WO2014073904A1 - Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient - Google Patents

Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient Download PDF

Info

Publication number
WO2014073904A1
WO2014073904A1 PCT/KR2013/010135 KR2013010135W WO2014073904A1 WO 2014073904 A1 WO2014073904 A1 WO 2014073904A1 KR 2013010135 W KR2013010135 W KR 2013010135W WO 2014073904 A1 WO2014073904 A1 WO 2014073904A1
Authority
WO
WIPO (PCT)
Prior art keywords
ylmethoxy
phenyl
indazol
hex
methyl
Prior art date
Application number
PCT/KR2013/010135
Other languages
French (fr)
Inventor
Sung Bae Lee
Seung Yup Paek
Sook Kyung Yoon
Seung Hyun Yoon
Jeung Soon Choi
Original Assignee
Lg Life Sciences Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lg Life Sciences Ltd. filed Critical Lg Life Sciences Ltd.
Priority to EP13852767.6A priority Critical patent/EP2917180A4/en
Priority to US14/441,591 priority patent/US9988379B2/en
Priority to AU2013341945A priority patent/AU2013341945B2/en
Priority to MX2015005418A priority patent/MX2015005418A/en
Priority to JP2015541689A priority patent/JP6442787B2/en
Priority to CN201380064394.0A priority patent/CN104837816A/en
Priority to RU2015121948A priority patent/RU2650506C2/en
Priority to BR112015010314-6A priority patent/BR112015010314B1/en
Priority to CA2889505A priority patent/CA2889505C/en
Publication of WO2014073904A1 publication Critical patent/WO2014073904A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—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
    • C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having GPR40 receptor agonist activity that promotes insulin secretion and inhibits blood sugar rise after glucose loading, and is thereby useful for the treatment of diabetes and complications thereof, or pharmaceutically acceptable salts and isomers thereof, and the pharmaceutical compositions containing them.
  • Diabetes negatively impacts many people's health and induces various complications. Diabetes is divided into type 1 diabetes and type 2 diabetes. Type 1 diabetes is presented when insulin is not produced due to destruction of pancreatic cells. Type 2 is presented when insulin is not produced for other reasons or the body is not responding to insulin. Type 2 diabetes is found in 90% or more of diabetic patients.
  • Sulfonylureas promoting insulin secretion from pancreatic cells
  • biguanide suppressing glucose production in the liver
  • ⁇ -glucosidase inhibitor inhibiting glucose absorption in the intestines
  • thiazolidine derivatives and the like are currently used for the treatment of diabetes.
  • Incretin-related drugs such as DPPIV inhibitors or Exenatide have recently entered the market.
  • GPR40 is a G-protein-coupled receptor.
  • GPR40 receptor is highly expressed in the pancreas, and it has been found that ligands for GPR40 receptor are saturated free fatty acids having 12-16 carbon atoms and unsaturated fatty acids having 18-22 carbon atoms. And it is confirmed that long-chain FFAs activate GPR40 receptor depending on blood glucose concentration, thereby stimulating insulin secretion from the beta cells of the pancreas via experiments that selectively inhibit the expression of GPR40 receptor in the pancreas using siRNA (small interfering RNA) technology and that measure how insulin secretion by blood glucose changes from beta cells of the pancreas in the presence of free fatty acids.
  • siRNA small interfering RNA
  • GPR40 agonists have a blood glucose concentration-dependent insulin-secretion stimulating activity, and thus are useful for the treatment and prevention of diabetes and complications thereof.
  • the object of the present invention is to provide novel compounds of Formula (1) as GPR40 receptor agonists.
  • Another object of the present invention is to provide a method for preparing the compounds of Formula (1).
  • Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes and complications of diabetes, which comprises as active components the compounds of Formula (1), and a method for preparing the composition.
  • a still further object of the present invention is to provide a method for preventing and treating diabetes and complications of diabetes which uses the compounds of Formula (1) as active components.
  • the compound of the present invention is a GPR40 receptor agonist.
  • the present invention provides a compound of Formula (1), or pharmaceutically acceptable salts or isomers thereof.
  • X represents C or N
  • Z represents C, N or O
  • Q represents O or NH
  • W represents C, N, C-alkyl or C-halogen
  • R1 represents H, alkyl, heteroalkyl, aryl, heterocycle, aryl-alkyl or heterocycle-alkyl,
  • R2 represents H, alkyl, heteroalkyl or halogen
  • R3 represents H, alkyl or halogen
  • R4 represents H, O, alkyl or halogen
  • R5 represents H, alkyl, alkoxy, CN, heterocycle or C ⁇ C-Me,
  • R4 and R5 can be connected together to form 5- or 6-membered ring
  • R6 represents H or alkyl
  • R5 and R6 can be connected together to form 3-membered ring.
  • the structure of is preferably selected from the following structures:
  • E represents H, alkyl or halogen
  • G represents alkyl, heteroalkyl or halogen
  • alkyl when used alone or in combination with “heteroalkyl,” means a linear, branched or cyclic hydrocarbon radical, preferably a linear or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from from 3 to 6 carbon atoms bonded to a linear and/or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms.
  • Each carbon atom can be optionally substituted with one or more cyano, hydroxy, C 1-6 alkoxy, oxo, halogen, or sulfonyl unsubstituted or substituted with alkyl and the like.
  • alkoxy means -O-alkyl, and alkyl is as defined above.
  • heteroalkyl means an alkyl comprising one or more, preferably one to four heteroatoms selected from N, O and S.
  • aryl means an aromatic group including phenyl, naphthyl and the like, and preferably means 6- to 10-membered aromatic groups.
  • Aryl may be optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, or sulfonyl unsubstituted or substituted with alkyl and the like.
  • heterocycle refers to a saturated, partially saturated or aromatic 3- to 14-membered ring containing 1 to 4 heteroatoms selected from N, O and S, which can optionally fused with benzo or C 3-8 cycloalkyl.
  • Examples of monocyclic heterocycle include oxetane, tetrahydrofuran, piperidine, morpholine, thiomorpholine, pyrrolidine, imidazolidine, piperazine, thiazole, oxazole, thiophene, furane, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like, but is not limited thereto.
  • bicyclic heterocycle examples include indole, indazole, azaindole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzothiadiazole, benzotriazole, quinoline, isoquinoline, purine, furopyridine and the like, but is not limited thereto.
  • Heterocycle may be optionally substituted with alkyl, halogen, heteroalkyl and the like.
  • halo(gen) refers to a substituent selected from the group consisting of fluoro, chloro, bromo or iodo.
  • the term “the compounds of Formula (1)” is used to mean all the compounds of Formula (1), including the pharmaceutical salts and isomers thereof.
  • the compounds according to the present invention can form pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts comprise acid-addition salts formed by acids containing pharmaceutically acceptable anions and forming nontoxic acid-addition salts ⁇ for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, preferably acid-addition salts formed by sulfuric acid, methanesulfonic acid or hydrogen halide acid and the like.
  • the compounds according to the present invention can have an asymmetric carbon center, they can exist as R- or S-isomers, racemic mixtures, diastereoisomer mixtures or each diastereoisomer, all of which are within the scope of the present invention. That is, if the asymmetric carbon(s) is included in the structure of Formula (1), as long as the direction is not described separately, it must be understood that all stereoisomers are included.
  • Representative compounds of Formula 1 according to the present invention include, but are not limited to, the following compounds:
  • the present invention also provides a process for preparing a compound of Formula (1).
  • the method for preparing the compounds of Formula (1) is explained based on exemplary reaction schemes in order to illustrate the present invention.
  • a person skilled in the art could prepare the compounds of Formula (1) by various methods based on the structure of Formula (1), and such methods should be interpreted as being within the scope of the present invention. That is, the compounds of Formula (1) may be prepared by the methods described herein or by combining various methods disclosed in the prior art, which should be interpreted as being within the scope of the present invention.
  • all substituents are as previously defined above.
  • the compound of Formula (1) according to the present invention may be obtained via hydrolysis of ester groups using compound (2) as shown in Reaction Scheme 1.
  • Compound (2) may be obtained via a coupling reaction of compound (3) and compound (4) or a coupling reaction of compound (5) and compound (6).
  • a is a reducing agent such as sodium triacetoxyborohydride ⁇ NaBH(OAc) 3 ⁇ and the like,
  • b is a binding agent such as 1,1’-(azodicarbonyl)dipiperidine (ADD) and the like and a phosphine such as tributylphosphin (Bu 3 P) and the like,
  • ADD 1,1’-(azodicarbonyl)dipiperidine
  • phosphine such as tributylphosphin (Bu 3 P) and the like
  • c is a reagent providing a leaving group such as methanesulfonylchloride and the like; and a base such as metal carbonate (for example, potassium carbonate) and the like,
  • d is a base such as metal hydroxide (for example, sodium hydroxide) and the like,
  • R1 ⁇ R6 are the same as defined in Formula (1), and
  • R7 is H, or alkyl such as methyl or ethyl and the like.
  • Compounds of Formula (1) may be obtained by reacting compound (2) in a solvent under heating or at room temperature in the presence of a base.
  • the base is preferably aqueous solution of sodium hydroxide or lithium hydroxide and the like.
  • the solvent is preferably tetrahydrofuran, alcohols such as methanol, or mixtures thereof.
  • Compound (2) may be obtained via a reductive alkylation between the aldehyde group of compound (3) and amine group of compound (4) in a solvent using a reducing agent.
  • the available reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the solvent is preferably dichloroethane or chloroform.
  • Compound (2) can also be obtained via a coupling reaction between compound (5) and compound (6) under Mitsunobu condition.
  • Mitsunobu condition is widely known in the art, there are numerous methods and reagents. Among them, binding reaction is included between the alcohol compound (5) and the phenol compound (6) using a phosphine such as tributylphosphin, triphenylphosphine and the like, and 1,1’-(azodicarbonyl)dipiperidine (ADD) or diethyl azodicarboxylate (DEAD) as a binding agent.
  • the solvent is preferably toluene, tetrahydrofuran and the like.
  • it can be obtained by binding the phenol compound (6) with compound (5) wherein the alcohol group is changed to a leaving group with the appropriate brominating agents, chlorinating agents or methanesulfonylation agents.
  • Compound (3) can be prepared by the method described in Reaction Scheme 2, and compound (4) is commercially available.
  • a is an alkylation agent such as R1-OSO 2 CH 3 , R1-halogen and the like, and a base such as sodium hydride,
  • b is an arylating agent such as R1-halogen and the like, cyclohexane 1,2-diamine, potassium phosphate tribasic and copper iodide, and
  • R1 ⁇ R3 are the same as defined in Formula (1).
  • compound (3) may be obtained by the alkylation or arylation of compound (7).
  • Compound (7) is a compound commercially available.
  • Alkylation condition is well known in the art, and it is possible to obtain by reacting compound (7) with an alkylating agent having a leaving group such as a halogen or methanesulfonate in the presence of a base such as sodium hydride or potassium carbonate in a solvent.
  • the solvent is preferably tetrahydrofuran, dimethylformamide or a mixture thereof.
  • Arylation condition is well known in the art and comprises a reaction between compound (7) and aryl halide in the presence of cyclohexane 1,2-diamine, potassium phosphate tribasic and copper iodide.
  • the solvent is preferably tetrahydrofuran or dioxane.
  • Compound (5) can be prepared by the method described in the following Reaction Schemes 3 and 4, and compound (6) may be prepared by known methods.
  • a is a reducing agent such as sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ) or lithium aluminum hydride (LiAlH 4 ),
  • R1 ⁇ R3 are the same as defined in Formula (1), and
  • R7 is H or alkyl such as methyl or ethyl and the like.
  • compound (5) may be obtained by reduction of the aldehyde group of compound (3) or the ester group of compound (8) using a reducing agent.
  • Sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ) or lithium aluminum hydride (LiAlH 4 ) and the like may be used as the reducing agent.
  • tetrahydrofuran may be used as the solvent.
  • Compound (8) may be selected from compounds which can be prepared by the method described in the following Reaction Schemes 5 to 14.
  • b is a reducing agent such as sodium borohydride (NaBH 4 ) or lithium borohydride (LiBH 4 ), and
  • R1 ⁇ R3 are the same as defined in Formula (1).
  • compound (5) can be obtained by reacting the acid group of compound (9) with alkyl chloroformate in the presence of a base to prepare the anhydride group and then reducing it to alcohol groups using a reducing agent.
  • the base is preferably triethylamine or N-methylmorpholine.
  • the reducing agent is preferably sodium borohydride (NaBH 4 ) or lithium borohydride (LiBH 4 ).
  • the solvent is preferably tetrahydrofuran.
  • Compound (9) can be purchased or can be selected from compounds which can be prepared by the method described in the following Reaction Schemes 5 to 14.
  • a is a cyanide such as zinc cyanide (ZnCN 2 ), and a palladium catalyst such as palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ ,
  • b is a basic aqueous solution, such as sodium hydroxide,
  • d is R1-OSO 2 CH 3 or R1-halogen, and a base such as sodium hydride,
  • R1 is the same as defined in Formula (1), and
  • R7 is H or alkyl such as methyl or ethyl.
  • Compound (10) is typically available for purchase.
  • Compound (11) can be obtained by reacting the bromide group of compound (10) with cyanide under a palladium catalyst.
  • Palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ is the most commonly used palladium catalyst, and the solvent is preferably dimethylformamide or N-methylpyrrolidone.
  • Compound (12) can be obtained by changing the carbonitrile group of compound (11) to acid group using an acidic or basic aqueous solution and then esterifying it with methanol or ethanol under acid catalyst such as anhydrous hydrochloric acid or anhydrous sulfuric acid. It can be also obtained via the methyl esterfication reaction of the acid group and diazomethane in the solvent of tetrahydrofuran or dichloromethane.
  • the acidic solution used in the condition for making acid group is preferably an aqueous solution of sulfuric or hydrochloric acid, and as the basic aqueous solution, sodium hydroxide or lithium hydroxide aqueous solution is generally used.
  • Compound (13) may be prepared using compound (10) by the alkylating or arylating method used to prepare the compound (3).
  • Compound (14) can be prepared using compound (13) under the same condition that is used for preparing compound (11).
  • Compound (15) can be prepared using compound (12) by the alkylating or arylating method used to prepare the compound (3) or using compound (14) by the method by which compound (12) is prepared.
  • R1 is the same as defined in Formula (1), and
  • R7 is H or alkyl such as methyl or ethyl.
  • Compound (16) is typically available for purchase.
  • Compound (17) can be prepared by reacting the nitrobenzene compound (16) and vinyl magnesium bromide with the method described in WO 2008/0221091.
  • Compound (18) may be made via an esterification reaction of compound (17).
  • the esterification reaction may be carried out using ethanol or methanol under the condition of the anhydrous sulfuric acid or hydrochloric acid. Alternatively, it can be performed using diazomethane in tetrahydrofuran or dichloromethane.
  • a is N,N-dimethylformamide dimethyl acetal
  • c is R1-OSO 2 CH 3 or R1-halogen and a base such as sodium hydride,
  • R3 is the same as defined in Formula (1), and
  • R7 is H or alkyl such as methyl or ethyl.
  • Compound (19) is commercially available or can be prepared by the method described in WO 2010/089127.
  • the compound (20) can be prepared by reacting the methyl group of compound (19) with N,N-dimethylformamide dimethyl acetal according to the method described in WO 2010/054138.
  • Compound (21) may be prepared by reacting compound (20) with hydrogen gas under Pd/C catalyst.
  • the suitable solvent is ethyl acetate, ethanol, etc.
  • Compound (22) may be prepared by alkylation or arylation of compound (21) according to the method used for compound (3).
  • a is R8-C ⁇ CH, copper (I) iodide (CuI), bis(triphenylphosphine) palladium (II) dichloride ⁇ Pd(Ph 3 P) 2 Cl 2 ⁇ ,
  • c is tetrabutylammonium fluoride
  • d is R1-OSO 2 CH 3 or R1-halogen and sodium hydride
  • R3 is the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R8 is trimethylsilyl ⁇ (CH 3 ) 3 Si ⁇ , alkyl or heteroalkyl.
  • Compound (23) can be purchased or can be prepared by the method described in Tetrahedron Letters, 38 (14), 2439, 1997.
  • Compound (24) can be made according to the method described in Journal of Organic Chemistry, 4 (18), 7052, 2009 by reacting R8-C ⁇ CH with compound (23) in the presence of copper (I) iodide (CuI), bis(triphenylphosphine) palladium (II) dichloride ⁇ Pd(Ph 3 P) 2 Cl 2 ⁇ and a base.
  • the base is preferably triethylamine or diethylamine, and as the solvent N,N-dimethylformamide or tetrahydrofuran can be used.
  • Compound (25) can be prepared by reacting compound (24) with tetrabutylammonium fluoride according to the method described in Example 58 of WO 2010/123975.
  • Compound (26) may be prepared by alkylation or arylation of compound (25) according to the method used for compound (3).
  • a is a halogenating agent such as N-fluoro-2,4,6-trimethyl pyridinium triplate or chlorine (Cl 2 ),
  • b is R1-Br, and a metal acid catalyst such as zinc bromide (ZnBr 2 ),
  • c is a halogenating agent such as N-bromosuccinimide; R10-boronic acid and palladium tetrakistriphenylphosphine ⁇ Pd(Ph 3 ) 4 ⁇ ,
  • R1 and R3 are the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R9 is H or halogen
  • R10 is halogen, alkyl, aryl or aryl-alkyl.
  • Compound (27) can be synthesized by carrying out one reaction under any of a to c reaction conditions.
  • the halogenation (the reaction condition of a) of compound (26) can be carried out using a fluorinating reagent (for example, N-fluoro-2,4,6-trimethyl pyridinium triplate), chlorine or brominating reagent (for example, N- bromosuccinimide, bromine).
  • a fluorinating reagent for example, N-fluoro-2,4,6-trimethyl pyridinium triplate
  • chlorine or brominating reagent for example, N- bromosuccinimide, bromine
  • the alkylation (the reaction condition of b) of compound (26) can be carried out by reacting with an alkyl-halogen compound (for example, benzyl bromide) in the presence of a metal acid catalyst such as zinc bromide (ZnBr 2 ).
  • an alkyl-halogen compound for example, benzyl bromide
  • a metal acid catalyst such as zinc bromide (ZnBr 2 ).
  • the arylation (the reaction condition of c) of compound (26) can be carried out by brominating the indole compound and then reacting with R10-boronic acid and a base (for example, palladium phosphate tribasic) under a palladium tetrakistriphenylphosphine ⁇ Pd(Ph 3 ) 4 ⁇ catalyst.
  • a base for example, palladium phosphate tribasic
  • a is acetic anhydride(Ac 2 O), isoamyl nitrite and potassium acetate (KOAc)
  • b is a cyanide such as zinc cyanide (ZnCN 2 ), and a palladium catalyst such as palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ ,
  • c is a base such as sodium hydroxide
  • e is palladium/carbon (Pd/C) and hydrogen
  • R3 is the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R11 is alkyl or aryl-alkyl.
  • Compound (28) is commercially available, or can be prepared by a known method.
  • Compound (29) can be prepared using the indazole synthesis method well known in the art.
  • the indazole synthesis conditions include the condition that the 1-amino-2-alkylphenyl compound (28) is reacted with acetic anhydride(Ac 2 O) in the presence of potassium acetate (KOAc), and then it is reacted with isoamyl nitrite.
  • Compound (30) may be obtained by reacting the bromide group of compound (29) with cyanide under a palladium catalyst.
  • a palladium catalyst palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ is commonly used, and the solvent is preferably dimethylformamide or N-methylpyrrolidone.
  • Compound (31) is commercially available or can be prepared by the method as described in US 2010/0040554.
  • Compound (32) can be prepared by reduction of the compound (31) with hydrogen gas under Pd/C catalyst.
  • the compound (33) is commercially available, or can be prepared by changing the carbonitrile of compound (30) to the acid group using an acidic or basic aqueous solution and then esterifying it with alcohol under acid catalyst or diazomethane. It can also be made using the compound (32) under the conditions by which to prepare compound (29) or by the method described in WO 2008/001883.
  • a is R1-amine
  • c is sodium nitride (NaNO 2 ) and an acidic aqueous solution such as hydrochloric acid,
  • d is triethylorthoformate and an acidic aqueous solution such as p-toluenesulfonic acid,
  • f is R11-halogen, and a base such as sodium hydride,
  • R1 and R3 are the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R11 is alkyl or aryl-alkyl.
  • Compound (34) is commercially available or can be prepared by a known method.
  • Compound (35) can be prepared by reacting compound (34) with amine according to the method described in WO 2007/095340.
  • Compound (36) can be prepared by reduction of compound (35) with hydrogen gas under Pd/C catalyst.
  • Compound (37) can be prepared by reacting compound (36) with sodium nitride (NaNO 2 ) under an acidic condition (for example, hydrochloric acid), according to the method described in WO 2010/027500.
  • an acidic condition for example, hydrochloric acid
  • Compound (38) can be prepared by reacting compound (36) with triethylorthoformate under an acidic condition (for example, p-toluenesulfonic acid), according to the method described in WO 2009/129335.
  • an acidic condition for example, p-toluenesulfonic acid
  • Compound (39) can be prepared by reacting compound (36) with triphosgene according to the method described in US 2008/0249101.
  • Compound (40) can be prepared by reacting compound (39) with an alkylating agent (for example, methyl iodide) in the presence of a base (for example, sodium hydride).
  • an alkylating agent for example, methyl iodide
  • a base for example, sodium hydride
  • b is zinc cyanide (ZnCN 2 ) and palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ ,
  • c is a basic aqueous solution such as sodium hydroxide
  • R1 and R3 are the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R11 is alkyl or aryl-alkyl.
  • Compound (41) is commercially available or can be prepared by the method described in US 2008/0153813.
  • Compound (42) can be prepared by reacting compound (41) with R1-hydrazine and then reacting with zinc cyanide (ZnCN 2 ) under palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ , or it can be prepared by reacting R1-hydrazine after reacting zinc cyanide (ZnCN 2 ).
  • Compound (43) can be prepared by changing the carbonitrile group of compound (42) to the acid group using an acidic or basic aqueous solution, and then esterifying it with alcohol under acid catalyst or diazomethane.
  • a ammonia
  • NCS N-chlorosuccinimide
  • c is zinc cyanide (ZnCN 2 ) and palladium tetrakistriphenylphosphine ⁇ Pd(PPh 3 ) 4 ⁇ ,
  • e is diazomethane (CH 2 N 2 )
  • R3 is the same as defined in Formula (1),
  • R7 is H or alkyl such as methyl or ethyl
  • R11 is alkyl or aryl-alkyl.
  • Compound (44) is commercially available or can be prepared by the method described in WO 95/04739.
  • Compound (45) can be prepared by reacting compound (44) with ammonia and then N-chlorosuccinimide (NCS) according to the method described in Organic Letter, 12(23), 6300, 2011.
  • Compound (46) can be prepared using compound (45) according to the method by which compound (12) was prepared.
  • the compounds of Formula (1) can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion-exchange chromatography.
  • the compounds according to the present invention can be prepared by a variety of methods, which should be interpreted as being within the scope of the present invention in connection with the preparation of the compounds of Formula (1).
  • the compounds of Formula (1), the pharmaceutically acceptable salts and isomers thereof are useful for the treatment and prevention for the diseases associated with GPR40 receptor.
  • the compound of Formula (1) according to the present invention has GPR40 receptor modulating activity and is especially useful as a GPR40 receptor agonist.
  • the compound of formula (1) according to the present invention has an excellent GPR40 receptor modulating activity in mammals, particularly in humans, and thus is useful as a therapeutic agent for the treatment or prevention of GPR40 receptor-related diseases which can be treated by controlling the efficacy of the GPR40 receptor.
  • the compound according to the present invention is useful as insulin secretion regulating agents, preferably insulin secretagogues, hypoglycemic agents and pancreatic beta-cell protective agents.
  • the compound of the present invention shows blood glucose concentration-dependent insulin secretion stimulating activity based on GPR40 receptor agonist activity, and thus it is useful as an insulin secretagogue that does not cause side effects such as hypoglycemia ⁇ namely, as a therapeutic agent for the treatment or prevention of diabetes, high blood sugar, glucose tolerance, and impaired fasting blood glucose. It is also effective in the treatment or prevention of diabetes complications such as hyperlipidemia, hypertension, retinopathy, renal failure and obesity.
  • the diabetes complications treatable by the compound of the present invention include, but are not limited to, hyperlipidemia, hypertension, retinopathy, renal failure, obesity, etc.
  • the relevance between the said diseases and the modulation of GPR40 receptor has already been known in the art and disclosed in detail in documents such as WO 2004/041266, WO 2004/106276, WO 2005/063729 and WO 2008/001931.
  • the present invention also provides a pharmaceutical composition as a GPR40 agonist comprising an effective amount of the compound of Formula (1), pharmaceutically acceptable salts or isomers thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising the compound of Formula (1) can be used for the treatment or prevention of diseases or conditions which can be treated by modulation of the GPR40 receptor such as diabetes, high blood sugar, glucose tolerance, impaired fasting blood glucose, diabetes complications, hyperlipidemia, hypertension, retinopathy, renal failure, obesity, etc., and is particularly useful for the treatment or prevention of type 2 diabetes.
  • the present invention provides a method for preparing the composition for preventing or treating diabetes and/or complications of diabetes which comprises the step of mixing the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof as an active component and a pharmaceutically acceptable carrier.
  • the “pharmaceutical composition” can include other chemical components such as carriers, diluents, etc., in addition to the active component of the present invention. Accordingly, the pharmaceutical composition can include pharmaceutically acceptable carriers, diluents, excipients or combinations thereof as necessary.
  • the pharmaceutical composition facilitates the administration of compounds into the body. Various methods for administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral and local administration.
  • carriers means compounds that facilitate the addition of compounds into the cell or tissue.
  • dimethylsulfoxide is a conventional carrier facilitating the administration of various organic compounds into the living cell or tissue.
  • the term “diluents” means compounds that not only stabilize a biologically active form but are also diluted in solvent dissolving the compounds. Dissolved salts in buffer are used as diluents in this field.
  • a conventionally used buffer is a phosphate buffer saline that copies salt form in bodily fluid. Since buffer solution can control the pH of the solution at low concentration, buffer diluents hardly modify the biological activity of compounds.
  • pharmaceutically acceptable means such property that does not impair the biological activity and physical property of compounds.
  • the compounds according to the present invention can be formulated as various pharmaceutically administered dosage forms.
  • an active component specifically, the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof ⁇ is mixed with selected pharmaceutically acceptable carriers considering the dosage form to be prepared.
  • the pharmaceutical composition of the present invention can be formulated as injections, oral preparations and the like, as needed.
  • the compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and inserted into a unit or multi-unit containers.
  • the formulations may be solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents.
  • the formulation may be, for example, dry powder form which is dissolved in sterilized pyrogen-free water before use.
  • the compounds of the present invention can be formulated into suppositories by using a conventional suppository base such as cocoa butter or other glycerides.
  • Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated.
  • Solid forms are manufactured by mixing the compounds of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • the compounds according to the present invention and the composition comprising them can be administered in combination with other drugs ⁇ for example, other antidiabetics, as required.
  • the dose of the compounds of Formula (1) is determined by a physician’s prescription considering the patient’s body weight, age and disease condition.
  • a typical dose for adults is in the range of about 1 to 500 mg per day according to the frequency and intensity of administration.
  • a typical daily dose of intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which can be administered in divided unit dosage. Some patients need a higher daily dose.
  • treatment is used to mean deterring, delaying or ameliorating the progress of diseases in a subject exhibiting symptoms of diseases.
  • prevention is used to mean deterring, delaying or ameliorating the sign of diseases in a subject at risk of exhibiting symptoms of diseases, even if he or she does not exhibit the symptoms.
  • Reagents and starting materials can be obtained readily commercially. Others can be produced by synthetic methods described in the following Examples, including known synthetic methods for structurally similar compounds. Unless otherwise noted, compounds used as starting materials are known ones or those which can be prepared by known synthetic methods or similar methods from known compounds.
  • M means molar concentration
  • N means normal concentration
  • room temperature means 1 to 40°C.
  • 1-H-indole-6-carbaldehyde (320mg, 2.2mmol) was dissolved in dimethylformamide (2ml), and isopropyl iodide (0.33ml, 3.3mmol) and sodium hydride (104mg, 2.6mmol) were slowly added thereto at 0°C, and then the mixture was stirred for 8 hours at 50°C. 1N hydrochloric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (300mg, 73%).
  • N-chlorosuccinimide N-chlorosuccinimide (NCS, 474mg, 3.5mmol) was added dropwise thereto, and then the mixture was stirred for 2 hours at 70°C. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (800mg, 76%).
  • N-chlorosuccinimide (NCS, 132mg, 1.0mmol) was added dropwise thereto, and then the mixture was stirred for 4 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (40mg, 30%).
  • N-chloro-succinimide (NCS, 40mg, 0.30mmol) was added dropwise thereto. The mixture was stirred for 4 hours at 60°C. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (70mg, 89%).
  • the compound (200mg, 1.06mmol) obtained from the Preparation Example 50-1 was dissolved in dioxane (7ml). Benzyl bromide (0.25ml, 2.11mmol) and zinc bromide (ZnBr 2 , 140mg, 0.53mmol) were added thereto, and the mixture was stirred for 3 hours at 60°C. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the mixture of the title compound and 2,3-dibenzyl-1-methyl-1H-indole-5-carboxylic acid methyl ester.
  • 1-Benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid was dissolved in methylenechloride (20ml) and 0.25M solution of diazomethane in diethyl ether (5.0ml, 1.38mmol) was slowly added dropwise. The mixture was stirred for 30 minutes at room temperature, and then distilled under reduced pressure to obtain 1-benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (310mg, 100%).
  • the first compound that passed through the column chromatography was 1-benzyl-1H-indazole-6-carboxylic acid methyl ester (209mg, 46%), and the second one was 2-benzyl-1H-indazole-6-carboxylic acid methyl ester (160mg, 35%).
  • N-methyl morpholine (0.50g, 4.95mmmol) and isobutylchloroformate (0.62g, 4.54mmol) were added dropwise at 0°C.
  • the mixture was filtered to remove insoluble solids.
  • sodium borohydride (0.31g, 8.26mmol) was added and the mixture was stirred for 3 hours.
  • the reaction was terminated with an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate.
  • the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.61g, 62%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to a novel compound having GPR40 receptor agonist activity that promotes insulin secretion and inhibits blood sugar rise after glucose loading, and is thereby useful for the treatment of diabetes and complications thereof, the preparation method thereof and pharmaceutical composition containing them as an active ingredient.

Description

GPR40 RECEPTOR AGONIST, METHODS OF PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE INGREDIENT
The present invention relates to a novel compound having GPR40 receptor agonist activity that promotes insulin secretion and inhibits blood sugar rise after glucose loading, and is thereby useful for the treatment of diabetes and complications thereof, or pharmaceutically acceptable salts and isomers thereof, and the pharmaceutical compositions containing them.
Diabetes negatively impacts many people's health and induces various complications. Diabetes is divided into type 1 diabetes and type 2 diabetes. Type 1 diabetes is presented when insulin is not produced due to destruction of pancreatic cells. Type 2 is presented when insulin is not produced for other reasons or the body is not responding to insulin. Type 2 diabetes is found in 90% or more of diabetic patients.
Sulfonylureas (promoting insulin secretion from pancreatic cells), biguanide (suppressing glucose production in the liver), α-glucosidase inhibitor (inhibiting glucose absorption in the intestines), thiazolidine derivatives (TZDs) and the like are currently used for the treatment of diabetes. Incretin-related drugs such as DPPIV inhibitors or Exenatide have recently entered the market.
However, these agents have unwanted side effects such as hypoglycemia, liver failure, gastrointestinal disorders and weight gain, or weak hypoglycemic function or the disadvantage that they must be used as an injection. Therefore, research has been conducted for new therapies based on a new mechanism that is able to avoid the drawbacks and side effects of existing diabetes therapies.
Recently, an insulinotropic mechanism by free fatty acid was revealed more clearly through the study of GPR40 which is a G-protein-coupled receptor. GPR40 receptor is highly expressed in the pancreas, and it has been found that ligands for GPR40 receptor are saturated free fatty acids having 12-16 carbon atoms and unsaturated fatty acids having 18-22 carbon atoms. And it is confirmed that long-chain FFAs activate GPR40 receptor depending on blood glucose concentration, thereby stimulating insulin secretion from the beta cells of the pancreas via experiments that selectively inhibit the expression of GPR40 receptor in the pancreas using siRNA (small interfering RNA) technology and that measure how insulin secretion by blood glucose changes from beta cells of the pancreas in the presence of free fatty acids.
Accordingly, GPR40 agonists have a blood glucose concentration-dependent insulin-secretion stimulating activity, and thus are useful for the treatment and prevention of diabetes and complications thereof.
The object of the present invention is to provide novel compounds of Formula (1) as GPR40 receptor agonists.
Another object of the present invention is to provide a method for preparing the compounds of Formula (1).
Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes and complications of diabetes, which comprises as active components the compounds of Formula (1), and a method for preparing the composition.
A still further object of the present invention is to provide a method for preventing and treating diabetes and complications of diabetes which uses the compounds of Formula (1) as active components.
The compound of the present invention is a GPR40 receptor agonist.
The present invention provides a compound of Formula (1), or pharmaceutically acceptable salts or isomers thereof.
[Formula (1)]
Figure PCTKR2013010135-appb-I000001
wherein,
X represents C or N,
Y represents C, N, C=O or C-halogen,
Z represents C, N or O,
Q represents O or NH,
W represents C, N, C-alkyl or C-halogen,
R1 represents H, alkyl, heteroalkyl, aryl, heterocycle, aryl-alkyl or heterocycle-alkyl,
R2 represents H, alkyl, heteroalkyl or halogen,
R3 represents H, alkyl or halogen,
R4 represents H, O, alkyl or halogen,
R5 represents H, alkyl, alkoxy, CN, heterocycle or C≡C-Me,
R4 and R5 can be connected together to form 5- or 6-membered ring,
R6 represents H or alkyl, and
R5 and R6 can be connected together to form 3-membered ring.
In the compound of Formula (1) according to the present invention,
the structure of
Figure PCTKR2013010135-appb-I000002
is preferably selected from the following structures:
Figure PCTKR2013010135-appb-I000003
wherein, E represents H, alkyl or halogen, and G represents alkyl, heteroalkyl or halogen.
Upon defining the compounds of Formula (1) herein, concepts defined as follows are used. Unless otherwise indicated, the following definitions are also applicable to the terms being used as part of a larger group, or individually throughout this specification.
The term “alkyl," when used alone or in combination with "heteroalkyl,” means a linear, branched or cyclic hydrocarbon radical, preferably a linear or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from from 3 to 6 carbon atoms bonded to a linear and/or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms. Each carbon atom can be optionally substituted with one or more cyano, hydroxy, C1-6 alkoxy, oxo, halogen, or sulfonyl unsubstituted or substituted with alkyl and the like.
The term “alkoxy” means -O-alkyl, and alkyl is as defined above.
The term “heteroalkyl" means an alkyl comprising one or more, preferably one to four heteroatoms selected from N, O and S.
The term “aryl” means an aromatic group including phenyl, naphthyl and the like, and preferably means 6- to 10-membered aromatic groups. Aryl may be optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, or sulfonyl unsubstituted or substituted with alkyl and the like.
The term “heterocycle” refers to a saturated, partially saturated or aromatic 3- to 14-membered ring containing 1 to 4 heteroatoms selected from N, O and S, which can optionally fused with benzo or C3-8 cycloalkyl. Examples of monocyclic heterocycle include oxetane, tetrahydrofuran, piperidine, morpholine, thiomorpholine, pyrrolidine, imidazolidine, piperazine, thiazole, oxazole, thiophene, furane, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like, but is not limited thereto. Examples of bicyclic heterocycle include indole, indazole, azaindole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzothiadiazole, benzotriazole, quinoline, isoquinoline, purine, furopyridine and the like, but is not limited thereto. Heterocycle may be optionally substituted with alkyl, halogen, heteroalkyl and the like.
The term “halo(gen)” refers to a substituent selected from the group consisting of fluoro, chloro, bromo or iodo.
The terms and abbreviations used herein have their original meanings unless defined otherwise.
In the following, for convenience, unless indicated otherwise, the term “the compounds of Formula (1)” is used to mean all the compounds of Formula (1), including the pharmaceutical salts and isomers thereof.
The compounds according to the present invention can form pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts comprise acid-addition salts formed by acids containing pharmaceutically acceptable anions and forming nontoxic acid-addition salts―for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, preferably acid-addition salts formed by sulfuric acid, methanesulfonic acid or hydrogen halide acid and the like. The compounds of Formula (1) according to the present invention can be converted into their salts by conventional methods.
Meanwhile, since the compounds according to the present invention can have an asymmetric carbon center, they can exist as R- or S-isomers, racemic mixtures, diastereoisomer mixtures or each diastereoisomer, all of which are within the scope of the present invention. That is, if the asymmetric carbon(s) is included in the structure of Formula (1), as long as the direction is not described separately, it must be understood that all stereoisomers are included.
Representative compounds of Formula 1 according to the present invention include, but are not limited to, the following compounds:
3-{4-[(1-isopropyl-1H-indol-6-ylmethyl)-amino-phenyl}-propanoic acid;
3-{4-[(1-benzyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(1-phenethyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(1-benzyl-3-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(1-benzyl-2,3-dichloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(1-benzyl-7-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-{4-[(7-chloro-1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
3-(4-{[7-chloro-1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid;
3-(4-{[1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid;
3-{4-[(7-chloro-1-cyclohexylmethyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
[6-(1-benzyl-3-chloro-1H-indol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
3-[4-(1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-{4-[1-(4-fluoro-phenyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-[4-(7-methyl-1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-[4-(1-cyclohexylmethyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-[4-(3-benzyl-1-methyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid;
3-[4-(1-methyl-3-o-tolyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid;
3-{4-[3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
3-{4-[5-fluoro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
{6-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid;
(S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(4-methanesulfonyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(4-methoxy-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(4-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2,6-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-benzyl-2-(2-methoxy-ethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(2-methyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2-chloro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2,6-dimethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-5-fluoro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(3-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(2-benzyl-2H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-5-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3,5-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
(S)-3-[4-(7-methyl-1-thiazol-4-ylmethyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(2-benzyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H- indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-methyl-1-pyrimidin-4-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-3-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-methyl-1-pyrimidin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-(4,5-dihydro-isoxazol-3-yl)-propanoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-pyrimidin-2-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(2-pyrimidin-2-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-pyrazin-2-ylmethyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-pyrimidin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(2-pyrimidin-4-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(2-pyridin-3-ylmethyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[7-methyl-1-(6-methyl-pyridin-3-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(2-isobutyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-isoxazol-3-yl-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
(S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-isoxazol-3-yl-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
(S)-3-{4-[1-(6-methyl-pyridin-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
(S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-cyclopropylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(2-isopropyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
[6-(1-isopropyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
(S)-3-isoxazol-3-yl-3-[4-(1-methyl-1H-indazol-6-ylmethoxy)-phenyl]-propanoic acid;
(S)-3-[4-(1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
(S)-3-isoxazol-3-yl-3-[4-(1-pyrazin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-propanoic acid;
[6-(1-benzyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
[6-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
[5-(1-benzyl-1H-indazol-6-ylmethoxy)-indan-1-yl]-acetic acid;
[6-(1-benzyl-1H-indazol-6-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid;
(S)-3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(2-benzyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[6-(2-benzyl-2H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
(S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-butyric acid;
[5-(1-benzyl-1H-indazol-5-ylmethoxy)-indan-1-yl]-acetic acid;
[6-(1-benzyl-1H-indazol-5-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid;
[7-(1-benzyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
[6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
(S)-3-[4-(1-benzyl-5-fluoro-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-indol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[6-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
[6-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(1-isobutyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-isobutyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(1-phenethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-phenethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-{4-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
7-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid;
(S)-3-[4-(1-cyclohexylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-cyclohexylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(2-isobutyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-chroman-4-yl]-acetic acid;
[7-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
(S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
[7-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
7-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid;
(S)-3-[4-(5-fluoro-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(tetrahydrofuran-2-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3-methanesulfonyl-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(tetrahydrofuran-3-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[2-(tetrahydrofuran-3-ylmethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-methoxy-propanoic acid;
(S)-3-[4-(1-isobutyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-butyric acid;
3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-pentanoic acid;
(S)-3-{4-[2-(2-ethoxy-ethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-cyano-propanoic acid;
(S)-3-[4-(1-cyclopentylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopentyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-isobutyl-3H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
2-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-cyclopropanecarboxylic acid;
(S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopentylmethyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopentyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopentyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(2-methanesulfonyl-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(2-methoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3-methoxy-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[1-(3-methyl-oxetan-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(2-isobutyl-3-methyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-isobutyl-benzo[d]isoxazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[1-(2,2-dimethyl-propyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-6-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-methoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-ethoxymethyl-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-chloro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-isopropoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoro-1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-bromo-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-methoxymethyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-butyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-butyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopropylmethyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-cyclopropylmethyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-chloro-1-methyl-1H-indazol-7-ylmethoxy)-methyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoro-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-butyl-3-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-butyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-isopropyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-methyl-3-propyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3,7-dimethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoro-1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-ethyl-3-fluoro-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-chloro-1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-3-piperidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-methyl-1-propyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoromethyl-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(3-fluoro-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-[4-(7-methyl-1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-[4-(1-isobutyl-7-methyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
(S)-3-{4-[3-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
(S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid; and
(S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid.
The present invention also provides a process for preparing a compound of Formula (1). Hereinafter, the method for preparing the compounds of Formula (1) is explained based on exemplary reaction schemes in order to illustrate the present invention. However, a person skilled in the art could prepare the compounds of Formula (1) by various methods based on the structure of Formula (1), and such methods should be interpreted as being within the scope of the present invention. That is, the compounds of Formula (1) may be prepared by the methods described herein or by combining various methods disclosed in the prior art, which should be interpreted as being within the scope of the present invention. In the following reaction schemes, unless indicated differently, all substituents are as previously defined above.
The compound of Formula (1) according to the present invention may be obtained via hydrolysis of ester groups using compound (2) as shown in Reaction Scheme 1. Compound (2) may be obtained via a coupling reaction of compound (3) and compound (4) or a coupling reaction of compound (5) and compound (6).
[Reaction Scheme 1]
Figure PCTKR2013010135-appb-I000004
In the above Reaction Scheme 1,
a is a reducing agent such as sodium triacetoxyborohydride{NaBH(OAc)3} and the like,
b is a binding agent such as 1,1’-(azodicarbonyl)dipiperidine (ADD) and the like and a phosphine such as tributylphosphin (Bu3P) and the like,
c is a reagent providing a leaving group such as methanesulfonylchloride and the like; and a base such as metal carbonate (for example, potassium carbonate) and the like,
d is a base such as metal hydroxide (for example, sodium hydroxide) and the like,
R1~R6 are the same as defined in Formula (1), and
R7 is H, or alkyl such as methyl or ethyl and the like.
Compounds of Formula (1) may be obtained by reacting compound (2) in a solvent under heating or at room temperature in the presence of a base. The base is preferably aqueous solution of sodium hydroxide or lithium hydroxide and the like. The solvent is preferably tetrahydrofuran, alcohols such as methanol, or mixtures thereof.
Compound (2) may be obtained via a reductive alkylation between the aldehyde group of compound (3) and amine group of compound (4) in a solvent using a reducing agent. The available reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The solvent is preferably dichloroethane or chloroform.
Compound (2) can also be obtained via a coupling reaction between compound (5) and compound (6) under Mitsunobu condition. Mitsunobu condition is widely known in the art, there are numerous methods and reagents. Among them, binding reaction is included between the alcohol compound (5) and the phenol compound (6) using a phosphine such as tributylphosphin, triphenylphosphine and the like, and 1,1’-(azodicarbonyl)dipiperidine (ADD) or diethyl azodicarboxylate (DEAD) as a binding agent. The solvent is preferably toluene, tetrahydrofuran and the like. Alternatively, it can be obtained by binding the phenol compound (6) with compound (5) wherein the alcohol group is changed to a leaving group with the appropriate brominating agents, chlorinating agents or methanesulfonylation agents.
Compound (3) can be prepared by the method described in Reaction Scheme 2, and compound (4) is commercially available.
[Reaction Scheme 2]
Figure PCTKR2013010135-appb-I000005
In the above Reaction Scheme 2,
a is an alkylation agent such as R1-OSO2CH3, R1-halogen and the like, and a base such as sodium hydride,
b is an arylating agent such as R1-halogen and the like, cyclohexane 1,2-diamine, potassium phosphate tribasic and copper iodide, and
R1~R3 are the same as defined in Formula (1).
Specifically, compound (3) may be obtained by the alkylation or arylation of compound (7). Compound (7) is a compound commercially available. Alkylation condition is well known in the art, and it is possible to obtain by reacting compound (7) with an alkylating agent having a leaving group such as a halogen or methanesulfonate in the presence of a base such as sodium hydride or potassium carbonate in a solvent. The solvent is preferably tetrahydrofuran, dimethylformamide or a mixture thereof. Arylation condition is well known in the art and comprises a reaction between compound (7) and aryl halide in the presence of cyclohexane 1,2-diamine, potassium phosphate tribasic and copper iodide. The solvent is preferably tetrahydrofuran or dioxane.
Compound (5) can be prepared by the method described in the following Reaction Schemes 3 and 4, and compound (6) may be prepared by known methods.
[Reaction Scheme 3]
Figure PCTKR2013010135-appb-I000006
In the above Reaction Scheme 3,
a is a reducing agent such as sodium borohydride (NaBH4), lithium borohydride (LiBH4) or lithium aluminum hydride (LiAlH4),
R1~R3 are the same as defined in Formula (1), and
R7 is H or alkyl such as methyl or ethyl and the like.
Specifically, compound (5) may be obtained by reduction of the aldehyde group of compound (3) or the ester group of compound (8) using a reducing agent. Sodium borohydride (NaBH4), lithium borohydride (LiBH4) or lithium aluminum hydride (LiAlH4) and the like may be used as the reducing agent. Preferably, tetrahydrofuran may be used as the solvent. Compound (8) may be selected from compounds which can be prepared by the method described in the following Reaction Schemes 5 to 14.
[Reaction Scheme 4]
Figure PCTKR2013010135-appb-I000007
In the above Reaction Scheme 4,
a is alkylchloroformate,
b is a reducing agent such as sodium borohydride (NaBH4) or lithium borohydride (LiBH4), and
R1~R3 are the same as defined in Formula (1).
Specifically, compound (5) can be obtained by reacting the acid group of compound (9) with alkyl chloroformate in the presence of a base to prepare the anhydride group and then reducing it to alcohol groups using a reducing agent. The base is preferably triethylamine or N-methylmorpholine. The reducing agent is preferably sodium borohydride (NaBH4) or lithium borohydride (LiBH4). The solvent is preferably tetrahydrofuran. Compound (9) can be purchased or can be selected from compounds which can be prepared by the method described in the following Reaction Schemes 5 to 14.
Compounds (8) and (9) can be selected from compounds which can be prepared by the method described in the following Reaction Schemes 5 to 14.
[Reaction Scheme 5]
Figure PCTKR2013010135-appb-I000008
In the above Reaction Scheme 5,
a is a cyanide such as zinc cyanide (ZnCN2), and a palladium catalyst such as palladium tetrakistriphenylphosphine {Pd(PPh3)4},
b is a basic aqueous solution, such as sodium hydroxide,
c is diazomethane (CH2N2),
d is R1-OSO2CH3 or R1-halogen, and a base such as sodium hydride,
R1 is the same as defined in Formula (1), and
R7 is H or alkyl such as methyl or ethyl.
Compound (10) is typically available for purchase.
Compound (11) can be obtained by reacting the bromide group of compound (10) with cyanide under a palladium catalyst. Palladium tetrakistriphenylphosphine {Pd(PPh3)4} is the most commonly used palladium catalyst, and the solvent is preferably dimethylformamide or N-methylpyrrolidone.
Compound (12) can be obtained by changing the carbonitrile group of compound (11) to acid group using an acidic or basic aqueous solution and then esterifying it with methanol or ethanol under acid catalyst such as anhydrous hydrochloric acid or anhydrous sulfuric acid. It can be also obtained via the methyl esterfication reaction of the acid group and diazomethane in the solvent of tetrahydrofuran or dichloromethane.
The acidic solution used in the condition for making acid group is preferably an aqueous solution of sulfuric or hydrochloric acid, and as the basic aqueous solution, sodium hydroxide or lithium hydroxide aqueous solution is generally used.
Compound (13) may be prepared using compound (10) by the alkylating or arylating method used to prepare the compound (3).
Compound (14) can be prepared using compound (13) under the same condition that is used for preparing compound (11).
Compound (15) can be prepared using compound (12) by the alkylating or arylating method used to prepare the compound (3) or using compound (14) by the method by which compound (12) is prepared.
[Reaction Scheme 6]
Figure PCTKR2013010135-appb-I000009
In the above Reaction Scheme 6,
a is vinyl magnesium bromide (CH2=CHMgBr),
b is diazomethane(CH2N2),
R1 is the same as defined in Formula (1), and
R7 is H or alkyl such as methyl or ethyl.
Compound (16) is typically available for purchase.
Compound (17) can be prepared by reacting the nitrobenzene compound (16) and vinyl magnesium bromide with the method described in WO 2008/0221091.
Compound (18) may be made via an esterification reaction of compound (17). The esterification reaction may be carried out using ethanol or methanol under the condition of the anhydrous sulfuric acid or hydrochloric acid. Alternatively, it can be performed using diazomethane in tetrahydrofuran or dichloromethane.
[Reaction Scheme 7]
Figure PCTKR2013010135-appb-I000010
In the above Reaction Scheme 7,
a is N,N-dimethylformamide dimethyl acetal,
b is palladium/carbon (Pd/C) and hydrogen,
c is R1-OSO2CH3 or R1-halogen and a base such as sodium hydride,
R3 is the same as defined in Formula (1), and
R7 is H or alkyl such as methyl or ethyl.
Compound (19) is commercially available or can be prepared by the method described in WO 2010/089127.
The compound (20) can be prepared by reacting the methyl group of compound (19) with N,N-dimethylformamide dimethyl acetal according to the method described in WO 2010/054138.
Compound (21) may be prepared by reacting compound (20) with hydrogen gas under Pd/C catalyst. The suitable solvent is ethyl acetate, ethanol, etc.
Compound (22) may be prepared by alkylation or arylation of compound (21) according to the method used for compound (3).
[Reaction Scheme 8]
Figure PCTKR2013010135-appb-I000011
In the above Reaction Scheme 8,
a is R8-C≡CH, copper (I) iodide (CuI), bis(triphenylphosphine) palladium (II) dichloride {Pd(Ph3P)2Cl2},
b is acetylchloride,
c is tetrabutylammonium fluoride,
d is R1-OSO2CH3 or R1-halogen and sodium hydride,
R3 is the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl, and
R8 is trimethylsilyl {(CH3)3Si}, alkyl or heteroalkyl.
Compound (23) can be purchased or can be prepared by the method described in Tetrahedron Letters, 38 (14), 2439, 1997.
Compound (24) can be made according to the method described in Journal of Organic Chemistry, 4 (18), 7052, 2009 by reacting R8-C≡CH with compound (23) in the presence of copper (I) iodide (CuI), bis(triphenylphosphine) palladium (II) dichloride {Pd(Ph3P)2Cl2} and a base. The base is preferably triethylamine or diethylamine, and as the solvent N,N-dimethylformamide or tetrahydrofuran can be used.
Compound (25) can be prepared by reacting compound (24) with tetrabutylammonium fluoride according to the method described in Example 58 of WO 2010/123975.
Compound (26) may be prepared by alkylation or arylation of compound (25) according to the method used for compound (3).
[Reaction Scheme 9]
Figure PCTKR2013010135-appb-I000012
In the above Reaction Scheme 9,
a is a halogenating agent such as N-fluoro-2,4,6-trimethyl pyridinium triplate or chlorine (Cl2),
b is R1-Br, and a metal acid catalyst such as zinc bromide (ZnBr2),
c is a halogenating agent such as N-bromosuccinimide; R10-boronic acid and palladium tetrakistriphenylphosphine {Pd(Ph3)4},
R1 and R3 are the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl,
R9 is H or halogen, and
R10 is halogen, alkyl, aryl or aryl-alkyl.
Compound (26) can be prepared under the condition described in Reaction Scheme 8.
Compound (27) can be synthesized by carrying out one reaction under any of a to c reaction conditions.
The halogenation (the reaction condition of a) of compound (26) can be carried out using a fluorinating reagent (for example, N-fluoro-2,4,6-trimethyl pyridinium triplate), chlorine or brominating reagent (for example, N- bromosuccinimide, bromine).
The alkylation (the reaction condition of b) of compound (26) can be carried out by reacting with an alkyl-halogen compound (for example, benzyl bromide) in the presence of a metal acid catalyst such as zinc bromide (ZnBr2).
The arylation (the reaction condition of c) of compound (26) can be carried out by brominating the indole compound and then reacting with R10-boronic acid and a base (for example, palladium phosphate tribasic) under a palladium tetrakistriphenylphosphine {Pd(Ph3)4} catalyst.
[Reaction Scheme10]
Figure PCTKR2013010135-appb-I000013
In the above Reaction Scheme 10,
a is acetic anhydride(Ac2O), isoamyl nitrite and potassium acetate (KOAc)
b is a cyanide such as zinc cyanide (ZnCN2), and a palladium catalyst such as palladium tetrakistriphenylphosphine {Pd(PPh3)4},
c is a base such as sodium hydroxide,
d is diazomethane (CH2N2),
e is palladium/carbon (Pd/C) and hydrogen,
R3 is the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl, and
R11 is alkyl or aryl-alkyl.
Compound (28) is commercially available, or can be prepared by a known method.
Compound (29) can be prepared using the indazole synthesis method well known in the art. The indazole synthesis conditions include the condition that the 1-amino-2-alkylphenyl compound (28) is reacted with acetic anhydride(Ac2O) in the presence of potassium acetate (KOAc), and then it is reacted with isoamyl nitrite.
Compound (30) may be obtained by reacting the bromide group of compound (29) with cyanide under a palladium catalyst. As a palladium catalyst, palladium tetrakistriphenylphosphine {Pd(PPh3)4} is commonly used, and the solvent is preferably dimethylformamide or N-methylpyrrolidone.
Compound (31) is commercially available or can be prepared by the method as described in US 2010/0040554.
Compound (32) can be prepared by reduction of the compound (31) with hydrogen gas under Pd/C catalyst.
The compound (33) is commercially available, or can be prepared by changing the carbonitrile of compound (30) to the acid group using an acidic or basic aqueous solution and then esterifying it with alcohol under acid catalyst or diazomethane. It can also be made using the compound (32) under the conditions by which to prepare compound (29) or by the method described in WO 2008/001883.
[Reaction Scheme 11]
Figure PCTKR2013010135-appb-I000014
In the above Reaction Scheme 11,
a is R1-amine,
b is palladium/carbon (Pd/C) and hydrogen,
c is sodium nitride (NaNO2) and an acidic aqueous solution such as hydrochloric acid,
d is triethylorthoformate and an acidic aqueous solution such as p-toluenesulfonic acid,
e is triphosgene,
f is R11-halogen, and a base such as sodium hydride,
R1 and R3 are the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl, and
R11 is alkyl or aryl-alkyl.
Compound (34) is commercially available or can be prepared by a known method.
Compound (35) can be prepared by reacting compound (34) with amine according to the method described in WO 2007/095340.
Compound (36) can be prepared by reduction of compound (35) with hydrogen gas under Pd/C catalyst.
Compound (37) can be prepared by reacting compound (36) with sodium nitride (NaNO2) under an acidic condition (for example, hydrochloric acid), according to the method described in WO 2010/027500.
Compound (38) can be prepared by reacting compound (36) with triethylorthoformate under an acidic condition (for example, p-toluenesulfonic acid), according to the method described in WO 2009/129335.
Compound (39) can be prepared by reacting compound (36) with triphosgene according to the method described in US 2008/0249101.
Compound (40) can be prepared by reacting compound (39) with an alkylating agent (for example, methyl iodide) in the presence of a base (for example, sodium hydride).
[Reaction Scheme 12]
Figure PCTKR2013010135-appb-I000015
In the above Reaction Scheme 12,
a is R1-hydrazine,
b is zinc cyanide (ZnCN2) and palladium tetrakistriphenylphosphine {Pd(PPh3)4},
c is a basic aqueous solution such as sodium hydroxide,
d is diazomethane (CH2N2),
R1 and R3 are the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl, and
R11 is alkyl or aryl-alkyl.
Compound (41) is commercially available or can be prepared by the method described in US 2008/0153813.
Compound (42) can be prepared by reacting compound (41) with R1-hydrazine and then reacting with zinc cyanide (ZnCN2) under palladium tetrakistriphenylphosphine {Pd(PPh3)4}, or it can be prepared by reacting R1-hydrazine after reacting zinc cyanide (ZnCN2).
Compound (43) can be prepared by changing the carbonitrile group of compound (42) to the acid group using an acidic or basic aqueous solution, and then esterifying it with alcohol under acid catalyst or diazomethane.
[Reaction Scheme 13]
Figure PCTKR2013010135-appb-I000016
In the above Reaction Scheme 13,
a is ammonia,
b is N-chlorosuccinimide (NCS) and potassium carbonate,
c is zinc cyanide (ZnCN2) and palladium tetrakistriphenylphosphine {Pd(PPh3)4},
d is sodium hydroxide,
e is diazomethane (CH2N2),
R3 is the same as defined in Formula (1),
R7 is H or alkyl such as methyl or ethyl, and
R11 is alkyl or aryl-alkyl.
Compound (44) is commercially available or can be prepared by the method described in WO 95/04739.
Compound (45) can be prepared by reacting compound (44) with ammonia and then N-chlorosuccinimide (NCS) according to the method described in Organic Letter, 12(23), 6300, 2011.
Compound (46) can be prepared using compound (45) according to the method by which compound (12) was prepared.
The compounds of Formula (1) can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion-exchange chromatography.
As described above, the compounds according to the present invention, starting materials or intermediates for the preparation thereof can be prepared by a variety of methods, which should be interpreted as being within the scope of the present invention in connection with the preparation of the compounds of Formula (1).
The compounds of Formula (1), the pharmaceutically acceptable salts and isomers thereof are useful for the treatment and prevention for the diseases associated with GPR40 receptor. The compound of Formula (1) according to the present invention has GPR40 receptor modulating activity and is especially useful as a GPR40 receptor agonist. The compound of formula (1) according to the present invention has an excellent GPR40 receptor modulating activity in mammals, particularly in humans, and thus is useful as a therapeutic agent for the treatment or prevention of GPR40 receptor-related diseases which can be treated by controlling the efficacy of the GPR40 receptor. Specifically, the compound according to the present invention is useful as insulin secretion regulating agents, preferably insulin secretagogues, hypoglycemic agents and pancreatic beta-cell protective agents. Particularly, the compound of the present invention shows blood glucose concentration-dependent insulin secretion stimulating activity based on GPR40 receptor agonist activity, and thus it is useful as an insulin secretagogue that does not cause side effects such as hypoglycemia―namely, as a therapeutic agent for the treatment or prevention of diabetes, high blood sugar, glucose tolerance, and impaired fasting blood glucose. It is also effective in the treatment or prevention of diabetes complications such as hyperlipidemia, hypertension, retinopathy, renal failure and obesity. The diabetes complications treatable by the compound of the present invention include, but are not limited to, hyperlipidemia, hypertension, retinopathy, renal failure, obesity, etc. The relevance between the said diseases and the modulation of GPR40 receptor has already been known in the art and disclosed in detail in documents such as WO 2004/041266, WO 2004/106276, WO 2005/063729 and WO 2008/001931.
The present invention also provides a pharmaceutical composition as a GPR40 agonist comprising an effective amount of the compound of Formula (1), pharmaceutically acceptable salts or isomers thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition comprising the compound of Formula (1) can be used for the treatment or prevention of diseases or conditions which can be treated by modulation of the GPR40 receptor such as diabetes, high blood sugar, glucose tolerance, impaired fasting blood glucose, diabetes complications, hyperlipidemia, hypertension, retinopathy, renal failure, obesity, etc., and is particularly useful for the treatment or prevention of type 2 diabetes.
In addition, the present invention provides a method for preparing the composition for preventing or treating diabetes and/or complications of diabetes which comprises the step of mixing the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof as an active component and a pharmaceutically acceptable carrier.
According to the present invention, the “pharmaceutical composition” can include other chemical components such as carriers, diluents, etc., in addition to the active component of the present invention. Accordingly, the pharmaceutical composition can include pharmaceutically acceptable carriers, diluents, excipients or combinations thereof as necessary. The pharmaceutical composition facilitates the administration of compounds into the body. Various methods for administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral and local administration.
Herein, the term “carriers” means compounds that facilitate the addition of compounds into the cell or tissue. For example, dimethylsulfoxide is a conventional carrier facilitating the administration of various organic compounds into the living cell or tissue.
Herein, the term “diluents” means compounds that not only stabilize a biologically active form but are also diluted in solvent dissolving the compounds. Dissolved salts in buffer are used as diluents in this field. A conventionally used buffer is a phosphate buffer saline that copies salt form in bodily fluid. Since buffer solution can control the pH of the solution at low concentration, buffer diluents hardly modify the biological activity of compounds.
Herein, the term “pharmaceutically acceptable” means such property that does not impair the biological activity and physical property of compounds.
The compounds according to the present invention can be formulated as various pharmaceutically administered dosage forms. In the preparation of the pharmaceutical composition of the present invention, an active component―specifically, the compound of Formula (1), a pharmaceutically acceptable salt or isomer thereof―is mixed with selected pharmaceutically acceptable carriers considering the dosage form to be prepared. For example, the pharmaceutical composition of the present invention can be formulated as injections, oral preparations and the like, as needed.
The compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and inserted into a unit or multi-unit containers. The formulations may be solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents. In addition, the formulation may be, for example, dry powder form which is dissolved in sterilized pyrogen-free water before use. The compounds of the present invention can be formulated into suppositories by using a conventional suppository base such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated. Solid forms are manufactured by mixing the compounds of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
The compounds according to the present invention and the composition comprising them can be administered in combination with other drugs─for example, other antidiabetics, as required.
The dose of the compounds of Formula (1) is determined by a physician’s prescription considering the patient’s body weight, age and disease condition. A typical dose for adults is in the range of about 1 to 500 mg per day according to the frequency and intensity of administration. A typical daily dose of intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which can be administered in divided unit dosage. Some patients need a higher daily dose.
Herein, the term “treatment” is used to mean deterring, delaying or ameliorating the progress of diseases in a subject exhibiting symptoms of diseases. The term “prevention” is used to mean deterring, delaying or ameliorating the sign of diseases in a subject at risk of exhibiting symptoms of diseases, even if he or she does not exhibit the symptoms.
The present invention is explained in more detail by the following Examples. However, the scope of the present invention is not limited by them. When preparing the compounds of the present invention, it is possible to appropriately change the reaction sequence. That is, it is possible to run first optional processes or insert optional processes to change substituents, and use any reagents other than exemplified reagents as needed. Compounds obtained in each process can be separated or purified by conventional methods such as recrystallization, distillation or silica gel column. Furthermore, the compound obtained in each process can be used in the next step without further purification or separation.
Reagents and starting materials can be obtained readily commercially. Others can be produced by synthetic methods described in the following Examples, including known synthetic methods for structurally similar compounds. Unless otherwise noted, compounds used as starting materials are known ones or those which can be prepared by known synthetic methods or similar methods from known compounds. Hereinafter, M means molar concentration, N means normal concentration and “room temperature” means 1 to 40℃.
Preparation Example 1: synthesis of 1-isopropyl-1H-indole-6-carbaldehyde
1-H-indole-6-carbaldehyde (320mg, 2.2mmol) was dissolved in dimethylformamide (2ml), and isopropyl iodide (0.33ml, 3.3mmol) and sodium hydride (104mg, 2.6mmol) were slowly added thereto at 0℃, and then the mixture was stirred for 8 hours at 50℃. 1N hydrochloric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (300mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.11 (s, 1H), 7.96 (s, 1H), 7.71 (d 1H), 7.62 (dd, 1H), 7.45 (d, 1H), 6.59 (d, 1H), 4.73-4.84 (m, 1H), 1.57 (d, 6H)
Preparation Example 2: synthesis of 1-benzyl-1H-indole-6-carbaldehyde
1-H-indole-6-carbaldehyde (320mg, 2.2mmol) and benzyl bromide (0.36ml, 3.3mmol) were reacted according to the method of Preparation Example 1 to obtain the title compound (400mg, 77%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.06 (s, 1H), 7.86 (s, 1H), 7.73 (d 1H), 7.64 (dd, 1H), 7.35 (d, 1H), 7.28-7.33 (m, 3H), 7.12 (dd, 2H), 6.62 (d, 1H), 5.41 (s, 2H)
Preparation Example 3: synthesis of 1-benzyl-3-chloro-1H-indole-6-carbaldehyde
1-Benzyl-1H-indole-6-carbaldehyde (835mg, 3.5mmol) obtained from Preparation Example 2 was dissolved in tetrahydrofuran (30ml). N-chlorosuccinimide (NCS, 474mg, 3.5mmol) was added dropwise thereto, and then the mixture was stirred for 2 hours at 70℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (800mg, 76%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.29 (s, 1H), 7.92 (s, 1H), 7.79 (m, 2H), 7.37 (m, 4H), 7.20 (d, 2H), 5.41 (s, 2H)
Preparation Example 4: synthesis of 1-benzyl-2,3-dichloro-1H-indole-6-carbaldehyde
1-Benzyl-3-chloro-1H-indole-6-carbaldehyde (100mg, 0.43mmol) obtained from Preparation Example 3 was dissolved in dichloromethane (25ml). N-chlorosuccinimide (NCS, 132mg, 1.0mmol) was added dropwise thereto, and then the mixture was stirred for 4 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (40mg, 30%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.06 (s, 1H), 7.86 (s, 1H), 7.76 (m, 2H), 7.34 (m, 3H), 7.14 (m, 1H), 5.53 (s, 2H)
Preparation Example 5: synthesis of 1-phenethyl-1H-indole-6-carbaldehyde
1-H-Indole-6-carbaldehyde (300mg, 2.1mmol) and (2-bromo-ethyl)-benzene (0.34ml, 2.48mmol) were reacted according to the method of Preparation Example 1 to obtain the title compound (80mg, 15%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.08 (s, 1H), 7.88 (s, 1H), 7.74 (m, 1H), 7.66 (m, 1H), 7.35 (m, 3H), 7.14 (d, 1H), 7.08 (m, 3H), 6.54 (m, 1H), 4.50 (t, 2H), 3.18 (t, 2H)
Preparation Example 6-1: synthesis of 1-thiophen-3-yl-1H-indole-6-carboxylic acid methyl ester
1H-indole-6- carboxylic acid methyl ester (560mg, 3.2mmol) was dissolved in xylene (30ml). 3-Bromothiophene (1.0g, 6.4mmol), copper (I) iodide (122mg, 0.64mmol), potassium carbonate (890mg, 6.4mmol) and cyclohexane 1,2-diamine (0.08ml, 0.64mmol) were added dropwise thereto, and then the mixture was stirred for 8 hours at 120℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (526mg, 64%).
Preparation Example 6-2: synthesis of (1-thiophen-3-yl-1H-indol-6-yl)-methanol
The compound (500mg, 1.9mmol) obtained from Preparation Example 6-1 was dissolved in tetrahydrofuran (20ml), and 2M solution of lithium borohydride in tetrahydrofuran (2.4ml, 4.8mmol) was added dropwise thereto. The mixture was stirred for 8 hours at 80℃, 1N hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (400mg, 90%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.65 (d, 1H), 7.58 (s, 1H), 7.46 (dd, 1H), 7.29-7.32 (m, 3H), 7.17 (dd, 1H), 6.64 (dd, 1H), 4.79 (d, 2H), 1.61 (br s, 1H)
Preparation Example 6-3: synthesis of 1-thiophen-3-yl-1H-indole-6-carbaldehyde
The compound (100mg, 0.44mmol) obtained from Preparation Example 6-2 was dissolved in dichloromethane (10ml), and pyridinium chlorochromate (PCC, 188mg, 0.87mmol) was added thereto. The mixture was stirred for 1 hour at 0℃ and then excess ethyl acetate was added thereto. The mixture was filtered with Celite. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (86mg, 69%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.05 (s, 1H), 8.06 (s, 1H), 7.77 (d, 1H), 7.70 (dd, 1H), 7.51-7.53 (m, 2H), 7.37 (dd, 1H), 7.31 (dd, 1H), 6.73 (d, 1H)
Preparation Example 7-1: synthesis of 7-chloro-1H-indole-6-carboxylic acid
2-Chloro-3-nitro-benzoic acid (3.0g, 14.9mmol) was dissolved in tetrahydrofuran (150ml), and 1M vinyl magnesium bromide solution in tetrahydrofuran (60ml, 60mmol) was added dropwise thereto at -45℃. The mixture was stirred while heating to 0℃. After completion of the reaction, a saturated solution of ammonium chloride and then 1N hydrochloric acid solution were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (800mg, 28%).
Preparation Example 7-2: synthesis of 7-chloro-1H-indole-6-carboxylic acid methyl ester
The compound (750mg, 3.8mmol) obtained from Preparation Example 7-1 was dissolved in tetrahydrofuran (150ml), and 0.25M solution of diazomethane in diethyl ether (18.4ml, 4.6mmol) was slowly added thereto. The mixture was stirred at room temperature for 30 minutes and distilled under reduced pressure to obtain the title compound (800mg, 99%).
Preparation Example 7-3: synthesis of 1-benzyl-7-chloro-1H-indole-6-carboxylic acid methyl ester
The compound (300mg, 1.43mmol) obtained from Preparation Example 7-2 was dissolved in dimethylformamide (10ml), and bromomethylbenzene (0.19ml, 1.7mmol) and sodium hydride (69mg, 1.7mmol) were slowly added dropwise thereto at 0℃. The mixture was stirred at room temperature for 8 hours, 1N hydrochloric acid solution was added thereto, and the mixture was extracted with ethyl acetate. Extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (380mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (s, 2H), 7.21-7.28 (m, 3H), 7.19 (d, 1H), 6.97 (d, 2H), 6.56 (d, 1H), 5.80 (s, 2H), 3.89 (s, 3H)
Preparation Example 7-4: synthesis of (1-benzyl-7-chloro-1H-indol-6-yl)-methanol
The compound (380mg, 1.3mmol) obtained from Preparation Example 7-3 was dissolved in tetrahydrofuran (25ml) and 2M solution of lithium borohydride in tetrahydrofuran (1.9ml, 3.9mmol) was added dropwise thereto. The mixture was stirred at 80℃ for 8 hours, 1N hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. Extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (250mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.21-7.30 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.00 (d, 2H), 6.55 (d, 1H), 5.79 (s, 2H), 4.85 (d, 2H), 1.84 (br t, 1H)
Preparation Example 7-5: synthesis of 1-benzyl-7-chloro-1H-indole-6-carbaldehyde
The compound (100mg, 0.44mmol) obtained from Preparation Example 7-4 was dissolved in dichloromethane (20ml), and pyridinium chlorochromate (PCC, 159mg, 0.74mmol) was added thereto. The mixture was stirred for 1 hour at 0℃, excess ethyl acetate was added and the mixture was filtered with Celite. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (100mg, 100%).
Preparation Example 8-1: synthesis of 7-chloro-1-thiophen-3-yl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 6-1, 7-chloro-1H-indole-6-carboxylic acid methyl ester (300mg, 1.43mmol) rather than 1H-indole-6-carboxylic acid methyl ester was used to obtain the title compound (33mg, 7.5%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.60 (d, 1H), 7.32 (m, 2H), 7.27 (d, 1H), 7.14 (dd, 1H), 6.68 (d, 1H), 3.92 (s, 3H)
Preparation Example 8-2: synthesis of 7-chloro-1-thiophen-3-yl-1H-indole-6-carbaldehyde
In the methods described in Preparation Examples 7-4 and 7-5, the compound (33mg, 0.11mmol) obtained from Preparation Example 8-1 rather than the compound obtained from Preparation Example 7-3 was used to obtain the title compound (17mg, 59%).
Preparation Example 9-1: synthesis of 7-chloro-1-(4-fluoro-phenyl)-1H-indole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 6-1, 7-chloro-1H-indole-6-carboxylic acid methyl ester (100mg, 0.48mmol) and 1-fluoro-4-iodo-benzene were used to obtain the title compound (15mg, 10%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.63 (d, 2H), 7.34 (m. 2H), 7.24 (d, 1H), 7.15 (m, 2H), 6.65 (d, 1H), 3.90 (s, 3H)
Preparation Example 9-2: synthesis of 7-chloro-1-(4-fluoro-phenyl)-1H-indole-6-carbaldehyde
In the methods described in Preparation Examples 7-4 and 7-5, the compound (15mg, 0.05mmol) obtained from Preparation Example 9-1 was used rather than the compound obtained from Preparation Example 7-3 to obtain the title compound (10mg, 74%).
Preparation Example 10-1: synthesis of 7-chloro-1-cyclohexylmethyl-1H-indole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 7-3, the compound (100mg, 0.51mmol) obtained from Preparation Example 7-2 and bromomethyl cyclohexane (181mg, 1.02mmol) were used to obtain the title compound (57mg, 36%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (s, 1H), 7.12 (d, 1H), 6.46 (s, 1H), 4.34 (d, 2H), 3.94 (s, 2H), 1.87-1.97 (m, 1H), 1.68-1.70 (m, 3H), 1.55 (s, 3H), 1.15-1.19 (m, 3H), 0.96-1.01 (m, 2H)
Preparation Example 10-2: synthesis of 7-chloro-1-cyclohexylmethyl-1H-indole-6-carbaldehyde
In the methods described in Preparation Examples 7-4 and 7-5, the compound (57mg, 0.19mmol) obtained from Preparation Example 10-1 rather than the compound obtained from Preparation Example 7-3 was used to obtain the title compound (32mg, 64%).
Preparation Example 11-1: synthesis of 1-(4-fluoro-2-methyl-phenyl)-1H-indole-6-carboxylic acid methyl ester
1H-indole-6-carboxylic acid methyl ester (200mg, 1.14mmol) was dissolved in dioxane (2ml). 1-Bromo-4-fluoro-2-methyl-benzene (0.3ml, 2.28mmol), copper (I) iodide (22mg, 0.11mmol), potassium phosphate tribasic (K3PO4, 509mg, 2.40mmol), dodecane (0.2ml, 0.11mmol) and cyclohexane 1,2-diamine (0.03ml, 0.23mmol) were added dropwise thereto, and then the mixture was stirred for 8 hours at 110℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (150mg, 46%).
Preparation Example 11-2: synthesis of [1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-yl]-methanol
The compound (150mg, 0.53mmol) obtained from Preparation Example 11-1 was dissolved in tetrahydrofuran (10ml), and lithium aluminium hydride (200mg, 5.27mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature, and then water (1ml), 6N sodium hydroxide (2ml) and water (3ml) were added sequentially. Ethyl acetate was added thereto. The mixture was filtered with Celite, distilled under reduced pressure and separated by column chromatography to obtain the title compound (135mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (d, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 7.12 (d, 1H), 7.08 (m, 1H), 7.01 (m, 2H), 6.65 (d, 1H), 4.74(d, 2H), 2.03 (s, 3H)
Preparation Example 12-1: synthesis of 3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indole-6-carboxylic acid methyl ester
The compound (70mg, 0.25mmol) obtained from Preparation Example 11-1 was dissolved in tetrahydrofuran (10ml), and N-chloro-succinimide (NCS, 40mg, 0.30mmol) was added dropwise thereto. The mixture was stirred for 4 hours at 60℃. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (70mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (dd, 1H), 7.72 (d, 1H), 7.70 (dd, 1H), 7.21-7.24 (m, 2H), 7.02-7.13 (m, 2H), 3.89 (s, 3H), 2.03 (s, 3H)
Preparation Example 12-2: synthesis of [3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-yl]-methanol
The compound (70mg, 0.22mmol) obtained from Preparation Example 12-1 was dissolved in tetrahydrofuran (10ml), and lithium aluminium hydride (200mg, 5.27mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature, and water (1ml), 6N sodium hydroxide (2ml) and water (3ml) were added sequentially. Ethyl acetate was added, and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (50mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.68 (d, 1H), 7.23-7.26 (m, 2H), 7.13-7.06 (m, 2H), 7.04-6.99 (m, 2H), 4.75 (s, 2H), 2.04 (s, 3H)
Preparation Example 13-1: synthesis of 2-fluoro-4-methyl-5-nitro-benzoic acid
2-Fluoro-4-methyl-benzoic acid (2.0g, 13mmol) was dissolved in 12N sulfuric acid solution (40ml). A mixture of 12N sulfuric acid solution (15.6mmol) and nitric acid solution (19.5mmol) was added dropwise thereto at 0℃. After stirring for 1 hour at 0℃, an excess of ice water was added. The resulting solid was filtered and dried to obtain the title compound (2.3g, 88%).
Preparation Example 13-2: synthesis of 2-fluoro-4-methyl-5-nitro-benzoic acid methyl ester
The compound (2.3g, 11.5mmol) obtained from Preparation Example 13-1 was dissolved in tetrahydrofuran (30ml), and 0.25M solution of diazomethane in diethyl ether (50ml, 12.5mmol) was added dropwise thereto. After stirring for 30 minutes at 0℃, the mixture was distilled under reduced pressure to obtain the title compound (2.4g, 98%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.63 (d, 1H), 7.12 (d, 1H), 7.09 (d, 1H), 3.95 (s, 3H), 2.66 (s, 3H)
Preparation Example 13-3: synthesis of 4-((E)-2-dimethylamine-vinyl)-2-fluoro-5-nitro-benzoic acid methyl ester
The compound (2.4g, 11.2mmol) obtained from Preparation Example 13-2 was dissolved in dimethylformamide (10ml). N, N-dimethylformamide dimethyl acetal (1.8ml, 13.4mmol) was added thereto, and the mixture was stirred for 1 hour at 100℃. Excess water was added, and then resulting solids were filtered and dried to obtain the title compound (2.0g, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.54 (d, 1H), 7.15 (d, 1H), 7.09 (d, 1H), 5.97 (dd, 1H), 3.90 (s, 3H), 3.01 (s, 6H)
Preparation Example 13-4: synthesis of 5-fluoro-1H-indole-6-carboxylic acid methyl ester
The compound (2.0g, 7.5mmol) obtained from Preparation Example 13-3 was dissolved in ethyl acetate (100ml). 5% Palladium/carbon (100mg) was added, and the mixture was stirred for 2 hours under hydrogen gas. After completion of the reaction, the mixture was filtered with Celite, distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.3g, 90%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.68 (br s, 1H), 8.04 (d, 1H), 7.40 (dd, 1H), 7.34 (d, 1H), 6.54 (dd, 1H), 3.95 (s, 3H)
Preparation Example 13-5: synthesis of [5-fluoro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 11-1 and 11-2, the compound (200mg, 1.14mmol) obtained from Preparation Example 13-4 was used rather than 1H-indole-6-carboxylic acid methyl ester to obtain the title compound (74mg, 23%).
Preparation Example 14-1: synthesis of 1-cyclohexylmethyl-1H-indole-6-carboxylic acid methyl ester
1H-indole-6-carboxylic acid methyl ester (300mg, 1.71mmol) was dissolved in dimethyl formamide (7ml). Bromomethyl cyclohexane (0.5ml, 3.42mmol) and sodium hydride (150mg, 3.42mmol) were added dropwise thereto at 0℃, and then the mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (150mg, 32%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.29-7.39 (m, 2H), 7.19 (d, 1H), 7.13 (m, 1H), 7.00-7.09 (m, 2H), 6.66 (m, 1H), 4.83 (s, 2H), 2.06 (s, 3H)
Preparation Example 14-2: synthesis of (1-cyclohexylmethyl-1H-indol-6-yl)-methanol
The compound (150mg, 0.55mmol) obtained from Preparation Example 14-1 was dissolved in tetrahydrofuran (10ml), and lithium aluminium hydride (200mg, 5.27mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature, and then water (1ml), 6N sodium hydroxide (1ml) and water (3ml) were added sequentially. Ethyl acetate was added and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (130mg, 97%).
Preparation Example 15-1: synthesis of 7-methyl-1H-indole-6-carboxylic acid methyl ester
In the methods described in Preparation Examples 7-1 and 7-2, 2-methyl-3-nitro-benzoic acid (5.0g, 27.6mmol) was used rather than 2-chloro-3-nitro-benzoic acid to obtain the title compound (1.4g, 27%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.39 (br s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.35 (dd, 1H), 6.58 (dd, 1H), 3.91 (s, 3H), 2.79 (s, 3H)
Preparation Example 15-2: synthesis of 1-(4-fluoro-phenyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
7-Methyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.53mmol) obtained from Preparation Example 15-1 was dissolved in dioxane (1ml). 1-Fluoro-4-iodo-benzene (0.12ml, 1.06mmol), copper (I) iodide (10mg, 0.05mmol), potassium phosphate tribasic (K3PO4, 236mg, 1.11mmol), dodecane (0.1ml, 0.05mmol) and cyclohexane 1,2-diamine (0.01ml, 0.11mmol) were added dropwise thereto and then the mixture was stirred for 18 hours at 110℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (100mg, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.71 (d, 1H), 7.57 (d, 1H), 7.36-7.41 (m, 2H), 7.18-7.25 (m, 3H), 6.67 (d, 1H), 3.93 (s, 3H), 2.22 (s, 3H)
Preparation Example 15-3: synthesis of [1-(4-fluoro-phenyl)-7-methyl-1H-indol-6-yl]-methanol
1-(4-Fluoro-phenyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.35mmol) obtained from Preparation Example 15-2 was dissolved in tetrahydrofuran (7ml), and lithium aluminium hydride (67mg, 1.76mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature and then water (1ml), 6N sodium hydroxide (1ml) and water (3ml) were added sequentially. Ethyl acetate was added thereto, and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (90mg, 100%).
Preparation Example 16: synthesis of (7-methyl-1-thiophen-3-yl-1H-indol-6-yl)-methanol
In the methods described in Preparation Examples 15-2 and 15-3, 3-bromothiophene was used rather than 1-fluoro-4-iodo-benzene to obtain the title compound (30mg, 23%).
Preparation Example 17-1: synthesis of 1-benzyl-7-methyl-1H-indole-6-carboxylic acid methyl ester
7-Methyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.53mmol) obtained from Preparation Example 15-1 was dissolved in dimethylformamide (5ml). Benzyl bromide (0.13ml, 1.06mmol) and sodium hydride (46mg, 1.06mmol) were added dropwise thereto and then the mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extacted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (100mg, 68%).
NMR:1H-NMR(400HMz, CDCl3)); δ 7.61 (d, 1H), 7.48 (d, 1H), 7.21-7.31 (m, 3H), 7.17 (d, 1H), 6.90 (d, 2H), 6.56 (d, 1H), 5.63 (s, 2H), 3.86 (s, 3H), 2.73 (s, 3H)
Preparation Example 17-2: synthesis of (1-benzyl-7-methyl-1H-indol-6-yl)-methanol
1-Benzyl-7-methyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.36mmol) obtained from Preparation Example 17-1 was dissolved in tetrahydrofuran (7ml), and lithium aluminium hydride (100mg, 2.63mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature and then water (1ml), 6N sodium hydroxide (2ml) and water (3ml) were added sequentially. Ethyl acetate was added thereto, and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (92mg, 100%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.53 (d, 1H), 7.31 (m, 3H), 7.11 (m, 2H), 6.96 (d, 2H), 6.59 (d, 1H), 5.60 (s, 1H), 4.73 (d, 2H), 2.55 (s, 3H), 1.89 (t, 1H)
Preparation Example 18-1: synthesis of 1-(2-fluoro-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 1-bromomethyl-2-fluoro-benzene was used rather than benzyl bromide to obtain the title compound (279mg, 94%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.55 (d, 1H), 7.40 (d, 1H), 7.22-7.30 (m 1H), 7.20 (d, 1H), 7.04-7.10 (m, 1H), 6.91-6.97 (m, 1H), 6.55 (d, 1H), 6.33 (dd, 1H), 5.68 (s, 2H), 3.85 (s, 3H), 2.71 (s, 3H)
Preparation Example 18-2: synthesis of [1-(2-fluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (279mg, 1.04mmol) obtained from Preparation Example 18-1 was used to obtain the title compound (161mg, 34%).
Preparation Example 19-1: synthesis of 1-(3-fluoro-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 3-fluorobenzyl bromide (270mg, 1.45mmol) was used rather than benzyl bromide to obtain the title compound (202mg, 94%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.54 (d, 1H), 7.48 (d, 1H), 7.23 (dd, 1H), 7.15 (d, 1H), 6.86-6.94 (m, 1H), 6.66 (d, 1H), 6.56 (d, 1H), 6.52 (s, 1H), 5.59 (s, 2H), 3.86 (s, 3H), 2.71 (s, 3H)
Preparation Example 19-2: synthesis of [1-(3-fluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (202mg, 0.682mmol) obtained from Preparation Example 19-1 was used to obtain the title compound (201mg, 100%).
Preparation Example 20-1: synthesis of 1-(4-fluoro-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 4-fluorobenzyl chloride (189mg, 1.31mmol) was used rather than benzyl bromide to obtain the title compound (152mg, 78%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.55 (d, 1H), 7.47 (d, 1H), 7.14 (d, 1H), 6.92-6.97 (m, 2H), 6.81-6.86 (m, 2H), 6.55 (d, 1H), 5.56 (s, 2H), 3.86 (s, 3H), 2.71 (s, 3H)
Preparation Example 20-2: synthesis of [1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (153mg, 0.51mmol) obtained from Preparation Example 20-1 was used to obtain the title compound (124mg, 90%).
Preparation Example 21-1: synthesis of 1-(3,4-difluoro-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 3,4-difluorobenzyl bromide (275mg, 1.33mmol) was used rather than benzyl bromide to obtain the title compound (203mg, 97%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.58 (d, 1H), 7.48 (d, 1H), 7.14 (d, 1H), 7.01-7.09 (m, 2H), 6.63-6.68 (m, 1H), 6.57 (d, 1H), 5.53 (s, 2H), 3.86 (s, 3H), 2.70 (s, 3H)
Preparation Example 21-2: synthesis of [1-(3,4-difluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (203mg, 0.64mmol) obtained from Preparation Example 21-1 was used to obtain the title compound (162mg, 57%).
Preparation Example 22: synthesis of [1-(2,6-difluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 2,6-difluorobenzyl bromide was used rather than benzyl bromide to obtain the title compound (200mg, 100%).
Preparation Example 23: synthesis of [1-(3,5-difluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 3,5-difluorobenzyl bromide (0.2g, 0.99mmol) was used rather than benzyl bromide to obtain the title compound (0.13g, 91%).
Preparation Example 24: synthesis of [1-(2,4-difluoro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 2,4-difluorobenzyl bromide (0.22g, 1.05mmol) was used rather than benzyl bromide to obtain the title compound (0.14g, 94%).
Preparation Example 25-1: synthesis of 1-(2-chloro-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 2-chlorobenzyl bromide (437mg, 2.13mmol) was used rather than benzyl bromide to obtain the title compound (302mg, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.56 (d, 1H), 7.48 (d, 1H), 7.20 (d, 1H), 7.17 (dd, 1H), 7.12 (d, 1H), 7.10 (dd, 1H), 6.51 (d, 1H), 6.27 (d, 1H), 5.67 (s, 2H), 5.66 (s, 3H), 3.84 (s, 3H), 2.63 (s, 3H)
Preparation Example 25-2: synthesis of [1-(2-chloro-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (302mg, 0.96mmol) obtained from Preparation Example 25-1 was used to obtain the title compound (275mg, 100%).
Preparation Example 26-1: synthesis of 7-methyl-1-(2-methyl-benzyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 2-methylbenzyl bromide (393mg, 2.13mmol) was used rather than benzyl bromide to obtain the title compound (278mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.54 (d, 1H), 7.47 (d, 1H), 7.09-7.20 (m, 2H), 7.04 (d, 1H), 6.98 (dd, 1H), 6.53 (d, 1H), 6.29 (d, 1H), 5.53 (s, 2H), 3.83 (s, 3H), 2.64 (s, 3H), 2.29 (s, 3H)
Preparation Example 26-2: synthesis of [7-methyl-1-(2-methyl-benzyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (186mg, 0.63mmol) obtained from Preparation Example 26-1 was used to obtain the title compound (125mg, 100%).
Preparation Example 27-1: synthesis of 7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 3-trifluoromethyl-benzyl (359mg, 1.50mmol) was used rather than benzyl bromide to obtain the title compound (239mg, 92%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.69 (d, 1H), 7.56 (d, 1H), 7.51 (d, 1H), 7.33 (dd, 2H), 7.12 (d, 1H), 6.89 (d, 1H), 6.31 (d, 1H), 5.79 (s, 2H), 3.84 (s, 3H), 2.59 (s, 3H)
Preparation Example 27-2: synthesis of [7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (239mg, 0.69mmol) obtained from Preparation Example 27-1 was used to obtain the title compound (203mg, 100%).
Preparation Example 28: synthesis of [7-methyl-1-(4-trifluoromethyl-benzyl)-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 4-trifluoromethylbenzyl bromide was used rather than benzyl bromide to obtain the title compound (488mg, 100%).
Preparation Example 29-1: synthesis of 1-(2,6-dimethyl-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 2,6-dimethylbenzyl bromide (210mg, 1.06mmol) was used rather than benzyl bromide to obtain the title compound(213mg, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.62 (d, 1H), 7.50 (d, 1H), 7.20 (dd, 1H), 7.11 (d, 2H), 6.62 (d, 1H), 6.32 (d, 1H), 5.67 (s, 2H), 3.92 (s, 3H), 3.14 (s, 3H), 2.24 (s, 6H)
Preparation Example 29-2: synthesis of [1-(2,6-dimethyl-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (189mg, 0.61mmol) obtained from Preparation Example 29-1 was used to obtain the title compound(181mg, 99%).
Preparation Example 30: synthesis of [1-(4-methoxy-benzyl)-7-methyl-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 4-methoxybenzyl bromide was used rather than benzyl bromide to obtain the title compound.
Preparation Example 31-1: synthesis of 1-[3-(t-butyl-dimethyl-silanyl oxymethyl)-benzyl]-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, t-butyl-(3-chloromethyl-benzyloxy)-dimethyl-silane (1.0g, 3.7mmol) was used rather than benzyl bromide to obtain the title compound (800mg, 51%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.55 (d, 2H), 7.48 (d, 1H), 7.23 (d, 21H), 7.18 (s, 1H), 7.17 (d, 1H), 6.87 (s, 1H), 6.78 (d, 1H), 6.55 (d, 1H), 5.62 (s, 2H), 4.64 (s, 2H), 3.85 (s, 3H), 2.70 (s, 3H), 1.56 (s, 2H), 0.86 (s, 9H), 0.01 (s, 6H)
Preparation Example 31-2: synthesis of 1-(3-hydroxymethyl-benzyl)-7-methyl-1H-indol-6-yl-carboxylic acid methyl
The compound (800mg, 1.9mmol) obtained from Preparation Example 31-1 was dissolved in tetrahydrofuran (20ml). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.7ml, 1.0M) was added thereto, and then the mixture was stirred for 2 hours at room temperature. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (350mg, 67%).
NMR:1H-NMR(400HMz, CDCl3); 7.56 (d, 1H), 7.50 (d, 1H), 7.26 (m, 2H), 7.18 (d, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.57 (d, 1H), 5.64 (s, 2H), 4.62 (d, 2H), 3.86 (s, 3H), 2.73 (s, 3H),
Preparation Example 31-3: synthesis of 1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-yl-carboxylic acid methyl ester
The compound (178mg, 0.58mmol) obtained from Preparation Example 31-2 was dissolved in tetrahydrofuran (10ml), and methyl iodide (0.11ml, 1.7mmol) and sodium hydride (69mg, 2.9mmol) were added dropwise at 0℃. The mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (141mg, 75%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.59 (d, 1H), 7.49 (d, 1H), 7.19-7.25 (m, 2H), 7.15 (d, 1H), 6.96 (s, 1H), 6.76 (d, 1H), 6.55 (d, 1H), 5.66 (s, 2H), 4.37 (s, 2H), 3.85 (s, 3H), 3.34 (s, 3H), 2.72 (s, 3H)
Preparation Example 31-4: synthesis of [1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (99.6mg, 0.31mmol) obtained from Preparation Example 31-3 was used to obtain the title compound (90.3mg, 98%).
Preparation Example 32: synthesis of [1-(4-methanesulfonyl-benzyl)-7-methyl-1H-indol-6-yl]-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 1-bromomethyl-4-methanesulfonyl-benzene was used rather than benzyl bromide to obtain the title compound (368mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (t, 2H), 7.58 (d, 2H), 7.42 (d, 1H), 7.10 (d, 2H), 6.51 (d, 1H), 4.62 (d, 2H), 4.51 (d, 2H), 2.51 (s, 3H), 2.38 (s, 3H)
Preparation Example 33-1: synthesis of 1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, methanesulfonic acid 3-methanesulfonylmethyl-benzyl ester was used rather than benzyl bromide to obtain the title compound (150mg, 51%)).
NMR:1H-NMR(400HMz, CDCl3); δ 7.54 (d, 1H), 7.49 (d, 1H), 7.28-7.36 (m, 2H), 7.20 (d, 1H), 6.94 (d, 1H), 6.78 (s, 1H), 6.59 (d, 1H), 5.66 (s, 2H), 4.12 (s, 2H), 3.86 (s, 3H), 2.68 (s, 3H), 2.56 (s, 3H)
Preparation Example 33-2: synthesis of [1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (150mg, 0.40mmol) obtained from Preparation Example 33-1 was used to obtain the title compound (130mg, 94%).
Preparation Example 34: synthesis of 1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, methanesulfonic acid 4-methanesulfonylmethyl-benzyl ester was used rather than benzyl bromide to obtain the title compound (250mg, 85%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.56 (d, 1H), 7.49 (d, 1H), 7.32 (dd, 2H), 7.17 (d, 1H), 6.93 (d, 2H), 6.58 (d, 1H), 5.66 (s, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 2.74 (s, 3H), 2.70 (s, 3H)
Preparation Example 35: synthesis of [1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (250mg, 0.67mmol) obtained from Preparation Example 34 was used to obtain the title compound (230mg, 100%).
Preparation Example 36-1: synthesis of 7-methyl-1-(6-methyl-pyridin-3-ylmethyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, methanesulfonic acid 6-methyl-pyridin-3-ylmethyl ester (1.20g, 5.96mmol) was used rather than benzyl bromide to obtain the title compound (0.38g, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.22 (s, 1H), 7.55 (d, 1H), 7.47 (d, 1H), 7.10 (d, 1H), 7.00 (d, 1H), 6.93 (dd, 1H), 6.56 (d, 1H), 5.58 (s, 2H), 3.86 (s, 3H), 2.73 (s, 3H), 2.50 (s, 3H)
Preparation Example 36-2: synthesis of [7-methyl-1-(6-methyl-pyridin-3-ylmethyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound obtained from Preparation Example 36-1 was used to obtain the title compound (137mg, 100%).
Preparation Example 37-1: synthesis of 1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 5-bromomethyl-2-chloro-pyridine (223mg, 1.38mmol) was used rather than benzyl bromide to obtain the title compound (178mg, 82%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.16 (d, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 7.03 (dd, 1H), 6.62 (d, 1H), 5.63 (s, 2H), 3.91 (s, 3H), 2.74 (s, 3H)
Preparation Example 37-2: synthesis of [1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound obtained from Preparation Example 37-1 was used to obtain the title compound (148mg, 89%).
Preparation Example 38-1: synthesis of 7-methyl-1-pyrazin-2-ylmethyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, methanesulfonic acid pyrazin-2-yl methyl ester (132mg, 0.70mmol) was used rather than benzyl bromide to obtain the title compound (59mg, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.54 (d, 1H), 8.47 (d, 1H), 7.90 (s, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 7.24 (d, 1H), 6.62 (d, 1H), 5.76 (s, 2H), 3.87 (s, 3H), 2.72 (s, 3H)
Preparation Example 38-2: synthesis of (7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-yl)-methanol
According to the method described in Preparation Example 17-2, the compound obtained from Preparation Example 38-1 was used to obtain the title compound (39.8mg, 75%).
Preparation Example 39: synthesis of (7-methyl-1-pyrimidin-4-ylmethyl-1H-indol-6-yl)-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 4-bromomethyl-pyrimidine (0.74g, 4.26mmol) was used rather than benzyl bromide to obtain the title compound (0.05g, 5%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.18 (s, 1H), 8.55 (d, 1H), 7.50 (d, 1H), 7.13 (d, 1H), 7.06 (d, 1H), 6.59 (d, 1H), 6.44 (d, 1H), 5.65 (s, 2H), 4.75 (d, 2H), 3.87 (t, 1H), 2.46 (s, 3H)
Preparation Example 40: synthesis of (7-methyl-1-pyrimidin-2-ylmethyl-1H-indol-6-yl)-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 2-bromomethyl-pyrimidine (0.39g, 2.22mmol) was used rather than benzyl bromide to obtain the title compound (0.09g, 18%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.62 (d, 2H), 7.38 (d, 1H), 7.17 (d, 1H), 7.12 (t, 1H), 7.02 (d, 1H), 6.53 (d, 1H), 5.73 (s, 2H), 4.71 (s, 2H), 2.57 (s, 3H)
Preparation Example 41: synthesis of 7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, methanesulfonic acid 5-methyl-pyrazin-2-yl methyl ester (144mg, 0.71mmol) was used rather than benzyl bromide to obtain the title compound (96mg, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.76 (s, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.22 (d, 1H), 6.59 (d, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 2.73 (s, 3H), 2.46 (s, 3H)
Preparation Example 42: synthesis of [7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (96mg, 0.33mmol) obtained from Preparation Example 41 was used to obtain the title compound (87mg, 100%).
Preparation Example 43-1: synthesis of 7-methyl-1-thiazol-4-ylmethyl-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 4-chloromethyl-thiazole (144mg, 0.85mmol) was used rather than benzyl bromide to obtain the title compound (159mg, 86%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.79 (d, 1H), 7.55 (d, 1H), 7.47 (d, 1H), 7.22 (d, 1H), 6.56 (d, 1H), 6.34 (s, 1H), 5.77 (s, 2H), 3.87 (s, 3H), 2.75 (s, 3H)
Preparation Example 43-2: synthesis of (7-methyl-1-thiazol-4-ylmethyl-1H-indol-6-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (108mg, 0.38mmol) obtained from Preparation Example 43-1 was used to obtain the title compound (93mg, 95%).
Preparation Example 44-1: synthesis of 7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 4-chloromethyl-2-methyl-thiazole (152mg, 0.83mmol) was used rather than benzyl bromide to obtain the title compound (118mg, 62%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.54 (d, 1H), 7.46 (d, 1H), 7.20 (s, 1H), 6.54 (d, 1H), 6.23 (s, 1H), 5.62 (s, 2H), 3.87 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H)
Preparation Example 44-2: synthesis of [7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (118mg, 0.39mmol) obtained from Preparation Example 44-1 was used to obtain the title compound (91mg, 85%).
Preparation Example 45: synthesis of [7-methyl-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indol-6-yl]-methanol
The compound obtained by using 4-bromomethyl-pyrazol-1-carboxylic acid―t-butyl ester (0.75g, 2.89mmol) rather than benzyl bromide in the method described in Preparation Example 17-1 was dissolved in methylene chloride (4ml). 4M hydrochloride solution was added thereto and the mixture was stirred for 1 hour. The mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in dimethylformamide (6ml), and sodium hydride (0.09g, 2.04mmol) and methyl iodide (0.33g, 2.36mmol) were added thereto. The mixture was stirred for 2 hours. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the ester compound. The tilte compound (0.06g, 9%) was obtained by using the ester compound according to the method described in Preparation Example 17-2.
NMR:1H-NMR(400HMz, CDCl3); δ 7.44 (d, 1H), 7.25 (s, 1H), 7.07 (d, 2H), 6.91 (s, 1H), 6.48 (d, 1H), 5.44 (s, 2H), 4.77 (s, 2H), 3.75 (s, 3H), 2.68 (s, 3H)
Preparation Example 46: synthesis of (1-benzyl-7-chloro-1H-indol-6-yl)-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 7-chloro-1H-indole-6-carboxylic acid methyl ester (300mg, 1.43mmol) was used rather than 7-methyl-1H-indole-6-carboxylic acid methyl ester to obtain the title compound (250mg, 64%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.21-7.30 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.00 (d, 2H), 6.55 (d, 1H), 5.79 (s, 2H), 4.85 (d, 2H), 1.84 (br t, 1H)
Preparation Example 47-1: synthesis of 1-benzyl-5-fluoro-1H-indole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 17-1, the compound (321mg, 1.66mmol) obtained from Preparation Example 13-4 and benzyl bromide (569mg, 3.33mmol) were used to obtain the title compound (391mg, 83%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.92 (d, 1H), 7.23-7.30 (m, 5H), 7.08 (d, 2H), 6.50 (d, 1H), 5.31 (s, 2H), 3.90 (s, 3H)
Preparation Example 47-2: synthesis of (1-benzyl-5-fluoro-1H-indol-6-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (391mg, 1.38mmol) obtained from Preparation Example 47-1 was used to obtain the title compound (352mg, 100%).
Preparation Example 48-1: synthesis of 3-amino-6-fluoro-4-iodo-2-methyl-benzoic acid methyl ester
3-Amino-6-fluoro-2-methyl-benzoic acid methyl ester (2.6g, 14.2mmol) was dissolved in acetic acid (20ml). N-iodo-succinimide (NIS, 2.53g, 14.2mmol) was added dropwise thereto, and the mixture was stirred for 4 hours at room temperature. The mixture was distilled under reduced pressure. Water was added thereto, and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.06g, 93%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.31 (d, 1H), 3.97 (br s, 2H), 3.92 (s, 3H), 2.21 (s, 3H)
Preparation Example 48-2: synthesis of 3-amino-6-fluoro-2-methyl-4-trimethylsilanyl ethinyl-benzoic acid methyl ester
The compound (2.0g, 6.47mmol) obtained from Preparation Example 48-1 was dissolved in tetrahydrofuran (50ml). Trimethylsilylacetylene (0.95ml, 9.7mmol), copper (I) iodide (25mg, 0.13mmol), bis(triphenylphosphine) palladium (II) dichloride (Pd(Ph3P)2Cl2, 91mg, 0.13mmol) and triethylamine (2.7ml, 19.4mmol) were added dropwise thereto, and then the mixture was stirred for 8 hours at 110℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.79mg, 98%).
NMR:1H-NMR(400HMz, CDCl3); δ 6.94 (d, 1H), 4.13 (br s, 2H), 3.92 (s, 3H), 2.13 (s, 3H), 0.27 (s, 9H)
Preparation Example 48-3: synthesis of 5-fluoro-7-methyl-1H-indole-6-carboxylic acid methyl ester
The compound (1.54g, 5.51mmol) obtained from Preparation Example 48-2 was dissolved in pyridine (40ml). Acetylchloride (3.9ml, 55.1mmol) was slowly added dropwise at -15℃, and the mixture was stirred while slowly raising the reaction temperature up to 0℃. The mixture was distilled under reduced pressure and 1N hydrochloric acid solution was added thereto. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain a compound. To the obtained compound, tetrahydrofuran (50ml) and 2 N solution of tetrabutylammonium fluoride in tetrahydrofuran (5.5ml, 11.0mml) were added. The mixture was stirred for 8 hours at 80℃ and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (810mg, 71%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.23 (br s, 1H), 7.32 (m, 1H), 7.18 (d, 1H), 6.52 (m, 1H), 3.95 (s, 3H), 2.55 (s, 3H)
Preparation Example 48-4: synthesis of (1-benzyl-5-fluoro-7-methyl-1H-indol-6-yl)-methanol
In the methods described in Preparation Examples 17-1 and 17-2, the compound (200mg, 1.04mmol) obtained from Preparation Example 48-3 was used rather than 7-methyl-1H-indole-6-carboxylic acid methyl ester to obtain the title compound (251mg, 96%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.29 (m, 3H), 7.18 (d, 1H), 7.12 (d, 1H), 6.87 (d, 1H), 6.49 (d, 1H), 5.59 (s, 2H), 4.82 (m, 2H), 2.57 (s, 3H)
Preparation Example 49-1: synthesis of 1-benzyl-3-fluoro-7-methyl-1H-indole-6-carboxylic acid methyl ester
The compound (258mg, 0.92mmol) obtained from Preparation Example 17-1 and N-fluoro-2,4,6-trimethylpyridinium triflate (321mg, 1.11mmol) were used to obtain the title compound (30mg, 11%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.59 (d, 1H), 7.54 (d, 1H), 7.30-7.36 (m, 3H), 7.00 (d, 1H), 6.97 (d, 1H), 6.95 (d, 1H), 3.92 (s, 2H), 3.92 (s, 3H), 2.77 (s, 3H)
Preparation Example 49-2: synthesis of (1-benzyl-3-fluoro-7-methyl-1H-indol-6-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (30mg, 0.10mmol) obtained from Preparation Example 49-1 was used to obtain the title compound (27mg, 100%).
Preparation Example 50-1: synthesis of 1-methyl-1H-indole-5-carboxylic acid methyl ester
1H-indole-6-carboxylic acid methyl ester (1.0g, 5.71mmol) was dissolved in dimethylformamide (10ml), and methyl iodide (0.53ml, 8.56mmol) and sodium hydride (374mg, 8.56mmol) were added dropwise thereto at 0℃. The mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (600mg, 56%).
Preparation Example 50-2: synthesis of 3-benzyl-1-methyl-1H-indole-5-carboxylic acid methyl ester
The compound (200mg, 1.06mmol) obtained from the Preparation Example 50-1 was dissolved in dioxane (7ml). Benzyl bromide (0.25ml, 2.11mmol) and zinc bromide (ZnBr2, 140mg, 0.53mmol) were added thereto, and the mixture was stirred for 3 hours at 60℃. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the mixture of the title compound and 2,3-dibenzyl-1-methyl-1H-indole-5-carboxylic acid methyl ester.
Preparation Example 50-3: synthesis of (3-benzyl-1-methyl-1H-indol-5-yl)-methanol
According to the method described in Preparation Example 17-2, the compound obtained from Preparation Example 50-2 was used to obtain a mixture of the title compound and (2,3-dibenzyl-1-methyl-1H-indol-5-yl)-methanol.
Preparation Example 51-1: synthesis of 3-bromo-1-methyl-1H-indole-5-carboxylic acid methyl ester
1-Methyl-1H-indole-5-carboxylic acid methyl ester (200mg, 1.06mmol) obtained from Preparation Example 50-1 was dissolved in dimethylformamide (5ml). N-bromosuccinimide (NBS, 208mg, 1.17mmol) was added dropwise thereto, and then the mixture was stirred for 2 hours at 0℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (250mg, 88%).
Preparation Example 51-2: synthesis of 1-methyl-3-o-tolyl-1H-indole-5-carboxylic acid methyl ester
The compound obtained from Preparation Example 51-1 was dissolved in dimethylformamide (5ml). 2-Methylphenylboronic acid (102mg, 0.75mmol), potassium phosphate tribasic (K3PO4, 509mg, 2.40mmol) and palladium tetrakistriphenylphosphine (Pd(PPh3)4, 86mg, 0.07mmol) were added dropwise thereto, and then the mixture was stirred for 8 hours at 100℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (85mg, 81%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.24 (d, 1H), 7.97 (dd, 1H), 7.33-7.39 (m, 2H), 7.29-7.31 (m, 1H), 7.26-7.28 (m, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 2.31 (s, 3H)
Preparation Example 51-3: synthesis of (1-methyl-3-o-tolyl-1H-indol-5-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (85mg, 0.30mmol) obtained from Preparation Example 51-2 was used to obtain the title compound (59mg, 78%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.49 (s, 1H), 7.24-7.42 (m, 6H), 7.06 (s, 1H), 4.74 (s, 2H), 3.85 (s, 3H), 2.33 (s, 3H)
Preparation Example 52-1: synthesis of 2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-6-carboxylic acid methyl ester
In the methods described in Preparation Examples 48-1 to 48-3, 3-amino-4-iodo-benzoic acid methyl ester (500mg, 1.8mmol) rather than 3-amino-6-fluoro-4-iodo-2-methyl-benzoic acid methyl ester and 2-buty-3-yloxy-tetrahydro-pyrane rather than trimethylsilylacetylene were used to obtain the title compound (200mg, 37%).
Preparation Example 52-2: synthesis of 1-benzyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 17-1, the compound (200mg, 0.66mmol) obtained from Preparation Example 52-1 was used to obtain the title compound (240mg, 92%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.78 (dd, 1H), 7.58 (d, 1H), 7.21-7.24 (m, 3H), 6.93 (d, 2H), 6.46 (s, 1H), 5.46 (s, 2H), 4.57 (t, 1H), 3.89 (s, 3H), 4.02-4.08 (m, 1H), 3.71 (t, 2H), 3.67-3.76 (m, 2H), 3.44-3.47 (m, 1H), 3.00 (t, 2H), 1.78-1.80 (m, 1H), 1.66-1.71 (m, 1H), 1.51-1.56 (m, 4H)
Preparation Example 52-3: synthesis of 1-benzyl-2-(2-hydroxy-ethyl)-1H-indole-6-carboxylic acid methyl ester
The compound (240mg, 0.61mmol) obtained from Preparation Example 52-2 was dissolved in ethanol (5ml) and p-toluenesulfonic acid (23mg, 0.12mmol) was added thereto. The mixture was stirred for 3 hours at room temperature and excess triethylamine was added. The mixture was distilled under reduced pressure and the residue was isolated by column chromatography to obtain the title compound (160mg, 85%).
Preparation Example 52-4: synthesis of 1-benzyl-2-(2-methoxy-ethyl)-1H-indole-6-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, the compound (160mg, 0.52mmol) prepared from Preparation Example 52-3 and methyl iodide rather than benzyl bromide were used to obtain the title compound (160mg, 94%).
Preparation Example 52-5: synthesis of [1-benzyl-2-(2-methoxy-ethyl)-1H-indol-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (160mg, 0.49mmol) obtained from Preparation Example 52-4 was used to obtain the title compound (130mg, 90%).
Preparation Example 53-1: synthesis of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid
1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (120mg, 0.84mmol) was dissolved in ethanol (10ml). 6N Sodium hydroxide (1.4ml, 8.4mmol) was added, and the mixture was stirred for 18 hours at 90℃. The mixture was distilled under reduced pressure, and then 1N hydrochloric acid solution was added. The resulting solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (100mg, 74%).
NMR:1H-NMR(400HMz, DMS)-d 6); δ 12.08(brs, 1H),8.11(d, 1H), 7.83(d, 1H), 7.70(d, 1H), 6.58(d, 1H)
Preparation Example 53-2: synthesis of 1H-pyrrolo[2,3-b] pyridine-6-carboxylic acid methyl ester
According to the method described in Preparation Example 7-2, the compound (100mg, 0.62mmol) obtained from Preparation Example 53-1 was used to obtain the title compound (90mg, 82%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.06 (dd, 1H), 8.00 (d, 1H), 7.73 (dd, 1H), 6.60 (dd, 1H), 4.06 (s, 3H)
Preparation Example 53-3: synthesis of 1-(4-fluoro-benzyl)-1H-pyrazolo[2,3-b] pyridine-6-carboxylic acid methyl ester
According to the method described in Preparation Example 17-1, the compound (90mg, 0.51mmol) obtained from Preparation Example 53-2 and 4-fluorobenzyl bromide were used to obtain the title compound (100mg, 69%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (d, 1H), 7.98 (d, 1H), 7.23-7.29 (m, 2H), 6.98-7.02 (m, 3H), 6.54 (d, 1H), 5.55 (s, 2H), 4.02 (s, 3H)
Preparation Example 53-4: synthesis of [1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-b] pyridin-6-yl]-methanol
According to the method described in Preparation Example 17-2, the compound (100mg, 0.35mmol) obtained from Preparation Example 53-3 was used to obtain the title compound (70mg, 77%).
Preparation Example 54-1: synthesis of 1-benzyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile
According to the method described in Preparation Example 17-1, 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (150mg, 1.18mmol) and benzyl bromide were used to obtain the title compound (270mg, 97%).
NMR:1H-NMR(400HMz, CDCl3); δ7.98 (d, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.21-7.35 (m, 5H), 6.56 (d, 1H), 5.50 (s, 2H)
Preparation Example 54-2: synthesis of (1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-methanol
The compound (270mg, 1.15mmol) obtained from Preparation Example 54-1 was dissolved in ethanol (50ml). 6N Sodium hydroxide (2.0ml, 11.57mmol) was added, and the mixture was stirred for 18 hours at 90℃. The mixture was distilled under reduced pressure, and then 1N hydrochloric acid solution was added. The resulting solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain 1-benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid.
1-Benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid was dissolved in methylenechloride (20ml) and 0.25M solution of diazomethane in diethyl ether (5.0ml, 1.38mmol) was slowly added dropwise. The mixture was stirred for 30 minutes at room temperature, and then distilled under reduced pressure to obtain 1-benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (310mg, 100%).
According to the method described in Preparation Example 17-2, 1-benzyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (310mg, 1.15mmol) was used to obtain the title compound (275mg, 99%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.90 (d, 1H), 7.12-7.37 (m, 6H), 6.98 (d, 1H), 6.48 (d, 1H), 5.50 (s, 2H), 4.85 (d, 2H), 3.92 (t, 1H)
Preparation Example 55: synthesis of 1-benzyl-1H-indazole-6-carboxylic acid methyl ester and 2-benzyl-1H-indazole-6-carboxylic acid methyl ester
1H-indazole-6-carboxylic acid methyl ester (300mg, 1.7mmol) was dissolved in dimethylformamide (7ml), and sodium hydride (82mg, 1.87mmol) and benzyl bromide (0.22ml, 1.87mmol) were slowly added dropwise at 0℃. The mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography. The first compound that passed through the column chromatography was 1-benzyl-1H-indazole-6-carboxylic acid methyl ester (209mg, 46%), and the second one was 2-benzyl-1H-indazole-6-carboxylic acid methyl ester (160mg, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.15 (s, 1H), 8.10 (s, 1H), 7.82 (q, 2H), 7.33 (m, 3H), 7.20 (d, 2H), 5.65 (s, 2H), 3.94 (s, 3H)
NMR:1H-NMR(400HMz, CDCl3); δ 8.53 (s, 1H), 7.91 (s, 1H), 7.72 (d 1H), 7.64 (d, 1H), 7.37 (m, 3H), 7.29 (d, 2H), 5.63 (s, 2H), 3.95 (s, 3H)
Preparation Example 56: synthesis of (1-benzyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 17-2, 1-benzyl-1H-indazole-6-carboxylic acid methyl ester (209mg, 0.78mmol) obtained from Preparation Example 55 was used to obtain the title compound (187mg, 100%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.02 (s, 1H), 7.72 (d, 1H), 7.37 (s, 1H), 7.27 (m, 3H), 7.18 (d, 2H), 7.13 (d, 1H), 5.59 (s, 2H), 4.80 (d, 2H), 1.80 (t, 1H)
Preparation Example 57: synthesis of (2-benzyl-2H-indazol-6-yl)-methanol
According to the method described in Preparation Example 17-2, 2-benzyl-1H-indazole-6-carboxylic acid methyl ester (160mg, 0.6mmol) obtained from Preparation Example 55 was used to obtain the title compound (143mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.64 (s, 1H), 7.59 (d, 1H), 7.28-7.36 (m, 5H), 7.08 (d, 1H), 5.27 (s, 2H), 4.72 (s, 2H), 2.39 (br s, 1H)
Preparation Example 58: synthesis of [1-(4-fluoro-benzyl)-1H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 56, 4-fluorobenzylchloride (1.81g, 12.50mmol) was used rather than benzyl bromide to obtain the title compound (870mg, 30%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.72 (d, 1H), 7.38 (s, 1H), 7.12~7.18 (m, 3H), 6.97 (t, 2H), 5.55 (s, 2H), 4.82 (d, 2H), 1.90 (t, 1H)
Preparation Example 59: synthesis of [2-(4-fluoro-benzyl)-2H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 57, 4-fluorobenzylchloride (1.81g, 12.50mmol) was used rather than benzyl bromide to obtain the title compound (580mg, 20%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.87 (s, 1H), 7.67 (s, 1H), 7. 61 (d, 1H), 7.25 (t, 2H), 7.12 (d, 1H), 7.10 (t, 2H), 5.56 (s, 2H), 4.78 (d, 2H), 1.75 (t, 1H)
Preparation Example 60-1: synthesis of 1-pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester and 2-pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester
In the method described in Preparation Example 55, 1H-indazole-6-carboxylic acid methyl ester (402mg, 2.3mmol), and 2-bromomethyl-pyrimidine rather than benzyl bromide were used to obtain 1-pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester (272mg, 44%) which was the first compound that passed through column chromatography and 2-pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester (110mg, 18%) which was the second one.
Preparation Example 60-2: synthesis of (1-pyrimidin-2-ylmethyl-1H-indazol-6-yl)-methanol
1-Pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester (1.27g, 4.75mmol) obtained from Preparation Example 60-1 was dissolved in the mixture of tetrahydrofuran (10ml) and methanol (3mL). 2N sodium hydroxide solution (3ml) was added dropwise, and then the mixture was stirred for 2 hours. The mixture was acidified with 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The residue was dissolved in tetrahydrofuran (15ml). N-methyl morpholine (0.50g, 4.95mmmol) and isobutylchloroformate (0.62g, 4.54mmol) were added dropwise at 0℃. The mixture was filtered to remove insoluble solids. To the filtrate, sodium borohydride (0.31g, 8.26mmol) was added and the mixture was stirred for 3 hours. The reaction was terminated with an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.61g, 62%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.51 (d, 2H), 7.97 (s, 1H), 7.61 (d, 1H), 7.36 (s, 1H), 7.04 (d, 1H), 7.02 (d, 1H), 5.68 (s, 2H), 4.69 (s, 2H), 3.83 (br s, 1H)
Preparation Example 61: synthesis of (2-pyrimidin-2-ylmethyl-2H-indazol-6-yl)-methanol
According to the method described in Preparation Example 60-2, 2-pyrimidin-2-ylmethyl-1H-indazole-carboxylic acid methyl ester obtained from Preparation Example 60-1 was used to the title compound (131mg, 24%)
NMR:1H-NMR(400HMz, CDCl3); δ 8.67 (d, 2H), 8.08 (s, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.19 (dd, 1H), 7.08 (dd, 1H), 5.81 (s, 2H), 4.70 (d, 2H), 2.61 (br t, 1H)
Preparation Example 62: synthesis of (1-pyrazin-2-ylmethyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, 2-bromomethylpyrazine (1.40g, 8.09mmol) was used rather than benzyl bromide to obtain the title compound (0.40g, 23%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.54 (d, 1H), 8.48 (d, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.75 (d, 1H), 7.47 (s, 1H), 7.17 (d, 1H), 5.76 (s, 2H), 4.84 (d, 2H), 1.82 (t, 1H)
Preparation Example 63: synthesis of [1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 56, methanesulfonic acid 5-methyl-pyrazin-2-ylmethyl ester (2.4g, 12.08mmol) was used rather than benzyl bromide to obtain the title compound (760mg, 28%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.39 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.73 (d, 1H), 7.47 (s, 1H), 7.16 (d, 1H), 5.76 (s, 2H), 4.85 (d, 2H), 2.52 (s, 3H), 1.92 (t, 1H)
Preparation Example 64: synthesis of [2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 57, methanesulfonic acid 5-methyl-pyrazin-2-ylmethyl ester (2.4g, 12.08mmol) was used rather than benzyl bromide to obtain the title compound (0.78g, 19%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.43 (d, 2H), 8.08 (s, 1H), 7.66 (d, 2H), 7.13 (d, 1H), 5.69 (s, 2H), 4.77 (d, 2H), 2.55 (s, 3H), 1.84 (t, 1H)
Preparation Example 65: synthesis of (1-pyrimidin-4-ylmethyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, 4-chloromethyl-pyrimidine (0.66g, 5.12mmol) was used rather than benzyl bromide to obtain the title compound (0.13g, 22%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.11 (s, 1H), 8.50 (d, 1H), 8.07 (s, 1H), 7.74 (d, 1H), 7.37 (s, 1H), 7.15 (d, 1H), 6.69 (d, 1H), 5.65 (s, 2H), 4.80 (s, 2H), 2.87 (brs, 1H)
Preparation Example 66: synthesis of (2-pyrimidin-4-ylmethyl-2H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 57, 4-chloromethyl-pyrimidine (0.66g, 5.12mmol) was used rather than benzyl bromide to obtain the title compound (0.03g, 5%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.18 (s, 1H), 8.64 (d, 1H), 8.07 (s, 1H), 7.64 (d, 1H), 7.16 (d, 1H), 6.90 (d, 1H), 5.69 (s, 2H), 4.78 (s, 2H), 2.09 (brs, 1H)
Preparation Example 67: synthesis of (1-pyridin-3-ylmethyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, 3-bromomethyl-pyridine was used rather than benzyl bromide to obtain the title compound (406mg, 60%).
Preparation Example 68: synthesis of (2-pyridin-3-ylmethyl-2H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 57, 3-bromomethyl-pyridine was used rather than benzyl bromide to obtain the title compound (237mg, 35%).
Preparation Example 69: synthesis of [1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-6-yl]-methanol
In the method described in Preparation Example 45, 1H-indazole-6-carboxylic acid methyl ester (0.56g, 3.19mmol) was used rather than 7-methyl-1H-indole-6-carboxylic acid methyl ester to obtain the title compound (0.16g, 20%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.94 (s, 1H), 7.66 (d, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 5.37 (s, 2H), 4.80 (s, 1H), 3.72 (s, 3H), 3.24 (brs, 1H)
Preparation Example 70: synthesis of (1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 17-2, 1H-indazole-6-carboxylic acid methyl ester (0.18g, 0.99mmol) was used to obtain the title compound (0.15g, 100%).
NMR:1H-NMR(400HMz, MeOD); δ 8.05 (s, 1H), 7.72 (d, 1H), 7.55 (s, 1H), 7.14 (d, 1H), 4.75 (s, 2H),
Preparation Example 71: synthesis of (1-methyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, methyl iodide (0.93g, 6.52mmol) was used rather than benzyl bromide to obtain the title compound (0.15g, 28%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (s, 1H), 7.62 (d, 1H), 7.27 (s, 1H), 7.09 (d, 1H), 4.81 (s, 2H), 3.92 (s, 3H), 3.59 (brs, 1H)
Preparation Example 72: synthesis of (1-isopropyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, 2-bromo-propane (1.42g, 11.55mmol) was used rather than benzyl bromide to obtain the title compound (0.19g, 17%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.87 (s, 1H), 7.65 (d, 1H), 7.47 (s, 1H), 7.08 (d, 1H), 4.87 (s, 2H), 4.75 (m, 1H), 3.39 (brs, 1H), 1.53 (d, 6H)
Preparation Example 73: synthesis of (2-isopropyl-2H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 57, 2-bromo-propane (1.42g, 11.55mmol) was used rather than benzyl bromide to obtain the title compound (0.14g, 12%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.82 (s, 1H), 7.56 (d, 2H), 7.07 (d, 1H), 4.74 (m, 1H), 4.68 (s, 2H), 4.00 (br s, 1H), 1.59 (d, 6H)
Preparation Example 74: synthesis of (1-cyclopropylmethyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, bromomethyl cyclopropane (1.46g, 10.84mmol) was used rather than benzyl bromide to obtain the title compound (0.16g, 15%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.90 (s, 1H), 7.63 (d, 1H), 7.42 (s, 1H), 7.09 (d, 1H), 4.82 (s, 2H), 4.16 (d, 2H), 3.50 (br s, 1H), 1.25 (m, 1H), 0.53 (m, 2H), 0.38 (m, 2H)
Preparation Example 75-1: synthesis of (1-isobutyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, 1-chloro-2-methyl-propane (1.16g, 12.5mmol) was used rather than benzyl bromide to obtain the title compound (0.70g, 29%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.81 (s, 1H), 7.60 (m, 2H), 7.09 (d, 1H), 4.71 (d, 2H), 4.11 (d, 2H), 2.38 (m, 1H), 1.86 (t, 1H), 0.91 (d, 6H)
Preparation Example 75-2: synthesis of (2-isobutyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 57, 1-chloro-2-methyl-propane (1.16g, 12.5mmol) was used rather than benzyl bromide to obtain the title compound (0.69g, 29%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.82 (s, 1H), 7.60 (d, 2H), 7.09 (d, 1H), 4.71 (s, 2H), 4.13(d, 2H), 3.30 (br s, 1H), 2.39 (m, 1H), 0.90 (d, 6H)
Preparation Example 76: synthesis of (1-cyclopentyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, cyclopentyl bromide (1.69g, 11.36mmol) was used rather than benzyl bromide to obtain the title compound (481mg, 88%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.70 (d, 1H), 7.49 (s, 1H), 7.11 (d, 1H), 5.01 (m, 1H), 4.86 (d, 2H), 2.16-2.21 (m, 4H), 1.98 (m, 2H), 1.73-1.77 (m, 2H)
Preparation Example 77: synthesis of (1- cyclopentylmethyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, cyclopentyl methyl methanesulfonate (4.05g, 22.7mmol) was used rather than benzyl bromide to obtain the title compound (1.13g, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.89 (s, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.11 (d, 1H), 4.82 (s, 2H), 4.19 (d, 2H), 3.58 (br s, 1H), 2.53 (m, 1H), 1.60 (m, 4H), 1.50 (m, 2H), 1.30 (m, 2H)
Preparation Example 78: synthesis of [1-(2,2-dimethyl-propyl)-1H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 56, neopentyl iodide (844mg, 4.26mmol) was used rather than benzyl bromide to obtain the title compound (270mg, 56%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.69 (d, 1H), 7.43 (s, 1H), 7.11 (d, 1H), 4.85 (d, 2H), 4.16 (s, 2H), 1.76 (t, 1H), 1.03 (s, 9H)
Preparation Example 79-1: synthesis of [1-(2-methanesulfonyl-ethyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) and methanesulfonic acid 2-methanesulfonyl-ethyl ester (2.02g, 10.0mmol) were used to obtain the title compound (0.20g, 16%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.05 (s, 1H), 7.72 (s, 1H), 7.56-7.46 (m, 2H), 4.86 (t, 2H), 4.80 (d, 2H), 3.71 (t, 2H), 2.45 (s, 3H), 1.70 (t, 1H)
Preparation Example 79-2: synthesis of [1-(3-methanesulfonyl-propyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1.0g, 5.15mmol) and methanesulfonic acid 3-methanesulfonyl-propyl ester (1.4g, 10.3mmol) were used to obtain the title compound (0.49g, 36%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.69 (s, 1H), 7.38-7.47 (m, 2H), 4.83 (s, 2H), 4.57 (t, 2H), 2.93 (t, 2H), 2.85 (s, 3H), 2.49 (pent, 2H)
Preparation Example 80: synthesis of [1-(2-methoxy-ethyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) amd 1-bromo-2-methoxy-ethane (0.7ml, 7.5mmol) were used to obtain the title compound (0.56g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.69 (s, 1H), 7.52-7.37 (m, 2H), 4.79 (d, 2H), 4.55 (t, 2H), 3.83 (t, 2H), 3.29 (s, 3H), 1.67 (t, 1H)
Preparation Example 81: synthesis of [1-(3-methoxy-propyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) and methanesulfonic acid 3-methoxy-propyl ester (1.26g, 7.5mmol) were used to obtain the title compound (0.60g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.70 (s, 1H), 7.48-7.37 (m, 2H), 4.79 (d, 2H), 4.49 (t, 2H), 3.29 (s, 3H), 3.27 (t, 2H), 2.25-2.12 (m, 2H), 1.71 (t, 1H)
Preparation Example 82: synthesis of [1-(3-methyl-oxetan-3-ylmethyl)-1H-indazol-6-yl]-methanol
In the methods described in Preparation Examples 55 and 56, 3-methyl-3-oxetane methanesulfonate (768mg, 4.26mmol) was used rather than benzyl bromide to obtain the title compound (297mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.67 (d, 1H), 7.37 (s, 1H), 7.10 (d, 1H), 4.82 (s, 2H), 4.77 (d, 2H), 4.49 (s, 2H), 4.40 (d, 2H), 2.74 (br s, 1H), 1.23 (s, 3H)
Preparation Example 83-1: synthesis of 5-amino-2-fluoro-4-methyl-benzoic acid methyl ester
The compound (2.4g, 11.3mmol) obtained from Preparation Example 13-2 was dissolved in methanol (100ml). 10% Palladium/carbon (100mg) was added thereto, and the mixture was stirred under hydrogen gas for 8 hours. After completion of the reaction, the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (2.0g, 97%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.19 (d, 1H), 6.84 (d, 1H), 3.89 (s, 3H), 3.54 (br s, 2H), 2.18 (s, 3H)
Preparation Example 83-2: synthesis of 1-acetyl-5-fluoro-1H-indazole-6-carboxylic acid methyl ester
The compound (1.83g, 10 mmol) obtained from Preparation Example 83-1 was dissolved in chloroform (50ml), and the solution was cooled to 0℃. Acetic anhydride (2.36ml, 25mmol) was added thereto, and the solution was stirred for 1 hour at room temperature. Potassium acetate (0.29g, 3mmol) and isopentylnitrite (2.69ml, 20mmol) were added thereto, and the mixture was heated to 70℃ and stirred for 16 hours. The mixture was cooled to room temperature, diluted with dichloromethane, washed with saturated solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.77g, 33%).
NMR:1H-NMR(500HMz, CDCl3); δ 9.00 (d, 1H), 8.14 (s, 1H), 7.46 (d, 1H), 3.98(s, 3H), 2.80 (s, 3H)
Preparation Example 83-3: synthesis of 5-fluoro-1H-indazole-6-carboxylic acid methyl ester
The compound (664mg, 2.81mmol) obtained from Preparation Example 83-2 was dissolved in a mixture of tetrahydrofuran (8ml) and methanol (4ml). 1M Sodium hydroxide aqueous solution 3.4ml was added, and the reaction solution was stirred for 10 minutes. The solution was cooled to 0℃, acidified with 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (484mg, 89%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.30 (br s, 1H), 8.14 (d, 1H), 8.10 (s, 1H), 7.48 (d, 1H), 3.98 (s, 3H)
Preparation Example 84: synthesis of (1-benzyl-5-fluoro-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (388mg, 2.0mmol) obtained from Preparation Example 83-3 was used to obtain the title compound (233mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.43-7.13 (m, 7H), 5.59 (s, 2H), 4.84 (d, 2H), 1.89 (t, 1H)
Preparation Example 85: synthesis of (5-fluoro-1-isobutyl-1H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 56, the compound (243mg, 1.3mmol) prepared from Preparation Example 83-3 and isobutylchloride rather than benzyl bromide were used to obtain the title compound (78mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.48 (d, 1H), 7.32 (d, 1H), 4.88 (s, 2H), 3.95 (d, 2H), 3.28 (s, 1H), 2.25-2.36 (m, 1H), 0.89 (d, 6H)
Preparation Example 86-1: synthesis of 4-ethyl-3-nitro-benzoic acid
4-Ethyl-benzoic acid (15g, 100mmol) was dissolved in concentrated sulfuric acid (80ml), and the solution was stirred for 2 hours while adding dropwise nitric acid (40ml) at 0℃. The reaction solution was added to ice water and resulting solids were filtered and dried to obtain the title compound (20g, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.62 (s, 1H), 8.25 (d, 1H), 7.53 (d, 1H), 3.01 (m, 2H), 1.39 (q, 3H)
Preparation Example 86-2: synthesis of 4-ethyl-3-nitro-benzoic acid methyl ester
The compound obtained form Preparation Example 86-1 was dissolved in methanol (200ml) to which hydrochloric acid had been added, and the solution was stirred for 20 hours under reflux. The solution was cooled to room temperature, distilled under reduced pressure to remove methanol and separated by column chromatography to obtain the title compound (12.30g, 59%)
NMR:1H-NMR(500HMz, CDCl3); δ 8.49 (s, 1H), 8.16 (d, 1H), 7.45 (d, 1H), 3.93 (s, 3H), 2.95 (q, 2H), 1.31 (t, 3H)
Preparation Example 86-3: synthesis of 3-amino-4-ethyl-benzoic acid methyl ester
The compound obtained from Preparation Example 86-2 was dissolved in methanol (100ml), and the solution was allowed to react using palladium (1.25g) and hydrogen and filtered using Celite pad. Filtrate was separated by column chromatography to obtain the title compound (9.75g, 93%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.34 (d, 1H), 7.25 (s, 1H), 7.12 (d, 1H), 3.87 (s, 3H), 3.71 (brs, 2H), 2.56 (q, 2H), 1.27 (t, 3H)
Preparation Example 86-4: synthesis of 3-methyl-1H-indazole-6-carboxylic acid methyl ester
The compound obtained from Preparation Example 86-3 was dissolved in chloroform (50ml), and potassium acetate (6.4g, 65.28mmol) was added thereto. The nixture was cooled to 0℃. Acetic anhydride (16.7g, 163.2mmol) was added dropwise, and the reaction solution was diluted with chloroform (100ml). After adding dropwise isoamylnitrite (12.8g, 108.8mmol), the solution was stirred for 18 hours under reflux. The solution was cooled to room temperature, distilled under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane and washed with brine, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and the residue was dissolved in tetrahydrofuran (100ml). 6N sodium hydroxide (20ml) was added thereto, and the solution was stirred for 2 hours and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (5.90g, 48%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.18 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 3.96 (s, 3H), 2.61 (s, 3H)
Preparation Example 87: synthesis of (1-isobutyl-3-methyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compounds (0.50g, 2.63mmol) obtained from Preparation Example 86-4 and 1-chloro-2-methyl-propane (0.48g, 5.26mmol) were used to obtain the title compound (0.40g, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.58 (d, 1H), 7.33 (s, 1H), 7.06 (d, 1H), 4.82 (s, 2H), 4.03 (d, 2H), 3.07 (brs, 1H), 2.53 (s, 3H), 2.33 (m, 1H), 0.88 (d, 6H)
Preparation Example 88: synthesis of (2-isobutyl-3-methyl-2H-indazol-6-yl)-methanol
In the methods described in Preparation Examples 55 and 57, the compound (0.50g, 2.63mmol) prepared from Preparation Example 86-4 and 1-chloro-2-methyl-propane (0.48g, 5.26mmol) rather than benzyl bromide were used to obtain the title compound (0.11g, 18%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (d, 2H), 7.04 (d, 1H), 4.65 (s, 2H), 4.10 (d, 2H), 3.44 (brs, 1H), 2.56 (s, 3H), 2.42 (m, 1H), 0.92 (d, 6H)
Preparation Example 89-1: synthesis of 1-(5-bromo-2-hydroxy-phenyl)-3-methyl-butan-1-one
1-Bromo-4-methoxy-benzene (5.0g, 26.7mmol) was dissolved in dichloromethane (100ml), and aluminium chloride (5.3g, 40.0mmol) was added thereto at 0℃. The mixture was stirred for 5 minutes, and then isovaleryl chloride (4.9ml, 40.0mmol) was added dropwise. The mixture was stirred for 8 hours at room temperature and 2N hydrochloride solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (3.0g, 44%).
Preparation Example 89-2: synthesis of 5-bromo-3-isobutyl-benzo[d]isoxazole
7N solution of ammonia in methanol (10ml) was added to the compound (2.0g, 7.8mmol) obtained from Preparation Example 89-1, and the solution was stirred for 3 hours at room temperature. Resulting solids were filtered, washed with diethyl ether and dried. The obtained yellow compound (1.6g, 6.2mmol) was dissolved in tetrahydrofuran (20ml). N-chlorosuccinimide (NCS, 1.3g, 9.7 mmol) and potassium carbonate (1.7g, 12.3mmol) were added, and the mixture was stirred for 8 hours at room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.2g, 60%).
Preparation Example 89-3: synthesis of 3-isobutyl-benzo[d]isoxazole-5-carbonitrile
5-Bromo-3-isobutyl-benzo[d]isoxazole (1.2g, 4.7mmol) obtained from Preparation Example 89-2 was dissolved in dimethylformamide (30ml). Zinc cyanide (ZnCN2, 0.73g, 6.2mmol) and palladium tetrakistriphenylphosphine (Pd(PPh3)4, 0.55g, 0.4mmol) were added dropwise thereto, and the mixture was stirred for 8 hours at 100℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (56mg, 6%).
NMR:1H-NMR(400HMz, CDCl3): δ 8.04 (s, 1H), 7.80 (dd, 1H), 7.67 (d, 1H), 2.89 (d, 2H), 2.16-2.34 (m, 1H), 1.04 (d, 6H)
Preparation Example 89-4: synthesis of (3-isobutyl-benzo[d]isoxazol-5-yl)-methanol
According to the method described in Preparation Example 54-2, the compound (56mg, 0.28mmol) prepared from Preparation Example 89-3 was used to obtain the title compound (40mg, 69%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.64 (s, 1H), 7.51 (s, 2H), 4.80 (s, 2H), 2.82 (d, 2H), 2.22 (m, 1H), 1.00 (d, 6H)
Preparation Example 90: synthesis of (1-benzyl-1H-indol-5-yl)-methanol
In the methods described in Preparation Examples 17-1 and 17-2, 1H-indole-5-carboxylic acid methyl ester (350mg, 2.0mmol) was used rather than 7-methyl-1H-indole-6-carboxylic acid methyl ester to obtain the title compound (444mg, 93%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (s, 1H), 7.07-7.33 (m, 8H), 6.55 (d, 1H), 5.33 (s, 2H), 4.76 (d, 2H), 1.51 (t, 1H)
Preparation Example 91: synthesis of (1-benzyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carbaldehyde (970mg, 4.11mmol) was used to obtain the title compound (755mg, 77%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.03 (s, 1H), 7.72 (s, 1H), 7.23-7.39 (m, 5H), 7.18 (d, 2H), 5.60 (s, 2H), 4.78 (d, 2H), 1.64 (t, 1H)
Preparation Example 92: synthesis of (2-benzyl-2H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 57, 1H-indazole-5-carbaldehyde (548mg, 2.32mmol) was used to obtain the title compound (322mg, 58%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.84 (s, 1H), 7.70 (d, 1H), 7.57 (s, 1H), 7.25-7.37 (m, 6H), 5.56 (s, 2H), 4.74 (d, 2H), 2.17 (br s, 1H)
Preparation Example 93: synthesis of (1-phenethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester and (2-bromo-ethyl)-benzene were used to obtain the title compound (630mg, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.68 (s, 1H), 7.32 (m, 1H), 7.11-7.24 (m, 4H), 7.11 (m, 2H), 4.76 (d, 2H), 4.59 (t, 3H), 3.22 (t, 2H)
Preparation Example 94: synthesis of (1-pyridin-2-ylmethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1g, 5.68mmol) and 2-bromomethyl-pyridine hydrobromide (4.31g, 17.04mmol) were used to obtain the title compound (222mg, 84%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.47 (dd, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.44-7.48 (m, 1H), 7.28-7.34 (m, 2H), 7.08-7.12 (m, 1H), 6.74 (d, 1H), 5.62 (s, 2H), 4.73 (s, 2H), 4.13 (br s, 1H)
Preparation Example 95: synthesis of (1-pyridin-3-ylmethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) and 3-bromomethyl-pyridine (1.52g, 6.0mmol) were used to obtain the title compound (0.42g, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.56 (d, 1H), 8.51 (dd, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.48-7.32 (m, 3H), 7.20 (dd, 1H), 5.61 (s, 2H), 4.79 (s, 2H), 1.83 (br s, 1H)
Preparation Example 96: synthesis of (1-isopropyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1.5g, 8.51mmol) and isopropyl iodide (2.17g, 12.77mmol) were used to obtain the title compound (866mg, 99%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.70 (s, 1H), 7.42 (dd, 2H), 4.83-4.86 (m, 1H), 4.78 (d, 2H), 1.70 (br t, 1H), 1.59 (d, 6H)
Preparation Example 97: synthesis of (1-isobutyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester and 1-iodo-2-methyl-propane were used to obtain the title compound (600mg, 52%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.70 (s, 1H), 7.40 (dd, 2H), 4.78 (d, 2H), 4.16 (d, 2H), 2.34 (m, 1H), 0.91 (d, 6H)
Preparation Example 98: synthesis of [1-(3-methyl-butyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) and 1-bromo-3-methyl-butane (1.8ml, 15.0mmol) were used to obtain the title compound (0.49g, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.70 (s, 1H), 7.41 (d, 2H), 4.78 (d, 2H), 4.40 (t, 2H), 1.82 (q, 2H), 1.66 (t, 1H), 1.58 (m, 1H), 0.97 (d, 6H)
Preparation Example 99: synthesis of (1-cyclopropylmethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester and bromomethyl-cyclopropane (0.84g, 6.24mmol) were used to obtain the title compound (0.59g, 51%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.94 (s, 1H), 7.67 (s, 1H), 7.40 (m, 2H), 4.76 (s, 2H), 4.25 (d, 2H), 2.26 (brs, 1H), 1.55 (m, 1H), 1.31 (m, 1H), 0.56 (m, 2H), 0.38 (m, 2H)
Preparation Example 100: synthesis of (1-cyclopentyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1g, 5.68mmol) and cyclopentyl bromide (1.22ml, 11.36mmol) were used to obtain the title compound (212mg, 42%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.82 (s, 1H), 7.59 (s, 1H), 7.28-7.41 (m, 2H), 4.83-4.91 (m, 1H), 4.67 (s, 2H), 4.45 (br s, 1H), 2.06-2.10 (m, 4H), 1.87-1.93 (m, 2H), 1.63-1.69 (m, 2H)
Preparation Example 101: synthesis of (1-cyclopentylmethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1g, 5.68mmol) and cyclopentyl methane sulfonate (2.02g, 11.36mmol) were used to obtain the title compound (549mg, 53%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.92 (s, 1H), 7.67 (s, 1H), 7.16-7.36 (m, 2H), 4.73 (d, 2H), 4.22 (d, 2H), 3.45 (t, 1H), 2.44-2.54 (m, 1H), 1.45-1.63 (m, 6H), 1.26-1.29 (m, 2H)
Preparation Example 102: synthesis of (1-cyclohexylmethyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (0.88g, 5.0mmol) and bromomethyl cyclohexane (2.1ml, 15.0mmol) were used to obtain the title compound (0.53g, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.70 (s, 1H), 7.41 (d, 2H), 4.79 (d, 2H), 4.20 (d, 2H), 2.00 (m, 1H), 1.77-1.53 (m, 5H), 1.28-0.96 (m, 5H)
Preparation Example 103: synthesis of [1-(tetrahydrofuran-2-ylmethyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester (1g, 5.68mmol) and methanesulfonic acid tetrahydrofuran-2-ylmethyl ester (2.52g, 11.36mmol) were used to obtain the title compound (533mg, 40%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.90 (s, 1H), 7.59 (s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 4.67 (d, 2H), 4.94-4.52 (m, 1H), 4.34 (d, 2H), 4.23-4.26 (m, 1H), 3.61-3.67 (m, 3H), 1.58-1.70 (m, 3H)
Preparation Example 104: synthesis of [1-(tetrahydro- furan-3-ylmethyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester and methanesulfonic acid tetrahydrofuran-3yl methyl ester (1.12g, 6.24mmol) were used to obtain the title compound (0.87g, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.70 (s, 1H), 7.42 (m, 2H), 4.78 (s, 2H), 4.33 (d, 2H), 3.95 (m, 1H), 3.74 (m, 2H), 3.64 (m, 1H), 2.97 (m, 1H), 2.03 (m, 1H), 1.72 (m, 1H)
Preparation Example 105: synthesis of [2-(tetrahydrofuran-3-ylmethyl)-2H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 57, 1H-indazole-5-carboxylic acid methyl ester and methanesulfonic acid tetrahydrofuran-3ylmethyl ester (1.12g, 6.24mmol) were used to obtain the title compound (0.38g, 26%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.85 (s, 1H), 7.64 (d, 1H), 7.59 (s, 1H), 7.31 (s, 1H), 4.73 (s, 2H), 4.34 (d, 2H), 3.94 (m, 1H), 3.77 (m, 2H), 3.59 (m, 1H), 3.01 (m, 1H), 2.07 (m, 1H), 1.70 (m, 1H)
Preparation Example 106: synthesis of [1-(2-ethoxy-ethyl)-1H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-5-carboxylic acid methyl ester and 1-chloro-2-ethoxy-ethane were used to obtain the title compound (670mg, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.69 (s, 1H), 7.49 (d, 1H), 7.42 (d, 1H), 4.79 (s, 2H), 4.55 (t, 2H), 3.86 (t, 2H), 3.42 (q, 2H), 1.09 (t, 3H)
Preparation Example 107: synthesis of [2-(2-ethoxy-ethyl)-2H-indazol-5-yl]-methanol
According to the methods described in Preparation Examples 55 and 57, 1H-indazole-5-carboxylic acid methyl ester and 1-chloro-2-ethoxy-ethane were used to obtain the title compound (280mg, 22%)
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.71 (d, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 4.75 (s, 2H), 4.57 (t, 2H), 3.91 (t, 2H), 3.46 (q, 2H), 1.14 (t, 3H)
Preparation Example 108-1: synthesis of 4-fluoro-3-formyl-benzonitrile
According to the method described in Preparation Example 89-3, 5-bromo-2-fluoro-benzaldehyde (10.15g, 50mmol) was used to obtain the title compound (4.54g, 61%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.35 (s, 1H), 8.22 (dd, 1H), 7.91 (m, 1H), 7.35 (t, 1H)
Preparation Example 108-2: synthesis of 4-fluoro-3-formyl-benzonitrile
The compound (4.54g, 30.44mmol) obtained from Preparation Example 108-1 was dissolved in tetrahydrofuran (100ml), and 2M solution of isobutyl magnesium bromide in diethyl ether (15.98ml, 31.96mmol) was added dropwise thereto at 0℃. The mixture was heated to room temperature, stirred for 1 hour and then cooled to 0℃. Reaction was terminated with a saturated aqueous solution of ammonium chloride. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.67g, 26%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.85 (dd, 1H), 7.55 (m, 1H), 7.11 (t, 1H), 5.09 (m, 1H), 2.02 (d, 1H), 1.78 (m, 1H), 1.67 (m, 1H), 1.49 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H)
Preparation Example 108-3: synthesis of 4-fluoro-3-(3-methyl-butyryl)-benzonitrile
According to the method described in Preparation Example 7-5, the compound (1.67g, 8.04mmol) obtained from Preparation Example 108-2 was used to obtain the title compound (1.56g, 95%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.16 (dd, 1H), 7.79 (m, 1H), 7.27 (m, 1H), 2.85 (dd, 2H), 2.27 (m, 1H), 0.99 (d, 6H)
Preparation Example 108-4: synthesis of 3-isobutyl-1-methyl-1H-indazole-5-carbonitrile
The compound (513mg, 2.5mmol) obtained from Preparation Example 108-3 was dissolved in tetrahydrofuran (100ml), and methylhydrazine sulfate (378mg, 2.63mmol) and 6M aqueous solution of sodium hydroxide (0.88ml, 5.25mmol) were added dropwise thereto. The mixture was stirred for 16 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (473mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.55 (d, 1H), 7.40 (d, 1H), 4.05 (s, 3H), 2.83 (d, 2H), 2.13 (m, 1H), 0.98 (d, 6H)
Preparation Example 108-5: synthesis of (3-isobutyl-1-methyl-1H-indazol-5-yl)-methanol
According to the method described in Preparation Example 54-2, the compound (473mg, 2.22mmol) obtained from Preparation Example 108-4 was used to obtain the title compound (475mg, 98%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (s, 1H), 7.42-7.30 (m, 2H), 4.79 (d, 2H), 4.01 (s, 3H), 2.82 (d, 2H), 2.15 (m, 1H), 1.65 (t, 1H), 0.98 (d, 6H)
Preparation Example 109-1: synthesis of 3,5-dimethyl-4-nitro-benzoic acid methyl ester
According to the method described in Preparation Example 86-2, 3,5-dimethyl-4-nitro-benzoic acid (5.3g, 27.15mmol) was used to obtain the title compound (5.80g, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.82 (s, 2H), 3.94 (s, 3H), 2.35 (s, 6H)
Preparation Example 109-2: synthesis of 4-amino-3,5-dimethyl-benzoic acid methyl ester
According to the method described in Preparation Example 86-3, the compound (5.80g, 27.15mmol) obtained from Preparation Example 109-1 was used to obtain the title compound (4.40g, 90%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (s, 2H), 3.98 (brs, 2H), 3.85 (s, 3H), 2.19 (s, 6H)
Preparation Example 109-3: synthesis of 7-methyl-1H-indazole-5-carboxylic acid methyl ester
According to the method described in Preparation Example 86-4, the compound (4.40g, 24.55mmol) obtained from Preparation Example 109-2 was used to obtain the title compound (3.80g, 82%).
NMR:1H-NMR(500HMz, CDCl3); δ 10. 40 (brs, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 3.94 (s, 3H), 2.59 (s, 3H)
Preparation Example 110: synthesis of (1-benzyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (500mg, 2.63mmol) was used to obtain the title compound (111mg, 17%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.17 (s, 1H), 7.47 (s, 1H), 7.15-7.23 (m, 3H), 7.03 (s, 1H), 6.91 (dd, 2H), 5.75 (s, 2H), 4.65 (br t, 2H), 3.21 (br s, 1H), 2.52 (s, 3H)
Preparation Example 111: synthesis of (2-benzyl-7-methyl-2H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 57, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (500mg, 2.63mmol) was used to obtain the title compound (395mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.73 (s, 1H), 7.24-7.28 (m, 4H), 7.16-7.20 (m, 2H), 6.99 (s, 1H), 5.54 (s, 2H), 4.62 (br t, 2H), 3.33 (br s, 1H), 2.62 (s, 3H)
Preparation Example 112: synthesis of (1-isobutyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and isobutyl chloride (1.46ml, 15.78mmol) were used to obtain the title compound (282mg, 25%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.87 (s, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 4.84 (s, 2H), 4.27 (d, 2H), 3.90 (br s, 1H), 2.62 (s, 3H), 2.10-2.22 (m, 1H), 0.86 (d, 6H)
Preparation Example 113: synthesis of (2-isobutyl-7-methyl-2H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 57, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and isobutyl chloride (1.46ml, 15.78mmol) were used to obtain the title compound (478mg, 42%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.77 (s, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 4.64 (br t, 3H), 4.04 (d, 2H), 2.81 (s, 3H), 2.21-2.29 (m, 1H), 0.82 (d, 6H)
Preparation Example 114: synthesis of (1-isopropyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and isobutyl iodide (1.58ml, 15.78mmol) were used to obtain the title compound (357mg, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 5.16-5.22 (m, 1H), 4.73 (d, 2H), 2.74 (s, 3H), 1.59 (d, 6H)
Preparation Example 115: synthesis of (1-cyclopentyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and cyclopentyl bromide (1.69ml, 15.78mmol) were used to obtain the title compound (146mg, 12%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.48 (s, 1H), 7.17 (s, 1H), 5.18-5.39 (m, 1H), 4.71 (s, 2H), 2.91 (br s, 1H), 2.75 (s, 3H), 2.21-2.25 (m, 2H), 2.09-2.15 (m, 2H), 1.96-2.03 (m, 2H), 1.73-1.78 (m, 2H)
Preparation Example 116: synthesis of (1-cyclopentylmethyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and cyclopentyl methylmethanesulfonate (1.88g, 10.52mmol) were used to obtain the title compound (406mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.93 (s, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 4.74 (d, 2H), 4.50 (d, 2H), 2.73 (s, 3H), 2.42-2.48 (m, 1H), 1.53-1.67 (m, 6H), 1.34-1.37 (m, 2H)
Preparation Example 117-1: synthesis of (5-bromo-2-fluoro-phenyl)-methanol
5-Bromo-2-fluoro-benzaldehyde (5.0g, 24.36mmol) was dissolved in tetrahydrofuran (100ml), and 3M solution of methylmagnesium bromide in tetrahydrofuran (10.26ml, 30.78mmol) was slowly added dropwise thereto at 0℃ for 3 minutes. 30 minutes later, the mixture was added to a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (3.3g, 61%).
Preparation Example 117-2: synthesis of 5-(bromo-2-fluoro-phenyl)-ethanone
The compound (3.3g, 15.07mmol) obtained from Preparation Example 117-1 was dissolved in dichloromethane (20ml), and pyridinium chlorochromate (3.9g, 18.08mmol) was added thereto. The mixture was stirred for 16 hours at room temperature and then filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (2.3g, 70%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (m, 1H), 7.61 (m, 1H), 7.02 (m, 1H), 2.63 (d, 3H)
Preparation Example 117-3: synthesis of 5-bromo-3-methyl-1H-indazole
The compound (2.3g, 1060mmol) obtained from Preparation Example 117-2 was dissolved in ethylene glycol (10ml), and hydrazine (2.57ml, 53.00mmol) was added thereto. The reactant was stirred under reflux at 160℃ for 16 hours in a pressure tube. The reactant was diluted with ethyl acetate, washed with water, distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.5g, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.77 (br s, 1H), 7.83 (m, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 2.56 (s, 3H)
Preparation Example 117-4: synthesis of 5-bromo-1-isobutyl-3-methyl-1H-indazole and 5-bromo-2-isobutyl-3-methyl-2H-indazole
The compound (1.5g, 7.11mmol) obtained from Preparation Example 117-3 was dissolved in dimethylformamide (20ml), and sodium hydride (340mg, 8.53mmol) and isobutyl iodide (2.45ml, 21.32mmol) were slowly added dropwise thereto at 0℃. The mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography. The first compound that passed through the column chromatography was 5-bromo-1-isobutyl-3-methyl-1H-indazole (1.16g, 61%), and the second one was 5-bromo-2-isobutyl-3-methyl-2H-indazole (0.39g, 21%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.78 (m, 1H), 7.39 (m, 1H), 7.20 (m, 1H), 4.05 (d, 2H), 2.53 (s, 3H), 2.27 (m, 1H), 0.90 (d, 6H)
NMR:1H-NMR(400HMz, CDCl3); δ 7.71 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 4.11 (d, 2H), 2.56 (s, 3H), 2.38 (m, 1H), 0.94 (d, 6H)
Preparation Example 117-5: synthesis of 1-isobutyl-3-methyl-1H-indazole-5-carbonitrile
5-Bromo-1-isobutyl-3-methyl-1H-indazole (1.16g, 4.34mmol) obtained from Preparation Example 117-4 was dissolved in dimethylformamide (30ml). Zinc cyanide (0.66g, 5.64mmol) and palladium tetrakistriphenylphosphine (0.50g, 0.43mmol) were added thereto, and then the mixture was stirred for 8 hours at 100℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (580mg, 63%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (m, 1H), 7.52 (m, 1H), 7.38 (m, 1H), 4.10 (d, 2H), 2.59 (s, 3H), 2.29 (m, 1H), 0.91 (d, 6H)
Preparation Example 117-6: synthesis of 1-isobutyl-3-methyl-1H-indazole-5-carboxylic acid methyl ester
The compound (580mg, 2.72mmol) obtained from Preparation Example 117-5 was dissolved in ethanol (50ml), and 6N sodium hydroxide (2.27ml, 13.60mmol) was added thereto. The mixture was stirred for 18 hours at 90℃ and then distilled under reduced pressure. 1N hydrochloric acid solution was added thereto, and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure, and 1-isobutyl-3-methyl-1H-indazole-5-carboxylic acid was obtained.
The obtained 1-isobutyl-3-methyl-1H-indazole-5-carboxylic acid was dissolved in methylenechloride (20ml), and 0.25M solution of diazomethane in diethyl ether (13.05ml, 3.25mmol) was slowly added dropwise thereto. The mixture was stirred for 30 minutes at room temperature and distilled under reduced pressure to obtain the title compound (670mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.43 (m, 1H), 8.01 (m, 1H), 7.31 (m, 1H), 4.09 (d, 2H), 3.95 (s, 3H), 2.30 (m, 1H), 0.92 (d, 6H)
Preparation Example 118: synthesis of (1-isobutyl-3-methyl-1H-indazol-5-yl)-methanol
The compound (670mg, 2.72mmol) obtained from Preparation Example 117-6 was dissolved in tetrahydrofuran (20ml), and lithium aluminium hydride (114mg, 2.99mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature, and water (1ml), 6N sodium hydroxide (1ml) and water (3ml) were added sequentially. Ethyl acetate was added and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (590mg, 99%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.61 (s, 1H), 7.36 (d, 1H), 7.34 (d, 1H), 4.80 (d, 1H), 4.10 (d, 2H), 2.57 (s, 3H), 2.32 (m, 1H), 0.91 (d, 6H)
Preparation Example 119-1: synthesis of N-(4-bromo-2,5-dimethyl-phenyl)-acetamide
N-(2,5-dimethyl-phenyl)-acetamide (5.0g, 30.6mmol) was dissolved in a mixture of dichloromethane (250ml) and methanol (100ml), and benzyl-trimethyl-ammonium dibromochloride (11.6g, 33.7mmol) was added dropwise thereto. The mixture was stirred for 2 hours at room temperature, and then distilled under reduced pressure. Water was added and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain N-(4-bromo-2,5-dimethyl-phenyl)-acetamide (7.0g, 94%).
NMR:1H-NMR(500HMz, DMSO-d 6); δ 9.28 (brs, 1H), 7.36(s, 1H), 7.34(s, 1H), 2.21(s, 3H), 2.10(s, 3H), 2.00(s, 3H)
Preparation Example 119-2: synthesis of 5-bromo-6-methyl-1H-indazole
According to the method described in Preparation Example 86-4, the compound (7.0g, 28.9mmol) obtained from Preparation Example 119-1 was used to obtain the title compound (4.1g, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.97 (br s, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.39 (s, 1H), 2.53 (s, 3H)
Preparation Example 119-3: synthesis of 5-bromo-1-isobutyl-6-methyl-1H-indazole
According to the method described in Preparation Example 55, the compound (2.11g, 10mmol) obtained from Preparation Example 119-2 and 1-bromo-2-methyl-propane (2.3ml, 20mmol) were used to obtain the title compound (1.45g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (s, 1H), 7.88 (s, 1H), 7.26 (s, 1H), 4.12 (d, 2H), 2.54 (s, 3H), 2.33 (m, 1H), 0.92 (d, 6H)
Preparation Example 119-4: synthesis of 1-isobutyl-6-methyl-1H-indazole-5-carbonitrile
According to the method described in Preparation Example 89-3, the compound (1.45g, 5.42mmol) obtained from Preparation Example 119-3 was used to obtain the title compound (0.81g, 70%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.07 (s, 1H), 8.03 (s, 1H), 7.28 (s, 1H), 4.15 (d, 2H), 2.67 (s, 3H), 2.34 (m, 1H), 0.93 (d, 6H)
Preparation Example 120: synthesis of (1-isobutyl-6-methyl-1H-indazol-5-yl)-methanol
According to the method described in Preparation Example 54-2, the compound (0.81g, 3.8mmol) obtained from Preparation Example 119-4 was used to obtain the title compound (0.54g, 65%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.92 (s, 1H), 7.67 (s, 1H), 7.20 (s, 1H), 4.79 (d, 2H), 4.14 (d, 2H), 2.53 (s, 3H), 2.34 (m, 1H), 1.53 (t, 1H), 0.92 (d, 6H)
Preparation Example 121: synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile
5-Bromo-1H-pyrrolo[2,3-b]-pyridine (2.0g, 10.1mmol) was dissolved in dimethylformamide (50ml). Zinc cyanide (ZnCN2, 2.4g, 20.2mmol) and palladium tetrakistriphenylphosphine ((Pd(PPh3)4, 1.3g, 1.0mmol) were added dropwise thereto, and then the mixture was stirred for 3 hours at 100℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain the title compound.
Preparation Example 122: synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester
The compound obtained from Preparation Example 121 was dissolved in ethanol (100ml), and 6N sodium hydroxide (17ml, 102mmol) was added thereto. The mixture was stirred for 3 days at 100℃ and then distilled under reduced pressure. 1 N hydrochloride solution was added and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and the residue was dissolved in tetrahydrofuran (400ml). 0.25M solution of diazomethane in diethyl ether (30ml, 7.5mmol) was slowly added dropwise. The mixture was stirred for 30 minutes at 0℃ and then distilled under reduced pressure to obtain the title compound (1.2g, 67%).
Preparation Example 123: synthesis of (1-benzyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanol
According to the methods described in Preparation Examples 17-1 and 17-2, 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (0.25g, 1.42mmol) and benzyl bromide (0.27g, 1.56mmol) were used to obtain the title compound (0.13g, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.35 (s, 1H), 7.95 (s, 1H), 7.19 ~ 7.31 (m, 6H), 6.48 (d, 1H), 5.50 (s, 2H), 4.80 (s, 2H), 1.82 (brs, 1H)
Preparation Example 124: synthesis of (1-isobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (0.25g, 1.42mmol) and 1-chloro-2-methyl-propane (0.39g, 4.26mmol) were used to obtain the title compound (0.1g, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.32 (s, 1H), 7.94 (s, 1H), 7.22 (d, 1H), 6.45 (d, 1H), 4.79 (s, 2H), 4.08 (m, 2H), 2.26 (m, 1H), 0.92 (d, 6H)
Preparation Example 125-1: synthesis of 4-benzylamine-3-nitro-benzoic acid methyl ester
4-Fluoro-3-nitro-benzoic acid (2.0g, 10.8mmol) was dissolved in ethanol (100ml), and benzyl amine (1.3ml, 11.9mmol) was added thereto. The mixture was stirred at 100℃ for 3 hours and then distilled under reduced pressure.
The obtained compound was dissolved in tetrahydrofuran (100ml) and 0.25M solution of diazomethane in diethyl ether (48ml, 11.9mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 30 minutes and then distilled under reduced pressure to obtain the title compound (1.8g, 58%).
Preparation Example 125-2: synthesis of 3-amino-4-benzylamine-benzoic acid methyl ester
The compound (1.8g, 6.3mmol) obtained from Preparation Example 125-1 was dissolved in a mixed solution of ethyl acetate and methanol (2/1, 100ml), and 10% palladium/carbon (200mg) was added. The mixture was stirred for 1 hour under hydrogen gas. After completion of the reaction, the mixture was filtered with Celite, and the filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.6g, 99%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.55 (dd, 1H), 7.42 (d, 1H), 7.35 (m, 4), 7.28 (m, 1H), 6.62 (d, 1H), 4.39 (d, 2H), 4.31 (brs, 1H), 3.80 (s, 3H), 3.27 (brs, 2H)
Preparation Example 125-3: synthesis of 1-benzyl-1H-benzotriazole-5-carboxylic acid methyl ester
3-Amino-4-benzylamine-benzoic acid methyl ester (500mg, 2.0mmol) obtained from Preparation Example 125-2 was dissolved in methanol (40ml). 1N Hydrochloric acid solution (30ml) was added, and then sodium nitrite (NaNO2, 148mg) was added thereto. The mixture was stirred for 1 hour at room temperature. After completion of the reaction, the mixture was distilled under reduced pressure. A saturated sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (320mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.84 (s, 1H), 8.14 (dd, 1H), 7.40 (m, 4H), 7.31 (m, 2H), 5.91 (s, 2H), 4.00 (s, 3H)
Preparation Example 125-4: synthesis of (1-benzyl-1H-benzotriazol-5-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (470mg, 1.76mmol) obtained from Preparation Example 125-3 was used to obtain the title compound (394mg, 94%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.92 (s, 1H), 7.76 (d, 1H), 7.47 (d, 1H), 7.29-7.36 (m, 5H), 5.96 (s, 2H), 5.32 (t, 1H), 4.62 (d, 2H)
Preparation Example 126-1: synthesis of 1-benzyl-1H-benzimidazole-5-carboxylic acid methyl ester
3-Amino-4-benzylamine-benzoic acid methyl ester (500mg, 2.0mmol) obtained from Preparation Example 125-2 was dissolved in toluene (50ml), and triethylorthoformate (0.65ml, 4.0mmol) and p-toluenesulfonic acid (50mg) were added thereto. The mixture was stirred at 120℃ for 2 hours and then distilled under reduced pressure. Water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (250mg, 47%).
NMR:1H-NMR(400HMz, CDCl3); 8.55 (s, 1H), 8.09 (s, 1H), 8.00 (d, 1H), 7.78 (d, 1H), 7.36 (m, 3H), 7.18 (m, 2H), 5.40 (s, 2H), 3.94 (s, 3H)
Preparation Example 126-2: synthesis of (1-benzyl-1H-benzimidazole-5-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (480mg, 1.80mmol) obtained from Preparation Example 126-1 was used to obtain the title compound (333mg, 78%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.37 (s, 1H), 7.58 (s, 1H), 7.43 (d, 1H), 7.27-7.35 (m, 5H), 7.16 (d, 1H), 5.48 (s, 2H), 5.10 (t, 1H), 4.56 (d, 2H)
Preparation Example 127-1: synthesis of 1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid methyl ester
3-Amino-4-benzylamine-benzoic acid methyl ester (2.38g, 8.8mmol) obtained from Preparation Example 125-2 was dissolved in toluene (50ml) and triphosgene (2.87g, 9.7mmol) was added thereto. The mixture was stirred at 120℃ for 2 hours and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography. The separated compound was dissolved in dimethylformamide (10ml), and potassium carbonate (1.4g, 10.4mmol) and methyl iodide (1.5g, 104mmol) were slowly added dropwise thereto. The mixture was stirred for 2 hours and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (2.30g, 90%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.78 (d, 1H), 7.67 (s, 1H), 7.31 (m, 4H), 7.26 (m, 1H), 6.89 (d, 1H), 5.09 (s, 2H), 3.50 (s, 3H)
Preparation Example 127-2: synthesis of 1-benzyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzimidazol-2-one
According to the method described in Preparation Example 17-2, the compound (0.68g, 2.30mmol) obtained from Preparation Example 127-1 was used to obtain the title compound (0.54g, 88%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.31 (m, 5H), 7.04 (s, 1H), 6.99 (d, 1H), 6.83 (d, 1H), 5.07 (s, 2H), 4.70 (d, 2H), 3.45 (s, 3H), 1.76 (t, 1H)
Preparation Example 128-1: synthesis of 3-isobutyl-3H-benzotriazole-5-carboxylic acid methyl ester
According to the methods described in Preparation Examples 125-1 to 125-3, 3-fluoro-4-nitro-benzoic acid rather than 4-fluoro-3-nitro-benzoic acid and isobutylamine rather than benzylamine were used to obtain the title compound (1.18g, 32%).
Preparation Example 128-2: synthesis of (3-isobutyl-3H-benzotriazol-yl)-methanol
According to the method described in Preparation Example 17-2, the compound obtained from Preparation Example 128-1 was used to obtain the title compound (950mg, 79%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (d, 1H), 7.56 (s, 1H), 7.31 (m, 1H), 4.90 (d, 2H), 4.43 (d, 2H), 2.41 (m, 1H), 2.01 (t, 1H), 0.97 (d, 6H)
Preparation Example 129-1: synthesis of 5-bromo-2-fluoro-pyridine-3-carbaldehyde
Diisopropylamine (2.6ml, 25mmol) was dissolved in tetrahydrofuran (100ml), 2.5M solution of butyllithium in tetrahydrofuran (10ml, 25mmol) was slowly added dropwise at 0℃ and then the mixture was stirred for 1 minute. A solution of 5-bromo-fluoro-2-pyridine (4.0g, 22.7mmol) in tetrahydrofuran (20ml) was slowly added dropwise at -78℃ and stirred for 30 minutes. Ethylformate (2.8ml, 34mmol) was added dropwise and then the mixture was stirred for 10 minutes at -78℃. After completion of the reaction, 1N hydrochloric acid solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.1g, 88%).
Preparation Example 129-2: synthesis of 5-bromo-1H-pyrazolo[3,4-b]pyridine
5-Bromo-2-fluoro-pyridine-3-carbaldehyde (4.1g, 20mmol) obtained from Preparation Example 129-1 was dissolved in ethanol (50ml). After adding hydrazine hydrate (5.0ml, 100mmol), the mixture was stirred for 8 hours at 100℃ and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.8g, 40%).
NMR:1H-NMR(400HMz, CDCl3); δ 11.29 (br s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H)
Preparation Example 129-3: synthesis of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester
According to the methods described in Preparation Examples 117-4 to 117-6, the compound (2.0g, 10.10mmol) obtained from Preparation Example 129-2 was used to obtain the title compound (1.38g, 59%).
Preparation Example 130: synthesis of (1-isobutyl-1H-pyrazol[3,4-b]pyridin-5-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (1.38g, 5.93mmol) obtained from Preparation Example 129-3 was used to obtain the title compound (950mg, 79%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.55 (m, 1H), 8.07 (m, 1H), 8.00 (s, 1H), 4.84 (d, 2H), 4.33 (d, 2H), 2.41 (m, 1H), 1.83 (t, 1H), 0.92 (d, 6H)
Preparation Example 131-1: synthesis of 1-benzyl-1H-indole-4-carboxylic acid methyl ester
In the method described in Preparation Example 17-1, 1H-indole-4-carboxylic acid methyl ester (370mg, 2.1mmol) was used rather than 7-methyl-1H-indole-6-carboxylic acid methyl ester to obtain the title compound (560mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (d, 1H), 7.47 (d, 1H), 7.25-7.32 (m, 4H), 7.16~7.23 (m, 2H), 7.07 (d, 2H), 5.16 (s, 2H), 3.97 (s, 3H)
Preparation Example 131-2: synthesis of (1-benzyl-1H-indol-4-yl)-methanol
According to the method described in Preparation Example 17-2, the compound (560mg, 2.11mmol) obtained from Preparation Example 131-1 was used to obtain the title compound (500mg, 99%).
Preparation Example 132-1: synthesis of [1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-yl]-carboxylic acid methyl ester
In the method described in Preparation Example 11-1, 1H-indole-4-carboxylic acid methyl ester (300mg, 1.7mmol) was used rather than 1H-indole-6-carboxylic acid methyl ester to obtain the title compound (280mg, 55%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.96 (d, 1H), 7.17-7.31 (m, 5H), 7.11 (m, 1H), 7.03 (m, 1H), 4.02 (s, 3H), 2.00 (s, 3H)
Preparation Example 132-2: synthesis of [1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-yl]-methanol
According to the method described in Preparation Example 11-2, the compound (280mg, 0.94mmol) obtained from Preparation Example 132-1 was used to obtain the title compound (150mg, 63%).
Preparation Example 133-1: synthesis of 1-benzyl-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (200mg, 1.13mmol) and benzyl bromide (0.15ml, 1.24mmol) were used to obtain the title compound (160mg, 53%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.54 (s, 1H), 7.91 (d, 1H), 7.55 (d, 1H), 7.38 (dd, 1H), 7.24-7.29 (m, 3H), 7.17 (dd, 2H), 5.65 (s, 2H), 4.01 (s, 3H)
Preparation Example 133-2: synthesis of (1-benzyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (160mg, 0.60mmol) obtained from Preparation Example 133-1 was used to obtain the title compound (140mg, 100%).
Preparation Example 134-1: synthesis of 2-benzyl-2H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (200mg, 1.13mmol) and benzyl bromide (0.15ml, 1.24mmol) were used to obtain the title compound (100mg, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.44 (s, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.30-7.37 (m, 6H), 5.63 (s, 2H), 3.95 (s, 3H)
Preparation Example 134-2: synthesis of (2-benzyl-2H-indazol-4-yl)-methanol
According to the method described in Preparation Example 57, the compound (100mg, 0.38mmol) obtained from Preparation Example 134-1 was used to obtain the title compound (90mg, 100%).
Preparation Example 135-1: synthesis of 1-(4-fluoro-benzyl)-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (300mg, 1.70mmol) and 4-fluorobenzyl bromide (0.22ml, 1.84mmol) were used to obtain the title compound (200mg, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.59 (s, 1H), 7.97 (dd, 1H), 7.59 (d, 1H), 7.44 (dd, 1H), 7.19-7.23 (m, 2H), 7.01-7.05 (m, 2H), 5.66 (s, 2H), 4.07 (s, 3H)
Preparation Example 135-2: synthesis of [1-(4-fluoro-benzyl)-1H-indazol-4-yl]-methanol
According to the method described in Preparation Example 56, the compound (200mg, 0.70mmol) obtained from Preparation Example 135-1 was used to obtain the title compound (190mg, 100%).
Preparation Example 136-1: synthesis of 2-(4-fluoro-benzyl)-2H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (300mg, 1.70mmol) and 4-fluorobenzyl bromide (0.22ml, 1.84mmol) were used to obtain the title compound (160mg, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.44 (s, 1H), 7.95 (dd, 1H), 7.91 (dd, 1H), 7.29-7.37 (m, 3H), 7.02-7.07 (m, 2H), 5.60 (s, 2H), 3.96 (s, 3H)
Preparation Example 136-2: synthesis of [2-(4-fluoro-benzyl)-2H-indazol-4-yl]-methanol
According to the method described in Preparation Example 57, the compound (160mg, 0.56mmol) obtained from Preparation Example 136-1 was used to obtain the title compound (150mg, 100%).
Preparation Example 137-1: synthesis of 1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (798mg, 4.53mmol) and methanesulfonic acid 5-methyl-pyrazin-2-ylmethyl ester (1.0g, 4.99mmol) were used to obtain the title compound (580mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.56 (s, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 7.94 (d, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 5.75 (s, 2H), 4.02 (s, 3H), 2.52 (s, 3H)
Preparation Example 137-2: synthesis of [1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-4-yl]-methanol
According to the method described in Preparation Example 56, the compound (580mg, 2.05mmol) obtained from Preparation Example 137-1 was used to obtain the title compound (522mg, 100%).
Preparation Example 138-1: synthesis of 2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (798mg, 4.53mmol) and methanesulfonic acid 5-methyl-pyrazin-2-ylmethyl ester (1.0g, 4.99mmol) were used to obtain the title compound (250mg, 20%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.60 (s, 1H), 8.45 (s, 1H), 8.42 (d, 1H), 7.93 (s, 1H), 7.91 (d, 1H), 7.34 (dd, 1H), 5.74 (s, 2H), 3.97 (s, 3H), 2.55 (s, 3H)
Preparation Example 138-2: synthesis of [2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-4-yl]-methanol
According to the method described in Preparation Example 57, the compound (250mg, 0.89mmol) obtained from Preparation Example 138-1 was used to obtain the title compound (225mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.42 (d, 1H), 8.26 (s, 1H), 7.63 (d, 1H), 7.24 (m, 2H), 7.01 (d, 1H), 5.70 (s, 2H), 4.93 (br s, 2H), 2.56 (s, 4H)
Preparation Example 139: synthesis of 1-(4-fluoro-phenyl)-1H-indole-6-carbaldehyde
According to the methods described in Preparation Examples 6-1 to 6-3, 1H-indole-carboxylic acid methyl ester and 1-fluoro-4-iodo-benzene were used to obtain the title compound.
Preparation Example 140: synthesis of (1-benzyl-3-chloro-1H-indol-6-yl)-methanol
1-Benzyl-3-chloro-1H-indole-6-carbaldehyde (177mg, 0.66mmol) obtained from Preparation Example 3 was dissloved in a mixed solution of tetrahydrofuran and methanol (1/1, 20ml), and sodium borohydride (37mg, 1.0mmol) was added thereto at 0℃. The mixture was stirred for 30 minutes, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (120mg, 67%).
Preparation Example 141: synthesis of (1-pyrazin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-methanol
According to the methods described in Preparation Examples 54-1 and 54-2, 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (170mg, 0.96mmol) and 2-bromomethyl-pyrazine (332mg, 1.92mmol) were used to obtain the title compound (140mg, 60%).
Preparation Example 142-1: synthesis of 1-isobutyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile
According to the method described in Preparation Example 17-1, 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (300mg, 2.1mmol) and 1-chloro-2-methyl-propane (0.86ml, 8.8mmol) were used to obtain the title compound (370mg, 89%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.96 (d, 1H), 7.44 (d, 1H), 7.42 (d, 1H), 6.54 (d, 1H), 4.11 (d, 2H), 2.17-2.31 (m, 1H), 0.92 (d, 6H)
Preparation Example 142-2: synthesis of (1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-methanol
According to the method described in Preparation Example 54-2, the compound (370mg, 1.86mmol) obtained from Preparation Example 142-1 was used to obtain the title compound (360mg, 88%).
Preparation Example 143: synthesis of (1-isopropyl-3-methyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 3-methyl-1H-indazole-6-carboxylic acid methyl ester (0.50g, 2.63mmol) and 2-bromo-propane (0.49g, 3.95mmol) were used to obtain the title compound (0.25g, 49%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.62 (d, 1H), 7.40 (s, 1H), 7.08 (d, 1H), 4.84 (s, 2H), 4.80 (m, 1H), 2.57 (s, 3H), 1.82 (brs, 1H), 1.57 (d, 6H)
Preparation Example 144: synthesis of (1-isopropyl-7-methyl-1H-indazol-5-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-5-carboxylic acid methyl ester (1g, 5.26mmol) and isobutyl iodide (1.58ml, 15.78mmol) were used to obtain the title compound (357mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 5.16-5.22 (m, 1H), 4.73 (d, 2H), 2.74 (s, 3H), 1.59 (d, 6H)
Preparation Example 145: synthesis of (1-isobutyl-1H-indazol-4-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-indazole-4-carboxylic acid methyl ester (500mg, 2.84mmol) and isobutyl chloride (0.6ml, 5.68mmol) were used to obtain the title compound (257mg, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.13 (s, 1H), 7.35 (d, 1H), 7.33 (d, 1H), 7.12 (dd, 1H), 5.03 (d, 2H), 4.19 (d, 2H), 2.30-2.40 (m, 1H), 1.84 (br t, 1H), 0.93 (d, 6H)
Preparation Example 146: synthesis of 1-(6-methyl-pyridin-3-ylmethyl)-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-6-carboxylic acid methyl ester and methanesulfonic acid 6-methyl-pyridin-3-ylmethyl ester were used to obtain the title compound (324mg, 26%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.52 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.87 (dd, 1H), 7.77 (dd, 1H), 7.42 (dd, 1H), 6.96 (d, 1H), 5.61 (s, 2H), 3.95 (s, 3H), 2.51 (s, 3H)
Preparation Example 147: synthesis of [1-(6-methyl-pyridin-3-ylmethyl)-1H-indazol-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (324mg, 1.15mmol) obtained from Preparation Example 146 was used to obtain the title compound (72.2mg, 24%).
Preparation Example 148: synthesis of (1-isopropyl-3-methyl-1H-indazol-5-yl)-methanol
In the method described in Preparation Example 118, 1-isopropyl-3-methyl-1H-indazole-5-carboxylic acid methyl ester (680mg, 2.93mmol) was used rather than 1-isobutyl-3-methyl-1H-indazole-5-carboxylic acid methyl ester to obtain the title compound (540mg, 90%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.63 (s, 1H), 7.37 (m, 2H), 4.78 (m, 3H), 2.57 (s, 3H), 1.56 (d, 6H)
Preparation Example 149: synthesis of 3-(2-fluoro-4-hydroxy-phenyl)-propanoic acid ethylester
The title compound was prepared according to the method described in WO 2012/011125.
NMR:1H-NMR(400HMz, CDCl3); δ 7.02 (m, 1H), 6.51 (m, 2H), 5.38 (s, 1H), 4.13 (q, 2H), 2.89 (t, 2H), 2.59 (t, 2H), 1.25 (t, 3H)
Preparation Example 150: synthesis of 3-(4-hydroxy-phenyl)-butyric acidethylester
The title compound was prepared according to the method described in Bioorganic & Medicinal Chemistry Letters, 22(2012), 1267~1270.
NMR:1H-NMR(400HMz, CDCl3); δ 7.08 (m, 2H), 6.71 (m, 2H), 4.84 (s, 1H), 4.08 (q, 2H), 3.22 (m, 1H), 2.52 (q, 2H), 1.27 (d, 3H), 1.20 (t, 3H)
Preparation Example 151: synthesis of 3-(4-hydroxy-phenyl)-pentanoic acid ethylester
The title compound was prepared according to the method described in Bioorganic & Medicinal Chemistry Letters, 22(2012), 1267~1270.
NMR:1H-NMR(400HMz, CDCl3); δ 7.04 (d, 2H), 6.74 (d, 2H), 4.70 (m, 1H), 4.03 (q, 2H), 2.94 (m, 1H), 2.46-2.66 (m, 2H), 1.47-1.73 (m, 2H), 1.14 (t, 3H), 0.78 (t, 3H)
Preparation Example 152: synthesis of 2-(4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
(E)-3-(4-benzyloxy-phenyl)-acrylic acid benzylester (3.5g,8.7mmol) was dissolved in tetrahydrofuran (100ml), palladium(II) acetate (100mg, 0.45mmol) was added at 0℃ and then 0.25M solution of diazomethane in diethyl ether (150ml, 37.5mmol) was slowly added dropwise. The mixture was stirred for 3 hours at 0℃, acetic acid (0.1ml) was added thereto and the mixture was stirred further for 10 minutes. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain 2-(4-benzyloxy-phenyl)-cyclopropanecarboxylic acid benzyl ester.
The obtained 2-(4-benzyloxy-phenyl)-cyclopropanecarboxylic acid benzyl ester was dissolved in dichloromethane (40ml) and trifluoroacetic acid (20ml) was added thereto. The mixture was stirred at room temperature for 8 hours and then distilled under reduced pressure. The residue was dissloved in tetrahydrofuran (100ml) and 0.25M solution of diazomethane in diethyl ether (50ml, 12.5mmol) was added thereto. The mixture was stirred at 0℃ for 30 minutes and then distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.72g, 43%).
NMR:1H-NMR(400HMz, CDCl3); δ 6.98 (dd, 2H), 6.74 (dd, 2H), 3.72 (s, 3H), 2.46-2.51 (m, 1H), 1.80-1.84 (m, 1H), 1.52-1.58 (m, 1H), 1.22-1.29 (m, 1H)
Preparation Example 153-1: synthesis of 3-[4-(t-butyl-dimethyl-silanyloxy)-phenyl]-3-hydroxy-propanoic acid ethylester
4-(t-Butyl-dimethyl-silanyloxy)-benzaldehyde (2.0g, 8.5mmol) was dissolved in tetrahydrofuran (100ml), and zinc (1.1g, 16.8mmol) and copper (I) iodide (80mg, 0.4mmol) were added thereto. At 80℃, ethylbromo acetate (1.4ml, 12.8mmol) was slowly added dropwise for 1 hour thereto. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.5g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.03 (d, 2H), 6.62 (d, 2H), 4.88 (m, 1H), 4.00 (q, 2H), 2.99 (d, 1H), 2.55 (m, 2H), 1.07 (t, 3H), 0.79 (s, 9H), 0.01 (s, 6H)
Preparation Example 153-2: synthesis of 3-[4-(t-butyl-dimethyl-silanyloxy)-phenyl]-3-methoxy-propanoic acid ethyl ester
The compound (700mg, 2.2mmol) obtained from Preparation Example 153-1 was dissolved in toluene (30ml). Methyl iodide (1.3ml, 22.0mmol) and silver oxide (1.2g, 5.2mmol) were added and the mixture was stirred under reflux for 8 hours. The mixture was filtered with Celite. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (470mg, 63%).
Preparation Example 153-3: synthesis of 3-(4-hydroxy-phenyl)-3-methoxy-propanoic acid ethyl ester
The compound (470mg, 1.4mmol) obtained from Preparation Example 153-2 was dissolved in tetrahydrofuran (30ml), tetrabutylammonium fluoride(786mg, 2.8mmol) was added thereto and the mixture was stirred for 1 hour. Afther completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (260mg, 83%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.05 (d, 2H), 6.71 (d, 2H), 4.45-4.52 (m, 1H), 3.95-4.18 (m, 2H), 3.08 (s, 3H), 2.72-2.81 (m, 1H), 2.45-2.59 (m, 1H), 1.10 (t, 3H)
Preparation Example 154: synthesis of 3-cyano-3-(4-hydroxy-phenyl)-propanoic acid ethyl ester
The title compound was obtained according to the method described in WO 2005/086661.
NMR:1H-NMR(400HMz, CDCl3); δ 7.21 (d, 2H), 6.83 (d, 2H), 4.07-4.25 (m, 3H), 2.95-3.01 (m, 1H), 2.78-2.84 (m, 1H), 1.23 (t, 3H)
Preparation Example 155: synthesis of (S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acidmethyl ester
The title compound was obtained according to the methods described in WO 2009/054479 and WO 2005/086661.
NMR:1H-NMR(400HMz, CDCl3); δ 7.22(d, 2H), 6.77(d, 2H), 5.11(s, 1H), 4.04(m, 1H), 3.67(s, 3H), 2.70(m, 2H), 1.82(s, 3H)
Preparation Example 156: synthesis of 3-(4,5-dihydro-isoxazol-3-yl)-3-(4-hydroxy-phenyl)-propanoic acid methyl ester
The title compound was obtained according to the methods described in the Example 6 of US 8,003,648 B2 (Synthetic methods 6-1 to 6-10).
NMR:1H-NMR(400HMz, CDCl3); δ 7.06 (d, 2H), 6.79 (d, 2H), 5.86 (s, 1H), 4.23 (m, 2H), 4.07 (t, 1H), 3.78 (m, 1H), 3.63 (s, 3H), 3.23 (dd, 1H), 2.83 (m, 2H)
Preparation Example 157: synthesis of (S)-3-(4-hydroxy-phenyl)-3-isoxazol-3-yl-propanoic acid methyl ester
The title compound was obtained according to the method described in the Example 6 of US 8,003,648 B2 (Synthetic method 6-8).
NMR:1H-NMR(400HMz, CDCl3); δ 8.27 (s, 1H), 7.08 (d, 2H), 6.76 (d, 2H), 6.08 (s, 1H), 6.00 (s, 1H), 4.56 (t, 1H), 3.63 (s, 3H), 3.32 (dd, 1H), 2.98 (dd, 1H)
Preparation Example 158: synthesis of (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
The title compound was obtained according to the methods described in WO 2012/011125.
NMR:1H-NMR(400HMz, CDCl3); δ 6.97 (d, 1H), 6.32-6.64 (m, 2H), 5.07 (br s, 1H), 4.75 (t, 1H), 4.15-4.28 (m, 1H), 3.75-3.81 (m, 1H), 3.72 (s, 3H), 2.72-2.77 (m, 1H), 2.53-2.59 (m, 1H)
Preparation Example 159: synthesis of (5-hydroxy-indan-1-yl)-acetic acid methyl ester
The title compound was obtained according to the methods described in Organic & Biomolecular Chemistry 2011, 9, 4570.
NMR:1H-NMR(400HMz, CDCl3); δ 7.03 (d, 1H), 6.69 (s, 1H), 6.62 (m, 1H), 4.62 (s, 1H), 4.17 (q, 2H), 3.51 (m, 1H), 2.76-2.92 (m, 2H), 2.70 (dd, 1H), 2.33-2.43 (m, 2H), 1.74 (m, 1H), 1.27 (t, 3H)
Preparation Example 160: synthesis of (7-hydroxy-chroman-4-yl)-acetic acid methyl ester
The title compound was obtained according to the methods described in Organic & Biomolecular Chemistry 2011, 9, 4570.
NMR:1H-NMR(500HMz, CDCl3); δ 6.97 (d, 1H), 6.37 (m, 1H), 6.29 (m, 1H), 4.82 (s, 1H), 4.14-4.17 (m, 4H), 3.27 (m, 1H), 2.72 (dd, 1H), 2.46 (dd, 1H), 2.11 (m, 1H), 1.08 (m, 1H), 1.26 (t, 3H)
Preparation Example 161: synthesis of (6-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester
The title compound was obtained according to the methods described in Organic & Biomolecular Chemistry 2011, 9, 4570.
NMR:1H-NMR(400HMz, CDCl3); δ 7.04 (d, 1H), 6.92 (m, 1H), 6.54 (m, 1H), 4.58 (s, 1H), 4.16 (q, 2H), 3.27 (m, 1H), 2.63-2.73 (m, 3H), 2.47 (dd, 1H), 1.66-1.89 (m, 4H), 1.26 (t, 3H)
Preparation Example 162-1: synthesis of 3-methyl-indazole-1,6-dicarboxylic acid 1-t-butyl ester-6-methyl ester
The compound (3.8g, 20mmol) obtained from Preparation Example 86-4 was dissolved in acetonitrile (40ml). 4-(Dimethylamino) pyridine (0.49g, 4mmol) and triethylamine (3.07ml, 22mmol) were added thereto. Di-t-butyl dicarbonate (5.24g, 24mmol) in acetonitrile (20ml) was added dropwise and then the mixture was stirred for 16 hours. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid aqueous solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.48g, 77%).
NMR: 1H -NMR(500HMz, CDCl3); δ 8.82 (s, 1H), 7.98 (d, 1H), 7.69 (d 1H), 3.97 (s, 3H), 2.62 (s, 3H), 1.74 (s, 9H)
Preparation Example 162-2: synthesis of 3-bromomethyl-indazole-1,6-dicarboxylic acid 1-t-butyl ester 6-methyl ester
The compound (2.9g, 10mmol) obtained from Preparation Example 162-1 was dissolved in dichloroethane (50ml). N-Bromosuccinimide (NBS, 1.96g, 11mmol) and 2,2′-azobis(2-methylpropionitrile)(0.33g, 2mmol) were added dropwise thereto. The mixture was stirred under reflux for 16 hours, cooled to room temperature, distilled under reduced pressure to remove the solvent and separated by column chromatography to obtain the title compound (2.13g, 58%).
NMR: 1H -NMR(400HMz, CDCl3); δ 8.86 (s, 1H), 8.05 (d, 1H), 7.92 (d 1H), 4.80 (s, 2H), 3.99 (s, 3H), 1.75 (s, 9H)
Preparation Example 162-3: synthesis of 3-methoxymethyl-1H-indazole-6-carboxylic acid methyl ester
The compound (1.11g, 3mmol) obtained from Preparation Example 162-2 was dissolved in methanol (30ml) and triethylamine (0.42ml, 3mmol) was added dropwise thereto. The mixture was stirred under reflux for 16 hours, cooled to room temperature, distilled under reduced pressure to remove the solvent. Water was added thereto and the residue was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure. Dichloromethane and hexane were used to produce solids, and the solids were filtered, washed with hexane and dried to obtain the title compound (0.5g, 76%).
NMR: 1H -NMR(500HMz, CDCl3); δ 11.0 (br s, 1H), 8.23 (s, 1H), 7.88 (d, 1H), 7.83 (d 1H), 4.89 (s, 2H), 3.96 (s, 3H), 3.45 (s, 3H)
Preparation Example 162-4: synthesis of (1-isobutyl-3-methoxymethyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (164mg, 0.745mmol) obtained from Preparation Example 162-3 and isobutyliodide (0.13ml, 1.118mmol) were used to obtain the title compound (90mg, 49%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.78 (d, 1H), 7.40 (s, 1H), 7.11 (d, 1H), 4.85 (d, 2H), 4.81 (s, 2H), 4.14 (d, 2H), 3.40 (s, 3H), 2.35 (m, 1H), 1.74 (t, 1H), 0.92 (d, 6H)
Preparation Example 163-1: synthesis of 1-isobutyl-1H-indazole-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (250mg, 1.42mmol) and isobutyl iodide (0.33ml, 2.84mmol) were used to obtain the title compound (57mg, 57%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.48 (s, 1H), 7.91 (d, 1H), 7.61 (d, 1H), 7.42 (dd, 1H), 4.21 (d, 2H), 4.01 (s, 3H), 2.32-2.36 (m, 1H), 0.91 (d, 6H)
Preparation Example 163-2: synthesis of 3-fluoro-1-isobutyl-1H-indazole-4-carboxylic acid methyl ester
1-Isobutyl-1H-indazole-4-carboxylic acid methyl ester (188mg, 0.81mmol) was dissolved in acetonitrile (8ml). Selectfluor (429mg, 1.21mmol) and acetic acid (1.5ml) were added thereto and then the mixture was stirred for 1 hour at 100℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (98.3mg, 48%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.75 (d, 1H), 7.44 (d, 1H), 7.36 (dd, 1H), 3.99 (d, 2H), 3.93 (s, 3H), 2.23 (m, 1H), 0.84 (d, 6H)
Preparation Example 163-3: synthesis of (3-fluoro-1-isobutyl-1H-indazol-4-yl)-methanol
The compound (98.3mg, 0.39mmol) obtained from Preparation Example 163-2 was dissolved in tetrahydrofuran (5ml) and lithium aluminium hydride (16.4mg, 0.43mmol) was added dropwise thereto. The mixture was stirred for 30 miniutes at room temperature, water (1ml), 6N sodium hydroxide (1ml) and water (3ml) were added sequentially. Ethyl acetate was added and the mixture was filtered with Celite. Filtrate was distilled under reduced pressure to obtain the title compound (64.7mg, 75%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.34 (dd, 1H), 7.24 (d, 1H), 7.14 (d, 1H), 5.02 (d, 2H), 3.99 (d, 2H), 2.27-2.30 (m, 1H), 1.92 (t, 1H), 0.91 (d, 6H)
Preparation Example 164-1: synthesis of 1-isopropyl-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (176mg, 1.0mmol) and isopropyl iodide (0.15ml, 1.5mmol) were used to obtain the title compound (116mg, 53%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.47 (s, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.33 (m, 1H), 4.84 (m, 1H), 3.98 (s, 3H), 1.68 (d, 6H)
Preparation Example 164-2: synthesis of (1-isopropyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (116mg, 0.531mmol) obtained from Preparation Example 164-1 was used to obtain the title compound (96mg, 95%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.14 (s, 1H), 7.41-7.31 (m, 2H), 7.12 (d, 1H), 5.02 (d, 2H), 4.86 (m, 1H), 1.76 (t, 1H), 1.59 (d, 6H)
Preparation Example 165-1: synthesis of 3-ethoxymethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 162-3, the compound (1.11g, 3.0mmol) obtained from Preparation Example 162-2 and ethanol (30ml) were used to obtain the title compound (0.25g, 36%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.13 (br s, 1H), 8.21 (s, 1H), 7.93-7.83 (m, 2H), 4.91 (s, 2H), 3.96 (s, 3H), 3.61 (q, 2H), 1.25 (t, 3H)
Preparation Example 165-2: synthesis of (3-ethoxymethyl-1-isobutyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (125mg, 0.533mmol) obtained from Preparation Example 165-1 and isobutyl iodide (0.1ml, 0.800mmol) were used to obtain the title compound (92mg, 65%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.81 (d, 1H), 7.38 (s, 1H), 7.11 (d, 1H), 4.86 (s, 2H), 4.85 (d, 2H), 4.13 (d, 2H), 3.56 (q, 2H), 2.34 (m, 1H), 1.74 (t, 1H), 1.22 (t, 3H), 0.92 (d, 6H)
Preparation Example 166-1: synthesis of 3-chloro-1-isobutyl-1H-indazole-4-carboxylic acid methyl ester
1-Isobutyl-1H-indazole-4-carboxylic acid methyl ester (98mg, 0.42mmol) was dissolved in acetonitrile (5ml). N-chlorosuccinimide (NCS, 62mg, 0.46mmol) was added thereto and then the mixture was stirred for 1 hour at 80℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain the title compound (112mg, 100%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.64 (d, 1H), 7.54 (d, 1H), 7.43 (dd, 1H), 4.13 (d, 2H), 4.01 (s, 3H), 2.33 (m, 1H), 0.92 (d, 6H)
Preparation Example 166-2: synthesis of (3-chloro-1-isobutyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 118, 3-chloro-1-isobutyl-1H-indazole-4-carboxylic acid methyl ester (112mg, 0.42mmol) was used to obtain the title compound (100mg, 100%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.34 (dd, 1H), 7.31 (d, 1H), 7.19 (d, 1H), 5.17 (d, 2H), 4.10 (d, 2H), 2.32 (m, 1H), 2.00 (t, 1H), 0.92 (d, 6H)
Preparation Example 167-1: synthesis of 3-isopropoxymethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 162-3, the compound (369mg, 1.0mmol) obtained from Preparation Example 162-2 and isopropanol (30ml) were used to obtain the title compound (136mg, 55%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.06 (br s, 1H), 8.20 (s, 1H), 7.92 (d, 1H), 7.84 (d, 1H), 4.90 (s, 2H), 3.96 (s, 3H), 3.76 (m, 1H), 1.24 (d, 6H)
Preparation Example 167-2: synthesis of (1-isobutyl-3- isopropoxymethyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (136mg, 0.548mmol) obtained from Preparation Example 167-1 and isobutyl iodide (0.1ml, 0.822mmol) were used to obtain the title compound (85mg, 56%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.81 (d, 1H), 7.37 (s, 1H), 7.10 (d, 1H), 4.86 (s, 2H), 4.84 (d, 2H), 4.12 (d, 2H), 3.72 (m, 1H), 2.33 (m, 1H), 1.74 (t, 1H), 1.21 (d, 6H), 0.92 (d, 6H)
Preparation Example 168-1: synthesis of 3-fluoro-1-isopropyl-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 163-2, the compound (146mg, 0.669mmol) obtained from Preparation Example 164-1 was used to obtain the title compound (103mg, 65%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.83 (d, 1H), 7.55 (d, 1H), 7.42 (m, 1H), 4.75 (m, 1H), 3.99 (s, 3H), 1.54 (d, 6H)
Preparation Example 168-2: synthesis of (3-fluoro-1-isopropyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (103mg, 0.436mmol) obtained from Preparation Example 168-1 was used to obtain the title compound (75mg, 82%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.36 (m, 1H), 7.27 (m, 1H), 7.14 (d, 1H), 5.02 (d, 2H), 4.71 (m, 1H), 1.94 (m, 1H), 1.51 (d, 6H)
Preparation Example 169-1: synthesis of 1H-indazole-7-carboxylic acid methyl ester
2-Amino-3-methyl-benzoic acid methyl ester (4.5g, 27mmol) was dissolved in chloroform (100ml) and the solution was cooled to 0℃. Acetic anhydride (7.7ml, 81mmol) and potassium acetate (3.2g, 32mmol) were added thereto and the mixture was stirred for 12 hours at 50℃. Isopentyl nitrite (7.3ml, 54mmol) was added thereto and the mixture was heated to 70℃ and stirred for 12 hours. The mixture was cooled to room temperature, diluted with dichloromethane, washed with saturated solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was dissolved in tetrahydrofuran (50ml). 6M aqueous solution of sodium hydroxide (4.8ml) was added and the solution was stirred for 1 hour. After acidifying with 1N hydrochloric acid aqueous solution, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.6g, 96%).
NMR:1H-NMR(500HMz, CDCl3); δ 11.3 (br s, 1H), 8.15 (s, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 7.23 (t, 1H), 4.03 (s, 3H)
Preparation Example 169-2: synthesis of 3-bromo-1H-indazole-7-carboxylic acid methyl ester
1H-indazole-7-carboxylic acid methyl ester (2.0g, 11mmol) obtained from Preparation Example 169-1 was dissolved in acetonitrile (50ml). N-bromosuccinimide (NBS, 2.0g, 11mmol) was added dropwise and then the mixture was stirred for 2 hours at 100℃. The mixture was distilled under reduced pressure and the residue was separated by column chromatography to obtain the title compound (720mg, 25%).
NMR:1H-NMR(500HMz, CDCl3); δ 11.2 (br s, 1H), 8.13 (d, 1H), 7.88 (d, 1H), 7.30 (t, 1H), 4.03 (s, 3H)
Preparation Example 169-3: synthesis of 3-bromo-1-methyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 3-bromo-1H-indazole-7-carboxylic acid methyl ester (720mg, 2.82mmol) obtained from Preparation Example 169-2 and methyl iodide (0.26ml, 4.23mmol) were used to obtain the title compound (500mg, 66%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.01 (d, 1H), 7.78 (d, 1H), 7.22 (t, 1H), 4.24 (s, 3H), 3.98 (s, 3H)
Preparation Example 169-4: synthesis of (3-bromo-1-methyl-1H-cyclo)-methanol
According to the method described in Preparation Example 56, the compound (425mg, 1.579mmol) obtained from Preparation Example 169-3 was used to obtain the title compound (375mg, 98%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.59 (d, 1H), 7.33 (d, 1H), 7.14 (t, 1H), 5.02 (d, 2H), 4.36 (s, 3H), 1.78 (t, 1H)
Preparation Example 170-1: synthesis of 3-formyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
7-Methyl-1H-indole-6-carboxylic acid methyl ester (2.0g, 10.6mmol) obtained from Preparation Example 15-1 was dissolved in a mixed solution of water (50ml) and tetrahydrofuran (100ml). To the mixture, sodium nitrite (3.6g, 52.8mmol) was added and then 1N hydrochloric acid aqueous solution (63ml) was slowly added dropwise at 0℃. After stirring for 12 hours, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain the title compound (750mg, 32%).
NMR:1H-NMR(500HMz, DMSO-d 6); δ 10.18 (s, 1H), 7.99 (d, 1H), 7.73 (d, 1H), 3.83 (s, 3H), 2.78 (s, 3H)
Preparation Example 170-2: synthesis of 3-formyl-1-isobutyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, the compound (400mg, 1.83mmol) obtained from Preparation Example 170-1 and isobutyl iodide (0.32ml, 2.75mmol) were used to obtain the title compound (310mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.49 (d, 1H), 5.00 (d, 2H), 4.36 (d, 2H), 3.93 (s, 3H), 2.80 (s, 3H), 2.18 (m, 1H), 1.81 (br s, 1H). 0.94 (d, 6H)
Preparation Example 170-3: synthesis of 3-hydroxymethyl-1-isobutyl-7-methyl-1H-indazole-carboxylic acid methyl ester
The compound (300mg, 1.09mmol) obtained from Preparation Example 170-2 was dissolved in tetrahydrofuran (10ml), sodium borohydride(62mg, 1.64mmol) was added thereto at 0℃, and then the mixture was stirred at room temperature for 30 minutes. The reaction was terminated with an aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (230mg, 76%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.49 (d, 1H), 5.00 (d, 2H), 4.36 (d, 2H), 3.93 (s, 3H), 2.80 (s, 3H), 2.18 (m, 1H), 1.81 (br s, 1H), 0.94 (d, 6H)
Preparation Example 170-4: synthesis of 1-isobutyl-3-methoxymethyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, the compound (220mg, 0.83mmol) obtained from Preparation Example 170-3 and methyl iodide (0.1ml, 15.9mmol) were used to obtain the title compound (237mg, 98%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.59 (d, 1H), 7.47 (d, 1H), 4.79 (s, 2H), 4.27 (d, 2H), 3.91 (s, 3H), 3.32 (s, 3H), 2.91 (s, 3H), 2.50 (m, 1H), 0.94 (d, 6H)
Preparation Example 170-5: synthesis of (1-isobutyl-3-methoxymethyl-7-methyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (230mg, 0.79mmol) obtained from Preparation Example 170-4 was used to obtain the title compound (100mg, 48%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.64 (d, 1H), 7.16 (d, 1H), 4.85 (d, 2H), 4.79 (s, 2H), 4.41 (d, 2H), 3.37 (s, 3H), 2.71 (s, 3H), 2.21 (m, 1H), 0.91 (d, 6H)
Preparation Example 171-1: synthesis of 1-butyl-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (800mg, 4.54mmol) and butyl iodide (1.04ml, 9.08mmol) were used to obtain the title compound (379mg, 36%)
NMR:1H-NMR(400HMz, CDCl3); δ 8.48 (s, 1H), 7.92 (d, 1H), 7.63 (d, 1H), 7.43 (dd, 1H), 4.43 (t, 2H), 4.02 (s, 3H), 1.88-1.96 (m, 2H), 1.29-1.36 (m, 2H), 0.94 (t, 3H)
Preparation Example 171-2: synthesis of (1-butyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (72mg, 0.31mmol) obtained from Preparation Example 171-1 was used to obtain the title compound (56mg, 88%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.13 (s, 1H), 7.35 (d, 2H), 7.12 (dd, 1H), 5.04 (d, 2H), 4.40 (t, 2H), 1.87-1.95 (m, 2H), 1.77 (t, 1H), 1.29-1.39 (m, 2H), 0.96 (t, 3H)
Preparation Example 172: synthesis of (1-butyl-3-fluoro-1H-indazol-4-yl)-methane
According to the methods described in Preparation Examples 163-2 and 163-3, the compound (306.5mg, 1.32mmol) obtained from Preparation Example 171-1 and Selectfluor (701mg, 1.98mmol) were used to obtain the title compound (73.6mg, 25%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.38 (dd, 1H), 7.23 (d, 1H), 7.15 (d, 1H), 5.03 (d, 2H), 4.21 (t, 2H), 1.93 (t, 1H), 1.82-1.90 (m, 2H), 1.30-1.35 (m, 2H), 0.93 (t, 3H)
Preparation Example 173-1: synthesis of 1-cyclopropylmethyl-1H-indazole-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-4-carboxylic acid methyl ester (800mg, 4.54mmol) and chloromethyl cyclopropane (0.84ml, 9.08mmol) were used to obtain the title compound (353mg, 34%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.49 (s, 1H), 7.92 (d, 1H), 7.65 (d, 1H), 7.44 (dd, 1H), 4.32 (d, 2H), 4.02 (s, 3H), 1.33 (m, 1H), 0.57-0.62 (m, 2H), 0.40-0.44 (m, 2H)
Preparation Example 173-2: synthesis of (1-cyclopropylmethyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (77mg, 0.33mmol) obtained from Preparation Example 173-1 was used to obtain the title compound (65.2mg, 98%)
NMR:1H-NMR(400HMz, CDCl3); δ 8.14 (s, 1H), 7.35 (dd, 2H), 7.14 (d, 1H), 5.04 (s, 2H), 4.29 (d, 2H), 1.35 (m, 1H), 0.56-0.61 (m, 2H), 0.40-0.44 (m, 2H)
Preparation Example 174: synthesis of (1-cyclopropylmethyl-3-fluoro-1H-indazol-4-yl)-methanol
According to the methods described in Preparation Examples 163-2 and 163-3, the compound (276mg, 1.2mmol) obtained from Preparation Example 173-1 and Selectfluor (638mg, 1.8mmol) were used to obtain the title compound (89.4mg, 34%)
NMR:1H-NMR(400HMz, CDCl3); δ 7.38 (dd, 1H), 7.25 (d, 1H), 7.16 (d, 1H), 5.04 (d, 2H), 4.10 (d, 2H), 1.69 (br s, 1H), 1.29 (m, 1H), 0.56-0.60 (m, 2H), 0.37-0.41 (m, 2H)
Preparation Example 175-1: synthesis of 3-chloro-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 12-1, 1H-indazole-7-carboxylic acid methyl ester (176mg, 1.0mmol) was used to obtain the title compound (126mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 11.03 (br s, 1H), 8.17 (d, 1H), 7.99 (d, 1H), 7.35 (t, 1H), 4.08 (s, 3H)
Preparation Example 175-2: synthesis of (3-chloro-1-methyl-1H-indazol-7-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (126mg, 0.598mmol) obtained from Preparation Example 175-1 and iodomethane (0.056ml, 0.897mmol) were used to obtain the title compound (66mg, 56%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.65 (d, 1H), 7.32 (d, 1H), 7.13 (m, 1H), 5.01 (d, 2H), 4.33 (s, 3H), 1.78 (t, 1H)
Preparation Example 176-1: synthesis of 1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 3-methyl-1H-indazole-6-carboxylic acid methyl ester and isopropylbromide were reacted to obtain a compound of 1-isopropyl-3-methyl-1H-indazole-6-carboxylic acid methyl ester. The compound (1.0g, 4.31mmol) was disolved in dichloroethane (30ml). N-bromosuccinimide (0.84g, 4.74mmol) and 2, 2’-azobis(2-methylpropionitrile) (0.14g, 0.86mmol) were added thereto. The mixture was stirred for 2 hours under reflux and cooled to room temperature. After removing solvent under reduced pressure, a compound of 3-bromomethyl-1-isopropyl-1H-indazole-6-carboxylic acid methyl ester was obtained by column chromatography. The compound (0.85g, 2.73mmol) was dissolved in acetone (30ml). Pyrazole (0.18g, 2.73mmol) and cesium carbonate (1.06g, 3.28mmol) were added and the mixture was stirred for 2 hours at 50℃. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.37g, 29%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.16 (s, 1H), 7.72 (d, 1H), 7.54 (s, 1H), 7.49 (d, 1H), 7.44 (s, 1H), 6.25 (d, 1H), 5.70 (s, 2H), 4.91 (m, 1H), 3.94 (s, 3H), 1.61 (d, 6H)
Preparation Example 176-2: synthesis of (1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazol-6-yl)methanol
According to the method described in Preparation Example 56, 1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazole-6-carboxylic acid methyl ester (0.37g, 1.24mmol) obtained from Preparation Example 176-1 was used to obtain the title compound (0.30g, 90%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.54 (s, 1H), 7.43 (s, 1H), 7.42 (m, 2H), 7.03 (d, 1H), 5.68 (s, 2H), 4.89 (m, 1H), 4.83 (d, 2H), 1.59 (d, 6H)
Preparation Example 177-1: synthesis of 1-methyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 55, 1H-indazole-7-carboxylic acid methyl ester (400mg, 2.27mmol) and methyl iodide (0.28ml, 4.54mmol) were used to obtain the title compound (165mg, 38%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.05 (s, 1H), 7.94 (d, 1H), 7.90 (d, 1H), 7.15 (dd, 1H), 4.26 (s, 3H), 3.98 (s, 3H)
Preparation Example 177-2: synthesis of (3-fluoro-1-methyl-1H-cyclo)-methanol
According to the methods described in Preparation Examples 163-2 and 163-3, the compound (114.4mg, 0.6mmol) obtained from Preparation Example 177-1 and Selectfluor (320mg, 0.9mmol) were used to obtain the title compound (40mg, 37%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.62 (d, 1H), 7.29 (d, 1H), 7.08 (dd, 1H), 4.98 (d, 2H), 4.21 (s, 3H), 1.74 (t, 1H)
Preparation Example 178-1: synthesis of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile
4-Chloro-1H-pyrrolo[2,3-b]-pyridine (1.0g, 6.55mmol) was dissolved in dimethylformamide (20ml). Zinc cyanide (ZnCN2, 0.77g, 6.55mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) {PdCl2(dppf), 1.3g, 1.0mmol} were added dropwise thereto and then the mixture was stirred for 3 hours at 100℃. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.85g, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.17 (br s, 1H), 8.43 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 6.76 (d, 1H)
Preparation Example 178-2: synthesis of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester
According to the method described in Preparation Example 122, 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.85g, 5.94mmol) obtained from Preparation Example 178-1 was used to obtain the title compound (0.73g, 70%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.34 (br s, 1H), 8.44 (d, 1H), 7.74 (d, 1H), 7.52 (d, 1H), 7.07 (d, 1H), 4.03 (s, 3H)
Preparation Example 178-3: synthesis of (1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester (0.20g, 1.14mmol) obtained from Preparation Example 178-2 and isobutyl iodide (0.31g, 1.70mmol) were used to obtain the title compound (0.19g, 72%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.29 (d, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 6.52 (d, 1H), 5.01 (s, 2H), 4.08 (d, 2H), 2.50 (br s, 1H), 2.29 (m, 1H), 0.92 (d, 6H)
Preparation Example 179-1: synthesis of 3-formyl-1H-indazole-4-carboxylic acid methyl ester
1H-indole-4-carboxylic acid methyl ester (2.17g, 12.39mmol) was dissolved in a mixed solution of water (120ml) and tetrahydrofuran (60ml) and sodium nitrite (4.48g, 61.95mmol) was added thereto. 1N hydrochloric acid aqueous solution (74ml) was slowly added dropwise at 0℃ and the mixture was stirred for 12 hours at room temperature. The mixture was extracted with ethyl acetate and the extrace was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain the title compound (2.31g, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.69 (s, 1H), 7.95 (dd, 2H), 7.54 (dd, 1H), 4.03 (s, 3H)
Preparation Example 179-2: synthesis of 3-methyl-1H-indazole-4-carboxylic acid methyl ester
The compound (1g, 4.9mmol) obtained from Preparation Example 179-1, p-toluenesulfonic acid (121.1mg, 0.64mmol), p-toluenesulfonyl hydrazide (1.19g, 6.37mmol) and sulfolane (11.2ml) were dissolved in dimethylformamide (11ml) and the mixture was stirred for 1 hour at 100℃. The mixture was cooled to room temperature and sodium cyanoborohydride (1.84g, 29.4mmol) was added. The mixture was stirred for 30 minutes and then further stirred for 3 hours at 100℃. After completion of the reaction, the mixture was cooled to room temperature, water was added thereto and then the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (897mg, 96%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.2 (br s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.38 (dd, 1H), 3.98 (s, 3H), 2.73 (s, 3H)
Preparation Example 179-3: synthesis of (1-butyl-3-methyl-1H-indazol-4-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (200mg, 1.05mmol) obtained from Preparation Example 179-2 and butyl iodide (0.24ml, 2.1mmol) were used to obtain the title compound (31mg, 14%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.28 (dd, 2H), 7.07 (dd, 1H), 5.02 (s, 2H), 4.26 (t, 2H), 2.70 (s, 3H), 1.76-1.88 (m, 2H), 1.65 (t, 1H), 1.23-1.37 (m, 2H), 0.92 (t, 3H)
Preparation Example 180-1: synthesis of 2-fluoro-3-(1-hydroxy-pentyl)-benzonitrile
N,N-diisopropylamine (1.47ml, 10.5mmol) was dissolved in tetrahydrofuran (10ml). At -30℃, 2.5M solution of butyl lithium in hexane (4.2ml, 10.5mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes. 2-Fluorobenzonitrile (1.06ml, 10mmol) in tetrahydrofuran (20ml) was cooled to -78℃, the prepared LDA solution was slowly added dropwise thereto, and the mixture was stirred for 2 hours. After adding pentanal (1.26ml, 12mmol) dropwise thereto, the mixture was heated slowly to 0℃ and stirred for 1 hour. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.58g, 28%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.77 (m, 1H), 7.53 (m, 1H), 7.27 (t 1H), 5.06 (m, 1H), 1.92 (d, 1H), 1.81-1.70 (m, 2H), 1.45-1.27 (m, 4H), 0.90 (t, 3H)
Preparation Example 180-2: synthesis of 2-fluoro-3-pentanoyl-benzonitrile
According to the method described in Preparation Example 6-3, the compound (0.58g, 2.799mmol) obtained from Preparation Example 180-1 was used to obtain the title compound (0.5g, 86%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.09 (m, 1H), 7.79 (m, 1H), 7.36 (t, 1H), 2.98 (m, 2H), 1.74~1.67 (m, 2H), 1.45~1.35 (m, 2H), 0.94 (t, 3H)
Preparation Example 180-3: synthesis of 3-butyl-1-methyl-1H-indazole-7-carbonitrile
The compound (496mg, 2.417mmol) obtained from Preparation Example 180-2 was dissolved in dimethyl sulfoxide (15ml). Methylhydrazine sulfate (383mg, 2.659mmol) and potassium carbonate (1.0g, 7.251mmol) were added thereto and the mixture was stirred for 16 hours at 100℃. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (355mg, 69%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.90 (d, 1H), 7.71 (d, 1H), 7.14 (t, 1H), 4.31 (s, 3H), 2.95 (t, 2H), 1.80~1.72 (m, 2H), 1.47~1.37 (m, 2H), 0.95 (t, 3H)
Preparation Example 180-4: synthesis of 3-butyl-1-methyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 122, the compound (355mg, 1.664mmol) obtained from Preparation Example 180-3 was used to obtain the title compound (381mg, 93%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.91 (d, 1H), 7.84 (d, 1H), 7.11 (t, 1H), 4.18 (s, 3H), 3.97 (s, 3H), 2.95 (t, 2H), 1.81~1.72 (m, 2H), 1.47~1.38 (m, 2H), 0.95 (t, 3H)
Preparation Example 180-5: synthesis of (3-butyl-1-methyl-1H-cyclo)-methanol
According to the method described in Preparation Example 56, the compound (381mg, 0.547mmol) obtained from Preparation Example 180-4 was used to obtain the title compound (332mg, 98%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.65 (d, 1H), 7.24 (d, 1H), 7.03 (t, 1H), 5.01 (d, 2H), 4.31 (s, 3H), 2.94 (t, 2H), 1.82~1.72 (m, 2H), 1.70 (t, 1H), 1.48~1.38 (m, 2H), 0.95 (t, 3H)
Preparation Example 181-1: synthesis of 2-fluoro-3-(1-hydroxy-3-methyl-butyl)-benzonitrile
According to the method described in Preparation Example 180-1, 2-fluorobenzonitrile (1.06ml, 10mmol) and 3-methylbutanal (1.29ml, 12mmol) were used to obtain the title compound (0.51g, 25%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.78 (m, 1H), 7.53 (m, 1H), 7.27 (t 1H), 5.14 (m, 1H), 1.87 (d, 1H), 1.82-1.66 (m,2H), 1.51 (m, 1H), 0.99 (d, 3H), 0.97 (d, 3H)
Preparation Example 181-2: synthesis of 2-fluoro-3-(3-methyl-butyryl)-benzonitrile
According to the method described in Preparation Example 6-3, the compound (0.51g, 2.461mmol) obtained from Preparation Example 181-1 was used to obtain the title compound (0.47g, 94%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.07 (m, 1H), 7.79 (m, 1H), 7.36 (t, 1H), 2.86 (dd, 2H), 2.26 (m, 1H), 0.99 (d, 6H)
Preparation Example 181-3: synthesis of 3-isobutyl-1-methyl-1H-indazole-7-carbonitrile
According to the method described in Preparation Example 180-3, the compound (0.474mg, 2.31mmol) obtained from Preparation Example 181-2 was used to obtain the title compound (378mg, 77%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.89 (d, 1H), 7.70 (d, 1H), 7.14 (t, 1H), 4.32 (s, 3H), 2.82 (d, 2H), 2.12 (m, 1H), 0.97 (d, 6H)
Preparation Example 181-4: synthesis of 3-isobutyl-1-methyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 122, the compound (378mg, 1.772mmol) obtained from Preparation Example 181-3 was used to obtain the title compound (393mg, 90%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.91 (d, 1H), 7.83 (d, 1H), 7.11 (t, 1H), 4.19 (s, 3H), 3.98 (s, 3H), 2.82 (d, 2H), 2.12 (m, 1H), 0.97 (d, 6H)
Preparation Example 181-5: synthesis of (3-isobutyl-1-methyl-1H-cyclo)-methanol
According to the method described in Preparation Example 56, the compound (393mg, 1.596mmol) obtained from Preparation Example 181-4 was used to obtain the title compound (339mg, 97%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.63 (d, 1H), 7.24 (d, 1H), 7.03 (t, 1H), 5.01 (d, 2H), 4.32 (s, 3H), 2.80 (d, 2H), 2.13 (m, 1H), 1.72 (t, 1H), 0.97 (d, 6H)
Preparation Example 182-1: synthesis of 4-bromo-7-methyl-1H-indazole
According to the method described in Preparation Example 86-4, 3-bromo-2,6-dimethylaniline (53.2g, 265mmol) was used to obtain the title compound (21g, 37%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.83 (br s, 1H), 8.10 (s, 1H), 7.25 (d, 1H), 7.02 (d, 1H), 2.57 (s, 3H)
Preparation Example 182-2: synthesis of 7-methyl-1H-indazole-4-carboxylic acid methyl ester
According to the methods described in Preparation Examples 178-1 and 178-2, 4-bromo-7-methyl-1H-indazole (10.0g, 47.38mmol) obtained from Preparation Example 182-1 was used to obtain the title compound (4.86g, 55%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.98 (br s, 1H), 8.60 (s, 1H), 7.88 (d, 1H), 7.25 (d, 1H), 4.01 (s, 3H), 2.64 (s, 3H)
Preparation Example 182-3: synthesis of (1-isobutyl-7-methyl-1H-indazol-4-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-4-carboxylic acid methyl ester (1.9g, 9.99mmol) obtained from Preparation Example 182-2 and isobutyl iodide (3.68g, 19.98mmol) were used to obtain the title compound (0.70g, 32%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.10 (s, 1H), 7.70 (d, 1H), 6.92 (d, 1H), 4.98 (d, 2H), 4.40 (d, 2H), 2.71 (s, 3H), 2.29 (m, 1H), 1.78 (m, 1H), 0.95 (d, 6H)
Preparation Example 183-1: synthesis of 2-fluoro-3-(1-hydroxy-2-methyl-propyl)-benzonitrile
According to the method described in Preparation Example 180-1, 2-fluorobenzonitrile (1.06ml, 10mmol) and 2-methylpropanal (1.1ml, 12mmol) were used to obtain the title compound (0.47g, 24%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.75 (m, 1H), 7.54 (m, 1H), 7.27 (t 1H), 4.82 (m, 1H), 1.98 (m, 1H), 1.90 (d, 1H), 0.97 (d, 3H), 0.89 (d, 3H)
Preparation Example 183-2: synthesis of 2-fluoro-3-isobutyryl-benzonitrile
According to the method described in Preparation Example 6-3, the compound (0.47g, 2.417mmol) obtained from Preparation Example 183-1 was used to obtain the title compound (0.43g, 93%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.02 (m, 1H), 7.79 (m, 1H), 7.37 (t, 1H), 3.36 (m, 1H), 1.21 (d, 6H)
Preparation Example 183-3: synthesis of 3-isopropyl-1-methyl-1H-indazole-7-carbonitrile
According to the method described in Preparation Example 180-3, the compound (429mg, 2.244mmol) obtained from Preparation Example 183-2 was used to obtain the title compound (324mg, 72%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.96 (d, 1H), 7.70 (d, 1H), 7.14 (t, 1H), 4.32 (s, 3H), 3.39 (m, 1H), 1.43 (d, 6H)
Preparation Example 183-4: synthesis of 3-isopropyl-1-methyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 122, the compound (324mg, 1.626mmol) obtained from Preparation Example 183-3 was used to obtain the title compound (344mg, 91%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.92-7.87 (m, 2H), 7.10 (t, 1H), 4.17 (s, 3H), 3.97 (s, 3H), 3.39 (m, 1H), 1.44 (d, 6H)
Preparation Example 183-5: synthesis of (3-isopropyl-1-methyl-1H-cyclo)-methanol
According to the method described in Preparation Example 56, the compound (344mg, 1.481mmol) obtained from Preparation Example 183-4 was used to obtain the title compound (300mg, 99%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.71 (d, 1H), 7.24 (d, 1H), 7.03 (t, 1H), 5.00 (d, 2H), 4.31 (s, 3H), 3.38 (m, 1H), 1.69 (t, 1H), 1.44 (d, 6H)
Preparation Example 184-1: synthesis of 2-fluoro-3-(1-hydroxy-2-butyl)-benzonitrile
According to the method described in Preparation Example 180-1, 2-fluorobenzonitrile (1.06ml, 10mmol) and butyladehyde (1.06ml, 12mmol) were used to obtain the title compound (0.63g, 33%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.78 (m, 1H), 7.53 (m, 1H), 7.26 (t 1H), 5.08 (m, 1H), 1.91 (br s, 1H), 1.81-1.30 (m, 4H), 0.95 (t, 3H)
Preparation Example 184-2: synthesis of 3-butyryl-2-fluoro-benzonitrile
According to the method described in Preparation Example 6-3, the compound (0.63g, 3.26mmol) obtained from Preparation Example 184-1 was used to obtain the title compound (0.53g, 85%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.10 (m, 1H), 7.79 (m, 1H), 7.36 (t, 1H), 3.00-2.94 (m, 2H), 1.80-1.70 (m, 2H), 1.00 (t, 3H)
Preparation Example 184-3: synthesis of 1-methyl-3-propyl-1H-indazole-7-carbonitrile
According to the method described in Preparation Example 180-3, the compound (327mg, 1.71mmol) obtained from Preparation Example 184-2 was used to obtain the title compound (233mg, 68%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.90 (d, 1H), 7.71 (d, 1H), 7.14 (t, 1H), 4.31 (s, 3H), 2.92 (t, 2H), 1.86-1.76 (m, 2H), 1.00 (t, 3H)
Preparation Example 184-4: synthesis of 1-methyl-3-propyl-1H-indazole-7-carboxylic acid methyl ester
According to the method described in Preparation Example 122, the compound (233mg, 1.169mmol) obtained from Preparation Example 184-3 was used to obtain the title compound (211mg, 78%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.91 (d, 1H), 7.84 (d, 1H), 7.11 (t, 1H), 4.18 (s, 3H), 3.97 (s, 3H), 2.92 (t, 2H), 1.86-1.77 (m, 2H), 1.00 (t, 3H)
Preparation Example 184-5: synthesis of (1-methyl-3-propyl-1H-cyclo)-methanol
According to the method described in Preparation Example 56, the compound (211mg, 0.908mmol) obtained from Preparation Example 184-4 was used to obtain the title compound (185mg, 100%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.64 (d, 1H), 7.24 (d, 1H), 7.03 (t, 1H), 5.01 (d, 2H), 4.31 (s, 3H), 2.91 (t, 2H), 1.86-1.77 (m, 2H), 1.73 (t, 1H), 1.00 (t, 3H)
Preparation Example 185-1: synthesis of 6-bromo-7-methyl-1H-indazole
According to the method described in Preparation Example 86-4, 3-bromo-2,6-dimethylaniline (53.2g, 265mmol) was used to obtain the title compound (11.3g, 20%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.62 (br s, 1H), 8.05 (s, 1H), 7.45 (d, 1H), 7.33 (d, 1H), 2.61 (s, 3H)
Preparation Example 185-2: synthesis of 7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the methods described in Preparation Examples 178-1 and 178-2, 6-bromo-7-methyl-1H-indazole (6.2g, 29.38mmol) obtained from Preparation Example 185-1 was used to obtain the title compound (3.14g, 56%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.10 (s, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 3.94 (s, 3H), 2.82 (s, 3H)
Preparation Example 185-3: synthesis of (1-isobutyl-7-methyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-6-carboxylic acid methyl ester (1.0g, 5.26mmol) obtained from Preparation Example 185-2 and isobutyl iodide (1.94g, 10.52mmol) were used to obtain the title compound (0.27g, 21%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.93 (s, 1H), 7.54 (d, 1H), 7.14 (d, 1H), 4.84 (d, 2H), 4.43 (d, 2H), 2.72 (s, 3H), 2.25 (m, 1H), 1.85 (m, 1H), 0.92 (d, 6H)
Preparation Example 186-1: synthesis of 3,7-dimethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 179-2, the compound (1.44g, 6.6mmol) obtained from Preparation Example 170-1 was used to obtain the title compound (317mg, 24%).
NMR:1H-NMR(500HMz, CDCl3); δ 9.84 (br s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 3.93 (s, 3H), 2.82 (s, 3H), 2.59 (s, 3H)
Preparation Example 186-2: synthesis of (1-isobutyl-3,7-dimethyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (164mg, 0.8mmol) obtained from Preparation Example 186-1 and isobutyl iodide (0.18ml, 1.6mmol) were used to obtain the title compound (70mg, 38%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.45 (d, 1H), 7.11 (d, 1H), 4.83 (d, 2H), 4.34 (d, 2H), 2.70 (s, 3H), 2.52 (s, 3H), 2.16-2.24 (m, 1H), 0.90 (d, 6H)
Preparation Example 187-1: synthesis of 3-fluoro-1-isobutyl-7-methyl-1H-indazole-4-carboxylic acid methyl ester
According to the methods described in Preparation Examples 163-1 and 163-2, 7-methyl-1H-indazole-4-carboxylic acid methyl ester (0.36g, 1.89mmol) obtained from Preparation Example 182-2 was used to obtain the title compound (0.17g, 34%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.70 (d, 1H), 7.16 (d, 1H), 4.24 (d, 2H), 3.97 (s, 3H), 2.71 (s, 3H), 2.22 (m, 1H), 0.93 (d, 6H)
Preparation Example 187-2: synthesis of (3-fluoro-1-isobutyl-7-methyl-1H-indazol-4-yl)-methanol
According to the method described in Preparation Example 17-2, 3-fluoro-1-isobutyl-7-methyl-1H-indazole-4-carboxylic acid methyl ester (0.17g, 0.64mmol) obtained from Preparation Example 187-1 was used to obtain the title compound (0.09g, 59%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.08 (d, 1H), 7.02 (d, 1H), 4.96 (s, 2H), 4.19 (d, 2H), 2.64 (s, 3H), 2.22 (m, 1H), 0.93 (d, 6H)
Preparation Example 188-1: synthesis of 3-fluoro-7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 163-2, 7-methyl-1H-indazole-6-carboxylic acid methyl ester (1.1g, 5.78mmol) obtained from Preparation Example 185-2 was used to obtain the title compound (0.08g, 7%).
NMR:1H-NMR(500HMz, CDCl3); δ 9.28 (br s, 1H), 7.72 (d, 1H), 7.56 (d, 1H), 3.95 (s, 3H), 2.75 (s, 3H)
Preparation Example 188-2: synthesis of (1-ethyl-3-fluoro-7-methyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 3-fluoro-7-methyl-1H-indazole-6-carboxylic acid methyl ester (0.08g, 0.39mmol) obtained from Preparation Example 188-1 and ethylbromide (0.08g, 0.79mmol) were used to obtain the title compound (0.08g, 98%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.44 (d, 1H), 7.14 (d, 1H), 4.80 (d, 2H), 4.48 (q, 2H), 2.65 (s, 3H), 1.84 (m, 1H), 1.42 (t, 3H)
Preparation Example 189-1: synthesis of 1-isobutyl-7-methyl-3-morpholin-4-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
The compound (172mg, 0.627mmol) obtained from Preparation Example 170-2 and morpholine (82mg, 0.941mmol) were dissolved in dichloroethane (5ml) and the mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (199mg, 0.941mmol) and acetic acid (0.054ml, 0.941mmol) were added thereto and then the mixture was stirred for 16 hours at room temperature. After completion of the reaction, a saturated solution of sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (60mg, 28%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.72 (d, 1H), 7.47 (d, 1H), 4.42 (d, 2H), 3.93 (s, 3H), 3.86 (s, 2H), 3.69 (t, 4H), 2.86 (s, 3H), 2.50 (t, 4H), 2.19 (m, 1H), 0.88 (d, 6H)
Preparation Example 189-2: synthesis of (1-isobutyl-7-methyl-3-morpholin-4-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (60mg, 0.174mmol) obtained from Preparation Example 189-1 was used to obtain the title compound (42mg, 76%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.69 (d, 1H), 7.13 (d, 1H), 4.84 (d, 2H), 4.39 (d, 2H), 3.85 (s, 2H), 3.69 (t, 4H), 2.71 (s, 3H), 2.50 (t, 4H), 2.19 (m, 1H), 0.89 (d, 6H)
Preparation Example 190-1: synthesis of 7-chloro-3-formyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 170-1, the compound (2.57g, 12.26mmol) obtained from Preparation Example 7-2 was used to obtain the title compound (1.53g, 52%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.29 (s, 1H), 8.24 (d, 1H), 7.88 (d, 1H), 4.00 (s, 3H)
Preparation Example 190-2: synthesis of 7-chloro-3-formyl-1-isobutyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, the compound (597mg, 2.5mmol) obtained from Preparation Example 190-1 and isobutyl iodide (0.58ml, 5.0mmol) were used to obtain the title compound (340mg, 46%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.22 (s, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 4.72 (d, 2H), 3.98 (s, 3H), 2.39 (m, 1H), 0.96 (d, 6H)
Preparation Example 190-3: synthesis of 7-chloro-1-isobutyl-3-morpholin-4-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 189-1, the compound (109mg, 0.37mmol) obtained from Preparation Example 190-2 and morpholine (48mg, 0.56mmol) were used to obtain the title compound (103mg, 76%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.82 (d, 1H), 7.43 (d, 1H), 4.58 (d, 2H), 3.99 (s, 3H), 3.86 (s, 2H), 3.69 (t, 4H), 2.49 (t, 4H), 2.29 (m, 1H), 0.89 (d, 6H)
Preparation Example 190-4: synthesis of (7-chloro-1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (103mg, 0.282mmol) obtained from Preparation Example 190-3 was used to obtain the title compound (75mg, 79%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.79 (d, 1H), 7.26 (d, 1H), 4.93 (d, 2H), 4.54 (d, 2H), 3.86 (s, 2H), 3.69 (t, 4H), 2.50 (t, 4H), 2.28 (m, 1H), 1.91 (t, 1H), 0.89 (d, 6H)
Preparation Example 191-1: synthesis of 1-isobutyl-7-methyl-3-pyrrolidin-1-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 189-1, the compound (192mg, 0.7mmol) obtained from Preparation Example 170-2 and pyrrolidine (75mg, 1.05mmol) were used to obtain the title compound (76mg, 33%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.68 (d, 1H), 7.46 (d, 1H), 4.42 (d, 2H), 3.98 (br s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.58 (br s, 4H), 2.20 (m, 1H), 1.76 (br s, 4H), 0.88 (d, 6H)
Preparation Example 191-2: synthesis of (1-isobutyl-7-methyl-3-pyrrolidin-1-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (76mg, 0.231mmol) obtained from Preparation Example 191-1 was used to obtain the title compound (59mg, 84%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.65 (d, 1H), 7.11 (d, 1H), 4.83 (d, 2H), 4.39 (d, 2H), 3.97 (s, 2H), 2.70 (s, 3H), 2.58 (br s, 4H), 2.20 (m, 1H), 1.76 (br s, 4H), 0.89 (d, 6H)
Preparation Example 192-1: synthesis of 1-isobutyl-7-methyl-3-piperidin-1-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 189-1, the compound (192mg, 0.7mmol) obtained from Preparation Example 170-2 and piperidine (89mg, 1.05mmol) were used to obtain the title compound (99mg, 41%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.73 (d, 1H), 7.46 (d, 1H), 4.42 (d, 2H), 3.93 (s, 3H), 3.84 (br s, 2H), 2.86 (s, 3H), 2.43 (br s, 4H), 2.19 (m, 1H), 1.68-1.34 (m, 64H), 0.88 (d, 6H)
Preparation Example 192-2: synthesis of (1-isobutyl-7-methyl-3-piperidin-1-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (99mg, 0.288mmol) obtained from Preparation Example 192-1 was used to obtain the title compound (83mg, 91%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.70 (d, 1H), 7.11 (d, 1H), 4.83 (d, 2H), 4.39 (d, 2H), 3.84 (s, 2H), 2.70 (s, 3H), 2.45 (br s, 4H), 2.19 (m, 1H), 1.64-1.33 (m, 6H), 0.89 (d, 6H)
Preparation Example 193-1: synthesis of 3-morpholin-4-ylmethyl-indazole-1,6-dicarboxylic acid 1-t-butyl ester 6-methyl ester
The compound (500mg, 1.354mmol) obtained from Preparation Example 162-2 was dissolved in acetonitrile (10ml). Morpholine (0.24ml, 2.708mmol) was added dropwise thereto and the mixture was stirred at 60℃ for 16 hours. The mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent. Water was added thereto and the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled reduced pressure to obtain the title compound (486mg, 96%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.81 (s, 1H), 8.07 (d, 1H), 7.97 (d 1H), 3.97 (s, 3H), 3.94 (s, 2H), 3.71 (t, 4H), 2.54 (br s, 4H), 1.74 (s, 9H)
Preparation Example 193-2: synthesis of 3-morpholin-4-ylmethyl-1H-indazole-6-carboxylic acidmethyl ester
The compound (486mg, 1.295mmol) obtained from Preparation Example 193-1 was dissolved in dichloromethane (6ml) and trifluoroacetic acid (3ml) was added dropwise. The mixture was stirred for 2 hours and distilled under reduced pressure to remove the solvent. A saturated solution of sodium hydrogen carbonate was added thereto and the residue was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled reduced pressure to obtain the title compound (335mg, 94%).
NMR:1H-NMR(500HMz, CDCl3); δ 10.12 (br s, 1H), 8.20 (s, 1H), 7.96 (d, 1H), 7.83 (d 1H), 3.96 (s, 3H), 3.93 (s, 2H), 3.72 (t, 4H), 2.54 (br s, 4H)
Preparation Example 193-3: synthesis of 1-isobutyl-3-morpholin-4-ylmethyl-1H-indazole-6-carboxylic acidmethyl ester
According to the method described in Preparation Example 55, the compound (165mg, 0.6mmol) obtained from Preparation Example 193-2 and isobutyl iodide (0.14ml, 1.2mmol) were used to obtain the title compound (93mg, 47%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.11 (s, 1H), 7.90 (d, 1H), 7.77 (d 1H), 4.19 (d, 2H), 3.97 (s, 3H), 3.91 (s, 2H), 3.71 (t, 4H), 2.52 (br s, 4H), 2.35 (m, 1H), 0.91 (d, 6H)
Preparation Example 193-4: synthesis of (1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (93mg, 0.281mmol) obtained from Preparation Example 193-3 was used to obtain the title compound (79mg, 93%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.83 (d, 1H), 7.38 (s, 1H), 7.10 (d 1H), 4.84 (d, 2H), 4.13 (d, 2H), 3.88 (s, 2H), 3.70 (t, 4H), 2.51 (t, 4H), 2.34 (m, 1H), 1.75 (t, 1H), 0.91 (d, 6H)
Preparation Example 194: synthesis of (1-isopropyl-7-methyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (2g, 10.52mmol) obtained from Preparation Example 185-2 and isopropyl iodide (2.1ml, 21.04mmol) were used to obtain the title compound (47.5mg, 2%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.54 (d, 1H), 7.13 (d, 1H), 5.27-5.31 (m, 1H), 4.86 (d, 2H), 2.77 (s, 3H), 1.69 (t, 1H), 1.60 (d, 6H)
Preparation Example 195: synthesis of (7-methyl-1-propyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (2g, 10.52mmol) obtained from Preparation Example 185-2 and propyl bromide (1.92ml, 21.04mmol) were used to obtain the title compound (32.4mg, 1.5%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.93 (s, 1H), 7.54 (d, 1H), 7.14 (d, 1H), 4.86 (d, 2H), 4.59 (t, 2H), 2.75 (s, 3H), 1.87-1.93 (m, 2H), 0.96 (t, 3H)
Preparation Example 196-1: synthesis of 3-fluoromethyl-1-isobutyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
The compound (69mg, 0.25mmol) obtained from Preparation Example 170-3 was dissolved in dichloromethane (5ml) and diethylamino-sulfur-trifluoride (DAST, 60.5mg, 0.38mmol) was added thereto. The mixture was stirred for 1 hour at room temperature and a saturated aqueous solution of sodiumbicarbonate was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (56mg, 80%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (d, 1H), 7.56 (d, 1H), 5.75 (s, 1H), 5.63 (s, 1H), 4.45 (d, 2H), 3.94 (s, 3H), 2.89 (s, 3H), 2.23 (m, 1H), 0.92 (d, 6H)
Preparation Example 196-2: synthesis of (3-fluoromethyl-1-isobutyl-7-methyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (12.8mg, 0.046mmol) obtained from Preparation Example 196-1 was used to obtain the title compound (11.5mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.63 (d, 1H), 7.20 (d, 1H), 5.72 (s, 1H), 5.62 (s, 1H), 4.84 (s, 2H), 4.39 (d, 2H), 2.71 (s, 3H), 2.22 (m, 1H), 0.91 (d, 6H)
Preparation Example 197: synthesis of (1-isopropyl-7-methyl-1H-indazol-4-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, 7-methyl-1H-indazole-4-carboxylic acid methyl ester (2.0g, 10.52mmol) obtained from Preparation Example 182-2 and isopropyl iodide (3.58g, 21.04mmol) were used to obtain the title compound (0.60g, 28%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.14 (s, 1H), 7.06 (d, 1H), 7.00 (d, 1H), 5.24 (m, 1H), 4.98 (d, 2H), 2.74 (s, 3H), 1.76 (t, 1H), 1.60 (d, 6H)
Preparation Example 198: synthesis of (1-isopropyl-1H-pyrrolo[2,3-b]pyridine-4-일)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (88mg, 0.5mmol) obtained from Preparation Example 178-2 and isopropyl iodide (0.1ml, 1.0mmol) were used to obtain the title compound (70mg, 74%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.32 (d, 1H), 7.34 (d, 1H), 7.11 (d, 1H), 6.55 (d, 1H), 5.22 (m, 1H), 5.02 (d, 2H), 1.81 (t, 1H), 1.52 (d, 6H)
Preparation Example 199-1: synthesis of 1-isobutyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester
According to the method described in Preparation Example 55, the compound (88mg, 0.5mmol) obtained from Preparation Example 178-2 and isobutyl iodide (0.12ml, 1.0mmol) were used to obtain the title compound (103mg, 89%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.40 (d, 1H), 7.67 (d, 1H), 7.36 (d, 1H), 6.98 (d, 1H), 4.13 (d, 2H), 4.01 (s, 3H), 2.26 (m, 1H), 0.91 (d, 6H)
Preparation Example 199-2: synthesis of 3-fluoro-1-isobutyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester
According to the method described in Preparation Example 163-2, the compound (103mg, 0.443mmol) obtained from Preparation Example 199-1 was used to obtain the title compound (44mg, 40%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.40 (d, 1H), 7.61 (d, 1H), 7.16 (d, 1H), 4.09 (d, 2H), 4.01 (s, 3H), 2.20 (m, 1H), 0.91 (d, 6H)
Preparation Example 199-3: synthesis of (3-fluoro-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-methanol
According to the method described in Preparation Example 56, the compound (44mg, 0.176mmol) obtained from Preparation Example 199-2 was used to obtain the title compound (26mg, 67%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.30 (d, 1H), 7.13 (d, 1H), 6.95 (d, 1H), 5.08 (d, 2H), 4.03 (d, 2H), 2.27-2.14 (m, 2H), 0.90 (d, 6H)
Preparation Example 200: synthesis of (7-methyl-1-pyridin-3-ylmethyl-1H-indazol-6-yl)-methanol
According to the methods described in Preparation Examples 55 and 56, the compound (0.95g, 5.0mmol) obtained from Preparation Example 185-2 and 3-(bromomethyl)pyridine hydrobromide (1.52g, 1.118mmol) were used to obtain the title compound (40mg, 3%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.49 (m, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.58 (d, 1H), 7.26-7.16 (m, 3H), 5.90 (s, 2H), 4.79 (d, 2H), 2.59 (s, 3H)
Preparation Example 201-1: synthesis of 3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
The compound (150mg, 0.55mmol) obtained from Preparation Example 170-2 and 3,3-difluoro-piperidine (113mg, 0.72mmol) were dissolved in dichloroethane (10ml). The mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (174mg, 0.82mmol) and acetic acid (0.047ml, 0.82mmol) were added thereto and the mixture was stirred for 3 hours at room temperature. After completion of the reaction, a saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (64.4mg, 31%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.73 (d, 1H), 7.48 (d, 1H), 4.42 (d, 2H), 3.98 (s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.72 (t, 2H), 2.47-2.50 (m, 2H), 2.18-2.22 (m, 1H), 1.80-1.88 (m, 2H), 1.71-1.77 (m, 2H), 0.91 (d, 6H)
Preparation Example 201-2: synthesis of [3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (64.4mg, 0.17mmol) obtained from Preparation Example 201-1 was used to obtain the title compound (57mg, 95%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.70 (d, 1H), 7.13 (d, 1H), 4.85 (d, 2H), 4.39 (d, 2H), 3.97 (s, 2H), 2.72 (m, 5H), 2.41-2.48 (m, 2H), 2.13-2.23 (m, 1H), 1.81-1.92 (m, 2H), 1.64-1.75 (m, 2H), 0.91 (d, 6H)
Preparation Example 202-1: synthesis of 1-isobutyl-3-methanesulfonyloxymethyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
The compound (107.3mg, 0.39mmol) obtained from Preparation Example 170-3 was dissolved in dichloromethane (5ml). Methanesulfonylchloride (0.39ml, 0.5mmol) was added dropwise thereto at 0℃ and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, a saturated sodium bicarbonate solution was added thereto and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (91.5mg, 66%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.51 (d, 1H), 5.02 (s, 2H), 4.42 (d, 2H), 3.94 (s, 3H), 3.49 (s, 3H), 2.88 (s, 3H), 2.22 (m, 1H), 0.91 (d, 6H)
Preparation Example 202-2: synthesis of 1-isobutyl-7-methyl-3-pyrazol-1-ylmethyl-1H-indazole-6-carboxylic acid methyl ester
The compound (91.5mg, 0.26mmol) obtained from Preparation Example 202-1, pyrazol (17.6mg, 0.26mmol) and cesium carbonate (102mg, 0.31mmol) were dissolved in acetone (5ml) and the mixture was stirred for 18 hours at 50℃. After completion of the reaction, the mixture was cooled to room temperature. Water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure to obtain the title compound (71.3mg, 84%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (s, 1H), 7.38-7.45 (m, 3H), 6.23 (dd, 1H), 5.66 (s, 2H), 4.44 (d, 2H), 3.91 (s, 3H), 2.86 (s, 3H), 2.18-2.25 (m, 1H), 0.92 (d, 6H)
Preparation Example 202-3: synthesis of (1-isobutyl-7-methyl-3-pyrazol-1-ylmethyl-1H-indazol-6-yl)-methanol
According to the method described in Preparation Example 56, the compound (71.3mg, 0.22mmol) obtained from Preparation Example 202-2 was used to obtain the title compound (64.4mg, 100%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (s, 1H), 7.37 (dd, 2H), 7.09 (d, 1H), 6.22 (s, 1H), 5.65 (s, 2H), 4.81 (s, 2H), 4.41 (d, 2H), 2.70 (s, 3H), 2.19 (m, 1H), 0.93 (d, 6H)
Preparation Example 203-1: synthesis of 3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 189-1, the compound (153mg, 0.558mmol) obtained from Preparation Example 170-2 and 3,3-difluoropyrrolidine hydrochloride (80mg, 0.558mmol) were used to obtain the title compound (124mg, 61%).
Preparation Example 203-2: synthesis of [3-(3,3-difluoro-pyridin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (124mg, 0.339mmol) obtained from Preparation Example 203-1 was used to obtain the title compound (37mg, 32%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.63 (d, 1H), 7.14 (d, 1H), 4.84 (d, 2H), 4.69 (d, 2H), 3.99 (s, 2H), 2.95 (t, 2H), 2.79 (t, 2H), 2.71 (s, 3H), 2.31-2.14 (m, 3H), 0.89 (d, 6H)
Preparation Example 204-1: synthesis of 3-formyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester
1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (850mg, 4.82mmol) obtained from Preparation Example 53-2 was dissloved in acetic acid (5ml) and water (10ml). Hexamethylenetetramine (815mg, 5.79mmol) was added thereto, the mixture was stirred at 100℃ for 6 hours and then water was added. The resulting solid was filtered, washed with water and dried to obtain the title compound (420mg, 43%).
NMR:1H-NMR(400HMz, CDCl3); δ 13.10 (br s, 1H), 9.98 (s, 1H), 8.71 (s, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 3.91 (s, 3H)
Preparation Example 204-2: synthesis of 3-formyl-1-isobutyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester
According to the method described in Preparation Example 55, the compound (420mg, 2.06mmol) obtained from Preparation Example 204-1 and isobutyl iodide (0.36ml, 3.09mmol) were used to obtain the title compound (140mg, 26%).
NMR:1H-NMR(400HMz, CDCl3); δ 10.02 (s, 1H), 8.64 (d, 1H), 8.10 (d, 1H), 8.04 (s, 1H), 4.27 (d, 2H), 4.02 (s, 3H), 2.37 (m, 1H), 0.96 (d, 6H)
Preparation Example 204-3: synthesis of 3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester
According to the method described in Preparation Example 203-1, the compound (65mg, 0.25mmol) obtained from Preparation Example 204-2 was used to obtain the title compound (80mg, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.09 (d, 1H), 7.94 (d, 1H), 7.32 (s, 1H), 4.17 (d, 2H), 4.00 (s, 3H), 3.81 (s, 2H), 2.90 (t, 2H), 2.74 (t, 2H), 2.29 (m, 3H), 0.92 (d, 6H)
Preparation Example 204-4: synthesis of [3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (80mg, 0.23mmol) obtained from Preparation Example 204-3 was used to obtain the title compound (65mg, 87%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (d, 1H), 7.08 (s, 1H), 6.96 (d, 1H), 4.84 (s, 2H), 4.06 (d, 2H), 3.79 (s, 2H), 2.89 (t, 2H), 2.74 (t, 2H), 2.28 (m, 3H), 2.26 (m, 2H), 0.92 (d, 6H)
Preparation Example 205-1: synthesis of 3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester
According to the method described in Preparation Example 201-1, the compound (65mg, 2.06mmol) obtained from Preparation Example 204-2 was used to obtain the title compound (70mg, 77%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.10 (d, 1H), 7.94 (d, 1H), 7.31 (s, 1H), 4.17 (d, 2H), 3.99 (s, 3H), 3.81 (s, 2H), 2.65 (t, 2H), 2.47 (m, 2H), 2.29 (m, 1H), 1.88 (m, 2H), 1.78 (m, 2H), 0.93 (d, 6H)
Preparation Example 205-2: synthesis of [3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (70mg, 0.19mmol) obtained from Preparation Example 205-1 was used to obtain the title compound (55mg, 84%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (d, 1H), 7.07 (s, 1H), 6.95 (d, 1H), 4.83 (s, 2H), 4.06 (d, 2H), 3.77 (s, 2H), 2.65 (t, 2H), 2.46 (m, 2H), 2.26 (m, 1H), 1.87 (m, 2H), 1.76 (m. 2H), 0.92 (d, 6H)
Preparation Example 206-1: synthesis of 3-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazole-6-carboxylic acid methyl ester
According to the method described in Preparation Example 201-1, the compound (150mg, 0.55mmol) obtained from Preparation Example 170-2 and (S)-3-fluoro-pyrrolidine (103mg, 0.82mmol) were used to obtain the title compound (37mg, 19%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.69 (d, 1H), 7.47 (d, 1H), 5.22 (br s, 0.5H), 5.08 (br s, 0.5H), 4.42 (d, 2H), 4.03 (s, 2H), 3.93 (s, 3H), 2.82-2.91 (m, 5H), 2.58 (m, 1H), 2.01-2.24 (m, 4H), 0.89 (d, 6H)
Preparation Example 206-2: synthesis of [3-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-yl]-methanol
According to the method described in Preparation Example 56, the compound (37mg, 0.11mmol) obtained from Preparation Example 206-1 was used to obtain the title compound (27.2mg, 77%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (d, 1H), 7.13 (d, 1H), 5.21 (br s, 0.5H), 5.03 (br s, 0.5H), 4.84 (s, 2H), 4.40 (d, 2H), 4.03 (s, 2H), 2.84-2.91 (m, 2H), 2.72 (s, 3H), 2.58 (m, 1H), 2.11(m, 1H), 2.04 (m, 1H), 1.82-1.85 (m, 2H), 0.91 (d, 6H)
Example 1: synthesis of 3-{4-[(1-isopropyl-1H-indol-6-ylmethyl)-amino-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000017
1-Isopropyl-1H-indole-6-carbaldehyde (68mg, 0.36mmol) obtained from Preparation Example 1 and 3-(4-amino-phenyl)-propanoic acid (50mg, 0.36mmol) were dissolved in dichloroethane (10mL). Sodium triacetoxyborohydride (96mg, 0.45mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, water was added and the reaction mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure, and the residue was purified via column chromatography to obtain the title compound (65mg, 53%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.58 (dd, 1H), 7.39 (d, 1H), 7.20-7.23 (d, 1H), 7.10 (d, 1H), 7.02 (d, 2H), 6.63 (dd, 2H), 6.50 (s, 1H), 4.61-4.72 (m, 1H), 4.40 (d, 2H), 2.85 (t, 2H), 2.61 (t, 2H), 1.52 (d, 6H)
The following compounds of Examples 2 to 11 were prepared according to the method described in Example 1.
Example 2: synthesis of 3-{4-[(1-benzyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000018
The compound (68mg, 0.36mmol) obtained from Preparation Example 2 and 3-(4-amino-phenyl)-propanoic acid (50mg, 0.3mmol) were used to obtain the title compound (65mg, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.21-7.28 (m, 4H), 7.06-7.11 (m, 4H), 6.98 (d, 2H), 6.56 (d, 2H), 6.52 (d, 1H), 5.26 (s, 2H), 4.33 (s, 2H), 2.83 (t, 2H), 2.59 (t, 2H)
Example 3: synthesis of 3-{4-[(1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000019
The compound (76mg, 0.33mmol) obtained from Preparation Example 6-3 and 3-(4-amino-phenyl)-propanoic acid (55mg, 0.33mmol) were used to obtain the title compound (65mg, 36%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.80 (d, 1H), 7.58 (s, 1H), 7.38 (dd, 1H), 7.26 (d, 1H), 7.21 (dd, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H), 7.00 (d, 2H), 6.60 (dd, 2H), 6.57 (s, 1H), 4.35 (s, 2H), 2.82 (t, 2H), 2.57 (t, 2H)
Example 4: synthesis of 3-{4-[(1-phenethyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000020
The compound (80mg, 0.36mmol) obtained from Preparation Example 5 and 3-(4-amino-phenyl)-propanoic acid (80mg, 0.48mmol) were used to obtain the title compound (90mg, 63%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.59 (d, 1H), 7.29 (s, 1H), 7.22-7.27 (m, 2H), 7.10 (d, 2H), 7.05 (d, 2H), 7.03 (d, 2H), 6.93 (d, 1H), 6.64 (d, 2H), 6.43 (d, 1H), 4.40 (s, 2H), 4.32 (t, 2H), 3.06 (t, 2H), 2.86 (t, 2H), 2.92 (t, 2H)
Example 5: synthesis of 3-{4-[(1-benzyl-3-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000021
The compound (44mg, 0.16mmol) obtained from Preparation Example 3 and 3-(4-amino-phenyl)-propanoic acid (33mg, 0.20mmol) were used to obtain the title compound (30mg, 45%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.59 (d, 1H), 7.26-7.32 (m, 4H), 7.18 (d, 1H), 7.09 (d, 2H), 7.05 (s, 1H), 7.00 (d, 2H), 6.57 (d, 2H), 5.22 (s, 2H), 4.37 (s, 2H), 2.84 (t, 2H), 2.61 (t, 2H)
Example 6: synthesis of 3-{4-[(1-benzyl-2,3-dichloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000022
The compound (40mg, 0.13mmol) obtained from Preparation Example 4 and 3-(4-amino-phenyl)-propanoic acid (33mg, 0.20mmol) were used to obtain the title compound (22mg, 37%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.53 (d, 1H), 7.23-7.28 (m, 5H), 7.05 (d, 1H), 7.04 (d, 1H), 6.98 (d, 2H), 6.54 (d, 2H), 5.34 (s, 2H), 4.35 (s, 2H), 2.84 (t, 2H), 2.60 (t, 2H)
Example 7: synthesis of 3-{4-[(1-benzyl-7-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000023
The compound (50mg, 0.19mmol) obtained from Preparation Example 7-5 and 3-(4-amino-phenyl)-propanoic acid (37mg, 0.22mmol) were used to obtain the title compound (68mg, 85%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.46 (d, 1H), 7.21-7.34 (m, 3H), 7.14 (d, 1H), 7.07 (d, 1H), 7.01 (d, 2H), 6.98 (d, 2H), 6.57 (d, 2H), 6.52 (d, 1H), 5.32(s, 2H), 4.44 (s, 2H), 2.83 (t, 2H), 2.59 (t, 2H)
Example 8: synthesis of 3-{4-[(7-chloro-1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000024
The compound (17mg, 0.06mmol) obtained from Preparation Example 8-2 and 3-(4-amino-phenyl)-propanoic acid (13mg, 0.08mmol) were used to obtain the title compound (10mg, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.50 (d, 1H), 7.33 (dd, 2H), 7.21 (d, 1H), 7.14 (dd, 1H), 7.13 (d, 1H), 7.00 (d, 2H), 6.59 (d, 2H), 6.57 (d, 1H), 4.46 (s, 2H), 2.83 (t, 2H), 2.60 (t, 2H)
Example 9: synthesis of 3-(4-{[7-chloro-1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid
Figure PCTKR2013010135-appb-I000025
The compound (10mg, 0.04mmol) obtained from Preparation Example 9-2 and 3-(4-amino-phenyl)-propanoic acid (9mg, 0.05mmol) were used to obtain the title compound (8mg, 47%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.35-7.38 (m, 2H), 7.22 (d, 1H), 7.11-7.15 (m, 3H), 7.00 (d, 2H), 6.60 (dd, 3H), 4.45 (s, 2H), 2.83 (t, 2H), 2.60 (t, 2H)
Example 10: synthesis of 3-(4-{[1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid
Figure PCTKR2013010135-appb-I000026
The compound (10mg, 0.04mmol) obtained from Preparation Example 139 and 3-(4-amino-phenyl)-propanoic acid (14mg, 0.08mmol) were used to obtain the title compound (12mg, 77%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.53 (s, 1H), 7.39-7.45 (m, 2H), 7.25 (dd, 1H), 7.12-7.21 (m, 3H), 7.00 (d, 2H), 6.65 (d, 1H), 6.58 (d, 2H), 4.32 (s, 2H), 2.84 (t, 2H), 2.60 (t, 2H)
Example 11: synthesis of 3-{4-[(7-chloro-1-cyclohexyl methyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000027
The compound (32mg, 0.12mmol) obtained from Preparation Example 10-2 and 3-(4-amino-phenyl)-propanoic acid (29mg, 0.17mmol) were used to obtain the title compound (17mg, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.44 (d, 1H), 7.12 (d, 1H), 7.00 (d, 2H), 6.99 (d, 1H), 6.62 (d, 2H), 6.41 (d, 1H), 4.51 (s, 2H), 4.29 (d, 2H), 2.85 (t, 2H), 2.62 (t, 2H), 1.87-1.94 (m, 1H), 1.59-1.70 (m, 5H), 1.16-1.21 (m, 3H), 0.97-1.03 (m, 2H)
Example 12: synthesis of [6-(1-benzyl-3-chloro-1H-indol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000028
(1-Benzyl-3-chloro-1H-indol-6-yl)-methanol (90mg, 0.33mmol) obtained from Preparation Example 140 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (60mg, 0.29mmol) obtained from Preparation Example 158 were dissolved in toluene (10mL). 1,1’-(Azodicarbonyl)dipiperidine (ADD, 125mg, 0.49mmol) and tributylphosphine(Bu3P, 100mg, 0.49mmol) were added thereto and the mixture was stirred for 1 hour. After completion of the reaction, resulting solids were removed by filteration with Celite and the filtrate was concentrated. The residue was purified via column chromatography to obtain the ester compound (130mg, 86%).
The ester compound (130mg, 0.28mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (2/1, 9ml) and then 1N NaOH solution (0.6ml, 0.56mmol) was added thereto. The mixture was stirred at room temperature for 4 hours, 1N hydrochloric acid solution was added thereto and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure. The residue was purified via column chromatography to obtain the title compound to obtain the title compound (100mg, 79%).
NMR:1H-NMR(400HMz, MeOD-d3); δ 7.62 (d, 1H), 7.36 (s, 1H), 7.29 (d, 3H), 7.22 (d, 1H), 7.12 (d, 2H), 7.09 (s, 1H), 7.03 (d, 1H), 6.49 (d, 1H), 6.46 (d, 1H), 5.38 (s, 2H), 5.09 (s, 2H), 4.76 (dd, 1H), 4.27 (dd, 1H), 3.79 (br s, 1H), 2.74 (dd, 1H), 2.54 (dd, 1H)
The following compounds of Examples 13 to 232 were prepared according to the method described in Example 12.
Example 13: synthesis of 3-[4-(1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000029
According to the method described in Example 12, the compound (160mg, 0.7mmol) obtained from Preparation Example 6-2 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (126mg, 0.7mmol) were used to obtain the title compound (200mg, 76%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (d, 1H), 7.62 (s, 1H), 7.44 (dd, 1H), 7.32 (d, 1H), 7.27 (d, 2H), 7.20 (dd, 1H), 7.11 (d, 2H), 6.92 (d, 2H), 6.64 (d, 1H), 4.94 (s, 2H), 2.89 (t, 2H), 2.64 (t, 2H)
Example 14: synthesis of 3-{4-[1-(4-fluoro-phenyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000030
The compound (96mg, 0.38mmol) obtained from Preparation Example 15-3 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (68mg, 0.38mmol) were used to obtain the title compound (100mg, 73%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.52 (d, 1H), 7.36 (dd, 1H), 7.35 (dd, 1H), 7.20 (d, 1H), 7.09-7.15 (m, 5H), 6.91 (d, 2H), 6.60 (d, 1H), 5.07 (s, 2H), 2.90 (t, 2H), 2.64 (t, 2H), 2.01 (s, 3H)
Example 15: synthesis of 3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000031
The compound (100mg, 0.40mmol) obtained from Preparation Example 17-2 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (72mg, 0.40mmol) were used to obtain the title compound (70mg, 44%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.48 (d, 1H), 7.21-7.29 (m, 3H), 7.08-7.14 (m, 4H), 6.89-6.94 (m, 4H), 6.54 (d, 1H), 5.63 (s, 2H), 5.04 (s, 2H), 2.89 (t, 2H), 2.64 (t, 2H), 2.50 (s, 3H)
Example 16: synthesis of 3-[4-(7-methyl-1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000032
The compound (30mg, 0.12mmol) obtained from Preparation Example 16 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (22mg, 0.12mmol) were used to obtain the title compound (20mg, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (d, 1H), 7.36 (dd, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 7.11-7.13 (m, 4H), 6.92 (d, 2H), 6.58 (d, 1H), 5.08 (s, 2H), 2.90 (t, 2H), 2.64 (t, 2H), 2.10 (s, 3H)
Example 17: synthesis of 3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000033
The compound (52mg, 0.20mmol) obtained from Preparation Example 11-2 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (36mg, 0.20mmol) were used to obtain the title compound (25mg, 30%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.68 (d, 1H), 7.22 (dd, 1H), 7.13 (d, 1H), 7.04-7.10 (m, 5H), 7.00 (dd, 1H), 6.88 (d, 2H), 6.65 (d, 1H), 5.06 (s, 2H), 2.88 (t, 2H), 2.63 (t, 2H), 2.00 (s, 3H)
Example 18: synthesis of 3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000034
The compound (158mg, 0.72mmol) obtained from Preparation Example 7-4 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (105mg, 0.58mmol) were used to obtain the title compound (210mg, 86%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.24-7.30 (m, 4H), 7.11 (d, 2H), 7.10 (s, 1H), 7.01 (d, 2H), 6.91 (d, 2H), 6.55 (d, 1H), 5.80 (s, 2H), 5.02 (s, 2H), 2.89 (t, 2H), 2.64 (t, 2H)
Example 19: synthesis of 3-[4-(1-cyclohexyl methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000035
The compound (140mg, 0.58mmol) obtained from Preparation Example 14-2 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (105mg, 0.58mmol) were used to obtain the title compound (35mg, 16%)
NMR:1H-NMR(400HMz, CDCl3); δ 7.66 (d, 1H), 7.43 (s, 1H), 7.14-7.20 (m, 3H), 7.11 (d, 1H), 7.00 (d, 2H), 6.51 (d, 1H), 5.21 (s, 2H), 3.97 (d, 2H), 2.95 (t, 2H), 2.70 (t, 2H), 1.85-1.91 (m, 1H), 1.64-1.73 (m, 5H), 1.19-1.26 (m, 3H), 0.92-1.04 (m, 2H)
Example 20: synthesis of 3-[4-(3-benzyl-1-methyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000036
The compound (100mg, 0.52mmol) obtained from Preparation Example 50-3 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (65mg, 0.36mmol) were used to obtain the title compound (7mg, 3%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.56 (s, 1H), 7.26-7.29 (m, 6H), 7.18-7.21 (m, 1H), 7.11 (d, 2H), 6.92 (dt, 2H), 6.75 (s, 1H), 5.09 (s, 2H), 4.09 (s, 2H), 3.73 (s, 3H), 2.90 (t, 2H), 2.64 (t, 2H)
Example 21: synthesis of 3-[4-(1-methyl-3-o-tolyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000037
The compound (59mg, 0.23mmol) obtained from Preparation Example 51-3 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (42mg, 0.23mmol) were used to obtain the title compound (65mg, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.55 (s, 1H), 7.38-7.41 (m, 1H), 7.37 (d, 1H), 7.35 (d, 1H), 7.30-7.33 (m, 1H), 7.24 (dd, 2H), 7.09 (d, 2H), 7.06 (s, 1H), 6.90 (d, 2H), 5.09 (s, 2H), 3.85 (s, 3H), 2.89 (t, 2H), 2.63 (t, 2H), 2.31 (s, 3H)
Example 22: synthesis of 3-{4-[3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000038
The compound (70mg, 0.24mmol) obtained from Preparation Example 12-2 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (49mg, 0.24mmol) were used to obtain the title compound (70mg, 66%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.72 (d, 1H), 7.33 (s, 1H), 7.27 (dd, 1H), 7.16 (s, 1H), 7.10-7.12 (m, 3H), 7.03-7.06 (m, 2H), 6.90 (d, 2H), 5.10 (s, 2H), 2.92 (t, 2H), 2.66 (t, 2H), 2.05 (s, 3H)
Example 23: synthesis of 3-{4-[5-fluoro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000039
The compound (74mg, 0.27mmol) obtained from Preparation Example 13-5 and 3-(4-hydroxy-phenyl)-propanoic acid methyl ester (49mg, 0.27mmol) were used to obtain the title compound (70mg, 61%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.35 (d, 1H), 7.23 (dd, 1H), 7.15 (d, 1H), 7.09 (d, 2H), 6.98-7.07 (m, 3H), 6.88 (d, 2H), 6.61 (d, 1H), 5.12 (s, 2H), 2.88 (t, 2H), 2.63 (t, 2H), 1.97 (s, 3H)
Example 24: synthesis of {6-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid
Figure PCTKR2013010135-appb-I000040
The compound (75mg, 0.29mmol) obtained from Preparation Example 11-2 and the compound (61mg, 0.29mmol) obtained from Preparation Example 158 were used to obtain the title compound (91mg, 72%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.73 (d, 1H), 7.30-7.33 (m, 1H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.12 (dd, 1H), 7.07 (dd, 2H), 7.04 (d, 1H), 6.71 (d, 1H), 6.53 (dd, 1H), 5.49 (d, 1H), 5.09 (s, 2H), 4.79 (t, 1H), 4.31 (q, 1H), 3.84 (br t, 1H), 2.81-2.86 (m, 1H), 2.61-2.68 (m, 1H), 2.09 (s, 3H)
Example 25: synthesis of (S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000041
The compound (500mg, 1.99mmol) obtained from Preparation Example 17-2 and the compound (435mg, 1.99mmol) obtained from Preparation Example 155 were used to obtain the title compound (550mg, 63%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.48 (d, 1H), 7.42 (d, 1H), 7.26-7.32 (m, 5H), 7.10 (d, 1H), 6.90-6.96 (m, 4H), 6.53 (d, 1H), 5.71 (s, 2H), 5.08 (s, 2H), 3.95 (br s, 1H), 2.59 (m, 1H), 2.44 (s, 3H), 2.41 (m, 1H), 1.79 (s, 3H)
Example 26: synthesis of (S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000042
The compound (420mg, 1.65mmol) obtained from Preparation Example 11-2 and the compound (360mg, 1.65mmol) obtained from Preparation Example 155 were used to obtain the title compound (600mg, 82%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.67 (d, 1H), 7.46 (d, 1H), 7.34-7.42 (m, 2H), 7.24 (d, 3H), 7.20 (d, 1H), 7.04 (s, 1H), 6.92 (dd, 2H), 6.69 (dd, 1H), 5.12 (s, 2H), 3.93 (br s, 1H), 2.59 (m, 1H), 2.57 (m, 1H), 1.97 (s, 3H), 1.78 (s, 3H)
Example 27: synthesis of (S)-3-{4-[1-(4-methanesulfonyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000043
The compound (100mg, 0.30mmol) obtained from Preparation Example 32 and the compound (65mg, 0.30mmol) obtained from Preparation Example 155 were used to obtain the title compound (15mg, 10%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.86 (d, 2H), 7.46 (d, 1H), 7.43 (d, 1H), 7.24 (d, 2H), 7.12 (dd, 3H), 6.92 (d, 2H), 6.56 (d, 1H), 5.81 (s, 2H), 5.06 (s, 2H), 3.16 (s, 3H), 2.57-2.59 (m, 1H), 2.52-2.53 (m, 1H), 2.39 (s, 3H), 1.76 (s, 3H)
Example 28: synthesis of (S)-3-{4-[1-(4-methoxy-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000044
The compound (280mg, 1.00mmol) obtained from Preparation Example 30 and the compound (217mg, 1.00mmol) obtained from Preparation Example 155 were used to obtain the title compound (280mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (d, 1H), 7.33 (dd, 2H), 7.17 (d, 1H), 7.12 (d, 1H), 6.98 (dd, 2H), 6.91 (d, 2H), 6.86 (dd, 2H), 6.56 (d, 1H), 5.59 (s, 2H), 5.12 (s, 2H), 4.10 (br s, 1H), 3.81 (s, 3H), 2.82-2.88 (m, 1H), 2.72-2.77 (m, 1H), 2.57 (s, 3H), 1.90 (s, 3H)
Example 29: synthesis of (S)-3-{4-[7-methyl-1-(4-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000045
The compound (250mg, 0.94mmol) obtained from Preparation Example 28 and the compound (206mg, 0.94mmol) obtained from Preparation Example 155 were used to obtain the title compound (300mg, 63%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.21-7.29 (m, 4H), 7.13 (d, 1H), 7.09 (d, 1H), 6.94 (d, 2H), 6.92 (d, 2H), 6.54 (d, 1H), 5.61 (s, 2H), 5.05 (s, 2H), 4.04 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.50 (s, 3H), 1.82 (s, 3H)
Example 30: synthesis of (S)-3-{4-[1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000046
The compound (90mg, 0.31mmol) obtained from Preparation Example 31-4 and the compound (67mg, 0.31mmol) obtained from Preparation Example 155 were used to obtain the title compound (57mg, 39%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.30 (d, 2H), 7.27 (s, 1H), 7.22 (d, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 7.00 (s, 1H), 6.92 (dd, 2H), 6.80 (d, 1H), 6.54 (d, 1H), 5.61 (s, 2H), 5.06 (s, 2H), 4.39 (s, 2H), 4.05 (br s, 1H), 3.35 (s, 3H), 2.77-2.83 (m, 1H), 2.68-2.73 (m, 1H), 2.50 (s, 3H), 1.83 (s, 3H)
Example 31: synthesis of (S)-3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000047
The compound (120mg, 0.5mmol) obtained from Preparation Example 131-2 and the compound (100mg, 0.46mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 47%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.54 (d, 1H), 7.43 (dd, 1H), 7.32 (dd, 2H), 7.22-7.27 (m, 5H), 7.08-7.12 (m, 2H), 6.93 (d, 2H), 6.61 (d, 1H), 5.45 (s, 2H), 5.31 (s, 2H), 3.98 (br s, 1H), 2.24-2.29 (m, 1H), 2.09-2.14 (m, 1H), 1.76 (s, 3H)
Example 32: synthesis of (S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000048
The compound (100mg, 0.4mmol) obtained from Preparation Example 132-2 and the compound (85mg, 0.39mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 57%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.33 (d, 2H), 7.24 (dd, 1H), 7.22 (dd, 1H), 7.18 (s, 1H), 7.15 (dd, 1H), 7.08 (dd, 1H), 6.96-7.02 (m, 4H), 6.76 (d, 1H), 5.44 (s, 2H), 4.07 (br t, 1H), 2.79-2.85 (m, 1H), 2.70-2.75 (m, 1H), 2.04 (s, 3H), 1.83 (s, 3H)
Example 33: synthesis of (S)-3-{4-[1-(2,6-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000049
The compound (200mg, 0.70mmol) obtained from Preparation Example 22 and the compound (153mg, 0.70mmol) obtained from Preparation Example 155 were used to obtain the title compound (200mg, 61%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.42 (d, 1H), 7.31 (d, 3H), 7.11 (d, 1H), 6.98 (d, 2H), 6.93 (d, 3H), 6.43 (d, 1H), 5.70 (s, 2H), 5.13 (s, 2H), 4.07 (br s, 1H), 2.79-2.84 (m, 1H), 2.81 (s, 3H), 2.70-2.75 (m, 1H), 1.83 (s, 3H)
Example 34: synthesis of (S)-3-{4-[1-benzyl-2-(2-methoxy-ethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000050
The compound (130mg, 0.44mmol) obtained from Preparation Example 52-5 and the compound (96mg, 0.44mmol) obtained from Preparation Example 155 were used to obtain the title compound (50mg, 23%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.56 (d, 1H), 7.19-7.30 (m, 5H), 7.13 (d, 1H), 6.93 (d, 2H), 6.90 (d, 3H), 6.37 (s, 1H), 5.35 (s, 2H), 5.07 (s, 2H), 4.03 (br s, 1H), 3.64 (t, 2H), 3.31 (s, 3H), 2.94 (t, 2H), 2.76-2.81 (m, 1H), 2.67-2.71 (m, 1H), 1.82 (s, 3H)
Example 35: synthesis of (S)-3-{4-[1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000051
The compound (130mg, 0.38mmol) obtained from Preparation Example 33-2 and the compound (83mg, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (60mg, 30%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.39 (dd, 1H), 7.31-7.34 (m, 4H), 7.18 (d, 1H), 7.15 (dd, 1H), 7.06 (d, 1H), 6.94 (dd, 1H), 6.76 (s, 1H), 6.61 (d, 1H), 5.67 (s, 2H), 5.09 (s, 2H), 4.14 (s, 2H), 4.08 (br s, 1H), 2.82-2.88 (m, 1H), 2.72-2.77 (m, 1H), 2.52 (s, 3H), 2.49 (s, 3H), 1.87 (s, 3H)
Example 36: synthesis of (S)-3-{4-[7-methyl-1-(2-methyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000052
The compound (0.21g, 0.70mmol) obtained from Preparation Example 26-2 and the compound (0.20g, 0.70mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.10g, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (d, 1H), 7.27 (dd, 2H), 7.13-7.19 (m, 3H), 7.01-7.04 (m, 2H), 6.92 (d, 2H), 6.53 (dd, 1H), 6.41 (d, 1H), 5.52 (s, 2H), 5.06 (s, 2H), 4.11 (br s, 1H), 2.78-2.82 (m, 1H), 2.67-2.72 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 1.82 (s, 3H)
Example 37: synthesis of (S)-3-{4-[1-(2-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000053
The compound (0.28g, 0.94mmol) obtained from Preparation Example 18-2 and the compound (0.20g, 0.70mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.16g, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.28 (d, 2H), 7.21 (dd, 1H), 7.14 (d, 1H), 7.09 (dd, 2H), 6.98 (d, 2H), 6.92 (d, 2H), 6.55 (d, 1H), 5.64 (s, 2H), 5.06 (s, 2H), 4.04 (br t, 1H), 2.76-2.82 (m, 1H), 2.66-2.72 (m, 1H), 2.48 (s, 3H), 1.82 (s, 3H)
Example 38: synthesis of (S)-3-{4-[1-(2-chloro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000054
The compound (0.19g, 0.64mmol) obtained from Preparation Example 25-2 and the compound (0.18g, 0.64mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 42%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.50 (d, 1H), 7.39 (d, 1H), 7.27 (d, 2H), 7.12-7.21 (m, 2H), 7.06 (d, 2H), 6.91 (d, 2H), 6.56 (d, 1H), 6.38 (d, 1H), 5.63 (s, 2H), 5.06 (s, 2H), 4.04 (br t, 1H), 2.76-2.82 (m, 1H), 2.67-2.72 (m, 1H), 2.40 (s, 3H), 1.82 (s, 3H)
Example 39: synthesis of (S)-3-{4-[1-(2,6-dimethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000055
The compound (0.18g, 0.62mmol) obtained from Preparation Example 29-2 and the compound (0.17g, 0.62mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 42%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.43 (d, 1H), 7.35 (d, 2H), 7.20 (d, 1H), 7.12 (d, 3H), 7.01 (d, 2H), 6.48 (d, 1H), 6.30 (d, 1H), 5.67 (s, 2H), 5.16 (s, 2H), 4.08 (br t, 1H), 2.93 (s, 3H), 2.77-2.83 (m, 1H), 2.72-2.74 (m, 1H), 2.27 (s, 6H), 1.83 (s, 3H)
Example 40: synthesis of (S)-3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000056
The compound (0.21g, 0.71mmol) obtained from Preparation Example 46 and the compound (0.18g, 0.71mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.16g, 49%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (d, 1H), 7.21-7.30 (m, 6H), 7.10 (d, 1H), 7.01 (d, 2H), 6.93 (d, 2H), 6.54 (d, 1H), 5.83 (s, 2H), 5.20 (s, 2H), 4.06 (br t, 1H), 2.76-2.82 (m, 1H), 2.66-2.72 (m, 1H), 1.82 (s, 3H)
Example 41: synthesis of (S)-3-[4-(1-benzyl-5-fluoro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000057
The compound (0.17g, 0.59mmol) obtained from Preparation Example 47-2 and the compound (0.15g, 0.59mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.09g, 32%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.60 (d, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.18-7.26 (m, 4H), 7.08 (d, 1H), 6.88 (d, 2H), 6.63 (d, 1H), 6.49 (d, 1H), 5.42 (s, 2H), 5.10 (s, 2H), 3.99 (br s, 1H), 2.23-2.31 (m, 1H), 2.09-2.16 (m, 1H), 1.75 (s, 3H)
Example 42: synthesis of (S)-3-{4-[1-(3-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000058
The compound (0.20g, 0.68mmol) obtained from Preparation Example 19-2 and the compound (0.18g, 0.68mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.06g, 19%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (d, 1H), 7.28 (dd, 2H), 7.22 (dd, 1H), 7.14 (d, 1H), 7.08 (dd, 1H), 6.92-6.94 (m, 3H), 6.71 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 5.59 (s, 2H), 5.07 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.49 (s, 3H), 1.82 (s, 3H)
Example 43: synthesis of (S)-3-{4-[7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000059
The compound (0.20g, 0.68mmol) obtained from Preparation Example 27-2 and the compound (0.18g, 0.68mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.15g, 49%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.70 (dd, 1H), 7.50 (d, 1H), 7.34 (dd, 2H), 7.26 (dd, 2H), 7.15 (d, 1H), 7.07 (d, 1H), 6.90 (d, 2H), 6.58 (d, 1H), 6.42 (dd, 1H), 5.80 (s, 2H), 5.04 (s, 2H), 4.11 (br t, 1H), 2.75-2.81 (m, 1H), 2.66-2.72 (m, 1H), 2.38 (s, 3H), 1.82 (s, 3H)
Example 44: synthesis of (S)-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000060
The compound (0.09g, 0.33mmol) obtained from Preparation Example 42 and the compound (0.09g, 0.33mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.07g, 49%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.51 (s, 1H), 7.96 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.23 (d, 2H), 7.11 (d, 1H), 6.88 (d, 2H), 6.51 (d, 1H), 5.81 (s, 2H), 5.07 (s, 2H), 3.98 (br s, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.23 (m, 1H), 2.12 (m, 1H), 1.76 (s, 3H)
Example 45: synthesis of (S)-3-{4-[1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000061
The compound (240mg, 0.70mmol) obtained from Preparation Example 35 and the compound (153mg, 0.70mmol) obtained from Preparation Example 155 were used to obtain the title compound (90mg, 24%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.31-7.37 (m, 4H), 7.18 (d, 1H), 7.12 (d, 1H), 7.00 (d, 2H), 6.96 (d, 2H), 6.60 (d, 1H), 5.66 (s, 2H), 5.11 (s, 2H), 4.29 (s, 2H), 4.09 (br s, 1H), 2.81-2.87 (m, 1H), 2.78 (s, 3H), 2.71-2.75 (m, 1H), 2.52 (s, 3H), 1.86 (s, 3H)
Example 46: synthesis of (S)-3-{4-[1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000062
The compound (0.17g, 0.57mmol) obtained from Preparation Example 37-2 and the compound (0.15g, 0.57mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.09g, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.13 (s, 1H), 7.48 (d, 1H), 7.29 (dd, 2H), 7.19 (d, 1H), 7.15 (d, 1H), 7.04 (d, 2H), 6.92 (d, 2H), 6.57 (d, 1H), 5.59 (s, 2H), 5.07 (s, 2H), 4.04 (br s, 1H), 2.78-2.84 (m, 1H), 2.66-2.72 (m, 1H), 2.44 (s, 3H), 1.82 (s, 3H)
Example 47: synthesis of (S)-3-[4-(2-benzyl-2H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000063
The compound (140mg, 0.60mmol) obtained from Preparation Example 134-2 and the compound (131mg, 0.60mmol) obtained from Preparation Example 155 were used to obtain the title compound (170mg, 68%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.16 (s, 1H), 7.31-7.32 (m, 5H), 7.27-7.28 (m, 2H), 7.16-7.21 (m, 3H), 6.97 (dd, 2H), 5.61 (s, 2H), 5.36 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 1.82 (s, 3H)
Example 48: synthesis of (S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000064
The compound (90mg, 0.38mmol) obtained from Preparation Example 133-2 and the compound (83mg, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 95%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.69 (d, 1H), 7.32-7.35 (m, 3H), 7.25-7.27 (m, 5H), 7.08 (d, 1H), 6.91 (d, 2H), 5.59 (s, 2H), 5.24 (s, 2H), 4.04 (br s, 1H), 2.76-2.82 (m, 1H), 2.66-2.71 (m, 1H), 1.82 (s, 3H)
Example 49: synthesis of (S)-3-[4-(1-benzyl-5-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000065
The compound (252mg, 0.94mmol) obtained from Preparation Example 48-4 and the compound (205mg, 0.94mmol) obtained from Preparation Example 155 were used to obtain the title compound (123mg, 29%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.24-7.31 (m, 5H), 7.18 (d, 1H), 7.12 (d, 1H), 6.91 (m, 4H), 6.50 (d, 1H), 5.58 (s, 2H), 5.13 (d, 2H), 4.04 (m, 1H), 2.81 (dd, 1H), 2.72 (dd, 1H), 2.51 (s, 3H), 1.82 (s, 3H)
Example 50: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000066
The compound (0.15g, 0.51mmol) obtained from Preparation Example 20-2 and the compound (0.13g, 0.51mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 52%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.28 (d, 2H), 7.14 (d, 1H), 7.07 (d, 1H), 6.87-6.99 (m, 6H), 6.54 (d, 1H), 5.57 (s, 2H), 5.06 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.49 (s, 3H), 1.82 (s, 3H)
Example 51: synthesis of (S)-3-{4-[1-(3,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000067
The compound (0.19g, 0.64mmol) obtained from Preparation Example 21-2 and the compound (0.17g, 0.64mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.13g, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.29 (d, 2H), 7.14 (d, 1H), 7.06 (d, 2H), 6.92 (d, 2H), 6.70-6.75 (m, 1H), 6.65 (m, 1H), 6.56 (d, 1H), 5.55 (s, 2H), 5.07 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.68-2.74 (m, 1H), 2.48 (s, 3H), 1.72 (s, 3H)
Example 52: synthesis of (S)-3-{4-[1-(3,5-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000068
The compound (0.14g, 0.49mmol) obtained from Preparation Example 23 and the compound (0.13g, 0.49mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (d, 1H), 7.31 (d, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 6.93 (dd, 2H), 6.67 (dddd, 1H), 6.52 (d, 1H), 6.38 (d, 2H), 5.55 (s, 2H), 5.07 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.68-2.73 (m, 1H), 2.47 (s, 3H), 1.82 (s, 3H)
Example 53: synthesis of (S)-3-{4-[1-(2,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000069
The compound (0.15g, 0.49mmol) obtained from Preparation Example 24 and the compound (0.13g, 0.49mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.14g, 63%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (d, 1H), 7.28 (d, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 6.92 (dd, 2H), 6.84 (dd, 1H), 6.70 (t, 1H), 6.55 (d, 1H), 6.44-6.47 (m, 1H), 5.59 (s, 2H), 5.07 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.68-2.73 (m, 1H), 2.48 (s, 3H), 1.82 (s, 3H)
Example 54: synthesis of 3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-2-fluoro-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000070
The compound (100mg, 0.42mmol) obtained from Preparation Example 131-2 and the compound (90mg, 0.42mmol) obtained from Preparation Example 149 were used to obtain the title compound (135mg, 80%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.47 (d, 1H), 7.27 (m, 3H), 7.08 (m, 3H), 6.91 (d, 2H), 6.66 (m, 2H), 6.53 (d, 1H), 5.60 (s, 2H), 5.02 (s, 2H), 2.89 (t, 2H), 2.63 (t, 2H), 2.48 (s, 3H)
Example 55: synthesis of 3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000071
The compound (100mg, 0.40mmol) obtained from Preparation Example 17-2 and the compound (84mg, 0.40mmol) obtained from Preparation Example 149 were used to obtain the title compound (90.5mg, 54%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 7.53 (d, 1H), 7.43 (m, 1H), 7.16-7.32 (m, 6H), 7.10 (m, 1H), 6.87 (m, 1H), 6.80 (m, 1H), 6.60 (m, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 2.75 (t, 2H), 2.47 (t, 2H)
Example 56: synthesis of (S)-3-[4-(7-methyl-1-thiazol-4-ylmethyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000072
The compound (0.11g, 0.38mmol) obtained from Preparation Example 43-2 and the compound (0.10g, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.07g, 43%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.82 (s, 1H), 7.47 (d, 1H), 7.28 (d, 2H), 7.12-7.14 (m, 2H), 6.92 (d, 2H), 6.54 (d, 2H), 5.75 (s, 2H), 5.10 (s, 2H), 4.04 (br s, 1H), 2.77-2.83 (m, 1H), 2.66-2.71 (m, 1H), 2.50 (s, 3H), 1.73 (s, 3H)
Example 57: synthesis of (S)-3-{4-[7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000073
The compound (0.10g, 0.33mmol) obtained from Preparation Example 44-2 and the compound (0.09g, 0.33mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.08g, 50%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.46 (d, 1H), 7.29 (d, 2H), 7.12 (d, 1H), 7.10 (d, 1H), 6.92 (d, 2H), 6.52 (d, 1H), 6.21 (s, 1H), 5.58 (s, 2H), 5.02 (s, 2H), 4.52 (t, 1H), 3.27-3.34 (m, 1H), 2.90-2.96 (m, 1H), 2.47 (s, 6H), 1.73 (s, 3H)
Example 58: synthesis of (S)-3-[4-(2-benzyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000074
The compound (209mg, 0.88mmol) obtained from Preparation Example 57 and the compound (192mg, 0.88mmol) obtained from Preparation Example 155 were used to obtain the title compound (220mg, 59%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.87 (s, 1H), 7.72 (s, 1H), 7.62 (d, 1H), 7.32-7.35 (m, 3H), 7.28-7.30 (m, 4H), 7.13 (dd, 1H), 6.94 (d, 2H), 5.59 (s, 2H), 5.13 (s, 2H), 4.04 (br s, 1H), 2.76-2.82 (m, 1H), 2.67-2.72 (m, 1H), 1.83 (s, 3H)
Example 59: synthesis of (S)-3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000075
The compound (150mg, 0.63mmol) obtained from Preparation Example 56 and the compound (137mg, 0.63mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 37%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.12 (s, 1H), 7.80 (d, 1H), 7.78 (s, 1H), 7.28-7.32 (m, 3H), 7.22-7.26 (m, 5H), 6.91 (d, 2H), 5.68 (s, 2H), 5.18 (s, 2H), 4.01 (br s, 1H), 2.21-2.23 (m, 1H), 2.09-2.10 (m, 1H), 1.76 (s, 3H)
Example 60: synthesis of (S)-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000076
The compound (0.06g, 0.21mmol) obtained from Preparation Example 38-2 and the compound (0.05g, 0.21mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.03g, 31%).
NMR:1H-NMR(500 MHz, DMSO-d 6); δ 8.57 (d, 1H), 8.51 (d, 1H), 8.02 (s, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 7.16 (d, 1H), 7.06 (d, 1H), 6.83 (d, 1H), 6.81 (d, 1H), 6.48 (d, 1H), 5.81 (s, 2H), 5.00 (s, 2H), 3.92 (br s, 1H), 2.40 (s, 3H), 2.17-2.21 (m, 1H), 2.03-2.06 (m, 1H), 1.70 (s, 3H)
Example 61: synthesis of (S)-3-[4-(7-methyl-1-pyrimidin-4-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000077
The compound (0.08g, 0.30mmol) obtained from Preparation Example 39 and the compound (0.07g, 0.30mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.02g, 13%).
NMR:1H-NMR(400HMz, CDCl3); δ 9.20 (s, 1H), 8.57 (d, 1H), 7.51 (d, 1H), 7.28 (d, 2H), 7.17 (d, 2H), 7.08 (d, 1H), 6.90 (d, 1H), 6.60 (d, 1H), 6.47 (d, 1H), 5.57 (s, 2H), 5.05 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.41 (s, 3H), 1.72 (s, 3H)
Example 62: synthesis of (S)-3-[4-(1-benzyl-3-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000078
The compound (50mg, 0.19mmol) obtained from Preparation Example 49-2 and the compound (41mg, 0.19mmol) obtained from Preparation Example 155 were used to obtain the title compound (50mg, 59%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.49 (d, 1H), 7.26-7.30 (m, 5H), 7.15 (d, 1H), 6.91-6.95 (m, 4H), 6.86 (d, 1H), 5.50 (s, 2H), 5.05 (s, 2H), 4.05 (br s, 1H), 2.77-2.83 (m, 1H), 2.68-2.73 (m, 1H), 2.49 (s, 3H), 1.82 (s, 3H)
Example 63: synthesis of (S)-3-{4-[7-methyl-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000079
The compound (0.06g, 0.24mmol) obtained from Preparation Example 45 and the compound (0.05g, 0.24mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.09g, 82%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.53 (d, 1H), 7.30 (d, 2H), 7.29 (s, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.90-6.95 (m, 3H), 6.47 (d, 1H), 5.47 (s, 2H), 5.09 (s, 2H), 4.09 (t, 1H), 3.77 (s, 3H), 2.73-2.82 (m, 1H), 2.62-2.72 (m, 1H), 2.57 (s, 3H), 1.81 (s, 3H)
Example 64: synthesis of (S)-3-[4-(7-methyl-1-pyrimidin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000080
The compound (0.12g, 0.45mmol) obtained from Preparation Example 40 and the compound (0.10g, 0.45mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.08g, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.67 (d, 2H), 7.45 (d, 1H), 7.27 (d, 2H), 7.20 (d, 1H), 7.16 (dd, 1H), 7.03 (d, 1H), 6.91 (d, 2H), 6.53 (d, 1H), 5.77 (s, 2H), 5.05 (s, 2H), 4.03 (t, 1H), 2.76-2.82 (m, 1H), 2.63-2.72 (m, 1H), 2.53 (s, 3H), 1.81 (s, 3H)
Example 65: synthesis of 3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-(4,5-dihydro-isoxazol-3-yl)-propanoic acid
Figure PCTKR2013010135-appb-I000081
The compound (0.27g, 1.20mmol) obtained from Preparation Example 56 and the compound (0.20g, 0.80mmol) obtained from Preparation Example 156 were used to obtain the title compound (0.11g, 29%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.10 (s, 1H), 7.79 (d, 2H), 7.31 (m, 3H), 7.24 (d, 3H), 7.16 (d, 2H), 6.95 (d, 2H), 5.66 (s, 2H), 5.16 (s, 2H), 4.13 (t, 1H), 4.06 (t, 2H), 2.79 (t, 2H), 2.53 (dd, 1H), 2.32 (dd, 1H)
Example 66: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000082
The compound (0.2g, 0.76mmol) obtained from Preparation Example 58 and the compound (0.15g, 0.69mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.15g, 47%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.10 (s, 1H), 7.81 (s, 1H), 7.78 (d, 1H), 7.20-7.29 (m, 5H), 7.15 (t, 2H), 6.93 (d, 2H), 5.65 (s, 2H), 5.17 (s, 2H), 4.00 (m, 1H), 2.32 (dd, 1H), 2.19 (dd, 1H), 1.75 (s, 3H)
Example 67: synthesis of (S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000083
The compound (0.2g, 0.76mmol) obtained from Preparation Example 59 and the compound (0.15g, 0.69mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.18g, 48%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt)); δ 8.47 (s, 1H), 7.72 (d, 1H), 7.64 (s, 1H), 7.39 (t, 2H), 7.15-7.24 (m, 4H), 7.10 (d, 1H), 6.91 (d, 2H), 5.62 (s, 2H), 5.12 (s, 2H), 3.97 (m, 1H), 2.30 (dd, 1H), 2.16 (dd, 1H), 1.74 (s, 3H)
Example 68: synthesis of (S)-3-[4-(1-pyrimidin-2-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000084
The compound (0.13g, 0.55mmol) obtained from Preparation Example 60-2 and the compound (0.14g, 0.55mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.10g, 39%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.73 (d, 2H), 8.10 (s, 1H), 7.80 (d, 1H), 7.72 (s, 1H), 7.43 (dd, 1H), 7.25 (d, 2H), 7.23 (d, 1H), 6.90 (d, 2H), 5.89 (s, 2H), 5.18 (s, 2H), 3.99 (br s, 1H), 2.26-2.31 (m, 1H), 2.10-2.16 (m, 1H), 1.77 (s, 3H)
Example 69: synthesis of (S)-3-[4-(2-pyrimidin-2-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000085
The compound (0.2g, 0.83mmol) obtained from Preparation Example 61 and the compound (0.15g, 0.69mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 27%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.79 (d, 2H), 8.52 (s, 1H), 7.76 (d, 1H), 7.62 (s, 1H), 7.46 (dd, 1H), 7.23 (d, 2H), 7.12 (d, 1H), 6.91 (d, 2H), 5.89 (s, 2H), 5.15 (s, 2H), 3.98 (br s, 1H), 2.23-2.28 (m, 1H), 2.08-2.11 (m, 1H), 1.75 (s, 3H)
Example 70: synthesis of (S)-3-[4-(1-pyrazin-2-ylmethyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000086
The compound (0.2g, 0.83mmol) obtained from Preparation Example 62 and the compound (0.15g, 0.69mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 27%)
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.56 (d, 2H), 8.49 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.80 (d, 1H), 7.24 (m, 3H), 6.92 (d, 2H), 5.85 (s, 2H), 5.18 (s, 2H), 4.01 (m, 1H), 2.34 (dd, 1H), 2.17 (dd, 1H), 1.75 (s, 3H)
Example 71: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000087
The compound (190mg, 0.74mmol) obtained from Preparation Example 135-2 and the compound (373mg, 1.48mmol) obtained from Preparation Example 155 were used to obtain the title compound (180mg, 55%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.23 (s, 1H), 7.70 (d, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 7.23 (d, 2H), 7.16 (d, 1H), 7.13 (d, 1H), 6.95 (d, 2H), 5.68 (s, 2H), 5.41 (s, 2H), 3.98 (br s, 1H), 2.23-2.28 (m, 1H), 2.08-2.11 (m, 1H), 1.75 (s, 3H)
Example 72: synthesis of (S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000088
The compound (150mg, 0.59mmol) obtained from Preparation Example 136-2 and the compound (295mg, 1.17mmol) obtained from Preparation Example 155 were used to obtain the title compound (150mg, 58%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.59 (s, 1H), 7.56 (d, 1H), 7.45 (d, 1H), 7.43 (d, 1H), 7.17-7.26 (m, 5H), 7.12 (d, 1H), 6.94 (d, 2H), 5.66 (s, 2H), 5.31 (s, 2H), 3.99 (br s, 1H), 2.25-2.30 (m, 1H), 2.09-2.15 (m, 1H), 1.76 (s, 3H)
Example 73: synthesis of (S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000089
The compound (0.20g, 0.82mmol) obtained from Preparation Example 63 and the compound (0.16g, 0.75mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.15g, 18%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.45 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.26 (m, 3H), 6.95 (d, 2H), 5.80 (s, 2H), 5.20 (s, 2H), 4.03 (m, 1H), 2.47 (s, 3H), 2.35 (dd, 1H), 2.22 (dd, 1H), 1.77 (s, 3H)
Example 74: synthesis of (S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000090
The compound (0.20g, 0.82mmol) obtained from Preparation Example 64 and the compound (0.16g, 0.75mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.08g, 22%).
NMR:1H-NMR(400HMz, DMSO- d 6, Na salt); δ 8.52 (d, 2H), 8.48 (s, 1H), 7.73 (d, 1H), 7.61 (s, 1H), 7.24 (d, 2H), 7.11 (d, 1H), 6.91 (d, 2H), 5.77 (s, 2H), 5.12 (s, 2H), 3.98 (m, 1H), 2.47 (s, 3H), 2.32 (dd, 1H), 2.16 (dd, 1H), 1.74 (s, 3H)
Example 75: synthesis of (S)-3-[4-(1-pyrimidin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000091
The compound (0.13g, 0.55mmol) obtained from Preparation Example 65 and the compound (0.14g, 0.55mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.05g, 21%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 9.12 (s, 1H), 8.72 (d, 1H), 8.18 (s, 1H), 7.83 (d, 1H), 7.78 (s, 1H), 7.28 (s, 1H), 7.24 (d, 2H), 7.00 (d, 1H), 6.91 (d, 2H), 5.83 (s, 2H), 5.18 (s, 2H), 3.99 (br s, 1H), 2.25-2.30 (m, 1H), 2.10-2.16 (m, 1H), 1.76 (s, 3H)
Example 76: synthesis of (S)-3-[4-(2-pyrimidin-4-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000092
The compound (0.03g, 0.13mmol) obtained from Preparation Example 66 and the compound (0.03g, 0.13mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.02g, 30%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 9.16 (s, 1H), 8.77 (d, 1H), 8.57 (s, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 7.24 (d, 2H), 7.16 (s, 1H), 7.14-7.16 (m, 1H), 6.92 (d, 2H), 5.83 (s, 2H), 5.16 (s, 2H), 3.99 (br s, 1H), 2.25-2.30 (m, 1H), 2.10-2.15 (m, 1H), 1.75 (s, 3H)
Example 77: synthesis of (S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000093
The compound (180mg, 0.71mmol) obtained from Preparation Example 137-2 and the compound (155mg, 0.71mmol) obtained from Preparation Example 155 were used to obtain the title compound (220mg, 70%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.46 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 7.26 (d, 3H), 6.95 (d, 2H), 5.81 (s, 2H), 5.41 (s, 2H), 3.97 (br s, 1H), 2.46 (s, 3H), 2.23-2.78 (m, 1H), 2.07-2.13 (m, 1H), 1.75 (s, 3H)
Example 78: synthesis of (S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000094
The compound (100mg, 0.39mmol) obtained from Preparation Example 138-2 and the compound (85mg, 0.39mmol) obtained from Preparation Example 155 were used to obtain the title compound (86mg, 50%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.63 (s, 1H), 8.55 (s, 1H), 8.51 (d, 1H), 7.53 (d, 1H), 7.24 (d, 3H), 7.14 (d, 1H), 6.95 (d, 2H), 5.81 (s, 2H), 5.32 (s, 2H), 4.00 (br s, 1H), 2.73-2.80 (m, 1H), 2.87-2.94 (m, 1H), 1.76 (s, 3H)
Example 79: synthesis of (S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000095
The compound (240mg, 1.00mmol) obtained from Preparation Example 67 and the compound (218mg, 1.00mmol) obtained from Preparation Example 155 were used to obtain the title compound (320mg, 75%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.55 (d, 1H), 8.48 (dd, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.59 (dd, 1H), 7.34 (dd, 1H), 7.25 (dd, 3H), 6.92 (d, 2H), 5.74 (s, 2H), 5.20 (s, 2H), 4.00 (br s, 1H), 2.24-2.30 (m, 1H), 2.09-2.14 (m, 1H), 1.76 (s, 3H)
Example 80: synthesis of (S)-3-[4-(2-pyridin-3-ylmethyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000096
The compound (150mg, 0.63mmol) obtained from Preparation Example 68 and the compound (137mg, 0.63mmol) obtained from Preparation Example 155 were used to obtain the title compound (98mg, 37%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.63 (s, 1H), 8.54 (s, 1H), 8.53 (d, 1H), 7.73 (d, 2H), 7.66 (s, 1H), 7.39 (d, 1H), 7.23 (d, 2H), 7.11 (d, 1H), 6.91 (d, 2H), 5.71 (s, 2H), 5.14 (s, 2H), 3.99 (br s, 1H), 2.25-2.31 (m, 1H), 2.10-2.16 (m, 1H), 1.76 (s, 3H)
Example 81: synthesis of (S)-3-{4-[7-methyl-1-(6-methyl-pyridin-3-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000097
The compound (0.12g, 0.49mmol) obtained from Preparation Example 36-2 and the compound (0.13g, 0.49mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.07g, 33%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.05 (s, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.21 (d, 2H), 7.16 (d, 1H), 7.08-7.11 (m, 2H), 6.86 (d, 2H), 6.51 (d, 1H), 5.68 (s, 2H), 5.04 (s, 2H), 3.97 (br s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.27-2.30 (m, 1H), 2.10-2.13 (m, 1H), 1.74 (s, 3H)
Example 82: synthesis of (S)-3-{4-[1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000098
The compound (0.16g, 0.65mmol) obtained from Preparation Example 69 and the compound (0.17g, 0.65mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.19g, 64%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.21 (d, 2H), 7.16 (d, 1H), 7.08-7.11 (m, 2H), 6.86 (d, 2H), 6.51 (d, 1H), 5.68 (s, 2H), 5.04 (s, 2H), 3.97 (br s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.27-2.30 (m, 1H), 2.10-2.13 (m, 1H), 1.74 (s, 3H)
Example 83: synthesis of (S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000099
The compound (0.20g, 0.80mmol) obtained from Preparation Example 17-2 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.21g, 57%).
NMR:1H-NMR(400HMz, DMSO- d 6, Na salt)); δ 8.65 (s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.29 (m, 2H), 7.22 (m, 1H), 7.16 (d, 2H), 7.08 (d, 1H), 6.89 (m, 4H), 6.50 (d, 1H), 6.41 (s, 1H), 5. 68 (s, 2H), 5.01 (s, 2H), 4.51 (t, 1H), 2.62 (dd, 1H), 2.48 (dd, 1H), 2.40 (s, 3H)
Example 84: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000100
The compound (0.20g, 0.80mmol) obtained from Preparation Example 20-2 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.18g, 43%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.65 (s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.14 (m, 4H), 7.09 (d, 1H), 6.93 (m, 2H), 6.89 (d, 1H), 6.50 (d, 1H), 6.40 (s, 1H), 5.67 (s, 2H), 5.02 (s, 2H), 4.48 (t, 1H), 2.51 (dd, 1H), 2.40 (dd, 1H), 2.39 (s, 3H)
Example 85: synthesis of (S)-3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000101
The compound (0.20g, 0.84mmol) obtained from Preparation Example 56 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.26g, 72%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.67 (s, 1H), 8.10 (s, 1H), 7.78 (d, 2H), 7.17-7.29 (m, 8H), 6.92 (d, 2H), 6.42 (s, 1H), 5.65 (s, 2H), 5.15 (s, 2H), 4.54 (t, 1H), 2.66 (dd, 1H), 2.50 (dd, 1H)
Example 86: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000102
The compound (0.20g, 0.80mmol) obtained from Preparation Example 58 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.25g, 67%).
NMR:1H-NMR(400HMz, DMSO-d 6,Na salt); δ 8.66 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 7.29 (m, 2H), 7.10-7.21 (m, 5H), 6.92 (d, 2H), 6.42 (s, 1H), 5.65 (s, 2H), 5.15 (s, 2H), 4.52 (t, 1H), 2.51 (dd, 1H), 2.47 (dd, 1H)
Example 87: synthesis of (S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000103
The compound (0.20g, 0.80mmol) obtained from Preparation Example 75-1 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.15g, 45%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.67 (s, 1H), 8.05 (s, 1H), 7.75 (d, 2H), 7.20 (d, 3H), 6.94 (d, 2H), 6.42 (s, 1H), 5.18 (s, 2H), 4.54 (t, 1H), 4.21 (d, 2H), 2.65 (dd, 1H), 2.55 (dd, 1H), 2.18 (m, 1H), 0.84 (d, 3H)
Example 88: synthesis of (S)-3-[4-(2-isobutyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000104
The compound (0.20g, 0.80mmol) obtained from Preparation Example 75-2 and the compound (0.18g, 0.76mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.20g, 60%).
NMR:1H-NMR(400HMz, DMSO-d 6, Na salt); δ 8.66 (s, 1H), 8.33 (s, 1H), 7.70 (d, 1H), 7.64 (s, 1H), 7.19 (d, 2H), 7.08 (d, 1H), 6.93 (d, 2H), 6.42 (s, 1H), 5.11 (s, 2H), 4.52 (t, 1H), 4.22 (d, 2H), 2.61 (dd, 1H), 2.51 (dd, 1H), 2.27 (m, 1H), 0.86 (d, 3H)
Example 89: synthesis of (S)-3-isoxazol-3-yl-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000105
The compound (180mg, 0.71mmol) obtained from Preparation Example 38-2 and the compound (175mg, 0.71mmol) obtained from Preparation Example 157 were used to obtain the title compound (120mg, 36%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.67 (d, 1H), 8.62 (d, 1H), 8.57 (d, 1H), 8.08 (s, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.16 (d, 1H), 7.14 (d, 1H), 7.10 (d, 1H), 6.88 (d, 2H), 6.53 (d, 1H), 6.41 (d, 1H), 5.86 (s, 2H), 5.05 (s, 2H), 4.51 (br s, 1H), 2.50-2.52 (m, 1H), 2.45 (s, 3H), 2.40-2.42 (m, 1H)
Example 90: synthesis of (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000106
The compound (140mg, 0.59mmol) obtained from Preparation Example 54-2 and the compound (139mg, 0.59mmol) obtained from Preparation Example 155 were used to obtain the title compound (90mg, 36%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.01 (d, 1H), 7.63 (d, 1H), 7.21-7.36 (m, 8H), 6.92 (d, 2H), 6.53 (d, 1H), 5.51 (s, 2H), 5.22 (s, 2H), 3.80 (br s, 1H), 2.22-2.27 (m, 1H), 2.07-2.12 (m, 1H)
Example 91: synthesis of (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
The compound (135mg, 0.57mmol) obtained from Preparation Example 54-2 and the compound (141mg, 0.57mmol) obtained from Preparation Example 157 were used to obtain the title compound (150mg, 62%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.61 (s, 1H), 7.95 (d, 1H), 7.57 (d, 1H), 7.20-7.26 (m, 6H), 7.09 (d, 2H), 6.87 (d, 2H), 6.46 (dd, 1H), 6.36 (d, 1H), 5.44 (s, 2H), 5.15 (s, 2H), 4.45 (t, 1H), 2.46-2.49 (m, 1H), 2.37-2.40 (m, 1H)
Example 92: synthesis of (S)-3-isoxazol-3-yl-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid
Figure PCTKR2013010135-appb-I000108
The compound (196mg, 0.73mmol) obtained from Preparation Example 42 and the compound (180mg, 0.79mmol) obtained from Preparation Example 157 were used to obtain the title compound (140mg, 40%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.62 (s, 1H), 8.45 (s, 1H), 7.89 (s, 1H), 7.44 (d, 1H), 7.34 (d, 1H), 7.10 (d, 2H), 7.04 (d, 1H), 6.83 (d, 2H), 6.46 (d, 1H), 6.37 (s, 1H), 5.74 (s, 2H), 4.99 (s, 2H), 4.45 (t, 1H), 2.46-2.49 (m, 1H), 2.38-2.41 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H)
Example 93: synthesis of (S)-3-{4-[1-(6-methyl-pyridin-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000109
The compound (72.2mg, 0.29mmol) obtained from Preparation Example 147 and the compound (70.4mg, 0.29mmol) obtained from Preparation Example 155 were used to obtain the title compound (94mg, 71%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.42 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.77 (d, 1H), 7.48 (dd, 1H), 7.24 (d, 2H), 7.21 (d, 1H), 7.16 (d, 1H), 6.91 (d, 2H), 5.66 (s, 2H), 5.17 (s, 2H), 3.98 (br s, 1H), 2.40 (s, 3H), 2.24-2.30 (m, 1H), 2.09-2.15 (m, 1H), 1.75 (s, 3H)
Example 94: synthesis of (S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000110
The compound (150mg, 0.63mmol) obtained from Preparation Example 133-2 and the compound (56mg, 0.63mmol) obtained from Preparation Example 157 were used to obtain the title compound (180mg, 63%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.62 (s, 1H), 8.16 (s, 1H), 7.62 (d, 1H), 7.12-7.32 (m, 9H), 6.89 (d, 2H), 6.38 (d, 1H), 5.62 (s, 2H), 5.33 (s, 2H), 4.46 (t, 1H), 2.50-2.52 (m, 1H), 2.42-2.46 (m, 1H)
Example 95: synthesis of (S)-3-{4-[1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000111
The compound (70mg, 0.27mmol) obtained from Preparation Example 53-4 and the compound (70mg, 0.27mmol) obtained from Preparation Example 157 were used to obtain the title compound (80mg, 62%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.62 (br s, 1H), 7.95 (d, 1H), 7.58 (br s, 1H), 7.26 (br s, 1H), 7.20 (d, 2H), 7.10 (br s, 4H), 6.87 (d, 2H), 6.45 (d, 1H), 6.36 (d, 1H), 5.42 (s, 2H), 5.14 (s, 2H), 4.52 (br s, 1H)
Example 96: synthesis of (S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000112
The compound (0.19g, 0.98mmol) obtained from Preparation Example 72 and the compound (0.24g, 0.98mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.28g, 63%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.59 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.11 (d, 3H), 6.86 (d, 2H), 6.35 (d, 1H), 5.10 (s, 2H), 4.87-4.94 (m, 1H), 4.45 (t, 1H), 2.49-2.55 (m, 1H), 2.37-2.41 (m, 1H), 1.40 (d, 6H)
Example 97: synthesis of (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000113
The compound (0.16g, 0.81mmol) obtained from Preparation Example 74 and the compound (0.20g, 0.81mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.26g, 71%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.67 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.18-7.20 (m, 3H), 6.93 (d, 2H), 6.43 (s, 1H), 5.18 (s, 2H), 4.54 (t, 1H), 4.29 (d, 2H), 2.62-2.68 (m, 1H), 2.50-2.54 (m, 1H), 1.25 (br s, 1H), 0.44-0.46 (m, 2H), 0.36-0.37 (m, 2H)
Example 98: synthesis of (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000114
The compound (190mg, 0.93mmol) obtained from Preparation Example 142-2 and the compound (230mg, 0.93mmol) obtained from Preparation Example 157 were used to obtain the title compound (220mg, 56%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.66 (d, 1H), 7.97 (d, 1H), 7.55 (d, 1H), 7.22 (d, 1H), 7.15 (d, 2H), 6.93 (d, 2H), 6.47 (d, 1H), 6.41 (d, 1H), 5.18 (s, 2H), 4.50 (t, 1H), 4.08 (d, 2H), 2.54-2.68 (m, 1H), 2.40-2.46 (m, 1H), 2.21-2.26 (m, 1H), 0.84 (d, 6H)
Example 99: synthesis of (S)-3-[4-(2-isopropyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000115
The compound (0.14g, 0.72mmol) obtained from Preparation Example 73 and the compound (0.18g, 0.72mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.34g, 100%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.66 (s, 1H), 8.38 (s, 1H), 7.66 (dd, 2H), 7.16 (d, 2H), 7.07 (d, 1H), 6.90 (d, 2H), 6.41 (s, 1H), 5.12 (s, 2H), 4.77-4.84 (m, 1H), 4.50 (t, 1H), 2.55-2.61 (m, 1H), 2.43-2.47 (m, 1H), 1.54 (d, 6H)
Example 100: synthesis of [6-(1-isopropyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000116
The compound (0.13g, 0.67mmol) obtained from Preparation Example 72 and the compound (0.14g, 0.67mmol) obtained from Preparation Example 158 were used to obtain the title compound (0.08g, 27%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.05 (s, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.18 (d, 1H), 7.09 (d, 1H), 6.47 (d, 1H), 6.44 (d, 1H), 5.15 (s, 2H), 4.95-5.02 (m, 1H), 4.66 (t, 1H), 4.13 (t, 1H), 3.59 (br t, 1H), 2.31-2.36 (m, 1H), 1.98-2.04 (m, 1H), 1.47 (d, 6H)
Example 101: synthesis of (S)-3-isoxazol-3-yl-3-[4-(1-methyl-1H-indazol-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000117
The compound (0.15g, 0.92mmol) obtained from Preparation Example 71 and the compound (0.23g, 0.92mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.15g, 36%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (d, 1H), 7.71 (s, 1H), 7.17-7.21 (m, 3H), 6.93 (d, 2H), 6.42 (s, 1H), 5.18 (s, 2H), 4.52 (t, 1H), 4.04 (s, 3H), 2.59-2.62 (m, 1H), 2.45-2.50 (m, 1H)
Example 102: synthesis of (S)-3-[4-(1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000118
The compound (0.15g, 1.00mmol) obtained from Preparation Example 70 and the compound (0.25g, 1.00mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.06g, 14%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.65 (s, 1H), 8.04 (s, 1H), 7.75 (d, 1H), 7.57 (s, 1H), 7.14-7.18 (m, 3H), 6.91 (d, 2H), 6.41 (s, 1H), 5.18 (s, 2H), 4.50 (t, 1H), 2.50-2.58 (m, 1H), 2.41-2.47 (m, 1H)
Example 103: synthesis of (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid
Figure PCTKR2013010135-appb-I000119
The compound (0.24g, 1.05mmol) obtained from Preparation Example 77 and the compound (0.26g, 1.05mmol) obtained from Preparation Example 157 were used to obtain the title compound (0.23g, 48%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.66 (s, 1H), 8.03 (s, 1H), 7.74 (d, 2H), 7.17 (dd, 3H), 6.93 (d, 2H), 6.42 (s, 1H), 5.18 (s, 2H), 4.52 (t, 1H), 4.31 (d, 2H), 2.50-2.59 (m, 1H), 2.41-2.48 (m, 1H), 1.46-1.60 (m, 6H), 1.24-1.28 (m, 2H)
Example 104: synthesis of (S)-3-isoxazol-3-yl-3-[4-(1-pyrazin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000120
The compound (140mg, 0.58mmol) obtained from Preparation Example 141 and the compound (160mg, 0.58mmol) obtained from Preparation Example 157 were used to obtain the title compound (60mg, 23%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.67 (d, 1H), 8.58 (d, 2H), 8.51 (s, 1H), 8.02 (d, 1H), 7.68 (d, 1H), 7.26 (d, 1H), 7.13 (d, 2H), 6.89 (d, 2H), 6.56 (d, 1H), 6.42 (d, 1H), 5.68 (s, 2H), 5.15 (s, 2H), 2.54-2.60 (m, 1H), 2.42-2.48 (m, 1H)
Example 105: synthesis of [6-(1-benzyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000121
The compound (200mg, 0.84mmol) obtained from Preparation Example 56 and the compound (157mg, 0.76mmol) obtained from Preparation Example 158 were used to obtain the title compound (187mg, 67%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.10 (s, 1H), 7.77 (d, 2H), 7.18-7.31 (m, 6H), 7.07 (d, 1H), 6.41-6.45 (m, 2H), 5.66 (s, 2H), 5.13 (s, 2H), 4.66 (t, 1H), 4.13 (t, 1H), 3.59 (pent, 1H), 2.33 (dd, 1H), 2.01 (dd, 1H)
Example 106: synthesis of 3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid
Figure PCTKR2013010135-appb-I000122
The compound (200mg, 0.84mmol) obtained from Preparation Example 56 and the compound (161mg, 0.76mmol) obtained from Preparation Example 149 were used to obtain the title compound (205mg, 66%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.04 (s, 1H), 7.73 (d, 1H), 7.70 (s, 1H), 7.08-7.24 (m, 7H), 6.75 (d, 1H), 6.68 (d, 1H), 5.59 (s, 2H), 5.11 (s, 2H), 2.60 (t, 2H), 2.01 (t, 2H)
Example 107: synthesis of 3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid
The compound (200mg, 0.87mmol) obtained from Preparation Example 77 and the compound (166mg, 0.78mmol) obtained from Preparation Example 149 were used to obtain the title compound (260mg, 84%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.04 (s, 1H), 7.75 (d, 2H), 7.17 (dd, 2H), 6.83 (d, 1H), 6.76 (d, 1H), 5.20 (s, 2H), 4.32 (d, 2H), 2.65 (t, 2H), 2.42-2.49 (m, 1H), 2.04 (t, 2H), 1.51-1.53 (m, 6H), 1.25 (m, 2H)
Example 108: synthesis of [6-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000124
The compound (200mg, 0.87mmol) obtained from Preparation Example 77 and the compound (162mg, 0.78mmol) obtained from Preparation Example 158 were used to obtain the title compound (154mg, 46%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.03 (s, 1H), 7.74 (d, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.42-6.46 (m, 2H), 5.16 (s, 2H), 4.65 (t, 1H), 4.31 (d, 2H), 4.12 (t, 1H), 3.57 (m, 1H), 2.42-2.49 (m, 1H), 2.31 (dd, 1H), 1.99 (dd, 1H), 1.49-1.60 (m, 6H), 1.24-1.26 (m, 2H)
Example 109: synthesis of [5-(1-benzyl-1H-indazol-6-ylmethoxy)-indan-1-yl]-acetic acid
Figure PCTKR2013010135-appb-I000125
The compound (200mg, 0.84mmol) obtained from Preparation Example 56 and the compound (177mg, 0.76mmol) obtained from Preparation Example 159 were used to obtain the title compound (210mg, 56%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.09 (s, 1H), 7.78 (m, 1H), 7.27 (m, 2H), 7.20 (m, 3H), 7.10 (m, 1H), 6.82 (m, 1H), 6.72 (m, 1H), 5.66 (s, 2H), 5.14 (s, 2H), 3.29 (m, 1H), 2.68 (m, 2H), 2.20 (m, 2H), 1.89 (dd, 1H), 1.56 (m, 1H)
Example 110: synthesis of [6-(1-benzyl-1H-indazol-6-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid
Figure PCTKR2013010135-appb-I000126
The compound (200mg, 0.84mmol) obtained from Preparation Example 56 and the compound (177mg, 0.76mmol) obtained from Preparation Example 161 were used to obtain the title compound (224mg, 63%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.10 (s, 1H), 7.78 (m, 2H), 7.29 (m, 2H), 7.21 (m, 3H), 7.08 (d, 1H), 6.71 (m, 1H), 6.65 (m, 1H), 5.66 (s, 2H), 5.13 (s, 2H), 3.07 (m, 1H), 2.62 (m, 2H), 2.16 (dd, 1H), 1.95 (dd, 1H), 1.70 (m, 2H), 1.59 (m, 2H)
Example 111: synthesis of (S)-3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000127
The compound (200mg, 0.84mmol) obtained from Preparation Example 91 and the compound (165mg, 0.76mmol) obtained from Preparation Example 155 were used to obtain the title compound (185mg, 57%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.11 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.44 (d, 1H), 7.20-7.32 (m, 7H), 6.90 (d, 2H), 5.66 (s, 2H), 5.13 (s, 2H), 3.97 (br s, 1H), 2.08-2.29 (m, 2H), 1.74 (s, 3H)
Example 112: synthesis of (S)-3-[4-(2-benzyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000128
The compound (160mg, 0.67mmol) obtained from Preparation Example 92 and the compound (132mg, 0.60mmol) obtained from Preparation Example 155 were used to obtain the title compound (178mg, 73%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.41 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.14-7.28 (m, 8H), 6.82 (d, 2H), 5.56 (s, 2H), 5.01 (s, 2H), 3.89 (br s, 1H), 2.01-2.20 (m, 2H), 1.67 (s, 3H)
Example 113: synthesis of [6-(2-benzyl-2H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000129
The compound (245mg, 1.03mmol) obtained from Preparation Example 57 and the compound (193mg, 0.93mmol) obtained from Preparation Example 158 were used to obtain the title compound (292mg, 76%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.40 (s, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.21-7.30 (m, 5H), 6.70 (d, 2H), 6.33-6.38 (m, 2H), 5.56 (s, 2H), 5.02 (s, 2H), 4.59 (dd, 1H), 4.06 (dd, 1H), 3.50-3.56 (m, 1H), 2.27 (dd, 1H), 1.69-1.98 (m, 1H)
Example 114: synthesis of (S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000130
The compound (0.20g, 0.98mmol) obtained from Preparation Example 75-1 and the compound (0.19g, 0.88mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.29g, 76%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.99 (s, 1H), 7.73 (d, 1H), 7.45 (s, 1H), 7.32 (d, 2H), 7.18 (d, 1H), 6.96 (d, 2H), 5.18 (s, 2H), 4.17 (d, 2H), 4.06 (m, 1H), 2.79 (dd, 1H), 2.72 (dd, 1H), 2.33 (m, 1H), 1.82 (s, 3H), 0.91 (d, 6H)
Example 115: synthesis of (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000131
The compound (0.20g, 0.98mmol) obtained from Preparation Example 142-2 and the compound (0.19g, 0.88mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.20g, 53%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.89 (d, 1H), 7.27 (m, 3H), 7.17 (s, 1H), 6.98 (d, 2H), 6.42 (s, 1H), 5.29 (s, 2H), 4.09 (d, 2H), 4.03 (m, 1H), 2.75 (dd, 1H), 2.66 (dd, 1H), 2.26 (m, 1H), 1.81 (s, 3H), 0.91 (d, 6H)
Example 116: synthesis of (S)-3-[4-(1-isopropyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000132
The compound (150mg, 0.79mmol) obtained from Preparation Example 96 and the compound (155mg, 0.71mmol) obtained from Preparation Example 155 were used to obtain the title compound (32mg, 12%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (s, 1H), 7.77 (s, 1H), 7.45-7.48 (m, 2H), 7.31 (d, 2H), 6.96 (d, 2H), 5.13 (s, 2H), 4.84-4.87 (m, 1H), 4.06 (br s, 1H), 2.69-2.84 (m, 2H), 1.84 (s, 3H), 1.60 (d, 6H)
Example 117: synthesis of 3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-butyric acid
Figure PCTKR2013010135-appb-I000133
The compound (200mg, 0.84mmol) obtained from Preparation Example 56 and the compound (157mg, 0.76mmol) obtained from Preparation Example 150 were used to obtain the title compound (217mg, 71%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.03 (s, 1H), 7.73 (d, 1H), 7.42 (s, 1H), 7.13-7.25 (m, 8H), 6.90 (d, 2H), 5.59 (s, 2H), 5.12 (s, 2H), 3.20-3.26 (m, 1H), 2.51-2.65 (m, 2H), 1.29 (d, 3H)
Example 118: synthesis of [5-(1-benzyl-1H-indazol-5-ylmethoxy)-indan-1-yl]-acetic acid
Figure PCTKR2013010135-appb-I000134
The compound (200mg, 0.84mmol) obtained from Preparation Example 91 and the compound (166mg, 0.76mmol) obtained from Preparation Example 159 were used to obtain the title compound (224mg, 65%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.79 (s, 1H), 7.37 (m, 2H), 7.27 (m, 3H), 7.19 (m, 2H), 7.09 (d, 1H), 6.88 (m, 1H), 6.80 (m, 1H), 5.61 (s, 2H), 5.11 (s, 2H), 3.54 (m, 1H), 2.84 (m, 3H), 2.45 (m, 2H), 1.81 (m, 1H)
Example 119: synthesis of [6-(1-benzyl-1H-indazol-5-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid
Figure PCTKR2013010135-appb-I000135
The compound (200mg, 0.84mmol) obtained from Preparation Example 91 and the compound (177mg, 0.76mmol) obtained from Preparation Example 161 were used to obtain the title compound (160mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.78 (s, 1H), 7.39 (m, 2H), 7.27 (m, 3H), 7.19 (m, 2H), 7.09 (d, 1H), 6.79 (m, 1H), 6.71 (d, 1H), 5.60 (s, 2H), 5.09 (s, 2H), 3.31 (m, 1H), 2.74 (m, 3H), 2.55 (dd, 1H), 1.95 (m, 1H), 1.77 (m, 3H)
Example 120: synthesis of [7-(1-benzyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000136
The compound (130mg, 0.55mmol) obtained from Preparation Example 91 and the compound (116mg, 0.49mmol) obtained from Preparation Example 160 were used to obtain the title compound (53mg, 23%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.78 (s, 1H), 7.36 (m, 2H), 7.27 (m, 3H), 7.19 (m, 2H), 7.02 (d, 1H), 6.54 (m, 1H), 6.45 (d, 1H), 5.60 (s, 2H), 5.08 (s, 2H), 4.17 (m, 2H), 3.30 (m, 1H), 2.81 (dd, 1H), 2.55 (dd, 1H), 2.12 (m, 1H), 1.87 (m, 1H)
Example 121: synthesis of [6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000137
The compound (210mg, 0.88mmol) obtained from Preparation Example 54-2 and the compound (167mg, 0.80mmol) obtained from Preparation Example 158 were used to obtain the title compound (287mg, 86%).
NMR:1H-NMR(400HMz, CDCl3+CD3OD); δ 7.93 (d, 1H), 6.87-7.40 (m, 8H), 6.40-6.60 (m, 3H), 5.50 (s, 2H), 5.24 (s, 2H), 4.75 (t, 2H), 4.27 (t, 2H), 3.78 (m, 1H), 2.45-2.88 (m, 2H)
Example 122: synthesis of (S)-3-[4-(1-benzyl-5-fluoro-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000138
The compound (113mg, 0.44mmol) obtained from Preparation Example 84 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (119mg, 67%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.12-7.48 (m, 9H), 5.61 (s, 2H), 5.17 (s, 2H), 4.06 (m, 1H), 2.64-2.86 (m, 2H), 1.82 (d, 3H)
Example 123: synthesis of (S)-3-[4-(1-benzyl-1H-indol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000139
The compound (131mg, 0.55mmol) obtained from Preparation Example 90 and the compound (109mg, 0.50mmol) obtained from Preparation Example 155 were used to obtain the title compound (89mg, 42%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.71 (s, 1H), 7.07-7.34 (m, 10H), 6.97 (d, 2H), 6.56 (d, 1H), 5.32 (s, 2H), 5.12 (s, 2H), 4.06 (m, 1H), 2.66-2.86 (m, 2H), 1.83 (d, 3H)
Example 124: synthesis of (S)-3-[4-(1-benzyl-1H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000140
The compound (100mg, 0.42mmol) obtained from Preparation Example 125-4 and the compound (82mg, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (60mg, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.09 (s, 1H), 7.47 (d, 1H), 7.26-7.36 (m, 8H), 6.92 (d, 2H), 5.84 (s, 2H), 5.15 (s, 2H), 4.05 (br s, 1H), 2.67-2.83 (m, 2H), 1.82 (s, 3H)
Example 125: synthesis of (S)-3-[4-(1-benzyl-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000141
The compound (100mg, 0.42mmol) obtained from Preparation Example 126-2 and the compound (82mg, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (34mg, 20%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.08 (s, 1H), 7.82 (s, 1H), 7.26-7.33 (m, 7H), 7.16-7.18 (m, 2H), 6.90 (d, 2H), 5.34 (s, 2H), 5.11 (s, 2H), 4.09 (br s, 1H), 2.68-2.85 (m, 2H), 1.81 (s, 3H)
Example 126: synthesis of (S)-3-[4-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000142
The compound (110mg, 0.44mmol) obtained from Preparation Example 110 and the compound (86mg, 0.39mmol) obtained from Preparation Example 155 were used to obtain the title compound (73mg, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.62 (s, 1H), 7.21-7.31 (m, 5H), 7.14 (s, 1H), 6.93-6.95 (m, 4H), 5.84 (s, 2H), 5.06 (s, 2H), 4.06 (br s, 1H), 2.67-2.83 (m, 2H), 2.40 (s, 3H), 1.82 (s, 3H)
Example 127: synthesis of (S)-3-[4-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000143
The compound (150mg, 0.59mmol) obtained from Preparation Example 111 and the compound (117mg, 0.54mmol) obtained from Preparation Example 155 were used to obtain the title compound (71mg, 30%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.78 (s, 1H), 7.46 (s, 1H), 7.17-7.33 (m, 7H), 7.10 (s, 1H), 6.93 (d, 2H), 5.61 (s, 2H), 5.02 (s, 2H), 4.05 (br s, 1H), 2.66-2.82 (m, 2H), 2.62 (s, 3H), 1.81 (s, 3H)
Example 128: synthesis of [6-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
Figure PCTKR2013010135-appb-I000144
The compound (0.17g, 0.66mmol) obtained from Preparation Example 110 and the compound (0.12g, 0.59mmol) obtained from Preparation Example 158 were used to obtain the title compound (0.10g, 39%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.62 (s, 1H), 7.25 (m, 3H), 7.13 (s, 1H), 7.07 (d, 1H), 6.96 (d, 2H), 6.53 (m, 2H), 5.84 (s, 2H), 5.03 (s, 2H), 4.78 (t, 1H), 4.28 (q, 1H), 3.82 (m, 1H), 2.81 (dd, 1H), 2.64 (dd, 1H), 2.57 (s, 3H)
Example 129: synthesis of [7-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000145
The compound (0.17g, 0.66mmol) obtained from Preparation Example 110 and the compound (0.14g, 0.59mmol) obtained from Preparation Example 160 were used to obtain the title compound (0.10g, 43%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.62 (s, 1H), 7.25 (m, 3H), 7.13 (s, 1H), 7.05 (d, 1H), 6.96 (d, 2H), 6.58 (dd, 1H), 6.47 (s, 1H), 4.18 (m, 2H), 3.34 (m, 1H), 2.85 (dd, 1H), 2.58 (s, 3H), 2.52 (m, 1H), 2.18 (m, 1H), 1.84 (m, 1H)
Example 130: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000146
The compound (141mg, 0.65mmol) obtained from Preparation Example 112 and the compound (127mg, 0.58mmol) obtained from Preparation Example 155 were used to obtain the title compound (171mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.91 (s, 1H), 7.73 (s, 1H), 7.31 (d, 2H), 7.21 (s, 1H), 6.95 (d, 2H), 5.05 (s, 2H), 4.37 (d, 2H), 4.08 (br s, 1H), 2.68-2.84 (m, 2H), 2.61 (s, 3H), 1.82 (s, 3H), 0.87 (d, 6H)
Example 131: synthesis of [7-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000147
The compound (141mg, 0.65mmol) obtained from Preparation Example 112 and the compound (138mg, 0.58mmol) obtained from Preparation Example 160 were used to obtain the title compound (102mg, 43%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (s, 1H), 7.59 (s, 1H), 7.16 (s, 1H), 7.05 (d, 1H), 6.57 (d, 1H), 6.48 (s, 1H), 5.03 (s, 2H), 4.38 (d, 2H), 4.18 (br s, 2H), 3.33 (br s, 1H), 2.82-2.86 (m, 1H), 2.71 (s, 3H), 2.51-2.58 (m, 1H), 2.18-2.23 (m, 1H), 1.88 (m, 1H), 0.92 (d, 6H)
Example 132: synthesis of (S)-3-[4-(1-isobutyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000148
The compound (100mg, 0.48mmol) obtained from Preparation Example 97 and the compound (95mg, 0.43mmol) obtained from Preparation Example 155 were used to obtain the title compound (69mg, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (s, 1H), 7.76 (s, 1H), 7.39-7.45 (m, 2H), 7.30-7.32 (m, 2H), 6.95 (d, 2H), 5.11 (s, 2H), 4.18 (d, 2H), 4.07 (br s, 1H), 2.68-2.84 (m, 2H), 2.30-2.36 (m, 1H), 1.98 (s, 3H), 0.92 (d, 6H)
Example 133: synthesis of [7-(1-isobutyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000149
The compound (100mg, 0.48mmol) obtained from Preparation Example 97 and the compound (102mg, 0.43mmol) obtained from Preparation Example 160 were used to obtain the title compound (41mg, 24%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.76 (s, 1H), 7.40-7.45 (m, 2H), 7.05 (d, 1H), 6.57 (d, 1H), 6.48 (s, 1H), 5.09 (s, 2H), 4.18 (d, 2H), 3.31-3.34 (m, 1H), 2.81-2.86 (m, 1H), 2.52-2.58 (m, 1H), 2.31-2.38 (m, 1H), 2.17-2.19 (m, 1H), 1.86-1.88 (m, 1H), 0.93 (d, 6H)
Example 134: synthesis of (S)-3-[4-(1-phenethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000150
The compound (117mg, 0.47mmol) obtained from Preparation Example 93 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (64mg, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.74 (s, 1H), 7.35 (dd, 1H), 7.30 (d, 2H), 7.16-7.25 (m, 4H), 7.11 (dd, 2H), 6.93 (d, 2H), 5.09 (s, 2H), 4.58 (t, 2H), 4.07 (br t, 1H), 3.19 (t, 2H), 2.78-2.84 (m, 1H), 2.63-2.72 (m, 1H), 1.81 (s, 3H)
Example 135: synthesis of [7-(1-phenethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000151
The compound (117mg, 0.47mmol) obtained from Preparation Example 93 and the compound (100mg, 0.42mmol) obtained from Preparation Example 160 were used to obtain the title compound (69mg, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.74 (s, 1H), 7.35 (d, 1H), 7.20-7.25 (m, 4H), 7.11 (d, 2H), 7.04 (d, 1H), 6.55 (dd, 1H), 6.46 (d, 1H), 5.06 (s, 2H), 4.59 (t, 2H), 4.13-4.20 (m, 2H), 3.30-3.34 (m, 1H), 3.19 (t, 2H), 2.83 (dd, 1H), 2.54 (dd, 1H), 2.13-2.21 (m, 1H), 1.84-1.88 (m, 1H)
Example 136: synthesis of (S)-3-{4-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000152
The compound (96mg, 0.44mmol) obtained from Preparation Example 98 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (109mg, 68%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.76 (s, 1H), 7.38-7.48 (m, 2H), 7.31 (d, 2H), 6.95 (d, 2H), 5.12 (s, 2H), 4.40 (t, 2H), 4.06 (m, 1H), 2.67-2.87 (m, 2H), 1.75-1.88 (m, 5H), 1.56 (m, 1H), 0.96 (d, 6H)
Example 137: synthesis of {7-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid
Figure PCTKR2013010135-appb-I000153
The compound (96mg, 0.44mmol) obtained from Preparation Example 98 and the compound (95mg, 0.40mmol) obtained from Preparation Example 160 were used to obtain the title compound (100mg, 61%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.03 (s, 1H), 7.76 (s, 1H), 7.38-7.48 (m, 2H), 7.04 (d, 2H), 6.56 (dd, 1H), 6.47 (d, 1H), 5.09 (s, 2H), 4.40 (t, 2H), 4.10-4.24 (m, 2H), 3.32 (m, 1H), 2.83 (dd, 1H), 2.55 (dd, 1H), 2.17 (m, 1H), 1.75-1.93 (m, 3H), 1.58 (m, 1H), 0.96 (d, 6H)
Example 138: synthesis of (S)-3-[4-(1-cyclohexyl methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000154
The compound (108mg, 0.44mmol) obtained from Preparation Example 102 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (120mg, 70%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.76 (s, 1H), 7.38-7.47 (m, 2H), 7.31 (d, 2H), 6.96 (d, 2H), 5.12 (s, 2H), 4.20 (d, 2H), 4.06 (m, 1H), 2.65-2.87 (m, 2H), 1.99 (m, 1H), 1.83 (d, 3H), 1.53-1.77 (m, 5H), 0.96-1.28 (m, 5H)
Example 139: synthesis of [7-(1-cyclohexyl methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000155
The compound (108mg, 0.44mmol) obtained from Preparation Example 102 and the compound (95mg, 0.40mmol) obtained from Preparation Example 160 were used to obtain the title compound (111mg, 64%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.98 (s, 1H), 7.75 (s, 1H), 7.38-7.47 (m, 2H), 7.04 (d, 1H), 6.57 (dd, 1H), 6.48 (d, 1H), 5.09 (s, 2H), 4.10-4.26 (m, 4H), 3.32 (m, 1H), 2.84 (m, 1H), 2.55 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.87 (m, 1H), 1.52-1.77 (m, 5H), 0.96-1.30 (m, 5H)
Example 140: synthesis of (S)-3-[4-(2-isobutyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000156
The compound (150mg, 0.69mmol) obtained from Preparation Example 113 and the compound (135mg, 0.62mmol) obtained from Preparation Example 155 were used to obtain the title compound (55mg, 22%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.84 (s, 1H), 7.51 (s, 1H), 7.31 (d, 2H), 7.09 (s, 1H), 6.95 (d, 2H), 5.05 (s, 2H), 4.22 (d, 2H), 4.07 (br t, 1H), 2.68-2.83 (m, 2H), 2.62 (s, 3H), 2.33-2.40 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H)
Example 141: synthesis of (S)-3-[4-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000157
The compound (111mg, 0.46mmol) obtained from Preparation Example 94 and the compound (91mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (90mg, 50%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.58 (d, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.55-7.58 (m, 1H), 7.18-7.40 (m, 4H), 6.91 (d, 1H), 6.83 (d, 3H), 5.75 (s, 2H), 5.06 (s, 2H), 4.09 (br s, 1H), 2.68-2.85 (m, 2H), 1.81 (s, 3H)
Example 142: synthesis of [7-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000158
The compound (111mg, 0.46mmol) obtained from Preparation Example 94 and the compound (99mg, 0.42mmol) obtained from Preparation Example 160 were used to obtain the title compound (26mg, 15%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.60 (d, 1H), 8.08 (s, 1H), 7.79 (s, 1H), 7.56-7.60 (m, 1H), 7.42 (s, 2H), 7.20-7.23 (m, 1H), 7.05 (d, 1H), 6.84 (d, 1H), 6.55 (dd, 1H), 6.46 (s, 1H), 5.78 (s, 2H), 5.07 (s, 2H), 4.17 (br t, 2H), 3.30-3.34 (m, 1H), 2.80-2.84 (m, 1H), 2.50-2.57 (m, 1H), 2.16-2.19 (m, 1H), 1.85-1.89 (m, 1H)
Example 143: synthesis of (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000159
The compound (0.12g, 0.53mmol) obtained from Preparation Example 123 and the compound (0.10g, 0.48mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.10g, 49%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.41 (s, 1H), 8.01 (s, 1H), 7.26-7.32 (m, 5H), 7.20 (m, 3H), 6.96 (d, 2H), 6.48 (d, 1H), 5.49 (s, 2H), 5.13 (s, 2H), 4.09 (m, 1H), 2.84 (dd, 1H), 2.72 (dd, 1H), 1.83 (s, 3H)
Example 144: synthesis of (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000160
The compound (0.10g, 0.47mmol) obtained from Preparation Example 124 and the compound (0.09g, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.07g, 42%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.38 (s, 1H), 7.99 (s, 1H), 7.33 (d, 2H), 7.20 (d, 1H), 6.96 (d, 2H), 6.45 (d, 1H), 5.12 (s, 2H), 4.08 (d, 2H), 4.06 (m, 1H), 2.85 (dd, 1H), 2.74 (dd, 1H), 2.25 (m, 1H), 1.83 (s, 3H), 0.91 (d, 6H)
Example 145: synthesis of [7-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000161
The compound (117mg, 0.47mmol) obtained from Preparation Example 17-2 and the compound (100mg, 0.42mmol) obtained from Preparation Example 160 were used to obtain the title compound (18mg, 9%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.48 (d, 1H), 7.28 (m, 3H), 7.12 (d, 1H), 7.08 (d, 1H), 7.00 (d, 1H), 6.92 (d, 1H), 6.54 (m, 2H), 6.46 (m, 1H), 5.61 (s, 2H), 5.03 (s, 2H), 4.16 (m, 2H), 3.30 (m, 1H), 2.81 (dd, 1H), 2.53 (m, 4H), 2.16 (m, 1H), 1.85 (m, 1H)
Example 146: synthesis of [7-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000162
The compound (107mg, 0.47mmol) obtained from Preparation Example 111 and the compound (100mg, 0.42mmol) obtained from Preparation Example 160 were used to obtain the title compound (40mg, 22%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.81 (s, 1H), 7.47 (s, 1H), 7.32 (m, 3H), 7.24 (m, 3H), 7.09 (s, 1H), 7.02 (d, 1H), 6.56 (m, 1H), 6.45 (d, 1H), 5.63 (s, 2H), 5.01 (s, 2H), 4.17 (m, 2H), 3.30 (m, 1H), 2.81 (dd, 1H), 2.65 (s, 3H), 2.53 (dd, 1H), 2.16 (m, 1H), 1.85 (m, 1H)
Example 147: synthesis of (S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000163
The compound (96mg, 0.40mmol) obtained from Preparation Example 95 and the compound (96mg, 0.44mmol) obtained from Preparation Example 155 were used to obtain the title compound (88mg, 52%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.51 (d, 1H), 8.43 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.20-7.60 (m, 6H), 6.90 (d, 2H), 5.61 (s, 2H), 5.13 (s, 2H), 4.05 (m, 1H), 2.63-2.87 (m, 2H), 1.81 (d, 3H)
Example 148: synthesis of [7-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid
Figure PCTKR2013010135-appb-I000164
The compound (96mg, 0.40mmol) obtained from Preparation Example 95 and the compound (104mg, 0.44mmol) obtained from Preparation Example 160 were used to obtain the title compound (91mg, 53%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 12.25 (br s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.78 (d, 1H), 7.59 (d, 1H), 7.45 (d, 1H), 7.32 (dd, 1H), 7.07 (d, 1H), 6.51 (dd, 1H), 6.39 (d, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.09 (t, 2H), 3.12 (m, 1H), 2.67 (dd, 1H), 2.38 (dd, 1H), 1.99 (m, 1H), 1.71 (m, 1H)
Example 149: synthesis of {7-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid
Figure PCTKR2013010135-appb-I000165
The compound (103mg, 0.47mmol) obtained from Preparation Example 106 and the compound (100mg, 0.42mmol) obtained from Preparation Example 160 were used to obtain the title compound (70mg, 36%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.75 (s, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 7.03 (d, 1H), 6.55 (m, 1H), 6.46 (d, 1H), 5.09 (s, 2H), 4.55 (t, 2H), 4.18 (m, 2H), 3.85 (t, 2H), 3.41 (q, 1H), 3.33 (m, 1H), 2.82 (dd, 1H), 2.55 (dd, 1H), 2.18 (m, 1H), 1.76 (m, 1H), 1.09 (t, 3H)
Example 150: synthesis of (S)-3-[4-(5-fluoro-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000166
The compound (78mg, 0.35mmol) obtained from Preparation Example 85 and the compound (69mg, 0.32mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 76%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.51 (d, 1H), 7.29-7.35 (m, 3H), 6.99 (d, 2H), 5.28 (s, 2H), 4.09 (d, 2H), 5.07 (br t, 1H), 2.64-2.80 (m, 2H), 2.25-2.32 (m, 1H), 1.82 (s, 3H), 0.90 (d, 6H)
Example 151: synthesis of (S)-3-{4-[1-(tetrahydrofuran-2-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000167
The compound (150mg, 0.65mmol) obtained from Preparation Example 103 and the compound (127mg, 0.58mmol) obtained from Preparation Example 155 were used to obtain the title compound (141mg, 58%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.31 (d, 2H), 6.94 (d, 2H), 5.10 (s, 2H), 4.84 (d, 2H), 4.34-4.48 (m, 1H), 4.07 (br s, 2H), 3.69-3.76 (m, 2H), 2.67-2.82 (m, 2H), 1.94-1.97 (m, 1H), 1.82 (s, 3H), 1.66-1.78 (m, 2H)
Example 152: synthesis of (S)-3-{4-[1-(3-methanesulfonyl-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000168
The compound (74mg, 0.28mmol) obtained from Preparation Example 79-2 and the compound (55mg, 0.25mmol) obtained from Preparation Example 155 were used to obtain the title compound (6mg, 5%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.78 (s, 1H), 7.41-7.50 (m, 2H), 7.31 (d, 2H), 6.94 (d, 2H), 5.14 (s, 2H), 4.58 (t, 2H), 4.06 (br t, 1H), 2.99 (t, 2H), 2.87 (s, 3H), 2.68-2.84 (m, 2H), 2.51 (pent, 2H), 1.83 (s, 3H)
Example 153: synthesis of (S)-3-{4-[1-(tetrahydrofuran-3-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000169
The compound (0.17g, 0.73mmol) obtained from Preparation Example 104 and the compound (0.14g, 0.66mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.19g, 70%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (s, 1H), 7.77 (s, 1H), 7.47 (q, 2H), 7.32 (d, 2H), 6.96 (d, 2H), 5.12 (s, 2H), 4.37 (d, 2H), 4.07 (m, 1H), 3.99 (m, 1H), 3.79 (m, 2H), 3.66 (m, 1H), 2.97 (m, 1H), 2.83 (dd, 1H), 2.73 (dd, 1H), 2.02 (m, 1H), 1.82 (s, 3H), 1.73 (m, 1H)
Example 154: synthesis of (S)-3-{4-[2-(tetrahydrofuran-3-ylmethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000170
The compound (0.17g, 0.73mmol) obtained from Preparation Example 105 and the compound (0.14g, 0.66mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.10g, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.89 (s, 1H), 7.71 (d, 1H), 7.67 (s, 1H), 7.35 (m, 2H), 6.95 (d, 2H), 5.08 (s, 2H), 4.39 (d, 2H), 4.07 (m, 1H), 3.96 (m, 1H), 3.79 (m, 2H), 3.62 (m, 1H), 3.03 (m, 1H), 2.83 (dd, 1H), 2.73 (dd, 1H), 2.06 (m, 1H), 1.82 (s, 3H), 1.70 (m, 1H)
Example 155: synthesis of 3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-methoxy-propanoic acid
Figure PCTKR2013010135-appb-I000171
The compound (117mg, 0.49mmol) obtained from Preparation Example 91 and the compound (100mg, 0.44mmol) obtained from Preparation Example 153-3 were used to obtain the title compound (164mg, 91%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.73 (s, 1H), 7.17-7.49 (m, 9H), 6.98 (d, 2H), 5.59 (s, 2H), 5.15 (s, 2H), 4.57-4.60 (m, 1H), 3.20 (s, 3H), 2.84 (dd, 1H), 2.61 (dd, 1H)
Example 156: synthesis of (S)-3-[4-(1-isobutyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000172
The compound (87mg, 0.47mmol) obtained from Preparation Example 130 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (95mg, 55%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.61 (m, 1H), 8.13 (m, 1H), 8.02 (s, 1H), 7.32 (d, 2H), 6.95 (d, 2H), 5.16 (s, 2H), 4.34 (d, 2H), 4.06 (m, 1H), 2.83 (dd, 1H), 2.71 (dd, 1H), 1.83 (d, 3H), 0.92 (d, 6H)
Example 157: synthesis of (S)-3-{4-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000173
The compound (103mg, 0.47mmol) obtained from Preparation Example 106 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (85mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.75 (s, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.30 (d, 2H), 6.94 (d, 2H), 5.13 (s, 2H), 4.55 (t, 2H), 4.06 (m, 1H), 3.86 (t, 2H), 3.43 (q, 2H), 2.81 (dd, 1H), 2.70 (dd, 1H), 1.83 (d, 3H), 1.09 (t, 3H)
Example 158: synthesis of 3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-butyric acid
Figure PCTKR2013010135-appb-I000174
The compound (105mg, 0.44mmol) obtained from Preparation Example 91 and the compound (83mg, 0.40mmol) obtained from Preparation Example 150 were used to obtain the title compound (124mg, 78%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.79 (s, 1H), 7.10-7.46 (m, 9H), 6.93 (d, 2H), 5.60 (s, 2H), 5.10 (s, 2H), 3.24 (m, 1H), 2.52-2.68 (m, 2H), 1.30 (d, 3H)
Example 159: synthesis of 3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-pentanoic acid
Figure PCTKR2013010135-appb-I000175
The compound (114mg, 0.48mmol) obtained from Preparation Example 91 and the compound (89mg, 0.40mmol) obtained from Preparation Example 151 were used to obtain the title compound (141mg, 86%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.79 (s, 1H), 7.16-7.44 (m, 7H), 7.10 (d, 2H), 6.92 (d, 2H), 5.60 (s, 2H), 5.10 (s, 2H), 2.95 (m, 1H), 2.52-2.70 (m, 2H), 1.49-1.78 (m, 2H), 0.79 (t, 3H)
Example 160: synthesis of (S)-3-{4-[2-(2-ethoxy-ethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000176
The compound (103mg, 0.47mmol) obtained from Preparation Example 107 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (67mg, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.69 (m, 2H), 7.31 (m, 4H), 6.95 (d, 2H), 4.57 (t, 2H), 4.06 (m, 1H), 3.90 (t, 2H), 3.47 (q, 2H), 2.78 (dd, 1H), 2.73 (dd, 1H), 1.83 (d, 3H), 1.14 (t, 3H)
Example 161: synthesis of (S)-3-[4-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000177
The compound (0.20g, 0.75mmol) obtained from Preparation Example 127-2 and the compound (0.14g, 0.68mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.16g, 41%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.23-7.30 (m, 7H), 7.07 (s, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 6.86 (d, 1H), 5.07 (s, 2H), 5.02 (s, 2H), 4.06 (m, 1H), 3.46 (s, 3H), 2.82 (dd, 1H), 2.72 (dd, 1H), 1.82 (s, 3H)
Example 162: synthesis of 3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-cyano-propanoic acid
Figure PCTKR2013010135-appb-I000178
The compound (0.12g, 0.51mmol) obtained from Preparation Example 91 and the compound (0.10g, 0.46mmol) obtained from Preparation Example 154 were used to obtain the title compound (0.06g, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.77 (s, 1H), 7.41 (q, 2H), 7.29 (m, 5H), 7.19 (d, 2H), 6.99 (d, 2H), 5.60 (s, 2H), 5.11 (s, 2H), 4.22 (m, 1H), 3.05 (dd, 1H), 2.88 (dd, 1H)
Example 163: synthesis of (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000179
The compound (150mg, 0.65mmol) obtained from Preparation Example 101 and the compound (128mg, 0.59mmol) obtained from Preparation Example 155 were used to obtain the title compound (145mg, 59%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.03 (s, 1H), 7.75 (s, 1H), 7.40-7.48 (m, 2H), 7.33 (dd, 2H), 6.92 (dd, 2H), 5.15 (s, 2H), 4.29 (d, 2H), 4.05-4.10 (m, 1H), 2.75-2.81 (m, 1H), 2.66-2.71 (m, 1H), 2.49-2.56 (m, 1H), 1.81 (s, 3H), 1.63-1.66 (m, 4H), 1.32-1.59 (m, 2H), 1.23-1.30 (m, 2H)
Example 164: synthesis of (S)-3-[4-(1-cyclopentyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000180
The compound (150mg, 0.69mmol) obtained from Preparation Example 100 and the compound (136mg, 0.62mmol) obtained from Preparation Example 155 were used to obtain the title compound (145mg, 58%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.93 (s, 1H), 7.75 (s, 1H), 7.41-7.47 (m, 2H), 7.28 (dd, 2H), 6.91 (dd, 2H), 5.11 (s, 2H), 4.96-5.02 (m, 1H), 4.06 (br s, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.16-2.17 (m, 4H), 1.97-2.09 (m, 2H), 1.82 (s, 3H), 1.73-1.75 (m, 2H)
Example 165: synthesis of (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000181
The compound (0.17g, 0.87mmol) obtained from Preparation Example 99 and the compound (0.17g, 0.78mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.10g, 34%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (s, 1H), 7.76 (s, 1H), 7.44 (s, 2H), 7.32 (d, 2H), 6.96 (d, 2H), 5.11 (s, 2H), 4.27 (d, 2H), 4.08 (m, 1H), 2.84 (dd, 1H), 2.73 (dd, 1H), 1.82 (s, 3H), 0.57 (m, 2H), 0.40 (m, 2H)
Example 166: synthesis of (S)-3-[4-(3-isobutyl-3H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000182
The compound (95mg, 0.47mmol) obtained from Preparation Example 128-2 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (60mg, 33%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (d, 1H), 7.58 (s, 1H), 7.40 (d, 1H), 7.32 (d, 2H), 6.95 (d, 2H), 5.22 (s, 2H), 4.43 (d, 2H), 4.07 (m, 1H), 2.83 (dd, 1H), 2.71 (dd, 1H), 2.40 (m, 1H), 1.83 (d, 3H), 0.96 (d, 6H)
Example 167: synthesis of 2-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
Figure PCTKR2013010135-appb-I000183
The compound (100mg, 0.42mmol) obtained from Preparation Example 56 and the compound (73mg, 0.38mmol) obtained from Preparation Example 152 were used to obtain the title compound (76mg, 51%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.13 (s, 1H), 7.72 (d, 1H), 7.40 (s, 1H), 7.20-7.26 (m, 3H), 7.14-7.17 (m, 3H), 7.01 (d, 2H), 6.86 (d, 2H), 5.57 (s, 2H), 5.11 (s, 2H), 2.51-2.56 (m, 1H), 1.79-1.83 (m, 1H), 1.56-1.62 (m, 2H), 1.26-1.32 (m, 2H)
Example 168: synthesis of (S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000184
The compound (150mg, 0.73mmol) obtained from Preparation Example 114 and the compound (144mg, 0.66mmol) obtained from Preparation Example 155 were used to obtain the title compound (150mg, 58%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.25 (s, 1H), 7.55 (s, 1H), 7.30 (d, 2H), 7.16 (s, 1H), 6.94 (d, 2H), 5.15-5.22 (m, 1H), 5.06 (s, 2H), 4.07 (br s, 1H), 2.77-2.83 (m, 1H), 2.73 (s, 3H), 2.57-2.70 (m, 1H), 1.82 (s, 3H), 1.58 (d, 6H)
Example 169: synthesis of (S)-3-[4-(1-cyclopentylmethyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000185
The compound (150mg, 0.61mmol) obtained from Preparation Example 116 and the compound (121mg, 0.55mmol) obtained from Preparation Example 155 were used to obtain the title compound (106mg, 45%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.96 (s, 1H), 7.58 (s, 1H), 7.31 (d, 2H), 7.16 (s, 1H), 6.95 (d, 2H), 5.05 (s, 2H), 4.50 (d, 2H), 4.07 (br s, 1H), 2.73-2.81 (m, 1H), 2.72 (s, 3H), 2.68 (m, 1H), 2.38-2.45 (m, 1H), 1.82 (s, 3H), 1.61-1.64 (m, 2H), 1.52-1.53 (m, 2H), 1.43 (m, 2H), 1.33-1.35 (m, 2H)
Example 170: synthesis of (S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000186
The compound (101mg, 0.47mmol) obtained from Preparation Example 118 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (30mg, 16%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.69 (s, 1H), 7.43 (m, 1H), 7.32 (m, 3H), 6.96 (m, 2H), 5.12 (s, 2H), 4.08 (m, 3H), 2.75 (m, 1H), 2.57 (s, 3H), 2.32 (m, 1H), 1.84 (d, 3H), 0.91 (d, 6H)
Example 171: synthesis of (S)-3-[4-(1-cyclopentyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000187
The compound (146mg, 0.57mmol) obtained from Preparation Example 115 and the compound (111mg, 0.51mmol) obtained from Preparation Example 155 were used to obtain the title compound (123mg, 57%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.03 (s, 1H), 7.57 (s, 1H), 7.30 (d, 2H), 7.19 (s, 1H), 6.88 (d, 2H), 5.34 (pent, 1H), 5.06 (s, 2H), 4.06 (br t, 1H), 2.77-2.83 (m, 1H), 2.75 (s, 3H), 2.68-2.73 (m, 1H), 2.18-2.23 (m, 2H), 2.08-2.13 (m, 2H), 1.95-1.98 (m, 2H), 1.83 (s, 3H), 1.69-1.73 (m, 2H)
Example 172: synthesis of (S)-3-[4-(1-cyclopentyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000188
The compound (130mg, 0.60mmol) obtained from Preparation Example 76 and the compound (118mg, 0.54mmol) obtained from Preparation Example 155 were used to obtain the title compound (160mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.71 (d, 1H), 7.52 (s, 1H), 7.32 (d, 2H), 7.16 (d, 1H), 6.87 (d, 2H), 5.18 (s, 2H), 4.99 (br t, 1H), 4.06 (br s, 1H), 2.78-2.84 (m, 1H), 2.68-2.74 (m, 1H), 2.16-2.18 (m, 4H), 1.98 (m, 2H), 1.83 (s, 3H), 1.74 (m, 2H)
Example 173: synthesis of (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000189
The compound (130mg, 0.56mmol) obtained from Preparation Example 77 and the compound (111mg, 0.51mmol) obtained from Preparation Example 155 were used to obtain the title compound (94mg, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.04 (s, 1H), 7.71 (d, 1H), 7.47 (s, 1H), 7.24 (d, 2H), 7.16 (d, 1H), 6.95 (d, 2H), 5.25 (s, 2H), 4.29 (d, 2H), 4.07 (br t, 1H), 2.78-2.84 (m, 1H), 2.68-2.73 (m, 1H), 2.53 (pent, 1H), 1.82 (s, 3H), 1.63-1.64 (m, 4H), 1.53-1.57 (m, 2H), 1.26-1.31 (m, 2H)
Example 174: synthesis of (S)-3-{4-[1-(2-methanesulfonyl-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000190
The compound (102mg, 0.40mmol) obtained from Preparation Example 79-1 and the compound (105mg, 0.48mmol) obtained from Preparation Example 155 were used to obtain the title compound (87mg, 49%).
NMR:1H-NMR(400HMz, DMSO-d 6); δ 8.15 (s, 1H), 7.84 (s, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.27 (d, 2H), 6.97 (d, 2H), 5.17 (s, 2H), 4.82 (t, 2H), 3.93 (m, 1H), 3.74 (t, 2H), 2.89 (s, 3H), 2.55-2.63 (m, 2H), 1.77 (d, 3H)
Example 175: synthesis of (S)-3-{4-[1-(2-methoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000191
The compound (99mg, 0.48mmol) obtained from Preparation Example 80 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (114mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.05 (s, 1H), 7.48 (s, 1H), 7.40-7.52 (m, 2H), 7.31 (d, 2H), 6.94 (d, 2H), 5.11 (s, 2H), 4.55 (t, 2H), 4.06 (m, 1H), 3.82 (t, 2H), 3.28 (s, 3H), 2.66-2.86 (dd, 1H), 1.82 (d, 3H)
Example 176: synthesis of (S)-3-{4-[1-(3-methoxy-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000192
The compound (106mg, 0.48mmol) obtained from Preparation Example 81 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (121mg, 75%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.01 (s, 1H), 7.76 (s, 1H), 7.42-7.52 (m, 2H), 7.31 (d, 2H), 6.95 (d, 2H), 5.12 (s, 2H), 4.50 (t, 2H), 4.07 (m, 1H), 3.29 (s, 3H), 3.28 (t, 2H), 2.66-2.86 (m, 2H), 2.12-2.23 (m, 2H), 1.83 (d, 3H)
Example 177: synthesis of (S)-3-{4-[1-(3-methyl-oxetan-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000193
The compound (135mg, 0.58mmol) obtained from Preparation Example 82 and the compound (114mg, 0.52mmol) obtained from Preparation Example 155 were used to obtain the title compound (81mg, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.00 (s, 1H), 7.71 (d, 1H), 7.45 (s, 1H), 7.30 (d, 2H), 7.16 (d, 1H), 6.93 (d, 2H), 5.18 (s, 2H), 4.77 (d, 2H), 4.54 (s, 2H), 4.39 (d, 2H), 4.06 (br s, 1H), 2.76-2.82 (m, 1H), 2.66-2.71 (m, 1H), 1.81 (s, 3H), 1.22 (s, 3H)
Example 178: synthesis of (S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000194
The compound (150mg, 0.69mmol) obtained from Preparation Example 87 and the compound (136mg, 0.62mmol) obtained from Preparation Example 155 were used to obtain the title compound (183mg, 74%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.62 (d, 1H), 7.38 (s, 3H), 7.32 (d, 1H), 7.13 (d, 1H), 6.95 (d, 2H), 5.25 (s, 2H), 4.09 (d, 3H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.56 (s, 3H), 2.25-2.31 (m, 1H), 1.82 (s, 3H), 0.89 (d, 6H)
Example 179: synthesis of (S)-3-[4-(2-isobutyl-3-methyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000195
The compound (100mg, 0.46mmol) obtained from Preparation Example 88 and the compound (90mg, 0.41mmol) obtained from Preparation Example 155 were used to obtain the title compound (120mg, 73%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.63 (s, 1H), 7.55 (d, 1H), 7.29 (d, 2H), 7.08 (d, 1H), 6.94 (d, 2H), 5.12 (s, 2H), 4.14 (d, 2H), 4.06 (br t, 1H), 2.77-2.83 (m, 1H), 2.67-2.73 (m, 1H), 2.59 (s, 3H), 2.34-2.43 (m, 1H), 1.83 (s, 3H), 0.93 (d, 6H)
Example 180: synthesis of (S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000196
The compound (0.17g, 0.92mmol) obtained from Preparation Example 72 and the compound (0.18g, 0.83mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.17g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.02 (s, 1H), 7.73 (d, 1H), 7.51 (s, 1H), 7.33 (d, 2H), 7.18 (d, 1H), 6.98 (d, 2H), 5.18 (s, 2H), 4.88 (m, 1H), 4.07 (m, 1H), 2.84 (dd, 1H), 2.74 (dd, 1H), 1.83 (s, 3H), 1.59 (d, 6H)
Example 181: synthesis of (S)-3-[4-(3-isobutyl-benzo[d]isoxazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000197
The compound (40mg, 0.19mmol) obtained from Preparation Example 89-4 and the compound (37mg, 0.17mmol) obtained from Preparation Example 155 were used to obtain the title compound (45mg, 59%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.76 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.32 (d, 2H), 6.95 (dd, 2H), 5.14 (s, 2H), 4.08 (br t, 1H), 2.91 (d, 2H), 2.78-2.84 (m, 1H), 2.68-2.73 (m, 1H), 2.20-2.28 (m, 1H), 1.83 (s, 3H), 1.00 (d, 6H)
Example 182: synthesis of (S)-3-{4-[1-(2,2-dimethyl-propyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000198
The compound (220mg, 1.01mmol) obtained from Preparation Example 78 and the compound (198mg, 0.91mmol) obtained from Preparation Example 155 were used to obtain the title compound (250mg, 68%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.99 (s, 1H), 7.72 (d, 1H), 7.45 (s, 1H), 7.30 (d, 2H), 7.16 (d, 1H), 6.95 (d, 2H), 5.19 (s, 2H), 4.16 (s, 2H), 3.97 (br s, 1H), 2.78-2.80 (m, 1H), 2.68-2.73 (m, 1H), 1.84 (s, 3H), 1.00 (s, 9H)
Example 183: synthesis of (S)-3-[4-(1-isobutyl-6-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000199
The compound (96mg, 0.44mmol) obtained from Preparation Example 120 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (109mg, 67%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.94 (s, 1H), 7.73 (s, 1H), 7.33 (d, 2H), 7.23 (s, 1H), 6.97 (d, 2H), 5.07 (s, 2H), 4.14 (d, 2H), 4.08 (m, 1H), 2.68-2.86 (m, 2H), 2.50 (s, 3H), 2.33 (m, 1H), 1.83 (d, 3H), 0.92 (d, 6H)
Example 184: synthesis of (S)-3-[4-(1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000200
The compound (257mg, 1.26mmol) obtained from Preparation Example 145 and the compound (247mg, 1.13mmol) obtained from Preparation Example 155 were used to obtain the title compound (140mg, 32%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.10 (s, 1H), 7.36 (d, 2H), 7.31 (d, 2H), 7.18 (d, 1H), 6.98 (d, 2H), 5.36 (s, 2H), 4.19 (d, 2H), 4.06 (br s, 1H), 2.78-2.84 (m, 1H), 2.69-2.74 (m, 1H), 2.34-2.35 (m, 1H), 1.83 (s, 3H), 0.94 (d, 6H)
Example 185: synthesis of (S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000201
The compound (0.25g, 1.29mmol) obtained from Preparation Example 143 and the compound (0.25g, 1.16mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.3g, 66%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.43 (s, 1H), 7.32 (d, 2H), 7.14 (d, 1H), 6.98 (d, 2H), 5.18 (s, 2H), 4.81 (m, 1H), 4.09 (m, 1H), 2.84 (dd, 1H), 2.74 (dd, 1H), 2.57 (s, 3H), 1.84 (s, 3H), 1.56 (d, 6H)
Example 186: synthesis of (S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000202
The compound (96mg, 0.44mmol) obtained from Preparation Example 108-5 and the compound (87mg, 0.40mmol) obtained from Preparation Example 155 were used to obtain the title compound (101mg, 62%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.69 (s, 1H), 7.28-7.47 (m, 4H), 6.96 (d, 2H), 5.12 (s, 2H), 4.06 (m, 1H), 4.01 (s, 3H), 2.66-2.87 (m, 4H), 2.14 (m, 1H), 1.84 (d, 3H), 0.97 (d, 6H)
Example 187: synthesis of (S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000203
The compound (111mg, 0.47mmol) obtained from Preparation Example 148 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (30mg, 14%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.69 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 6.95 (m, 2H), 5.12 (s, 2H), 4.78 (m, 1H), 2.82 (dd, 1H), 2.71 (dd, 1H), 2.58 (s, 3H), 1.83 (d, 3H), 1.56 (d, 6H)
Example 188: synthesis of (S)-3-[4-(1-isobutyl-3-methoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000204
The compound (90mg, 0.632mmol) obtained from Preparation Example 162-4 and the compound (72mg, 0.329mmol) obtained from Preparation Example 155 were used to obtain the title compound (104mg, 72%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.80 (d, 1H), 7.42 (s, 1H), 7.30 (d, 2H), 7.17 (d, 1H), 6.95 (d, 2H), 5.18 (s, 2H), 4.82 (s, 2H), 4.13 (d, 2H), 4.05 (m, 1H), 3.39 (s, 3H), 2.83-2.66 (m, 2H), 2.32 (m, 1H), 1.82 (d, 3H), 0.90 (d, 6H)
Example 189: synthesis of (S)-3-[4-(3-fluoro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000205
The compound (64.7mg, 0.29mmol) obtained from Preparation Example 163-3 and the compound (57.2mg, 0.26mmol) obtained from Preparation Example 155 were used to obtain the title compound (52mg, 49%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.36 (dd, 1H), 7.30 (d, 1H), 7.25 (s, 2H), 7.21 (d, 1H), 6.96 (d, 2H), 5.37 (s, 2H), 4.05 (br s, 1H), 4.00 (d, 2H), 2.79 (m, 1H), 2.72 (m, 1H), 2.28 (m, 1H), 1.82 (s, 3H), 0.92 (d, 6H)
Example 190: synthesis of (S)-3-[4-(1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000206
The compound (42mg, 0.22mmol) obtained from Preparation Example 164-2 and the compound (44mg, 0.20mmol) obtained from Preparation Example 155 were used to obtain the title compound (61mg, 81%).
NMR:1H-NMR(500HMz, DMSO-d 6); δ 12.25 (br s), 8.12(s, 1H), 7.62 (d, 1H), 7.32 (t, 1H), 7.23 (d, 2H), 7.16 (d, 1H), 6.96 (d, 2H), 5.36 (s, 2H), 4.96 (m, 1H), 3.89 (m, 1H), 2.62-2.49 (m, 2H), 1.72 (d, 3H), 1.44 (d, 6H)
Example 191: synthesis of (S)-3-[4-(3-ethoxymethyl-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000207
The compound (92mg, 0.351mmol) obtained from Preparation Example 165-2 and the compound (70mg, 0.319mmol) obtained from Preparation Example 155 were used to obtain the title compound (112mg, 78%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.83 (d, 1H), 7.41 (s, 1H), 7.30 (d, 2H), 7.17 (d, 1H), 6.95 (d, 2H), 5.17 (s, 2H), 4.86 (s, 2H), 4.12 (d, 2H), 4.05 (m, 1H), 3.56 (q, 2H), 2.83-2.66 (m, 2H), 2.31 (m, 1H), 1.82 (d, 3H), 1.22 (t, 3H), 0.90 (d, 6H)
Example 192: synthesis of (S)-3-[4-(3-chloro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
The compound (111.4mg, 0.47mmol) obtained from Preparation Example 166-2 and the compound (92mg, 0.42mmol) obtained from Preparation Example 155 were used to obtain the title compound (87mg, 49%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.37 (dd, 1H), 7.31 (dd, 3H), 7.25 (d, 1H), 6.98 (d, 2H), 5.55 (s, 2H), 4.10 (d, 2H), 4.07 (br s, 1H), 2.80 (m, 1H), 2.72 (m, 1H), 2.31-2.35 (m, 1H), 1.83 (s, 3H), 0.93 (d, 6H)
Example 193: synthesis of (S)-3-[4-(1-isobutyl-3-isopropoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000209
The compound (85mg, 0.308mmol) obtained from Preparation Example 167-2 and the compound (61mg, 0.280mmol) obtained from Preparation Example 155 were used to obtain the title compound (100mg, 77%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.84 (d, 1H), 7.39 (s, 1H), 7.30 (d, 2H), 7.16 (d, 1H), 6.94 (d, 2H), 5.17 (s, 2H), 4.86 (s, 2H), 4.11 (d, 2H), 4.05 (m, 1H), 3.73 (m, 1H), 2.83-2.66 (m, 2H), 2.30 (m, 1H), 1.82 (d, 3H), 1.21 (d, 6H), 0.90 (d, 6H)
Example 194: synthesis of (S)-3-[4-(3-fluoro-1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000210
The compound (73mg, 0.350mmol) obtained from Preparation Example 168-2 and the compound (69mg, 0.318mmol) obtained from Preparation Example 155 were used to obtain the title compound (90mg, 71%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.40-7.26(m, 4H), 7.22 (d, 1H), 6.97 (d, 2H), 5.37 (s, 2H), 4.72 (m, 1H), 4.06 (m, 1H), 2.85-2.66 (m, 2H), 1.83 (d, 3H), 1.53 (d, 6H)
Example 195: synthesis of (S)-3-[4-(3-bromo-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000211
The compound (33mg, 0.15mmol) obtained from Preparation Example 169-4 and the compound (40mg, 0.17mmol) obtained from Preparation Example 155 were used to obtain the title compound (41.5mg, 65%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (d, 2H), 7.16 (dd, 1H), 6.96 (d, 2H), 5.29 (s, 2H), 4.19 (s, 3H), 4.07 (br s, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 1.83 (s, 3H)
Example 196: synthesis of (S)-3-[4-(1-isobutyl-3-methoxymethyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000212
The compound (66.5mg, 0.25mmol) obtained from Preparation Example 170-5 and the compound (50mg, 0.23mmol) obtained from Preparation Example 155 were used to obtain the title compound (76.7mg, 74%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.65 (d, 1H), 7.32 (d, 2H), 7.18 (d, 1H), 6.96 (d, 2H), 5.15 (s, 2H), 4.80 (s, 2H), 4.40 (d, 2H), 4.07 (br s, 1H), 3.37 (s, 3H), 2.83 (m, 1H), 2.73 (m, 1H), 2.69 (s, 3H), 2.23 (m, 1H), 1.84 (s, 3H), 0.92 (d, 6H)
Example 197: synthesis of (S)-3-[4-(1-butyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000213
The compound (56mg, 0.27mmol) obtained from Preparation Example 171-2 and the compound (54mg, 0.25mmol) obtained from Preparation Example 155 were used to obtain the title compound (34.1mg, 35%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.11 (s, 1H), 7.37 (dd, 2H), 7.30 (d, 2H), 7.17 (d, 1H), 6.98 (d, 2H), 5.36 (s, 2H), 4.40 (t, 2H), 4.04 (br s, 1H), 2.81 (m, 1H), 2.71(m, 1H), 1.87-1.95 (m, 2H), 1.83 (s, 3H), 1.30-1.43 (m, 2H), 0.94 (t, 3H)
Example 198: synthesis of (S)-3-[4-(1-butyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000214
The compound (73.6mg, 0.33mmol) obtained from Preparation Example 172 and the compound (65mg, 0.30mmol) obtained from Preparation Example 155 were used to obtain the title compound (54mg, 44%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.36 (dd, 1H), 7.31 (d, 3H), 7.22 (d, 1H), 6.97 (d, 2H), 5.38 (s, 2H), 4.21 (t, 2H), 4.18 (br s, 1H), 2.79 (m, 1H), 2.74 (m, 1H), 1.84-1.87 (m, 2H), 1.83 (s, 3H), 1.33-1.35 (m, 2H), 0.94 (t, 3H)
Example 199: synthesis of (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000215
The compound (65.2mg, 0.32mmol) obtained from Preparation Example 173-2 and the compound (63.3mg, 0.29mmol) obtained from Preparation Example 155 were used to obtain the title compound (64.8mg, 58%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.12 (s, 1H), 7.34-7.42 (m, 2H), 7.31 (d, 2H), 7.18 (d, 1H), 6.98 (d, 2H), 5.37 (s, 2H), 4.29 (d, 2H), 4.06 (br s, 1H), 2.81 (m, 1H), 2.71 (m, 1H), 1.83 (s, 3H), 1.35 (m, 1H), 0.56-0.61 (m, 2H), 0.40-0.44 (m, 2H)
Example 200: synthesis of (S)-3-[4-(1-cyclopropylmethyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000216
The compound (89.4mg, 0.41mmol) obtained from Preparation Example 174 and the compound (80mg, 0.37mmol) obtained from Preparation Example 155 were used to obtain the title compound (82mg, 30%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.37 (dd, 1H), 7.30 (d, 2H), 7.28 (d, 1H), 7.22 (d, 1H), 6.96 (d, 2H), 5.38 (s, 2H), 4.10 (d, 2H), 4.06 (br s, 1H), 2.80 (m, 1H), 2.71 (m, 1H), 1.83 (s, 3H), 1.27 (m, 1H), 0.57-0.58 (m, 2H), 0.39-0.40 (m, 2H)
Example 201: synthesis of (S)-3-[4-(3-chloro-1-methyl-1H-indazol-7-ylmethoxy)-methyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000217
The compound (66mg, 0.336mmol) obtained from Preparation Example 175-2 and the compound (67mg, 0.305mmol) obtained from Preparation Example 155 were used to obtain the title compound (87mg, 74%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.68 (d, 1H), 7.38 (d, 1H), 7.34 (d, 2H), 7.15 (m, 1H), 6.96 (d, 2H), 5.28 (s, 2H), 4.16 (s, 3H), 4.07 (m, 1H), 2.85-2.67 (m, 2H), 1.83 (d, 3H)
Example 202: synthesis of (S)-3-[4-(1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000218
The compound (0.26g, 0.96mmol) obtained from Preparation Example 176-2 and the compound (0.18g, 0.86mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.21g, 54%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.55 (s, 1H), 7.46 (d, 2H), 7.41 (s, 1H), 7.31 (d, 2H), 7.09 (d, 1H), 6.93 (d, 2H), 6.24 (d, 1H), 5.70 (s, 2H), 5.12 (s, 2H), 4.83 (m, 1H), 4.06 (m, 1H), 2.79 (dd, 1H), 2.72 (dd, 1H), 1.81 (s, 3H), 1.58 (d, 6H)
Example 203: synthesis of (S)-3-[4-(3-fluoro-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000219
The compound (40mg, 0.19mmol) obtained from Preparation Example 177-2 and the compound (38mg, 0.17mmol) obtained from Preparation Example 155 were used to obtain the title compound (36.1mg, 58%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.66 (d, 1H), 7.38 (d, 1H), 7.34 (d, 2H), 7.10 (dd, 1H), 6.97 (d, 2H), 5.28 (s, 2H), 4.06 (s, 3H), 3.75 (br s, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 1.84 (s, 3H)
Example 204: synthesis of (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000220
The compound (0.19g, 0.93mmol) obtained from Preparation Example 178-3 and the compound (0.14g, 0.66mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.13g, 50%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.35 (d, 1H), 7.32 (d, 2H), 7.23 (d, 1H), 7.17 (d, 1H), 6.97 (d, 2H), 6.57 (d, 1H), 5.37 (s, 2H), 4.13 (d, 2H), 4.07 (m, 1H), 2.85 (dd, 1H), 2.74 (dd, 1H), 2.30 (m, 1H), 1.83 (s, 3H), 0.94 (d, 6H)
Example 205: synthesis of (S)-3-[4-(1-butyl-3-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000221
The compound (31mg, 0.14mmol) obtained from Preparation Example 179-3 and the compound (28mg, 0.13mmol) obtained from Preparation Example 155 were used to obtain the title compound (13.1mg, 25%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.28-7.33 (m, 4H), 7.11 (d, 1H), 6.97 (dd, 2H), 5.33 (s, 2H), 4.30 (t, 2H), 4.07 (br s, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 2.63 (s, 3H), 1.84-1.88 (m, 2H), 1.83 (s, 3H), 1.34-1.38 (m, 2H), 0.93 (t, 3H)
Example 206: synthesis of (S)-3-[4-(3-butyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000222
The compound (332mg, 1.521mmol) obtained from Preparation Example 180-5 and the compound (302mg, 1.383mmol) obtained from Preparation Example 155 were used to obtain the title compound (454mg, 81%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.69 (d, 1H), 7.37-7.29 (m, 3H), 7.06 (t, 1H), 6.97 (d, 2H), 5.29 (s, 2H), 4.15 (s, 3H), 4.08 (m, 1H), 2.94 (t, 2H), 2.86-2.68 (m, 2H), 1.83 (d, 3H), 1.81-1.73 (m, 2H), 1.48-1.39 (m, 2H), 0.95 (t, 3H)
Example 207: synthesis of (S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000223
The compound (72mg, 0.33mmol) obtained from Preparation Example 181-5 and the compound (65mg, 0.30mmol) obtained from Preparation Example 155 were used to obtain the title compound (71mg, 59%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.67 (d, 1H), 7.37-7.29 (m, 3H), 7.06 (t, 1H), 6.98 (d, 2H), 5.29 (s, 2H), 4.16 (s, 3H), 4.08 (m, 1H), 2.86-2.68 (m, 4H), 2.13 (m, 1H), 1.83 (d, 3H), 0.98 (d, 6H)
Example 208: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000224
The compound (0.70g, 3.21mmol) obtained from Preparation Example 182-3 and the compound (0.70g, 3.21mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.59g, 46%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.06 (s, 1H), 7.31 (d, 2H), 7.06 (d, 1H), 6.98 (d, 2H), 5.31 (s, 2H), 4.40 (d, 2H), 4.06 (m, 1H), 2.80 (dd, 1H), 2.74 (dd, 1H), 2.71 (s, 3H), 2.24 (m, 1H), 1.83 (s, 3H), 0.95 (d, 6H)
Example 209: synthesis of (S)-3-[4-(3-isopropyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
The compound (67mg, 0.33mmol) obtained from Preparation Example 183-5 and the compound (65mg, 0.3mmol) obtained from Preparation Example 155 were used to obtain the title compound (65mg, 55%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.75 (d, 1H), 7.34 (d, 2H), 7.31 (d, 1H), 7.05 (t, 1H), 6.97 (d, 2H), 5.29 (s, 2H), 4.15 (s, 3H), 4.08 (m, 1H), 3.39 (m, 1H), 2.86-2.68 (m, 2H), 1.83 (d, 3H), 1.44 (d, 6H)
Example 210: synthesis of (S)-3-[4-(1-methyl-3-propyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000226
The compound (67mg, 0.33mmol) obtained from Preparation Example 184-5 and the compound (65mg, 0.3mmol) obtained from Preparation Example 155 were used to obtain the title compound (67mg, 57%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.68 (d, 1H), 7.34 (d, 2H), 7.32 (d, 1H), 7.06 (t, 1H), 6.97 (d, 2H), 5.29 (s, 2H), 4.15 (s, 3H), 4.08 (m, 1H), 2.92 (t, 2H), 2.86-2.68 (m, 2H), 1.87-1.76 (m, 5H), 1.01 (t, 3H)
Example 211: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000227
The compound (0.10g, 0.41mmol) obtained from Preparation Example 185-3 and the compound (0.13g, 0.41mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.12g, 76%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.94 (s, 1H), 7.54 (d, 1H), 7.33 (d, 2H), 7.18 (d, 1H), 6.97 (d, 3H), 5.14 (s, 2H), 4.43 (d, 2H), 4.07 (m, 1H), 2.79 (dd, 1H), 2.70 (dd, 1H), 2.69 (s, 3H), 2.24 (m, 1H), 1.83 (s, 3H), 0.92 (d, 6H)
Example 212: synthesis of (S)-3-[4-(1-isobutyl-3,7-dimethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000228
The compound (70mg, 0.30mmol) obtained from Preparation Example 186-2 and the compound (59.2mg, 0.27mmol) obtained from Preparation Example 155 were used to obtain the title compound (44.8mg, 40%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.46 (d, 1H), 7.32 (d, 2H), 7.14 (d, 1H), 6.96 (d, 2H), 5.13 (s, 2H), 4.34 (d, 2H), 4.07 (br s, 1H), 2.81 (m, 1H), 2.70-2.75 (m, 1H), 2.66 (s, 3H), 2.52 (s, 3H), 2.18-2.22 (m, 1H), 1.83 (s, 3H), 0.91 (d, 6H)
Example 213: synthesis of (S)-3-[4-(3-fluoro-1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000229
The compound (0.09g, 0.38mmol) obtained from Preparation Example 187-2 and the compound (0.08g, 0.38mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.04g, 27%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.31 (d, 2H), 7.09 (s, 2H), 6.97 (d, 2H), 5.33 (s, 2H), 4.21 (d, 2H), 4.05 (m, 1H), 2.79 (dd, 1H), 2.72 (dd, 1H), 2.65 (s, 3H), 2.23 (m, 1H), 1.83 (s, 3H), 0.93 (d, 6H)
Example 214: synthesis of (S)-3-[4-(1-ethyl-3-fluoro-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000230
The compound (0.08g, 0.36mmol) obtained from Preparation Example 188-2 and the compound (0.08g, 0.36mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.07g, 54%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.46 (d, 1H), 7.32 (d, 2H), 7.19 (d, 1H), 6.96 (d, 2H), 5.12 (s, 2H), 4.51 (q, 2H), 4.07 (m, 1H), 2.81 (dd, 1H), 2.73 (dd, 1H), 2.66 (s, 3H), 1.83 (s, 3H), 1.44 (t, 3H)
Example 215: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000231
The compound (42mg, 0.132mmol) obtained from Preparation Example 189-2 and the compound (26mg, 0.12mmol) obtained from Preparation Example 155 were used to obtain the title compound (17mg, 28%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.62 (d, 1H), 7.32 (d, 2H), 7.10 (d, 1H), 6.94 (d, 2H), 5.11 (s, 2H), 4.39 (d, 2H), 4.06 (m, 1H), 4.00-3.90 (m, 2H), 3.71 (t, 4H), 2.82-2.58 (m, 9H), 2.20 (m, 1H), 1.81 (d, 3H), 0.90 (d, 6H)
Example 216: synthesis of (S)-3-[4-(7-chloro-1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000232
The compound (75mg, 0.222mmol) obtained from Preparation Example 190-4 and the compound (53mg, 0.244mmol) obtained from Preparation Example 155 were used to obtain the title compound (88mg, 76%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.71 (d, 1H), 7.31 (d, 2H), 7.26 (d, 1H), 6.93 (d, 2H), 5.24 (s, 2H), 4.55 (d, 2H), 4.04 (m, 1H), 3.91 (s, 2H), 3.70 (t, 4H), 2.79-2.54 (m, 6H), 2.29 (m, 1H), 1.81 (d, 3H), 0.90 (d, 6H)
Example 217: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000233
The compound (59mg, 0.196mmol) obtained from Preparation Example 191-2 and the compound (47mg, 0.216mmol) obtained from Preparation Example 155 were used to obtain the title compound (63mg, 66%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.64 (d, 1H), 7.32 (d, 2H), 7.16 (d, 1H), 6.89 (d, 2H), 5.09 (s, 2H), 4.52-4.37 (m, 4H), 4.07 (m, 1H), 3.31 (br s, 4H), 2.80-2.59 (m, 5H), 2.20 (m, 1H), 1.93 (br s, 4H), 1.79 (d, 3H), 0.91 (d, 6H)
Example 218: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-3-piperidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000234
The compound (78mg, 0.247mmol) obtained from Preparation Example 192-2 and the compound (59mg, 0.272mmol) obtained from Preparation Example 155 were used to obtain the title compound (76mg, 61%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.56 (d, 1H), 7.37 (d, 2H), 7.09 (d, 1H), 6.90 (d, 2H), 5.08-5.01 (m, 2H), 4.39 (d, 2H), 4.31-4.07 (m, 5H), 2.92 (br s, 4H), 2.83-2.59 (m, 5H), 2.19 (m, 1H), 1.86-1.82 (m, 7H), 1.40 (br s, 2H), 0.90 (d, 6H)
Example 219: synthesis of (S)-3-[4-(1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000235
The compound (79mg, 0.260mmol) obtained from Preparation Example 193-4 and the compound (62mg, 0.286mmol) obtained from Preparation Example 155 were used to obtain the title compound (89mg, 70%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.79 (d, 1H), 7.39 (s, 1H), 7.30 (d, 2H), 7.11 (d, 1H), 6.93 (d, 2H), 5.15 (s, 2H), 4.12 (d, 2H), 4.05 (m, 1H), 4.00-3.90 (m, 2H), 3.71 (t, 4H), 2.80-2.56 (m, 6H), 2.30 (m, 1H), 1.81 (d, 3H), 0.89 (d, 6H)
Example 220: synthesis of (S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000236
The compound (47.5mg, 0.23mmol) obtained from Preparation Example 194 and the compound (51mg, 0.23mmol) obtained from Preparation Example 155 were used to obtain the title compound (32.3mg, 36%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.99 (s, 1H), 7.55 (d, 1H), 7.32 (d, 2H), 7.16 (d, 1H), 6.97 (d, 2H), 5.29 (m, 1H), 5.15 (s, 2H), 4.07 (br s, 1H), 2.81 (m, 1H), 2.70-2.75 (m, 4H), 1.83 (s, 3H), 1.65 (d, 6H)
Example 221: synthesis of (S)-3-[4-(7-methyl-1-propyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000237
The compound (32.4mg, 0.16mmol) obtained from Preparation Example 195 and the compound (35mg, 0.16mmol) obtained from Preparation Example 155 were used to obtain the title compound (32.8mg, 52%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.94 (s, 1H), 7.54 (d, 1H), 7.32 (d, 2H), 7.16 (d, 1H), 6.96 (d, 2H), 5.14 (s, 2H), 4.59 (t, 2H), 4.07 (br s, 1H), 2.77 (m, 1H), 2.70 (m, 4H), 1.89-1.92 (m, 2H), 1.83 (s, 3H), 0.96 (t, 3H)
Example 222: synthesis of (S)-3-[4-(3-fluoromethyl-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000238
The compound (11.5mg, 0.043mmol) obtained from Preparation Example 196-2 and the compound (9.4mg, 0.043mmol) obtained from Preparation Example 155 were used to obtain the title compound (12.4mg, 66%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.73 (d, 1H), 7.31 (d, 2H), 7.25 (d, 1H), 6.95 (d, 2H), 5.28 (s, 2H), 4.82 (q, 2H), 4.02 (br s, 1H), 3.86 (s, 2H), 3.71 (dd, 4H), 2.76-2.78 (m, 1H), 2.69-2.71 (m, 1H), 2.55 (br s, 4H), 1.83 (s, 3H), 1.48 (t, 3H)
Example 223: synthesis of (S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000239
The compound (0.60g, 2.94mmol) obtained from Preparation Example 197 and the compound (0.64g, 2.94mmol) obtained from Preparation Example 155 were used to obtain the title compound (0.72g, 63%).
NMR:1H-NMR(400HMz, CDCl3); δ 8.12 (s, 1H), 7.31 (d, 2H), 7.07 (s, 2H), 6.98 (d, 2H), 5.31 (s, 2H), 5.24 (m, 1H), 4.05 (m, 1H), 2.83 (dd, 1H), 2.74 (s, 3H), 2.72 (dd, 1H), 1.83 (s, 3H), 1.60 (d, 6H)
Example 224: synthesis of (S)-3-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000240
The compound (70mg, 0.368mmol) obtained from Preparation Example 198 and the compound (88mg, 0.405mmol) obtained from Preparation Example 155 were used to obtain the title compound (98mg, 70%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.31 (d, 1H), 7.34 (d, 1H), 7.30 (d, 2H), 7.13 (d, 1H), 6.95 (d, 2H), 6.56 (d, 1H), 5.34 (s, 2H), 4.21 (m, 1H), 4.05 (m, 1H), 2.84-2.65 (m, 2H), 1.82 (d, 3H), 1.52 (d, 6H)
Example 225: synthesis of (S)-3-[4-(3-fluoro-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000241
The compound (26mg, 0.117mmol) obtained from Preparation Example 199-3 and the compound (28mg, 0.129mmol) obtained from Preparation Example 155 were used to obtain the title compound (22mg, 46%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.31 (d, 1H), 7.31 (d, 2H), 7.21 (d, 1H), 6.98-6.93 (m, 3H), 4.06 (m, 1H), 4.03 (d, 2H), 2.84-2.66 (m, 2H), 2.19 (m, 1H), 1.82 (d, 3H), 0.91 (d, 6H)
Example 226: synthesis of (S)-3-[4-(7-methyl-1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000242
The compound (40mg, 0.158mmol) obtained from Preparation Example 200 and the compound (41mg, 0.190mmol) obtained from Preparation Example 155 were used to obtain the title compound (37mg, 53%).
NMR:1H-NMR(500HMz, CDCl3); δ 8.50 (br s, 1H), 8.30 (br s, 1H), 8.04 (s, 1H), 7.58 (d, 1H), 7.33-7.18 (m, 5H), 6.88 (d, 2H), 5.89 (s, 2H), 5.10 (s, 2H), 4.05 (m, 1H), 2.84-2.64 (m, 2H), 2.54 (s, 3H), 1.81 (d, 3H)
Example 227: synthesis of (S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000243
The compound (57mg, 0.16mmol) obtained from Preparation Example 201-2 and the compound (35.4mg, 0.16mmol) obtained from Preparation Example 155 were used to obtain the title compound (51.2mg, 60%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.71 (d, 1H), 7.33 (d, 2H), 7.16 (d, 1H), 6.97 (d, 2H), 5.14 (s, 2H), 4.39 (d, 2H), 4.02 (br s, 1H), 3.98 (s, 2H), 2.81 (m, 1H), 2.68-2.76 (m, 5H), 2.48-2.51 (m, 2H), 2.21 (m, 1H), 1.84 (s, 5H), 1.71-1.74 (m, 2H), 0.89 (d, 6H)
Example 228: synthesis of (S)-3-[4-(1-isobutyl-7-methyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000244
The compound (64.4mg, 0.22mmol) obtained from Preparation Example 202-3 and the compound (49mg, 0.22mmol) obtained from Preparation Example 155 were used to obtain the title compound (72.5mg, 68%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.52 (d, 1H), 7.37 (d, 2H), 7.31 (d, 2H), 7.11 (d, 1H), 6.93 (d, 2H), 6.22 (d, 1H), 5.65 (s, 2H), 5.11 (s, 2H), 4.41 (d, 2H), 4.02 (br s, 1H), 2.79 (m, 1H), 2.72 (m, 1H), 2.67 (s, 3H), 2.22 (m, 1H), 1.83 (s, 3H), 0.93 (d, 6H)
Example 229: synthesis of (S)-3-{4-[3-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000245
The compound (27.2mg, 0.09mmol) obtained from Preparation Example 206-2 and the compound (18.6mg, 0.09mmol) obtained from Preparation Example 155 were used to obtain the title compound (22.7mg, 50%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.64 (d, 1H), 7.33 (d, 2H), 7.15 (d, 1H), 6.94 (d, 2H), 5.22 (br s, 0.5H), 5.12 (s, 2H), 5.08 (br s, 0.5H), 4.40 (d, 2H), 4.09 (s, 2H), 3.38-3.40 (m, 4H), 2.73 (m, 1H), 2.68 (s, 3H), 2.65 (m, 1H), 2.23 (m, 1H), 1.98-2.08 (m, 2H), 1.81 (s, 3H), 0.95 (d, 6H)
Example 230: synthesis of (S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000246
The compound (37mg, 0.110mmol) obtained from Preparation Example 203-2 and the compound (26mg, 0.121mmol) obtained from Preparation Example 155 were used to obtain the title compound (38mg, 65%).
NMR:1H-NMR(500HMz, CDCl3); δ 7.61 (d, 1H), 7.32 (d, 2H), 7.14 (d, 1H), 6.95 (d, 2H), 5.13 (s, 2H), 4.39 (d, 2H), 4.06 (m, 1H), 4.00 (s, 2H), 2.99 (t, 2H), 2.86-2.63 (m, 7H), 2.31-2.15 (m, 3H), 1.82 (d, 3H), 0.90 (d, 6H)
Example 231: synthesis of (S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000247
The compound (65mg, 0.20mmol) obtained from Preparation Example 204-4 and the compound (48mg, 0.22mmol) obtained from Preparation Example 155 were used to obtain the title compound (42mg, 37%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.95 (d, 1H), 7.29 (d, 2H), 7.25 (d, 1H), 7.13 (s, 1H), 6.96 (d, 2H), 5.22 (s, 2H), 4.04 (m, 3H), 3.82 (2H), 2.99 (t, 2H), 2.83 (t, 2H), 2.66 (m. 2H), 2.28 (m, 3H), 1.80 (s, 3H), 0.91 (d, 6H)
Example 232: synthesis of (S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
Figure PCTKR2013010135-appb-I000248
The compound (55mg, 0.16mmol) obtained from Preparation Example 205-2 and the compound (39mg, 0018mmol) obtained from Preparation Example 155 were used to obtain the title compound (39mg, 47%).
NMR:1H-NMR(400HMz, CDCl3); δ 7.97 (d, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 6.98 (d, 2H), 5.24 (s, 2H), 4.06 (m, 3H), 3.81 (s, 2H), 2.73 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.23 (m, 1H), 1.84 (m, 2H), 1.80 (s, 3H), 1.75 (m, 2H), 0.91 (d, 6H)
Experimental Example 1: Evaluation of the test compounds for induction of Ca2+ using human GPR40 expression cell line
(1) Cell line
The cell line expressing human GPR40 was generated by transfection of the GPR40 expression vector into CHO-K1 cell, and used in the following calcium flux assay.
(2) Preparation of cell-culture medium and cell culture
The cell line was cultured in cell-culture medium (F-12 (Invitrogen) supplemented with 10% (v/v) FBS(Fetal Bovine Serum; Invitrogen), 0.5mg/ml Geneticin (Invitrogen) and 1% (v/v) Antibiotic-Antimycotic solution (Invitrogen)) under the condition of 5% CO2 and 37℃. For calcium flux assay, the cells were diluted with the cell-culture medium to a concentration of 5×105 cells/ml, and the diluted cell suspension was dispensed in amount of 100 ㎕/well to a 96-well transparent bottom black polystyrene cell culture plate (Corning) and then cultured for 24 hours. The following concentrations of test compounds were added to these cells, and then the changes in intracellular calcium concentration were measured by FlexStation II384 (Molecular Devices). The following solution was prepared before the measurement.
(3) Preparation of buffer solution for measurement of calcium concentration change in FlexStation II384
First, a buffer solution for assay was prepared for use in the manufacture of fluorescent dye solution. This buffer solution was prepared by adding 1M HEPES solution (Invitrogen) to HBSS (Hanks' Balanced Salt Solution) (Invitrogen) and then adding 1M NaOH (Nacalai Tesque) to adjust pH to 7.4. Then the fluorescent dye solution was prepared according to the manufacturer’s instruction attached to Calcium 5 Assay Kit (Molecular Devices), and the final DMSO concentration was adjusted to 2%.
(4) Pre-treatment for measurement by FlexStation II384
The fluorescent dye solution was added in an amount of 100 ㎕/well to supernatant of the cell culture plate cultured for 24 hours. The plate was cultured for 1 hour under the condition of 5% CO2 and 37℃ so that the fluorescent dye was inserted into the cell.
Test compounds (i.e., the compounds prepared in the Examples) dissolved in dimethyl sulfoxide (DMSO ACROS) were diluted 200-fold in the buffer solution for assay to prepare compound solutions corresponding to the respective concentrations. As a positive-control solution, the compound of TAK-875 was diluted 200-fold in the buffer solution for assay. TAK-875 is a GPR40 receptor agonist disclosed in WO 2008/001931 (Applicant: to Takeda Pharmaceuticals Company), and it was prepared according to the method described in ACS Med. Chem. Lett., 2010, 290. 50㎕ of the prepared sample solutions was added to each well of 96-well polypropylene plates (NUNC), and thereby a compound plate was prepared. Finally, the compound plate and the cell culture plate cultured for 1 hour with the fluorescent dye were placed in FlexStation II384.
(5) Measurement by FlexStation II384
After the above pre-treatment, the change in the intracellular calcium concentration when each concentration of the test compound solutions was added at 50 ㎕ was measured by FlexStation II384.
GPR40 agonist activity of the test compound solutions in each concentration was calculated as relative activity value (%) when the change in intracellular calcium concentration induced by 10μM of TAK-875 compound which was used as a positive control is 100%. Then, the relative activity values depending on the concentration of the compound were plotted using Prism 4 software (GraphPad) to calculate the EC0.5 value. The EC0.5 value represents the concentration of the compound that exhibits 50% activity compared to the positive control and was used to compare the agonist activities between the test compounds.
(6) Results
The results are shown in Table 1. In the table, “+ + +” indicates that EC0.5 value is greater than or equal to 0.001 μM to less than 0.05 μM, “+ +” indicates that EC0.5 value is greater than or equal to 0.05 μM to less than 0.5 μM, and “+” indicates that EC0.5 value is greater than or equal to 0.5 μM.
Table 1
Figure PCTKR2013010135-appb-T000001

Claims (10)

  1. A compound of Formula (1), or pharmaceutically acceptable salts or isomers thereof:
    [Formula (1)]
    Figure PCTKR2013010135-appb-I000249
    wherein,
    X represents C or N,
    Y represents C, N, C=O or C-halogen,
    Z represents C, N or O,
    Q represents O or NH,
    W represents C, N, C-alkyl or C-halogen,
    R1 represents H, alkyl, heteroalkyl, aryl, heterocycle, aryl-alkyl or heterocycle-alkyl,
    R2 represents H, alkyl, heteroalkyl or halogen,
    R3 represents H, alkyl or halogen,
    R4 represents H, O, alkyl or halogen,
    R5 represents H, alkyl, alkoxy, CN, heterocycle or C≡C-Me,
    R4 and R5 can be connected together to form 5- or 6-membered ring,
    R6 represents H or alkyl, and
    R5 and R6 can be connected together to form 3-membered ring.
  2. The compound, or pharmaceutically acceptable salts or isomers thereof according to Claim 1,
    wherein the structure of
    Figure PCTKR2013010135-appb-I000250
    is selected from the following structures:
    Figure PCTKR2013010135-appb-I000251
    wherein, E represents H, alkyl or halogen, and G represents alkyl, heteroalkyl or halogen.
  3. The compound, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein the compound is selected from the following compounds:
    3-{4-[(1-isopropyl-1H-indol-6-ylmethyl)-amino-phenyl}-propanoic acid;
    3-{4-[(1-benzyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(1-phenethyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(1-benzyl-3-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(1-benzyl-2,3-dichloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(1-benzyl-7-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-{4-[(7-chloro-1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    3-(4-{[7-chloro-1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid;
    3-(4-{[1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid;
    3-{4-[(7-chloro-1-cyclohexyl methyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid;
    [6-(1-benzyl-3-chloro-1H-indol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    3-[4-(1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-{4-[1-(4-fluoro-phenyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
    3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-[4-(7-methyl-1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
    3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-[4-(1-cyclohexyl methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-[4-(3-benzyl-1-methyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid;
    3-[4-(1-methyl-3-o-tolyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid;
    3-{4-[3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    3-{4-[5-fluoro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    {6-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid;
    (S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-methanesulfonyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-methoxy-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(4-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2,6-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-benzyl-2-(2-methoxy-ethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(2-methyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2-chloro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2,6-dimethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-5-fluoro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(2-benzyl-2H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-5-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3,5-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
    3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
    (S)-3-[4-(7-methyl-1-thiazol-4-ylmethyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(2-benzyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H- indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-methyl-1-pyrimidin-4-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-3-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-methyl-1-pyrimidin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-(4,5-dihydro-isoxazol-3-yl)-propanoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-pyrimidin-2-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(2-pyrimidin-2-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-pyrazin-2-ylmethyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-pyrimidin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(2-pyrimidin-4-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(2-pyridin-3-ylmethyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[7-methyl-1-(6-methyl-pyridin-3-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(2-isobutyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-isoxazol-3-yl-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid;
    (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-isoxazol-3-yl-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid;
    (S)-3-{4-[1-(6-methyl-pyridin-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-{4-[1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(2-isopropyl-2H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    [6-(1-isopropyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    (S)-3-isoxazol-3-yl-3-[4-(1-methyl-1H-indazol-6-ylmethoxy)-phenyl]-propanoic acid;
    (S)-3-[4-(1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-3-isoxazol-3-yl-propanoic acid;
    (S)-3-isoxazol-3-yl-3-[4-(1-pyrazin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-propanoic acid;
    [6-(1-benzyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
    3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid;
    [6-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    [5-(1-benzyl-1H-indazol-6-ylmethoxy)-indan-1-yl]-acetic acid;
    [6-(1-benzyl-1H-indazol-6-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid;
    (S)-3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(2-benzyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [6-(2-benzyl-2H-indazol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    (S)-3-[4-(1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-butyric acid;
    [5-(1-benzyl-1H-indazol-5-ylmethoxy)-indan-1-yl]-acetic acid;
    [6-(1-benzyl-1H-indazol-5-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetic acid;
    [7-(1-benzyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    [6-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    (S)-3-[4-(1-benzyl-5-fluoro-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-indol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [6-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid;
    [6-(1-benzyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(1-isobutyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-isobutyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(1-phenethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-phenethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-{4-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    7-[1-(3-methyl-butyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid;
    (S)-3-[4-(1-cyclohexyl methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-cyclohexyl methyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(2-isobutyl-7-methyl-2H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-pyridine-2-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-chroman-4-yl]-acetic acid;
    [7-(2-benzyl-7-methyl-2H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    (S)-3-[4-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    [7-(1-pyridin-3-ylmethyl-1H-indazol-5-ylmethoxy)-chroman-4-yl]-acetic acid;
    7-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-chroman-4-yl}-acetic acid;
    (S)-3-[4-(5-fluoro-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(tetrahydrofuran-2-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-methanesulfonyl-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(tetrahydrofuran-3-ylmethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[2-(tetrahydrofuran-3-ylmethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-methoxy-propanoic acid;
    (S)-3-[4-(1-isobutyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(2-ethoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-butyric acid;
    3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-pentanoic acid;
    (S)-3-{4-[2-(2-ethoxy-ethyl)-2H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    3-[4-(1-benzyl-1H-indazol-5-ylmethoxy)-phenyl]-3-cyano-propanoic acid;
    (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopentyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-isobutyl-3H-benzotriazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    2-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-cyclopropanecarboxylic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopentylmethyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopentyl-7-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopentyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopentylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(2-methanesulfonyl-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(2-methoxy-ethyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-methoxy-propyl)-1H-indazol-5-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[1-(3-methyl-oxetan-3-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(2-isobutyl-3-methyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-isobutyl-benzo[d]isoxazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[1-(2,2-dimethyl-propyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-6-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-3-methyl-1H-indazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-methoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-ethoxymethyl-1-isobutyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-chloro-1-isobutyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-isopropoxymethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoro-1-isopropyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-bromo-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-methoxymethyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-butyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-butyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopropylmethyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-cyclopropylmethyl-3-fluoro-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-chloro-1-methyl-1H-indazol-7-ylmethoxy)-methyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoro-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-butyl-3-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-butyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-isobutyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-isopropyl-1-methyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-methyl-3-propyl-1H-indazol-7-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3,7-dimethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoro-1-isobutyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-ethyl-3-fluoro-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-chloro-1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-3-piperidin-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-3-morpholin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-methyl-1-propyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoromethyl-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-7-methyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(3-fluoro-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-[4-(7-methyl-1-pyridin-3-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-[4-(1-isobutyl-7-methyl-3-pyrazol-1-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid;
    (S)-3-{4-[3-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-7-methyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid;
    (S)-3-{4-[3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid; and
    (S)-3-{4-[3-(3,3-difluoro-piperidin-1-ylmethyl)-1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid.
  4. The compound or pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3, wherein the compound is for the treatment of diabetes.
  5. A pharmaceutical composition comprising the compound, pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3 and a pharmaceutically acceptable carrier.
  6. An insulin secretagogue or hypoglycemic agent comprising as an active ingredient, the compound, pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3.
  7. A GPR40 receptor agonist comprising the compound, pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3 as an active ingredient.
  8. A pharmaceutical composition for preventing or treating diseases or disorders selected from the group consisting of diabetes, high blood sugar, glucose tolerance, and impaired fasting blood glucose and diabetes complications, comprising the compound, pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3 as an active ingredient.
  9. The pharmaceutical composition according to Claim 8 wherein the diabetes complication is hyperlipidemia, hypertension, retinopathy, renal failure or obesity.
  10. A method for treating diseases or disorders selected from the group consisting of diabetes, high blood sugar, glucose tolerance, impaired fasting blood glucose and diabetes complications in mammals comprising administration of the compound, pharmaceutically acceptable salts or isomers thereof according to any one of Claims 1 to 3 to the mammals.
PCT/KR2013/010135 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient WO2014073904A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP13852767.6A EP2917180A4 (en) 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
US14/441,591 US9988379B2 (en) 2012-11-09 2013-11-08 GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
AU2013341945A AU2013341945B2 (en) 2012-11-09 2013-11-08 GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
MX2015005418A MX2015005418A (en) 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient.
JP2015541689A JP6442787B2 (en) 2012-11-09 2013-11-08 GPR40 receptor agonist, method for producing the same, and pharmaceutical composition containing the same as an active ingredient
CN201380064394.0A CN104837816A (en) 2012-11-09 2013-11-08 GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing same as active ingredient
RU2015121948A RU2650506C2 (en) 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing same, and pharmaceutical compositions containing same as active ingredient
BR112015010314-6A BR112015010314B1 (en) 2012-11-09 2013-11-08 COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALTS OR ISONERS THEREOF, PHARMACEUTICAL COMPOSITION, INSULIN SECRETAGOGUE OR HYPOGLYCEMIC AGENT, AND, GPR40 RECEIVER AGONIST
CA2889505A CA2889505C (en) 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0127005 2012-11-09
KR20120127005 2012-11-09

Publications (1)

Publication Number Publication Date
WO2014073904A1 true WO2014073904A1 (en) 2014-05-15

Family

ID=50684927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2013/010135 WO2014073904A1 (en) 2012-11-09 2013-11-08 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient

Country Status (12)

Country Link
US (1) US9988379B2 (en)
EP (1) EP2917180A4 (en)
JP (2) JP6442787B2 (en)
KR (1) KR101984629B1 (en)
CN (2) CN104837816A (en)
AU (1) AU2013341945B2 (en)
BR (1) BR112015010314B1 (en)
CA (1) CA2889505C (en)
MX (1) MX2015005418A (en)
RU (1) RU2650506C2 (en)
TW (1) TWI692469B (en)
WO (1) WO2014073904A1 (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015097713A1 (en) 2013-11-14 2015-07-02 Cadila Healthcare Limited Novel heterocyclic compounds
US9120793B2 (en) 2013-12-13 2015-09-01 Eli Lilly And Company Triazolo-pyridine compound
WO2016022742A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022446A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [5,6]-fused bicyclic antidiabetic compounds
WO2016022448A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016019863A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
WO2016057731A1 (en) * 2014-10-08 2016-04-14 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
JP2017507115A (en) * 2014-01-10 2017-03-16 イーライ リリー アンド カンパニー Isopropyltriazolopyridine compound
JP2017516771A (en) * 2014-05-22 2017-06-22 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Antidiabetic tricyclic compound
WO2017180571A1 (en) * 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
WO2017184662A1 (en) 2016-04-20 2017-10-26 Bristol-Myers Squibb Company Substituted bicyclic heterocyclic compounds
EP3281937A1 (en) 2016-08-09 2018-02-14 Dompé farmaceutici S.p.A. Sulfonamides as gpr40- and gpr120-agonists
WO2018048762A1 (en) * 2016-09-06 2018-03-15 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
WO2018048763A1 (en) * 2016-09-06 2018-03-15 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
US10195178B2 (en) 2016-04-11 2019-02-05 Janssen Pharmaceutica Nv GPR40 agonists in anti-diabetic drug combinations
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101942752B1 (en) * 2012-11-05 2019-01-28 주식회사 엘지화학 Thioaryl derivatives as gpr120 agonists
TWI692469B (en) * 2012-11-09 2020-05-01 南韓商Ｌｇ化學股份有限公司 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
KR101939657B1 (en) * 2013-02-20 2019-01-17 주식회사 엘지화학 Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
CN107176944B (en) * 2016-03-11 2020-05-01 中国科学院上海药物研究所 Thiophene carboxylic acid compound or derivative thereof, pharmaceutical composition, preparation method and application thereof
CN109516914A (en) * 2017-09-20 2019-03-26 华东师范大学 Phenylpropiolic acid micromolecular organic compound and its preparation method and use

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004739A1 (en) 1993-08-05 1995-02-16 Merck & Co., Inc. 3-aryl or heteroaryl-7-heteroaralkylamido cephalosporin compounds, compositions and methods of use
WO2004041266A1 (en) 2002-11-08 2004-05-21 Takeda Pharmaceutical Company Limited Receptor function controlling agent
WO2004106276A1 (en) 2003-05-30 2004-12-09 Takeda Pharmaceutical Company Limited Condensed ring compound
WO2005063729A1 (en) 2003-12-25 2005-07-14 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl)propanoic acid derivatives
WO2005066136A1 (en) * 2003-12-22 2005-07-21 Eli Lilly And Company Bicyclic derivatives as ppar modulators
WO2005086661A2 (en) 2004-02-27 2005-09-22 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
WO2007095340A2 (en) 2006-02-15 2007-08-23 Dendreon Corporation Small-molecule modulators of trp-p8 activity
WO2008001883A1 (en) 2006-06-29 2008-01-03 Nissan Chemical Industries, Ltd. α-AMINO ACID DERIVATIVE AND PHARMACEUTICAL COMPRISING THE SAME AS ACTIVE INGREDIENT
WO2008001931A2 (en) 2006-06-27 2008-01-03 Takeda Pharmaceutical Company Limited Fused cyclic compounds
WO2008021091A2 (en) 2006-08-11 2008-02-21 Packetvideo Corp. 'system and method for delivering interactive audiovisual experiences to portable devices'
WO2008066097A1 (en) * 2006-12-01 2008-06-05 Astellas Pharma Inc. Carboxylic acid derivative
US20080153813A1 (en) 2006-12-21 2008-06-26 Alcon Manufacturing, Ltd. 6-AMINOIMIDAZO[1,2-b]PYRIDAZINE ANALOGS AS RHO KINASE INHIBITORS FOR THE TREATMENT OF RHO KINASE-MEDIATED DISEASES AND CONDITIONS
US20080249101A1 (en) 2007-04-04 2008-10-09 Konrad Bleicher BENZOIMIDAZOLE, TETRAHYDRO-QUINOXALINE, BENZOTRIAZOLE, DIHYDRO-IMIDAZO[4,5-c] PYRIDINONE AND DIHYDRO-ISOINDOLONE DERIVATIVES
WO2009054479A1 (en) 2007-10-26 2009-04-30 Japan Tobacco Inc. Spiro-ring compound and use thereof for medical purposes
WO2009129335A2 (en) 2008-04-15 2009-10-22 Pharmacyclics, Inc. Selective inhibitors of histone deacetylase
US20100040554A1 (en) 2008-07-01 2010-02-18 Board Of Regents Conjugates of photo-activatable dyes
WO2010027500A1 (en) 2008-09-08 2010-03-11 Signal Pharmaceuticals, Llc Aminotriazolopyridines and their use as kinase inhibitors
WO2010054138A2 (en) 2008-11-06 2010-05-14 Vertex Pharmaceuticals, Incorporated Modulators of atp-binding cassette transporters
WO2010080537A1 (en) * 2008-12-18 2010-07-15 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2010089127A1 (en) 2009-02-06 2010-08-12 Grünenthal GmbH Substituted spiro-amides as b1r modulators
WO2010123975A1 (en) 2009-04-22 2010-10-28 Resverlogix Corp. Novel anti-inflammatory agents
US8003648B2 (en) 2006-09-07 2011-08-23 Amgen Inc. Heterocyclic GPR40 modulators
US20110313003A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2011159297A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2012011125A1 (en) 2010-07-23 2012-01-26 Connexios Life Sciences Pvt. Ltd. Agonists of gpr40

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU8750298A (en) * 1997-08-28 1999-03-22 Ono Pharmaceutical Co. Ltd. Peroxisome proliferator-activated receptor controllers
CA2509202A1 (en) * 2003-01-06 2004-07-29 Eli Lilly And Company Fused heterocyclic derivatives as ppar modulators
US7244763B2 (en) 2003-04-17 2007-07-17 Warner Lambert Company Llc Compounds that modulate PPAR activity and methods of preparation
JP4875978B2 (en) * 2004-03-15 2012-02-15 武田薬品工業株式会社 Aminophenylpropanoic acid derivatives
JP2010524932A (en) * 2007-04-16 2010-07-22 アムジエン・インコーポレーテツド Substituted biphenylphenoxy-, thiophenyl- and aminophenylpropanoic acid GPR40 modulators
TWI692469B (en) * 2012-11-09 2020-05-01 南韓商Ｌｇ化學股份有限公司 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
KR101939657B1 (en) * 2013-02-20 2019-01-17 주식회사 엘지화학 Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004739A1 (en) 1993-08-05 1995-02-16 Merck & Co., Inc. 3-aryl or heteroaryl-7-heteroaralkylamido cephalosporin compounds, compositions and methods of use
WO2004041266A1 (en) 2002-11-08 2004-05-21 Takeda Pharmaceutical Company Limited Receptor function controlling agent
WO2004106276A1 (en) 2003-05-30 2004-12-09 Takeda Pharmaceutical Company Limited Condensed ring compound
WO2005066136A1 (en) * 2003-12-22 2005-07-21 Eli Lilly And Company Bicyclic derivatives as ppar modulators
WO2005063729A1 (en) 2003-12-25 2005-07-14 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl)propanoic acid derivatives
WO2005086661A2 (en) 2004-02-27 2005-09-22 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
WO2007095340A2 (en) 2006-02-15 2007-08-23 Dendreon Corporation Small-molecule modulators of trp-p8 activity
WO2008001931A2 (en) 2006-06-27 2008-01-03 Takeda Pharmaceutical Company Limited Fused cyclic compounds
WO2008001883A1 (en) 2006-06-29 2008-01-03 Nissan Chemical Industries, Ltd. α-AMINO ACID DERIVATIVE AND PHARMACEUTICAL COMPRISING THE SAME AS ACTIVE INGREDIENT
WO2008021091A2 (en) 2006-08-11 2008-02-21 Packetvideo Corp. 'system and method for delivering interactive audiovisual experiences to portable devices'
US8003648B2 (en) 2006-09-07 2011-08-23 Amgen Inc. Heterocyclic GPR40 modulators
WO2008066097A1 (en) * 2006-12-01 2008-06-05 Astellas Pharma Inc. Carboxylic acid derivative
US20080153813A1 (en) 2006-12-21 2008-06-26 Alcon Manufacturing, Ltd. 6-AMINOIMIDAZO[1,2-b]PYRIDAZINE ANALOGS AS RHO KINASE INHIBITORS FOR THE TREATMENT OF RHO KINASE-MEDIATED DISEASES AND CONDITIONS
US20080249101A1 (en) 2007-04-04 2008-10-09 Konrad Bleicher BENZOIMIDAZOLE, TETRAHYDRO-QUINOXALINE, BENZOTRIAZOLE, DIHYDRO-IMIDAZO[4,5-c] PYRIDINONE AND DIHYDRO-ISOINDOLONE DERIVATIVES
WO2009054479A1 (en) 2007-10-26 2009-04-30 Japan Tobacco Inc. Spiro-ring compound and use thereof for medical purposes
WO2009129335A2 (en) 2008-04-15 2009-10-22 Pharmacyclics, Inc. Selective inhibitors of histone deacetylase
US20100040554A1 (en) 2008-07-01 2010-02-18 Board Of Regents Conjugates of photo-activatable dyes
WO2010027500A1 (en) 2008-09-08 2010-03-11 Signal Pharmaceuticals, Llc Aminotriazolopyridines and their use as kinase inhibitors
WO2010054138A2 (en) 2008-11-06 2010-05-14 Vertex Pharmaceuticals, Incorporated Modulators of atp-binding cassette transporters
WO2010080537A1 (en) * 2008-12-18 2010-07-15 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2010089127A1 (en) 2009-02-06 2010-08-12 Grünenthal GmbH Substituted spiro-amides as b1r modulators
WO2010123975A1 (en) 2009-04-22 2010-10-28 Resverlogix Corp. Novel anti-inflammatory agents
US20110313003A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2011159297A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2012011125A1 (en) 2010-07-23 2012-01-26 Connexios Life Sciences Pvt. Ltd. Agonists of gpr40

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ACS MED. CHEM. LETT., vol. 290, 2010, pages 50
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 1267 - 1270
JOURNAL OF ORGANIC CHEMISTRY, vol. 4, no. 18, 2009, pages 7052
ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 9, 2011, pages 4570
ORGANIC LETTER, vol. 12, no. 23, 2011, pages 6300
See also references of EP2917180A4
TETRAHEDRON LETTERS, vol. 38, no. 14, 1997, pages 2439

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10011609B2 (en) 2013-11-14 2018-07-03 Cadila Healthcare Limited Heterocyclic compounds
US10246470B2 (en) 2013-11-14 2019-04-02 Cadila Healthcare Limited Heterocyclic compounds
WO2015097713A1 (en) 2013-11-14 2015-07-02 Cadila Healthcare Limited Novel heterocyclic compounds
US9120793B2 (en) 2013-12-13 2015-09-01 Eli Lilly And Company Triazolo-pyridine compound
JP2017507115A (en) * 2014-01-10 2017-03-16 イーライ リリー アンド カンパニー Isopropyltriazolopyridine compound
JP2017516771A (en) * 2014-05-22 2017-06-22 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Antidiabetic tricyclic compound
WO2016022448A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016019863A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
US10100042B2 (en) 2014-08-08 2018-10-16 Merck Sharp & Dohme Corp. [5,6]—fused bicyclic antidiabetic compounds
US10968193B2 (en) 2014-08-08 2021-04-06 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10662171B2 (en) 2014-08-08 2020-05-26 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022446A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [5,6]-fused bicyclic antidiabetic compounds
US10131651B2 (en) 2014-08-08 2018-11-20 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
WO2016022742A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016057731A1 (en) * 2014-10-08 2016-04-14 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
US9790198B2 (en) 2014-10-08 2017-10-17 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
US10662170B2 (en) 2014-10-08 2020-05-26 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
US10131648B2 (en) 2014-10-08 2018-11-20 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
WO2017180571A1 (en) * 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
US10106553B2 (en) 2016-04-11 2018-10-23 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
US10195178B2 (en) 2016-04-11 2019-02-05 Janssen Pharmaceutica Nv GPR40 agonists in anti-diabetic drug combinations
WO2017184662A1 (en) 2016-04-20 2017-10-26 Bristol-Myers Squibb Company Substituted bicyclic heterocyclic compounds
US10508090B2 (en) 2016-08-09 2019-12-17 Dompé Farmaceutici S.P.A. Sulfonamides as GPR40- and GPR120-agonists
EP3281937A1 (en) 2016-08-09 2018-02-14 Dompé farmaceutici S.p.A. Sulfonamides as gpr40- and gpr120-agonists
WO2018029150A1 (en) 2016-08-09 2018-02-15 Dompe' Farmaceutici S.P.A. Sulfonamides as gpr40- and gpr120-agonists
US11098016B2 (en) 2016-09-06 2021-08-24 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
US10214493B2 (en) 2016-09-06 2019-02-26 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
WO2018048762A1 (en) * 2016-09-06 2018-03-15 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
US10774048B2 (en) 2016-09-06 2020-09-15 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
AU2017324724B2 (en) * 2016-09-06 2020-11-12 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
WO2018048763A1 (en) * 2016-09-06 2018-03-15 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
US10000473B2 (en) 2016-09-06 2018-06-19 Janssen Pharmaceutica Nv Indazole derivatives useful as glucagon receptor antagonists
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

Also Published As

Publication number Publication date
CN104837816A (en) 2015-08-12
KR101984629B1 (en) 2019-05-31
MX2015005418A (en) 2015-07-23
KR20140060242A (en) 2014-05-19
CA2889505A1 (en) 2014-05-15
TW201427943A (en) 2014-07-16
TWI692469B (en) 2020-05-01
AU2013341945B2 (en) 2018-07-12
CA2889505C (en) 2020-12-29
EP2917180A1 (en) 2015-09-16
BR112015010314B1 (en) 2021-11-16
US9988379B2 (en) 2018-06-05
BR112015010314A8 (en) 2018-08-14
CN110003169A (en) 2019-07-12
RU2650506C2 (en) 2018-04-16
JP2018184454A (en) 2018-11-22
AU2013341945A1 (en) 2015-05-14
JP2016503409A (en) 2016-02-04
BR112015010314A2 (en) 2017-07-11
RU2015121948A (en) 2017-01-10
JP6442787B2 (en) 2018-12-26
US20150291584A1 (en) 2015-10-15
EP2917180A4 (en) 2016-04-27

Similar Documents

Publication Publication Date Title
WO2014073904A1 (en) Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
WO2010093191A2 (en) Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
WO2011043568A2 (en) Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
AU2014260605B2 (en) Novel compounds for selective histone deacetylase inhibitors, and pharmaceutical composition comprising the same
EP3362445A1 (en) Oxadiazole amine derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2015137750A1 (en) Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
WO2013073875A1 (en) Novel antiviral pyrrolopyridine derivative and a production method for same
WO2013081400A2 (en) Novel benzamide derivative and use thereof
WO2015102426A1 (en) Novel indole derivative compound and pharmaceutical composition comprising the same
WO2022035303A1 (en) Novel dioxoloisoquinolinone derivatives and use thereof
EP3681877A1 (en) Pyrazole derivative compound and use thereof
AU2021226297B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2021162493A1 (en) Protein kinase degradation inducing compound, and use thereof
WO2012030170A2 (en) Novel compound acting as a cannabinoid receptor-1 inhibitor
AU2021327622B2 (en) Novel compounds having inhibitory activity on prostaglandin E2 receptor and uses thereof
WO2020022787A1 (en) Novel imidazole derivative having jnk inhibitory activity, and pharmaceutical composition comprising same
WO2021221445A1 (en) Compound as ubr box domain ligand
AU2021255176B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2021246781A1 (en) Pyridine derivatives as immunomodulators
EP4038062A1 (en) N-(1h-imidazol-2-yl)benzamide compound and pharmaceutical composition comprising the same as active ingredient
WO2023074936A1 (en) Bifunctional compound using ubr box domain-binding ligand
WO2022250224A1 (en) Piperidinedione derivative
WO2021096335A1 (en) Novel quinoline compound and use thereof
WO2021107656A2 (en) Novel quercetin redox derivative and use thereof as bet inhibitor
WO2022098108A1 (en) Nlrp3 protein degradation inducing compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13852767

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2889505

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2015/005418

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2015/05513

Country of ref document: TR

ENP Entry into the national phase

Ref document number: 2015541689

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14441591

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2013341945

Country of ref document: AU

Date of ref document: 20131108

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2013852767

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2015121948

Country of ref document: RU

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015010314

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112015010314

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150506