C6)alkyl, (d-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(Cr C6)alkyl, alkylamino, cyano, formyl, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted with a provisio that when 'A' represents— NR4R5 and either of R4 or R5 is H the other one does not represent
Figure imgf000046_0001
Alternatively, R4 and R5 wherever possible, together may form optionally substituted 4 to 7 membered saturated or partially saturated ring containing from 0- 2 additional heteroatoms selected from the group consisting of N, O, and S(0)q; 'q' represents integers from 0 to 2; Ύ' represents either a bond, or O, S(0)q or NR8 wherein Rg represents H, (Ci-C6) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, heterocyclyl groups; 'W represents (Ci-C6) linear or branched alkyl or (C3-C6) linear or branched cycloalkyl; 'V represents O or S; 'U' represents either a bond, or O, S(0)q or NRg wherein Rg is as defined earlier and 'p' represents integers from 0 to 2.
The compound as claimed in claim 1 wherein each of 'X' or 'Z' or 'ΖΑ' is independently selected from optionally substituted aryl or heterocyclyl groups. The compound as claimed in claim 2 wherein when any of 'X' or 'Z' or 'ZA' represents an aryl group, the aryl group is selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups.
The compound as claimed in claim 3 wherein the aryl group is an optionally substituted phenyl group.
The compound as claimed in claim 2 wherein when any of 'X,' 'Z' 'ΖΑ' represents a heterocyclyl group, the heterocyclyl group is selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S.
The compound as claimed in claim 5 wherein the heterocyclyl group is selected from pyridyl, thienyi, 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, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl groups.
The compound as claimed in claim 1 selected from
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)pheno y)-l-mo holinoethanone;
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)-N-(2-(4-methylpiperazin-l-yl)-2- oxoethyl)acetamide;
2-(4-(5-Methyl-4-phenylisoxazol-3-yl)phenoxy)- 1 -moφholinoethanone;
2-(4-(5-Methyl-4-phenylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
1- (4-Hydroxypiperidin-l-yl)-2-(4-(4-methyl-5-phenylisoxazol-3- yl)phenoxy)ethanone;
2- (4-(4-Methyl-5-phenyliso azol-3-yl)pheno y)-N-moφholinoacetamide;
2-(4-(4-Methyl-5-phenylisoxazol-3-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone;
2-(4-(5-(4-Fluorophe yl)-4-methylisoxazoi-3-yl)phenoxy)-l-moφholinoethanone; 2-(4-(5-(4-Fluorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l -(4-methylpiperazin- 1- yl)ethanone;
2-(4-(5-(4-Chlorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l-moφholinoethanone; 2-(4-(5-(4-Chlorophenyl)-4-methylisoxazol-3-yl)phenoxy)-l -(4-methylpiperazin- 1- yl)ethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l- morpholinoethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(4-Methyl-5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)phenoxy)-l-(piperidin-
1- yl)ethanone;
2- (4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-l-moφholinoethanone;
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(4-Methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-l-(piperidin-l-yl)ethanone; 2-(4-(4-Methyl-5-(p-tolyl)ίsoxazol-3-yl)phenoxy)-N-moφholinoacetamide; 2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 - morpholinoethanone;
2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)-N-(4- methylpyrimidin-2-yl)acetamide;
N-(l,3-Dimethyl-lH-pyrazol-5-yl)-2-(4-(5-methoxy-l-(4-(trifluoromethyl)phenyl)- lH-pyrazol-3-yI)phenoxy)acetamide;
2-(4-( 1 -(4-Fluoropheny l)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 - morpholinoethanone;
2-(4-( 1 -(4-Fluorophenyl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(5 -Methoxy- 1 -phenyl - 1 H-pyrazol-3 -y l)phenoxy)- 1 -morpholinoethanone ; 2-(4-(5-Methoxy- 1 -phenyl- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(4-Methyl-2-phenylthiazol-5-yl)phenoxy)- 1 -morpholinoethanone;
2-(4-(4-Methyl-2-phenylthiazol-5-yl)phenoxy)-l -(4-methylpiperazin- l-yl)ethanone; 2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l- morpholinoethanone;
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)-l-(piperidin-l- yl)ethanone;
2-(4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)phenoxy)- 1-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-mo holinoethanone; 2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - yl)ethanone;
2-(4-(2-(4-Fluorophenyl)-4-methylthiazol-5-yl)phenoxy)-l-(piperidin-l- yl)ethanone;
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)- 1 -mo holinoethanone;
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone;
2-(4-(5-Methyl-2-phenyloxazol-4-yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; 2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l- moφholinoethanone;
2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone; 2-(4-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanone;
2-(4-(5-Methyl-2-(pyridin-3-yl)oxazol-4-yl)phenoxy)-l-morpholinoethanone;
1 - Μθ 1ιο1ίηο-2-(4-(5-(4-(Ιπί1υοΓθηΐ6^1)ρ1ιβη>Ί)- 1 ,2,4-oxadiazol-3- yl)phenoxy)ethanone;
2- (4-(5-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)phenoxy)-l -(4-methylpiperazin- 1 - yl)ethanone;
3- (4-F!uorophenyl)-5-(4-(2-(4-methylpiperazin-l-yl)-2- oxoethoxy)phenyl)oxazolidin-2-one;
2- (4-(3-(4-Fluorophenyl)-2-oxooxazolidin-5-yl)phenoxy)-N-(4-methylpyrimidin-2- yl)acetamide;
3- (4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin-l-yl)-2- oxoethoxy)phenyl)oxazoIidin-2-one;
3-(4-Methoxyphenyl)-5-(4-(2-(4-methylpiperazin- l-yl)-2- oxoethoxy)phenyl)oxazolidin-2-one;
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)ethanethioamide;
2-(4-(3-([l,l'-Biphenyl]-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,4-dihydro-2H- pyran-4-yl)methyl)acetamide;
2-(4-(3-([ 1 , 1 '-Biphenyl]-3-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)-N- (cyc lohexy lmethy l)acetam ide ;
N-(Byclohexylmethyl)-2-(4-(3-(2'-methyl-[l, -biphenyl]-3-yl)-l,2,4-oxadiazol-5- yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol- 5-yl)phenoxy)ethanethioamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-5-yl)phenoxy)ethanethioamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(p-tolyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide;
N-((3,4-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(p-tolyl)-l,2,4-oxadiazol-5- yl)phenoxy)ethanethioamide;
2-((4-(3-(4-Fluorophenyl)-l ,2,4-oxadiazol-5-yl)phenyl)thio)- 1 -(piperidin- 1 - yl)ethanethione; 2-(4-(3-(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(piperidin- 1 - yl)ethanethione;
2-(4-(3 -(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 - morpholinoethanethione;
1 -(4-Ethylpiperazin- 1 -yl)-2-(4-(3-(4-fluorophenyl)- 1 ,2,4-oxadiazol-5- yl)phenoxy)ethanethione;
1 -(4-BenzyIpiperazin- 1 -yl)-2-(4-(3-(4-fluorophenyl)- l,2,4-oxadiazol-5- yl)phenoxy)ethanethione;
8-(2-(4-(3-(4-(Trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)phenoxy)acetyl)-l- oxa-3,8-diazaspiro[4.5]decan-2-one
8-(2-(4-(3-(4-FluorophenyI)-l,2,4-oxadiazol-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-((4-(3-(4-Fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)thio)acetyl)-3-methyl-l- oxa-3,8-diazaspiro[4.5]decan-2-one;
8-(2-(4-(3-([l, -Biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)acetyl)-l-oxa- 3,8-diazaspiro[4.5]decan-2-one;
8-(2-(4-(3-([ 1 , 1 '-Biphenyl]-4-yI)-2-oxooxazolidin-5-yl)phenoxy)acetyl)- 1 -oxa-3,8- diazaspiro [4.5 ]decan-2-one ;
8-(2-(4-(2-Oxo-3-(p-tolyl)oxazolidin-5-yl)phenoxy)acetyl)-l-oxa-3,8- diazaspiro[4.5]decan-2-one;
8-(2-(4-(2-Oxo-3-(4-(trifluoromethyl)phenyl)oxazolidin-5-yl)phenoxy)acetyl)-l- oxa-3 ,8-diazaspiro[4.5 ]decan-2-one;
2-(4-(3-(2 4'-Dimethyl-[l,l'-biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l- morpholinoethanone;
2-(4-(3-(2',4'-Dimethyl-[l, -biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l- (4-methylpiperazin- 1 -yl)ethanone;
2-(4-(3-([ 1 , 1 '-Biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l -(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(3-([l,r-Biphenyl]-4-yl)-2-iminooxazolidin-5-yl)phenoxy)-l-(4- ethylpiperazin- 1 -yI)ethanone; 3-([ 1 , 1 '-Biphenyl]-4-yl)-5-(4-(2-(4-methylpiperazin- 1 -yl)-2- oxoethoxy)ptienyl)oxazolidin-2-one;
3-([l, -Biphenyl]-4-yl)-5-(4-(2-mo holino-2-oxoethoxy)phenyl)oxazolidin-2-one; 3-(2'-Methyl-[ 1 , 1 '-bipheny 1]-4- 1)-5-(4-(2-ιηοφ1ιο1ίηο-2- oxoethoxy)phenyl)oxazolidin-2-one;
3-(2',4'-Dimethyl-[ 1 , 1 '-biphenyl]-4-yl)-5-(4-(2-morpholino-2- oxoethoxy)phenyl)oxazo 1 idin-2-one ;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy-j -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenyl)amino)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-((4-(5-ethoxy-l-(4-methoxyphenyl)-lH- pyrazol-3-yl)phenyl)thio)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3 -(4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenyl)propanamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-3-(4-(5-ethoxy-l-(4- (trifluoromethyl)phenyl)-lH-pyrazol-3-yl)phenyl)propanamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-methoxy-l-(4- (trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy- 1 -(4- (trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy-l-(4-fluorophenyl)-lH- pyrazol-3 -yl)phenoxy)acetam ide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(5-ethoxy- 1 -(4-methoxyphenyl)- 1 H- pyrazol-3-yl)phenoxy)acetamide;
2-(4-(5-([l,l'-Biphenyl]-4-yl)-4-methylisoxazol-3-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-( 1 -([ 1 , 1 '-Biphenyl]-4-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 - morpholinoethanone;
2-(4-(l-(4'-Fluoro-[l,r-biphenyl]-4-yl)-5-methoxy-lH-pyrazol-3-yl)phenoxy)-l- morpholinoethanone;
2-(4-(5-Methoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- y l)phenoxy)- 1 -mo hol inoethanone;
2-(4-(5-Methoxy- 1 -(4'-(trifluoromethyl)-[l , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- y l)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone; N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-5-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol- 5-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-methoxyphenyl)-l ,2,4- oxadiazol-5-yl)phenoxy)acetamide;
N-((3,6-Dihydro-2H-pyran-4-yl)methyl)-2-(4-(3-(4-nitrophenyl)-l,2,4-oxadiazol-5- y l)phenoxy)acetam ide ;
2-(4-(3-(4-Bromophenyl)-l,2,4-oxadiazol-5-yl)phenoxy)-N-((3,6-dihydro-2H- pyran-4-yI)methyl)acetamide;
1 -(4-Methylpiperazin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 ,2,4- oxadiazol-5-yl)phenoxy)ethanone;
1 -(4-(2-Hydroxyethyl)piperazin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-
4- yl)-l,2,4-oxadiazol-5-yl)phenoxy)ethanone;
2-(4-(3 -(4-Ethylphenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(4-(2- hydroxyethyl)piperazin- 1 -yl)ethanone;
2-(4-(3 -(4-Ethylphenyl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(4-phenethy lpiperazin- 1 - yl)ethanone;
2-(4-(2-([l,l'-Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)-l-(4- methylpiperazin- 1 -yl)ethanone;
2-(4-(2-([l , 1 '-Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 - morpholinoethanone;
2-(4-(2-([ 1 , -Biphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-ethylpiperazin-
1- yl)ethanone;
2- (4-(2-([ 1 , 1 '-B iphenyl]-4-yl)-4-methylthiazol-5-yl)phenoxy)- 1 -(4-benzylpiperazin-
1- yl)ethanone;
1 -(4-Benzylpiperazin- 1 -yl)-2-(4-(2-(4'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-4-methylthiazol-
5- yl)
phenoxy)ethanone;
1 -(4-Benzylpiperazin- 1 -yl)-2-((4-(2-(4'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-4- methylthiazol-5-yl)phenyl)amino)ethanone;
2- (4-(3-(Dibenzo[b,d]thiophen-3-yl)-l,2,4-oxadiazol-5-yl)phenoxy)-l-(6- azaspiro[2.5]octan-6-yl)ethanone; 2-(4-(3 -([1,1 '-Bipheny l]-4-yl)- 1 ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(3-([l , 1 '-Biphenyl]-4-yl)-l ,2,4-oxadiazol-5-yl)phenoxy)- 1 -(piperidin- 1 - yI)ethanone;
1- (Piperidin- 1 -yl)-2-(4-(3-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 ,2,4- oxadiazol-5-yl)phenoxy)ethanone;
2- (4-(5-Ethoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- : azaspiro[2.5]octan-6-yl)ethanone;
: 2-(4-(5-Methoxy- 1 -(4-(trifluoromethyl)phenyI)- 1 H-pyrazol-3-yl)phenoxy)-l -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-( 1 -([ 1 , 1 '-Biphenyl]-4-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-( 1 -(Dibenzo[b,d]thiophen-3-yl)-5-methoxy- 1 H-pyrazol-3-yl)phenoxy)- 1 -(6- azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(5 -Methoxy- 1 -(2'-methyl-[ 1 , 1 -biphenyl]-4-yl)- 1 H-pyrazol-3-yl)phenoxy)- 1 - (6-azaspiro[2.5]octan-6-yl)ethanone;
2-(4-(5 -Ethoxy- 1 -(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-4-yl)- 1 H-pyrazol-3- yl)phenoxy)- 1 -(4-methylpiperazin- 1 -yl)ethanone;
2-(4-(5-Ethoxy- 1 -(p-tolyl)- lH-pyrazol-3-yl)phenoxy)- 1 -(4-methylpiperazin- 1 - ; yl)ethanone;
2-(4-(5 -Ethoxy- 1 -(p-tolyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-propylpiperazin- 1 - yl)ethanone;
; 2-(4-(5-Ethoxy-l -(p-tolyl)- lH-pyrazol-3 -yl)phenoxy)-l -(4-(2- hydroxyethyl)piperazin- 1 -yl)ethanone;
2-(4-(5 -Ethoxy- 1 -(4-(trifluoromethyl)phenyl)- 1 H-pyrazol-3-yl)phenoxy)- 1 -(4-(2- hydroxyethyl)piperazin- 1 -yl)ethanone.
The compounds as claimed in any preceding claims suitably formulated into a suitable pharmaceutical composition.
The compounds of formula (I) or their pharmaceutical compositions as claimed in any preceding claims for the treatment of hyperlipidemia, dyslipidemia and other similar diseases.
10. Use of the compounds of formula (I) or their pharmaceutical compositions as claimed in any preceding claims for the treatment of hyperlipidemia, dysiipidemia and other similar diseases.
1.1. A pharmaceutical composition comprising compounds of formula (I) 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, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 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.
12. The use of the pharmaceutical composition as claimed in claim 11 for the treatment of dysiipidemia, hyperlipidemia and associated disorders.
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CN115109011A (en) * 2022-08-10 2022-09-27 河北师范大学 Benzothiazole compound, preparation method and application
CN115109011B (en) * 2022-08-10 2023-12-15 河北师范大学 Benzothiazole compound, preparation method and application
CN116082325A (en) * 2022-12-25 2023-05-09 浙江工业大学 Benzoxazinone compound containing isoxazole heterocycle, and preparation method and application thereof
CN116082325B (en) * 2022-12-25 2024-04-16 浙江工业大学 Benzoxazinone compound containing isoxazole heterocycle, and preparation method and application thereof

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