[go: up one dir, main page]

WO2021026479A1 - Small molecule inhibitors of s1p2 receptor and uses thereof - Google Patents

Small molecule inhibitors of s1p2 receptor and uses thereof Download PDF

Info

Publication number
WO2021026479A1
WO2021026479A1 PCT/US2020/045455 US2020045455W WO2021026479A1 WO 2021026479 A1 WO2021026479 A1 WO 2021026479A1 US 2020045455 W US2020045455 W US 2020045455W WO 2021026479 A1 WO2021026479 A1 WO 2021026479A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
clathrate
polymorph
prodrug
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2020/045455
Other languages
French (fr)
Other versions
WO2021026479A9 (en
Inventor
Teresa Sanchez
Lee YUN-KYOUNG
William J. Polvino
Yasufimi WADA
Yoshiyuki Fukase
Asato Kina
Hiroki TAKAHAGI
Hideyuki Igawa
Peter Meinke
Michael Foley
Ayumu Sato
Sabyasachi DASH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of WO2021026479A1 publication Critical patent/WO2021026479A1/en
Publication of WO2021026479A9 publication Critical patent/WO2021026479A9/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • 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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Rho/ Rho kinase (ROCK)-dependent fibrogenic factors for example, connective tissue growth factor (CTGF) and the Hippo/ YAP signaling pathway are key downstream mediators that induce pathologic fibrosis.
  • CTGF connective tissue growth factor
  • YAP connective tissue growth factor
  • S1P 2 receptor induces inflammatory responses, promotes vascular permeability and is induced during pathologic responses.
  • CGF connective tissue growth factor
  • YAP connective tissue growth factor
  • S1P 2 receptor induces inflammatory responses, promotes vascular permeability and is induced during pathologic responses.
  • the S1P signaling system is unique in that the ligand S1P is present abundantly in circulation during homeostatic conditions. Thus, receptor expression on the cell surface is critical for biological events such as cell migration and junction assembly.
  • FIG. 1 The first FDA-approved S1P receptor inhibitor, Fingolimod/Gilenya induces irreversible receptor internalization, followed by ubiquitinylation, and protesomal degradation.
  • Fingolimod belongs to a class of S1P receptor inhibitors called functional antagonists and it appears that this class of compounds work better than competitive inhibitors against the receptor.
  • Fingolimod and related molecules that were designed to block lymphocyte trafficking by targeting the S1P 1 receptor do not interact with S1P 2 receptor. Thus, there is a need to develop effective inhibitors of the S1P 2 inhibitor.
  • FIG. 1 is plots showing, among other things, Infarct Volume, Edema Ratio, and Neurological Deficits After Intraperitoneal Administration of compound 39120 mg/kg Twice a Day in a tMCAO Model of Male C57BL/6 Mice.
  • Compounds (Vehicle [20% HPBCD], TDI-6621 120 mg/kg b.i.d.) were administered 1.3 and 9.3 hours after the onset of ischemia.
  • mice were assessed for infarct size, edema ratio, and neurological deficit scoring. Infarct size corrected for edema, infarct volume, and edema ratio was calculated from TTC staining images of brains. Neurological deficits were assigned as follows (4-unable to move, 3- spontaneous circling, 2-circling when held by tail, 1-weakness in right forelimb, 0- no deficit). (*P ⁇ 0.05, **P ⁇ 0.005, Mann-Whitney test).
  • FIG.2 is plots of Infarct Volume, Edema Ratio, and Neurological Deficits After Delayed Intraperitoneal Administration of compound 39120 mg/kg Twice a Day in a tMCAO Model of Male C57BL/6 Mice.
  • Compounds (Vehicle [20% HPBCD], TDI-6621120 mg/kg b.i.d.) were administered 4.5 h after the onset of ischemia.
  • FIG. 3 is plots showing that reatment with compound 39 significantly tprevented vascular permeability and blood brain barrier leakage in sepsis model.
  • mice Male C57BL/6 mice (left) or S1PR2+/+ and S1PR2-/- mice (right) were subjected to CLP model of sepsis.
  • the CLP surgery was performed on animals for 15 minutes followed by administration of compounds (vehicle, compound 3960 mg/kg IP, JTE-01330 mg/kg IP).
  • Vascular permeability in the brain was calculated as RFU/g wet weight.
  • Evans blue dye is injected into animals 3 hours prior to endpoint.
  • the mice were transcardially perfused with cold PBS/5 mM EDTA, and the brains were harvested, weighed, and frozen. Brains were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C.
  • FIG. 4 is plots showing that genetic deletion of S1pr2 prevented vascular leakage in the lung and increased survival in the mouse sepsis model.
  • S1pr2 +/+ and S1pr2 -/- mice were subjected to cecal ligation and puncture (CLP) model of sepsis.
  • CLP cecal ligation and puncture
  • mice were transcardially perfused with cold PBS/5 mM EDTA, and lungs were harvested, weighed, and frozen. Lungs were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C. Fluorescence intensity was measured at Ex 620/ Em 680. (*P ⁇ 0.05, **P ⁇ 0.005, ****P ⁇ 0.00005, unpaired t test).
  • the present disclosure provides a compound of the Formula (1): Het 1 —L 1 —Ar 1 —L 2 —G 1 Formula (1) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: Het 1 is cycloalkyl or heterocyclyl; G 1 is aryl, heterocyclyl, heterocyclyl alkyl, carboxyalkyl, carboxyalkyloxy (-O-alkyl- C(O)O-), carboxyalkyloxyalkyl (-alkyl-O-alkyl-C(O)O-), amidoalkyl, carboxy, alkoxycarbonyl or amido; Ar 1 is a divalent aryl group or a divalent heteroaryl group; L 1 is a bond, an acyl linker or an amido linker; L 2 is a bond, heterocycloalkyl linker, cycloalkyloxy linker or an aryloxy linker; Het 1 and
  • Het 1 can be a heterocycyclyl group, such as a four-, five- or six- membered heterocyclyl group.
  • Het 1 can be a four-, five- or six- membered heterocyclyl group, wherein a heteroatom in Het 1 is directly attached to L 1 .
  • Het 1 can be thiolane, thiane, thiophene, thiazole, thiazole, isothiazole, tetrahydrofuranyl, tetrahydropyranyl, indole, quinoline, isoquinoline, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, oxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, benzo[d][1,3]dioxole, pyridinyl or pyrimidinyl.
  • Het 1 can be pyrrolidinyl, piperidinyl or azetidinyl.
  • G 1 can be pyrrolidinyl, piperidinyl or oxazolyl.
  • Het 1 can be substituted with one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, s
  • Het 1 can be: wherein: X is -(CH 2 ) n C(R 2 )(R 3 )(CH 2 ) n -, each n is independently 0, 1 or 2, R 2 and R 3 together with the carbon atom to which they are attached form a cycloalkyl group or R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, aryl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl,
  • Het 1 can also be: wherein: each m is independently 0 or 1, R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR 1 ) 2 ,
  • G 1 can be aryl or G 1 can be a heterocyclyl group, such as a four-, five- or six-membered heterocyclyl group.
  • G 1 can be thiolane, thiane, thiophene, thiazole, thiazole, isothiazole, tetrahydrofuranyl, tetrahydropyranyl, indole, quinoline, isoquinoline, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, oxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4
  • G 1 can be pyrrolidinyl, piperidinyl or oxazolyl.
  • G 1 including when G 1 is aryl or heterocycyclyl, can be substituted with one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamin
  • G 1 can be: wherein m is 0, 1 or 2; A 1 , A 2 , and A 3 is independently CH, C-alkyl, N, NR 5 or O, provided that at least one of A 1 , A 2 , and A 3 is N or NR 5 ; each R 4 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylami
  • G 1 can be: wherein m is 0, 1 or 2; and each R 4 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido.
  • G 1 can also be carboxyalkyl, amidoalkyl, carboxy, alkoxycarbonyl or amido, such as a carboxyalkyl group having the formula -alkyl-C(O)O-R 6 , wherein R 6 is H, alkyl or a counterion (e.g., Na + or K + ); a carboxy group having the formula C(O)OH, also known as a “carboxylic acid” group; an alkoxycarbonyl group of the formula C(O)O-R 6 ; an amidoalkyl group having the formula -alkyl- C(O)NR 7 R 8 , wherein R 7 and R 8 are each, independently, hydrogen, alkyl, aryl or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a heterocyclyl group; and an amido group having the formula C(O)NR 7 R 8 .
  • R 6 is H, alkyl or a counterion (e.g., Na
  • Ar 1 can be a divalent aryl group.
  • divalent aryl groups include groups of the formula: wherein p is 0, 1, 2 or 3; and each R 9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido or two R
  • R 9 is aryl, aryloxy, alkoxy, trihaloalkyl (e.g., CF3), and SF 5 .
  • Ar 1 can be a divalent heteroaryl group.
  • divalent heteroaryl groups include groups of the formula: , wherein: each p is independently 0, 1, 2 or 3; each of A 1 and A 2 is independently, CR 10 or N; A 3 is NR 10 , O or S; A 4 is CR 10 or N; A 5 is CR 10 or N; A 6 is NR 10 , O or S; A 7 is CR 10 or N; each R 9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloal
  • each p is independently 0, 1, 2 or 3; each R 9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R 10 is independently H, alkyl or aryl
  • each p is independently 0, 1, 2 or 3; each R 9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R 10 is independently H, alkyl or aryl.
  • Ar 1 can be:
  • each R 9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF 5 , alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R 10 is independently H, alkyl or aryl.
  • L 1 can be a bond or an acyl linker, such as an acyl linker having the formula -C(O)-R 11 -, wherein R 11 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl.
  • R 11 is alkyl.
  • L 1 can be amido linker, such as an amido linker having the formula -C(O)-N(R 12 )-, wherein R 12 is H or alkyl.
  • L 2 can be a bond, heterocycloalkyl linker, cycloalkyloxy linker or an aryloxy linker.
  • L 2 can be, for example, a cycloalkyloxy linker having the formula -cycloalkyl-O-.
  • L 2 can be, for example, an aryloxy linker having the formula -aryl- O-.
  • cycloalkyloxy linkers include: , each of which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dial
  • cycloalkyloxy linkers can be: [0029]
  • aryloxy linkers include: , which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido.
  • heterocycloalkyl linkers include: , which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido.
  • Het 1 can be a four-, five- or six- membered heterocyclyl group, wherein a heteroatom in Het 1 is directly attached to L 1 .
  • Het 1 —L 1 can have the formula: wherein X is -(CH 2 ) n C(R 2 )(R 3 )(CH 2 ) n -, each n is independently 0, 1 or 2, R 2 and R 3 together with the carbon atom to which they are attached form a cycloalkyl group or R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitro
  • L 2 —G 1 can have the formula: wherein d is 0, 1, 2, 3, 4, or 5; R 13 and R 14 are each independently H, alkyl or aryl, wherein each repeating CR 13 R 14 unit can be the same or different; and G 2 is OR 15 or NR 16 R 17 , wherein R 15 is H or alkyl and R 16 and R 17 are each independently H or alkyl or R 16 and R 17 together with the nitrogen atom to which they are attached, form a heterocyclyl group.
  • Compounds of the Formula (1) include compounds of the Formula (A) and Formula (B): wherein: X is -(CH 2 ) n C(R 2 )(R 3 )(CH 2 ) n -, each n is independently 0, 1 or 2, R 2 and R 3 together with the carbon atom to which they are attached form a cycloalkyl group or R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alky
  • Examples of compounds of the Formula (A) and Formula (B) include: [0035] Examples of compounds of the Formula (A) and Formula (B) also include: [0036] Examples of compounds of the Formula (A) and Formula (B) also include: [0037] Examples of compounds of the Formula (A) and Formula (B) also include: wherein X 3 is O or NR 20 , wherein R 20 is H or alkyl; and R 19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy. [0038] Examples of compounds of the Formula (A) and Formula (B) also include: ,
  • Compounds of the Formula (1) include compounds of the Formula (C) and Formula (D): wherein: each m is independently 0, 1 or 2, R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)
  • Examples of compounds of the Formula (C) and Formula (D) also include: wherein X 3 is O or NR 20 , wherein R 20 is H or alkyl; and R 19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy. [0043] Examples of compounds of the Formula (C) and Formula (D) also include:
  • X 3 can be O in any of the foregoing examples of compounds of the Formula (C) and Formula (D).
  • Compounds of the Formula (1) also include compounds of the Formula (E)-(M): wherein: X is -(CH 2 ) n C(R 2 )(R 3 )(CH 2 ) n -, each n is independently 0, 1 or 2, R 2 and R 3 together with the carbon atom to which they are attached form a cycloalkyl group or R 2 and R 3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, tri
  • Y can be N.
  • the present disclosure also provides a compound of the Formula (2) and (3): ( ) ( ) wherein Z, X, L 1 , R 8 , d, R 13 and R 14 are defined herein; G 3 is selected from: , wherein q is 1 to 25 (e.g., 1 to 3, 1 to 5 or 1 to 10); X 1 is O or NH; and X 2 is alkyl, OR 21 or N(R 21 )2, wherein each R 21 is H, alkyl, aryl or OP(O)(OR 1 ) 2 , wherein each R 1 is a counterion (e.g., Na + ), hydrogen or alkyl, or combination thereof, or wherein the two R 21 groups, together with the nitrogen atoms to which they are attached, form a heterocyclyl group; N(R 22 )2, wherein the R 22 groups, along with the nitrogen
  • the compound can meet the requirements of more than one of Formula (1) and (A)-(M).
  • the compound can have the structure of Formula (1) and Formula (A) or the compound can have the structure of Formula (1) and Formula (M).
  • Compounds of the Formulae (1)-(3) and (A)-(M) exhibit sphingosine 1-phosphate receptor 2 (S1P 2 ) agonisitc activity.
  • compounds of the Formulae (1)-(3) and (A)-(M) exhibit S1P 2 agonistic activity at concentrations of from about 100 nM to about 100 mM (e.g., from about 100 nM to about 10 mM; about 100 nM to about 900 nM; about 250 nM to about 1 mM; or about 750 nM to about 100 mM).
  • the present invention also provides a pharmaceutical composition comprising a compound of any of the preceding formulae and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of one of Formulae (1)-(3) and (A)-(M), and a pharmaceutically acceptable carrier.
  • compositions contemplated herein are those comprising one or more compounds of the various embodiments of the present invention and one or more pharmaceutically acceptable excipients.
  • a “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal).
  • compositions can be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
  • administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.
  • a “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated.
  • the excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and/or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.
  • pharmaceutically acceptable carrier includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible.
  • the carrier is suitable for parenteral administration.
  • the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions can be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.
  • PLG polyglycolic copolymers
  • Many methods for the preparation of such formulations are known to those skilled in the art.
  • Oral forms of administration are also contemplated herein.
  • the pharmaceutical compositions of the present invention can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension).
  • the formulations can be conveniently prepared by any of the methods well-known in the art.
  • the pharmaceutical compositions of the present invention can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.
  • suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.
  • the compounds can be administered by a variety of dosage forms as known in the art. Any biologically- acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated.
  • dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.
  • Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrose-saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin
  • Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions.
  • the syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the amount of active compound in a therapeutic composition can vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.
  • a “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
  • the compounds of the present invention can be administered in an effective amount.
  • the dosages as suitable for this invention can be a composition, a pharmaceutical composition or any other compositions described herein.
  • the dosage is typically administered once, twice, or thrice a day, although more frequent dosing intervals are possible.
  • the dosage can be administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and/or every 7 days (once a week).
  • the dosage can be administered daily for up to and including 30 days, preferably between 7-10 days.
  • the dosage can be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage can be administered for as long as signs and/or symptoms persist.
  • the patient can require "maintenance treatment” where the patient is receiving dosages every day for months, years, or the remainder of their lives.
  • the composition of this invention can be to effect prophylaxis of recurring symptoms.
  • the dosage can be administered once or twice a day to prevent the onset of symptoms in patients at risk, especially for asymptomatic patients.
  • compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
  • routes of administration are buccal and oral.
  • the administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease.
  • Local administration can be administration to, for example, tissue, organ, and/or organ system, which encompasses and/or is affected by the disease, and/or where the disease signs and/or symptoms are active or are likely to occur.
  • Administration can be topical with a local effect, composition is applied directly where its action is desired.
  • Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract.
  • the present disclosure also provides a method for treating a fibrotic disease, abnormal vascular leak and pathological angiogenesis, and tumor-associated angiogenesis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the abnormal vascular leak and pathological angiogenesis is associated with the wet form of age-related macular degeneration.
  • the fibrotic disease is fibrosis of the lung, liver, kidney, retina, skin or heart.
  • the present disclosure also provides a method for treating multiple sclerosis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for treating highly vascular tumors comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the highly vascular tumors are renal carcinoma, glioblastoma, and neuroblastoma.
  • the tumors can be highly fibrotic such as in the case of pancreatic cancer.
  • the present disclosure also provides a method for chimeric antigen receptor T-cell (CAR-T) therapy, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject.
  • CAR-T therapy represents an emerging breakthrough in oncology with rapidly increasing uptake by clinicians due to its promise for patients.
  • CAR-T can be associated with significant toxicity, sequelae from treatment-related inflammation and leaky vessels, including cytokine release syndrome (CRS; 50%-100% of patients) and/or neurologic side effects (10%-50% of patients). These side effects often prove fatal, limiting the potential utility of CAR-T and many of the drugs currently used to manage the CRS side effects significantly reduce CAR-T efficacy.
  • Compounds described herein may have an advantage of abrogating this significant CAR-T risk without eliminating its effectiveness. Without being limited by theory, compounds described herein may provide such advantages by merit of protecting the blood-brain barrier from vascular leakage.
  • the present disclosure also provides a method for treating cytokine release syndrome, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject.
  • a method for treating pathological angiogenesis in a subject comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject.
  • the present disclosure also provides a method for treating atherosclerosis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • a method for treating diabetes comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for treating stroke (e.g., ischemic stroke and stroke related conditions, such as cerebral vasogenic edema) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • Antagonism of S1PR 2 may be a useful approach to ameliorate the brain damage associated with stroke and reperfusion by preserving neurovascular integrity, thereby reducing the entry of toxic plasma proteins and blood cells into the brain parenchyma and diminishing downstream inflammatory and mechanical injury.
  • the present disclosure also provides a method for preventing or treating sepsis-induced changes in blood-brain barrier permeability (e.g., decreasing BBB permeability during septic infenctions) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • a method for preventing or treating sepsis-induced changes in blood-brain barrier permeability e.g., decreasing BBB permeability during septic infenctions
  • administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for treating nonalcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • NASH nonalcoholic steatohepatitis
  • the present disclosure also provides a method for treating nonalcoholic fatty liver disease (NAFLD) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • NAFLD nonalcoholic fatty liver disease
  • the present disclosure also provides a method for treating hepatobiliary conditions, including cholangiocarcinoma, as well as glucose and lipid management, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • a method for treating hepatobiliary conditions including cholangiocarcinoma, as well as glucose and lipid management, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for at least one of regulating proliferation of cholangiocytes and promoting ductular reaction comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for ameliorating blood brain barrier dysfunction and brain damage associated with chronic traumatic encephalopathy; and at least one of traumatic brain injury, hypertensive encephalopathy, neurodegenerative diseases, vascular dementias, and multiple sclerosis, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • a method for ameliorating blood brain barrier dysfunction and brain damage associated with chronic traumatic encephalopathy comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • the present disclosure also provides a method for at least one of treating and preventing at least one of inflammatory response syndrome and sepsis; restoring endothelial function, preventing vascular leak, disseminated intravascular coagulation, systemic vascular failure, ischemia and acute multiple organ dysfunction, including acute respiratory distress syndrome, kidney, heart, liver and brain injury (delirium and coma) and death; treating or preventing vascular complications of diabetes, such as cardiovascular disease, coronary artery disease, stroke, retinopathy, nephropathy and neuropathy, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • a therapeutically effective amount of any of the preceding compounds e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof
  • causes of sepsis and systemic inflammatory response syndrome include, but are not limited to systemic trauma, burns, viral infections, surgery, cancer and cancer treatments, among others.
  • the present disclosure also provides a method of treating and preventing chronic complications of systemic inflammatory response syndrome and sepsis, including lung, kidney, heart and liver chronic dysfunction, and central nervous system pathologies such as depression, anxiety, cognitive decline and accelerated dementia, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • Middle-East respiratory syndrome coronavirus MERS- CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of 2,494 individuals and claiming 858 lives.
  • SARS-CoV-2 A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 SARSCoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 400,000 people and killed more than 10,000 of those affected in >60 countries as of March 26, 2020. [0085] On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern. MERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels. Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses.
  • HCoV-OC43 In addition to the highly pathogenic zoonotic pathogens SARS- CoV, MERS-CoV, and SARS-CoV-2, all belonging to the b-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoVHKU1, HCoV-NL63, and HCoV-229E.
  • the present disclosure also provides a method of treating and preventing conditions caused by one or more coronaviruses, including SARS-CoV-2 (COVID-19), characterized by at least one of acute lung injury, vascular leakage, endothelial inflammation (endotheliitis), disseminated intravascular coagulation and systemic vascular dysfunction leading to at least one of hypoxia, ischemia, multiple organ failure (kidney, heart, liver and brain injury), coma, and death, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • SARS-CoV-2 COVID-19
  • endothelial inflammation endotheliitis
  • disseminated intravascular coagulation and systemic vascular dysfunction leading to at least one of hypoxia, ischemia, multiple organ failure (kidney, heart, liver and brain injury
  • the present disclosure also provides a method of treating and preventing chronic complications of coronavirus-associated dieseases (e.g., COVID-19), including lung, kidney, heart and liver chronic dysfunction and central nervous system pathologies such as depression, anxiety, cognitive decline and accelerated dementia, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • coronavirus-associated dieseases e.g., COVID-19
  • COVID-19 coronavirus-associated dieseases
  • lung, kidney, heart and liver chronic dysfunction and central nervous system pathologies such as depression, anxiety, cognitive decline and accelerated dementia
  • the present disclosure also provides a method of treating and preventing conditions caused by one or more viruses characterized by at least one of vascular leakage and endothelial inflammation (endotheliitis), the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof.
  • viruses include, but are not limited to the Filoviridae family of viruses and the Flaviviridae family of viruses.
  • Two members of the Filoviridae family have been identified: EBOV and MARV.
  • Ebolavirus Two key pathogenic types of the Filoviridae family have been identified: Ebolavirus and MARV. There is one identified variant of MARV and five identified species of ebolavirus: Zaire (e.g., Ebola virus, EBOV), Sudan, Tai Forest, Bundibugyo, and Reston. The exact origin, locations, and natural habitat of Filoviridae are unknown. However, because of available evidence and the nature of similar viruses, it is postulated that Filoviridae are zoonotic (i.e., animal- borne) and are normally maintained in an animal host that is native to the African continent.
  • Zaire e.g., Ebola virus, EBOV
  • Sudan e.g., Tai Forest, Bundibugyo, and Reston.
  • Filoviridae are zoonotic (i.e., animal- borne) and are normally maintained in an animal host that is native to the African continent.
  • the Ebola virus genus includes five known species: (1) Bundibugyo ebolavirus, also known as Bundibugyo virus (BDBV, previously BEBOV); (2) Reston ebolavirus, also known as Reston virus or Ebola-Reston (RESTV, previously REBOV); (3) Sudan ebolavirus, also known as Sudan virus or Ebola-Sudan (SUDV, previously SEBOV); (4) Tai Forest ebolavirus, also known as Tai Forest virus or Ebola-Tai (TAFV, previously CIEBOV); and (5) Zaire ebolavirus, also known as Ebola virus or Ebola-Zaire (EBOV, previously ZEBOV).
  • Bundibugyo ebolavirus also known as Bundibugyo virus (BDBV, previously BEBOV
  • Reston ebolavirus also known as Reston virus or Ebola-Reston (RESTV, previously REBOV)
  • Sudan ebolavirus also known as Sudan virus or Ebola
  • the Marburg virus genus includes the species Marburg marburgvirus, also known as Marburg virus (MARV) or Ravn virus (RAVV).
  • the Cuevavirus genus includes the species Lloviu cuevavirus, also known as the Lloviu virus (LLOV).
  • Viruses included in the Flaviviridae family include at least three distinguishable genera including pestiviruses, flaviviruses, and hepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43).
  • BVDV bovine viral diarrhea virus
  • CSFV classical swine fever virus
  • BDV border disease of sheep
  • Flaviviridae family Other important viral infections caused by the Flaviviridae family include West Nile virus (WNV) Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis, St Louis enchaplitis, Omsk hemorrhagic fever virus and Zika virus. Combined, infections from the Flaviviridae virus family cause significant mortality, morbidity and economic losses throughout the world. Therefore, there is a need to develop effective treatments for Flaviviridae virus infections. [0093] The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al.
  • Various compounds disclosed herein have ⁇ -arrestin-determined IC50 values of less than 1 mM, less than 500 nM, less than 200 nM, less than 100 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM or less than 10 nM; for example, ⁇ -arrestin-determined IC 50 values IC 50 values of from about 1 nM to about 100 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 100 nM to about 1 mM, about 1 mM to about 5 mM or between about 5 mM and 10 mM.
  • therapeutically effective amount refers to that amount of one or more compounds of the various examples of the present invention that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the therapeutically effective amount is that which can treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions described herein can be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.
  • alkyl refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having from 1 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 1 to 10 carbons atoms, 1 to 8 carbon atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 1 to 3 carbon atoms.
  • Examples of straight chain mono-valent (C 1 -C 20 )-alkyl groups include those with from 1 to 8 carbon atoms such as methyl (i.e., CH 3 ), ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl groups.
  • Examples of branched mono-valent (C1-C20)-alkyl groups include isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, and isopentyl.
  • Examples of straight chain bi-valent (C1-C20)alkyl groups include those with from 1 to 6 carbon atoms such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • Examples of branched bi-valent alkyl groups include –CH(CH 3 )CH 2 - and –CH 2 CH(CH 3 )CH 2 -.
  • cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and bicyclo[2.2.1]heptyl.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.
  • alkyl includes a combination of substituted and unsubstituted alkyl.
  • alkyl, and also (C1)alkyl includes methyl and substituted methyl.
  • (C1)alkyl includes benzyl.
  • alkyl can include methyl and substituted (C 2 -C 8 )alkyl.
  • Alkyl can also include substituted methyl and unsubstituted (C 2 -C 8 )alkyl.
  • alkyl can be methyl and C 2 -C 8 linear alkyl.
  • alkyl can be methyl and C 2 -C 8 branched alkyl.
  • methyl is understood to be -CH 3 , which is not substituted.
  • methylene is understood to be -CH 2 -, which is not substituted.
  • (C1)alkyl is understood to be a substituted or an unsubstituted -CH 3 or a substituted or an unsubstituted -CH 2 -.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, cycloalkyl, heterocyclyl, aryl, amino, haloalkyl, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • representative substituted alkyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
  • representative substituted alkyl groups can be substituted from a set of groups including amino, hydroxy, cyano, carboxy, nitro, thio and alkoxy, but not including halogen groups.
  • alkyl can be substituted with a non-halogen group.
  • representative substituted alkyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro.
  • representative substituted alkyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups.
  • alkyl can be trifluoromethyl, difluoromethyl, or fluoromethyl, or alkyl can be substituted alkyl other than trifluoromethyl, difluoromethyl or fluoromethyl.
  • Alkyl can be haloalkyl or alkyl can be substituted alkyl other than haloalkyl.
  • alkyl also generally refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain.
  • alkyl also encompasses groups such as –[(CH 2 ) p O] q H and the like.
  • alkenyl refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having at least one carbon-carbon double bond and from 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.
  • the double bonds can be be trans or cis orientation.
  • the double bonds can be terminal or internal.
  • the alkenyl group can be attached via the portion of the alkenyl group containing the double bond, e.g., vinyl, propen-1-yl and buten-1-yl, or the alkenyl group can be attached via a portion of the alkenyl group that does not contain the double bond, e.g., penten-4-yl.
  • Examples of mono-valent (C 2 -C 20 )-alkenyl groups include those with from 1 to 8 carbon atoms such as vinyl, propenyl, propen-1-yl, propen-2-yl, butenyl, buten-1-yl, buten-2-yl, sec-buten-1-yl, sec-buten-3-yl, pentenyl, hexenyl, heptenyl and octenyl groups.
  • Examples of branched mono- valent (C2-C20)-alkenyl groups include isopropenyl, iso-butenyl, sec-butenyl, t- butenyl, neopentenyl, and isopentenyl.
  • Examples of straight chain bi-valent (C2- C 20 )alkenyl groups include those with from 2 to 6 carbon atoms such as -CHCH- , -CHCHCH 2 -, -CHCHCH 2 CH 2 -, and -CHCHCH 2 CH 2 CH 2 -.
  • Examples of branched bi-valent alkyl groups include –C(CH 3 )CH- and –CHC(CH 3 )CH 2 -.
  • Examples of cyclic alkenyl groups include cyclopentenyl, cyclohexenyl and cyclooctenyl. It is envisaged that alkenyl can also include masked alkenyl groups, precursors of alkenyl groups or other related groups.
  • substituted alkenyl also includes alkenyl groups which are substantially tautomeric with a non-alkenyl group.
  • substituted alkenyl can be 2-aminoalkenyl, 2-alkylaminoalkenyl, 2-hydroxyalkenyl, 2- hydroxyvinyl, 2-hydroxypropenyl, but substituted alkenyl is also understood to include the group of substituted alkenyl groups other than alkenyl which are tautomeric with non-alkenyl containing groups.
  • alkenyl can be understood to include a combination of substituted and unsubstituted alkenyl.
  • alkenyl can be vinyl and substituted vinyl.
  • alkenyl can be vinyl and substituted (C 3 -C 8 )alkenyl.
  • Alkenyl can also include substituted vinyl and unsubstituted (C 3 -C 8 )alkenyl.
  • Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio, alkoxy, and halogen groups.
  • representative substituted alkenyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
  • representative substituted alkenyl groups can be substituted from a set of groups including monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio and alkoxy, but not including halogen groups.
  • alkenyl can be substituted with a non-halogen group.
  • representative substituted alkenyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro.
  • alkenyl can be 1-fluorovinyl, 2-fluorovinyl, 1,2-difluorovinyl, 1,2,2-trifluorovinyl, 2,2- difluorovinyl, trifluoropropen-2-yl, 3,3,3-trifluoropropenyl, 1-fluoropropenyl, 1- chlorovinyl, 2-chlorovinyl, 1,2-dichlorovinyl, 1,2,2-trichlorovinyl or 2,2- dichlorovinyl.
  • representative substituted alkenyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups.
  • alkynyl refers to substituted or unsubstituted straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to 50 carbon atoms, 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.
  • Examples include, but are not limited to ethynyl, propynyl, propyn- 1-yl, propyn-2-yl, butynyl, butyn-1-yl, butyn-2-yl, butyn-3-yl, butyn-4-yl, pentynyl, pentyn-1-yl, hexynyl, Examples include, but are not limited to –CoCH, -CoC(CH 3 ), -CoC(CH 2 CH 3 ), -CH 2 CoCH, -CH 2 CoC(CH 3 ), and -CH 2 CoC(CH 2 CH 3 ) among others.
  • aryl refers to substituted or unsubstituted univalent groups that are derived by removing a hydrogen atom from an arene, which is a cyclic aromatic hydrocarbon, having from 6 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 20 carbon atoms, 6 to about 10 carbon atoms or 6 to 8 carbon atoms.
  • Examples of (C 6 -C 20 )aryl groups include phenyl, napthalenyl, azulenyl, biphenylyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, anthracenyl groups.
  • Examples include substituted phenyl, substituted napthalenyl, substituted azulenyl, substituted biphenylyl, substituted indacenyl, substituted fluorenyl, substituted phenanthrenyl, substituted triphenylenyl, substituted pyrenyl, substituted naphthacenyl, substituted chrysenyl, and substituted anthracenyl groups.
  • Examples also include unsubstituted phenyl, unsubstituted napthalenyl, unsubstituted azulenyl, unsubstituted biphenylyl, unsubstituted indacenyl, unsubstituted fluorenyl, unsubstituted phenanthrenyl, unsubstituted triphenylenyl, unsubstituted pyrenyl, unsubstituted naphthacenyl, unsubstituted chrysenyl, and unsubstituted anthracenyl groups.
  • Aryl includes phenyl groups and also non- phenyl aryl groups.
  • (C 6 -C 20 )aryl encompasses mono- and polycyclic (C 6 -C 20 )aryl groups, including fused and non- fused polycyclic (C 6 -C 20 )aryl groups.
  • heterocyclyl refers to substituted aromatic, unsubstituted aromatic, substituted non-aromatic, and unsubstituted non-aromatic rings containing 3 or more atoms in the ring, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (C 3 -C 8 ), 3 to 6 carbon atoms (C 3 -C 6 ) or 6 to 8 carbon atoms (C 6 -C 8 ).
  • a heterocyclyl group designated as a C2-heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • heterocyclyl group includes fused ring species including those that include fused aromatic and non-aromatic groups.
  • Representative heterocyclyl groups include, but are not limited to piperidynyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups.
  • heterocyclyl groups include, without limitation: wherein X 1 represents H, (C 1 - C 20 )alkyl, (C 6 -C 20 )aryl or an amine protecting group (e.g., a t-butyloxycarbonyl group) and wherein the heterocyclyl group can be substituted or unsubstituted.
  • a nitrogen-containing heterocyclyl group is a heterocyclyl group containing a nitrogen atom as an atom in the ring.
  • the heterocyclyl is other than thiophene or substituted thiophene.
  • the heterocyclyl is other than furan or substituted furan.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy examples include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • alkyoxy also includes an oxygen atom connected to an alkyenyl group and oxygen atom connected to an alkynyl group.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
  • aryloxy refers to an oxygen atom connected to an aryl group as are defined herein.
  • aralkyl and “arylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • aralkyl groups include benzyl, biphenylmethyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • halo halogen
  • halide as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • amine and “amino” as used herein refers to a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each, except for -NR 3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
  • An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, group or the like.
  • formyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to a hydrogen atom.
  • alkoxycarbonyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyl group.
  • Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyenyl group.
  • Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkynyl group.
  • alkoxycarbonyl as the term is defined herein, and is also included in the term “aryloxycarbonyl,” the carbonyl carbon atom is bonded to an oxygen atom which is bonded to an aryl group instead of an alkyl group.
  • arylcarbonyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to an aryl group.
  • alkylamido as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to a nitrogen group which is bonded to one or more alkyl groups.
  • the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more aryl group instead of, or in addition to, the one or more alkyl group.
  • the carbonyl carbon atom is bonded to an nitrogen atom which is bonded to one or more alkenyl group instead of, or in addition to, the one or more alkyl and or/aryl group.
  • the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more alkynyl group instead of, or in addition to, the one or more alkyl, alkenyl and/or aryl group.
  • the term “carboxy” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to a hydroxy group or oxygen anion so as to result in a carboxylic acid or carboxylate.
  • Carboxy also includes both the protonated form of the carboxylic acid and the salt form.
  • carboxy can be understood as COOH or CO 2 H.
  • amido refers to a group having the formula C(O)NRR, wherein R is defined herein and can each independently be, e.g., hydrogen, alkyl, aryl or each R, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
  • alkylthio refers to a sulfur atom connected to an alkyl, alkenyl,or alkynyl group as defined herein.
  • arylthio refers to a sulfur atom connected to an aryl group as defined herein.
  • alkylsulfonyl refers to a sulfonyl group connected to an alkyl, alkenyl,or alkynyl group as defined herein.
  • alkylsulfinyl refers to a sulfinyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.
  • dialkylaminosulfonyl refers to a sulfonyl group connected to a nitrogen further connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen.
  • dialkylamino refers to an amino group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen.
  • dialkylamido refers to an amido group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen.
  • substituted refers to a group that is substituted with one or more groups including, but not limited to, the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CH 2 OH), OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , methylenedioxy, ethylenedioxy, (C 3 - C 20 )heteroaryl, N(R) 2 , Si(R) 3 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, P(O)(OR)2, OP(O)(OR) 2 , C(O)R, C(O)C(O)R, C(O)CH 2 C(
  • Substituted also includes a group that is substituted with one or more groups including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
  • groups including, but not limited to, the following groups: fluoro, chloro, bromo,
  • the substituents can be linked to form a carbocyclic or heterocyclic ring.
  • Such adjacent groups can have a vicinal or germinal relationship, or they can be adjacent on a ring in, e.g., an ortho-arrangement.
  • Each instance of substituted is understood to be independent.
  • a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl.
  • a substituted group can be substituted with one or more non-fluoro groups.
  • a substituted group can be substituted with one or more non-cyano groups.
  • a substituted group can be substituted with one or more groups other than haloalkyl.
  • a substituted group can be substituted with one or more groups other than tert-butyl.
  • a substituted group can be substituted with one or more groups other than trifluoromethyl.
  • a substituted group can be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than thiophenyl, or other than nitrophenyl, or groups meeting a combination of such descriptions.
  • substituted is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups.
  • the compounds described herein e.g., the compounds of the Formulae (1)-(3) and (A)-(M) can contain chiral centers.
  • salts and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic
  • salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.
  • solvate means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention.
  • prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
  • Prodrugs can typically be prepared using well-known methods, such as those
  • the term “subject” or “patient” refers to any organism to which a composition described herein can be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes.
  • Subject refers to a mammal receiving the compositions disclosed herein or subject to disclosed methods. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs.
  • a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.
  • the term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.
  • Each embodiment described above is envisaged to be applicable in each combination with other embodiments described herein.
  • embodiments corresponding to Formula (I) are equally envisaged as being applicable to Formulae (A)-(M).
  • b-Arrestin assay was performed using this stable cell line to determine the IC50 value of the compounds with minor modifications in manufacturer’s instruction. Briefly, 1 x 104 cells/well reconstituted in a final volume of 100 ⁇ l of cell plating reagent were plated into a 96 well white clear bottom plate (Corning TM Costar TM , USA) and incubated 16 h at 37 °C in a humidified 95 % air and 5 % CO2 incubator. Compounds were diluted in 0.4 % fatty acid free BSA (Sigma Aldrich, USA) prepared in 1XPBS, pH7.4 (GIBCO). Plated cells were first pretreated with the compounds for 30 min.
  • pretreated cells were exposed to 5 ⁇ l of agonist treatment i.e, Sphingosine1- phosphate(S1P) (Enzo Lifescience, USA) at EC 80 concentration and incubated for 90 min under normal incubation conditions. Then, 55 ⁇ L of substrate solution was added to each well of the assay plate and incubated further for 60 min in dark at room temperature. Thereafter, the intensity of luminescence was measured using a luminometer (Promega,USA). The IC 50 value for each of the compounds with antagonist activity was calculated using the appropriate statistical parameters in Prism/Graphpad7.
  • Sphingosine1- phosphate(S1P) Enzo Lifescience, USA
  • E-Selectin assay and Dextran leakage assay 1 E-Selectin assay Cell culture and treatment [00136]
  • the mouse brain endothelial cell line, bEnd.3 was obtained from ATCC and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10 % fetal bovine serum (ATCC), 1x GlutaMax (GIBCO, USA), and 100 U/ml penicillin/streptomycin (GIBCO, USA) at 37 °C in a humidified 95 % air and 5 % CO 2 incubator.
  • DMEM Dulbecco's Modified Eagle Medium
  • ATCC % fetal bovine serum
  • GlutaMax GlutaMax
  • penicillin/streptomycin GIBCO, USA
  • RNA isolation [00137] First, cells were gently rinsed with ice-cold PBS on ice twice after the treatment to remove media and debris. Then 100 ⁇ l of lysis buffer reagent (Qiagen, Germany) was added to each well and incubated for 3 min at room temperature. Thereafter, RNA was extracted from the total cell lysate with RNeasy Kit (QIAGEN, Germany) constituting on-column DNAseI digestion according to the manufacturer’s instruction.
  • RNeasy Kit QIAGEN, Germany
  • RNA preps were processed for cDNA synthesis.
  • Reverse transcription of RNA and quantitative real-time (qRT) PCR 100 ng of total RNA was used as template to prepare cDNA for each sample in the presence of Verso-Reverse Transcriptase and Random Hexamer Primers (Thermo Scientific, USA) at 42 °C for 30 min in a final reaction volume of 20 ⁇ l.
  • the cDNA prep was diluted 5-fold with nuclease free water to obtain a final volume of 100 ⁇ l.
  • TMR Tetramethylrhodamine Isothiocyanate
  • trichloropyridine 8 was subject to S N Ar reaction to give di-chlorobenzene 9 and 11.
  • Di-chloropyridine 9 and 11 were subject to S N Ar reaction to give mono-chloropyridine 10 and 12.
  • Mono- chloropyridine 10 and 12 was subject to coupling reaction with BocNH 2 followed by deprotection to give A-4 and A-5.
  • Example 2 N-(3-(4-(1-(Ethylamino)-2-methyl-1-oxopropan-2-yl)phenoxy)-5-(4- fluorophenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1-carboxamide
  • DIPEA 95.2 uL
  • 2-(4-(3-(4- fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid 100 mg
  • 2 M EtNH 2 (454 uL) and COMU 91.9 mg
  • DMF 4.0 mL
  • Example 3 Ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine- 1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00151]
  • the target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and ethanol.
  • Example 4 Isopropyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00153] To a mixture of 2-methyl-6-nitrobenzoic anhydride (125 mg), DMAP (11.1 mg), and DMF (3.0 mL) was added Et3N (25.2 uL).
  • Example 5 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid [00155]
  • the target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and (2R)-2-amino-2- phenyl-ethanol.
  • Example 6 2-Hydroxyethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00157]
  • the target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and ethylene glycol.
  • Example 7 Methyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine- 1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00159]
  • the target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and methanol.
  • Example 8 N-(3-(4-Fluorophenoxy)-5-(4-(1-(4-hydroxypiperidin-1-yl)-2-methyl- 1-oxopropan-2-yl)phenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1- carboxamide [00161]
  • the target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and piperidin-4-ol.
  • Example 9 Isopentyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00163]
  • the target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and 3-methyl-1-butanol.
  • Example 10 2-(Phosphonooxy)ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate sodium salt
  • Example 11 N-(3-(4-Fluorophenoxy)-5-(4-(1-(4-hydroxypiperidin-1-yl)-2- methyl-1-oxopropan-2-yl)phenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1- carboxamide
  • the target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and 2-aminoethan-1-ol.
  • Example 12 2-(4-(3-(4-Fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid sodium salt [00171] A mixture of 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoic acid (225 mg), NaOH (16.4 mg), and EtOH (2.0 mL) was stirred at 25°C for 0.25 h . The mixture was concentrated, and the residue was collected to give the target compound (220 mg) as a solid.
  • Example 13 Methyl 4-((6-(4-fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)pyridin-2-yl)oxy)benzoate
  • a solution of methyl 4-hydroxybenzoate (307 mg), tert-butyl 2,6- dichloropyridine-4-carboxylate (500 mg), and Cs2CO3 (658 mg) in DMF was stirred at rt for 24 h. The mixture was quenched with brine and extracted with EtOAc.
  • Example 14 4-((6-(4-Fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid [00179]
  • the target compound was obtained in a similar manner to step I in Example 63 using methyl 4-((6-(4-fluorophenoxy)-4-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)pyridin-2-yl)oxy)benzoate.
  • Example 15 4-((6-Butoxy-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid A) Methyl 4-((6-butoxy-4-((tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)benzoate [00181] The target compound was obtained in a similar manner to step B in Example 13 using methyl 4-((4-((tert-butoxycarbonyl)amino)-6-chloropyridin-2- yl)oxy)benzoate and butan-1-ol.
  • Example 16 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid
  • a mixture of methyl 4-hydroxybenzoate (3.3 g), 1,3-dinitro-5- (trifluoromethyl)benzene (5.1 g), K2CO3 (3.3 g), and DMF (30 mL) was stirred at 80°C for 4 h. The mixture was quenched with brine and extracted with EtOAc.
  • Example 17 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid [00187]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and piperidin-4-ol.
  • Example 18 N-(3-(4-Fluorophenoxy)-5-(4-(4-hydroxypiperidine-1- carbonyl)phenoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00189]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid and piperidin-4-ol.
  • Example 19 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid
  • the target compound was obtained in a similar manner to step G to I of Example 63 using methyl 4-(3-amino-5-(4-fluorophenoxy)phenoxy)benzoate.
  • Example 20 4-Hydroxy-N-(3-(4-((2-(2- hydroxyethoxy)ethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide [00191]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-aminoethoxy)ethanol.
  • Example 21 4-Hydroxy-N-(3-(4-((2-(2-(2- hydroxyethoxy)ethoxy)ethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide [00193]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-(2-aminoethoxy)ethoxy)ethanol.
  • Example 22 4-Hydroxy-N-(3-(4-((2-hydroxyethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-isobutylpiperidine-1-carboxamide [00195]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-aminoethanol.
  • Example 23 N-(3-(4-(Bis(2-hydroxyethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00197]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-hydroxyethylamino)ethanol.
  • Example 24 N-(3-(4-((2-(Dimethylamino)ethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00199]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and N',N'-dimethylethane-1,2-diamine.
  • Example 25 4-Hydroxy-4-isobutyl-N-(3-(4-((2- methoxyethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1- carboxamide [00201]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-methoxyethanamine.
  • Example 26 4-Hydroxy-4-isobutyl-N-(3-(4-((2- morpholinoethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1- carboxamide
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-morpholinoethanamine ⁇ MS: (M+H + ): 593.3.
  • Example 27 4-Hydroxy-N-(3-(4-((2-hydroxy-2- methylpropyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 1-amino-2-methyl-propan-2-ol.
  • Example 28 4-Hydroxy-4-isobutyl-N-(3-(4-(3-(methylsulfonyl)pyrrolidine-1- carbonyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1-carboxamide [00206]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 3-methylsulfonylpyrrolidine.
  • Example 29 4-Hydroxy-4-isobutyl-N-(3-(4-(methylcarbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)piperidine-1-carboxamide
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and methanamine.
  • Example 30 4-Hydroxy-N-(3-(4-(3-hydroxypyrrolidine-1-carbonyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-isobutylpiperidine-1-carboxamide [00209]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and pyrrolidin-3-ol.
  • Example 31 N-(3-(4-Fluorophenoxy)-5-(4-((2- hydroxyethyl)carbamoyl)phenoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid and 2-aminoethanol.
  • Example 32 N-(3-(4-((2-(1,1-Dioxidothiomorpholino)ethyl)carbamoyl)phenoxy)- 5-(trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00213]
  • the target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(1,1-dioxo-1,4-thiazinan-4- yl)ethanamine.
  • Example 33 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid potassium salt [00214] To a mixture of 4-(3-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-5-(trifluoromethyl)phenoxy)benzoic acid (400 mg) and iPrOH (7.0 mL) was added 6 M KOH (43.0 mg). After stirring at rt for 5 min, the solvent was concentrated to give the target compound (320 mg) as a solid.
  • Example 34 (1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid A) Methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-nitrophenoxy)cyclobutane-1- carboxylate [00216] To a solution of 3-(4-fluorophenoxy)-5-nitrophenol (32.8 g), methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate (20.6 g) and PPh 3 (69.1 g) in THF (160 mL) was added DEAD (45.9 g) at 0°C dropwise, and the reaction mixture was stirred at 40°C for 16 h.
  • Example 35 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylic acid
  • Example 36 N-(3-(4-Fluorophenoxy)-5-(1-((2- hydroxyethyl)carbamoyl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00235] To a mixture of 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylic acid (100 mg), 2-aminoethan-1-ol (14.6 mg) in DCM (5.0 mL) was added diisopropylethylamine (51.6 mg) and HATU (114 mg), and the mixture was stirred at 20°C for 1 h.
  • Example 37 N-(3-(4-Fluorophenoxy)-5-(1-(4-hydroxypiperidine-1- carbonyl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00237] To a mixture of 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylic acid (100 mg), piperidin-4-ol (24.2 mg) and DCM (5 mL) was added diisopropylethylamine (51.6 mg) and HATU (114 mg), and the mixture was stirred at 20°C for 1 h.
  • Example 38 N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-((2- hydroxyethyl)carbamoyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00239] To a mixture of (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid (100 mg), HATU (114 mg) and DMF (2.0 mL) was added DIPEA (65 mg), and the mixture was stirred at 20°C for 10 minutes.
  • Example 39 N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00241] To a mixture of (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid (16.3 g), HATU (18.6 g) and DMF (75 mL) was added DIPEA (10.5 g) at 0°C, and the mixture was stirred at 20°C for 30 minutes.
  • Example 40 N-(3-(4-Fluorophenoxy)-5-(1-(5-(hydroxymethyl)-4-methyloxazol- 2-yl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide
  • ethyl 2-chloro-3-oxobutanoate 181 mg
  • 1-(3-(4- fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylic acid (0.50 g) and DMF (5.0 mL) was added potassium carbonate (276 mg), and the mixture was stirred
  • Example 41 N-(3-(4-Fluorophenoxy)-5-(3-(5-(hydroxymethyl)-4-methyloxazol- 2-yl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00248]
  • the target compound was obtained in a similar manner to Example 40 using 3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 2-chloro-3- oxobutanoate.
  • Example 42 (1r,3r)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid
  • the target compound was obtained in a similar manner to Example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl 3- hydroxycyclobutane-1-carboxylate [00251]
  • Example 43 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylazepane-1- carboxamido)phenoxy)benzoic acid [00252]
  • the target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 4-isobutyl-1 ⁇ 2 -azepan-4- ol.
  • Example 44 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-isobutyl-2- azaspiro[3.3]heptane-2-carboxamido)phenoxy)benzoic acid [00254]
  • the target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 6-isobutyl-2L 2 - azaspiro[3.3]heptan-6-ol.
  • Example 45 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-isobutyl-3- azabicyclo[3.1.1]heptane-3-carboxamido)phenoxy)benzoic acid [00256]
  • the target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 6-isobutyl-3L 2 - azabicyclo[3.1.1]heptan-6-ol.
  • Example 46 4-(3-(4-Fluoro-4-isobutylpiperidine-1-carboxamido)-5-(4- fluorophenoxy)phenoxy)benzoic acid A) Methyl 4-(3-(4-fluorophenoxy)-5-nitro-phenoxy)benzoate [00258] To a solution of 1-fluoro-3-(4-fluorophenoxy)-5-nitro-benzene (7.0 g), methyl 4-hydroxybenzoate (4.2 g) in DMA (40 mL) was added Cs 2 CO 3 (27.24 g). The mixture was stirred at 100 o C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc.
  • Example 47 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-(2-methylallyl)-2- azaspiro[3.3]heptane-2-carboxamido)phenoxy)benzoic acid [00265]
  • the target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate (500 mg) and 6-(2-methylallyl)- 2L 2 -azaspiro[3.3]heptan-6-ol.
  • Example 48 4-(Cyclopropylmethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to step H to I in example 63 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4- (cyclopropylmethyl)-1L 2 -piperidin-4-ol.
  • Example 49 4-Hydroxy-N-(3-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-5-(pentafluoro-L 6 -sulfaneyl)phenyl)-4-isobutylpiperidine- 1-carboxamide A) (3-Bromo-5-nitrophenyl)pentafluoro-L 6 -sulfane [00270] To a solution of pentafluoro-(3-nitrophenyl)-sulfane (7.8 g) in TFA (15 mL) and H2SO4 (80 mL) was added NBS (8.3 g). The mixture was stirred at 25°C for 7 h.
  • Example 50 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl methyl hydrogen phosphate [00279] To a suspension of 1-((1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- hydroxy-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carbonyl)piperidin-4-yl dimethyl phosphate (0.3 g) in DCM (6.0 mL) was added TMSBr (169 uL), and the mixture was stirred at 25 o C for 6 h.
  • Example 51 4-(2-Fluoro-2-methylpropyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3- (4-hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide [00281]
  • the target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(2- fluoro-2-methylpropyl)piperidin-4-ol.
  • Example 52 4-(Cyclopropylmethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxy-4-methylpiperidine-1-carbonyl)cyclobutoxy)phenyl)-4- hydroxypiperidine-1-carboxamide
  • the target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1- carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylic acid and 4- methylpiperidin-4-ol.
  • Example 53 N-(3-(4-Fluorophenoxy)-5-((1r,3r)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) (1r,3r)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid [00285] The target compound was obtained in a similar manner to Example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl (1s,3s)-3- hydroxycyclobutane-1-carboxylate.
  • Example 54 N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxy-4- methylpiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine- 1-carboxamide
  • the target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 4-methylpiperidin-4-ol.
  • Example 55 4-(4-Bromophenyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(4- bromophenyl)piperidin-4-ol.
  • Example 56 4-(4-Chlorophenyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(4- chlorophenyl)piperidin-4-ol.
  • Example 57 4-(3-(3-Fluoro-3-isobutylpyrrolidine-1-carboxamido)-5-(4- fluorophenoxy)phenoxy)benzoic acid [00294]
  • the target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 3-fluoro-3- isobutylpyrrolidine.
  • Example 58 4-((4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid
  • the target compound was obtained in a similar manner to step D in Example 59 using methyl 4-((6-((tert-butoxycarbonyl)amino)-4-(4- fluorophenoxy)pyridin-2-yl)oxy)benzoate.
  • Example 59 4-((2-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-4-yl)oxy)benzoic acid
  • K 2 CO 3 22.7 g
  • Example 60 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl dihydrogen phosphate
  • A) 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4-yl dimethyl phosphate
  • the target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid and dimethyl (1L 2 -piperidin-4-yl) phosphate.
  • Example 61 N-(6-(4-Fluorophenoxy)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)pyridin-2-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide
  • DEAD 4.3 g
  • the reaction mixture was stirred at 40°C for 12 h.
  • Example 62 4-((1-(4-Fluorophenyl)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-6-yl)oxy)benzoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 4-bromo-6-methoxy-1H-indazole and (4- fluorophenyl)boronic acid.
  • Example 63 4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid
  • a mixture of 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (4.0 g), 4- fluorophenol (2.3 g), K 2 CO 3 (2.8 g) and DMF (60 mL) was stirred at 120°C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc.
  • Example 64 4-((1-(4-Fluorophenyl)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-4-yl)oxy)benzoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-methoxy-1H-indazole and (4- fluorophenyl)boronic acid.
  • Example 65 4-(6-(4-Fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid
  • a mixture of 4-fluorophenol (6.7 g), 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (10 g), K 2 CO 3 (6.5 g), and DMA (70 mL) was stirred at 120°C for 24 h. The reaction mixture was diluted with water and extracted with EtOAc.
  • Example 66 N-(1-(4-Fluorophenyl)-6-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-4-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide
  • Example 67 N-(1-(4-Fluorophenyl)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to step A in Example 66 using 6-bromo-1-(4-fluorophenyl)-1H-indazol-4-ol and methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate.
  • Example 68 ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1s,4S)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone
  • 1 M LiHMDS 32.8 mL
  • Methyl (1s,3s)-3-(2,3-diamino-5-(4-fluorophenoxy)phenoxy)cyclobutane-1- carboxylate [00377] Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2- nitrophenoxy)cyclobutane-1-carboxylate (1.0 g) in MeOH (20 mL) and EtOAc (10 mL) was added into 10% Pd/C (1.0 g) in EtOAc (20 mL) at 20°C. Then the mixture was stirred at 20°C for 24 h under H 2 atmosphere (15 psi).
  • the reaction mixture was diluted with EtOAc, filtered through Celite, and concentrated under the reduced pressure.
  • the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated under the reduced pressure.
  • the mixture was stirred at 25°C for 12 h.
  • the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated under the reduced pressure.
  • the residue was purified by neutral HPLC to give the target compound (54.3 mg) as a solid.
  • Example 69 ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1r,4R)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone
  • the target compound was obtained in a similar manner to step G in Example 68 using methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2-(4- hydroxy-4-isobutylcyclohexane-1-carbox
  • Example 70 4-((6-(4-Fluorophenoxy)-2-((1r,4r)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)benzoic acid [00388]
  • the target compound was obtained in a similar manner to step F to H in Example 68 using ethyl 4-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)benzoate and 4-hydroxy-4-isobutyl- cyclohexanecarboxylic acid.
  • Example 71 4-((6-(4-Fluorophenoxy)-2-((1s,4s)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)benzoic acid [00390]
  • the target compound was obtained in a similar manner to step F to H in Example 68 using ethyl 4-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)benzoate and 4-hydroxy-4-isobutyl- cyclohexanecarboxylic acid.
  • Example 72 ((1s,3s)-3-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin- 1-yl)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutyl)(4-hydroxypiperidin-1- yl)methanone
  • THF 4.0 mL
  • Example 73 4-Hydroxy-4-isobutyl-N-(1-(4-(methylcarbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)piperidine-1-carboxamide [00399] To a mixture of 4-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-1H-indazol-1-yl)benzoic acid (100 mg) in DMF (1.0 mL) was added HOBt (40.2 mg), EDCI (57.0 mg), DIPEA (207 uL), and methanamine hydrochloride (20.1 mg).
  • Example 74 N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H-indazol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00401]
  • the target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and ethanamine hydrochloride.
  • Example 75 4-Hydroxy-N-(1-(4-((2-hydroxyethyl)carbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-isobutylpiperidine-1-carboxamide [00403]
  • the target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 2-aminoethanol.
  • Example 76 4-Hydroxy-4-isobutyl-N-(1-(4-((2-methoxyethyl)carbamoyl)phenyl)- 4-(trifluoromethyl)-1H-indazol-6-yl)piperidine-1-carboxamide [00405]
  • the target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 2-methoxyethanamine.
  • Example 77 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid
  • a mixture of 6-nitro-4-(trifluoromethyl)-1H-indazole (2.0 g) in dioxane (20 mL) was added ethyl 4-iodobenzoate (2.9 mL), CuI (824 mg), K3PO4 (3.7 g) and (1S,2S)-cyclohexane-1,2-diamine (988 mL).
  • Ethyl 4-(6-(((2,2,2-trichloroethoxy)carbonyl)amino)-4-(trifluoromethyl)-1H- indazol-1-yl)benzoate [00411] To a mixture of ethyl 4-(6-amino-4-(trifluoromethyl)-1H-indazol-1- yl)benzoate (500 mg) in EtOAc (5 mL) was added 2,2,2-trichloroethyl carbonochloridate (230 uL) and NaHCO 3 (240 mg). Then the mixture was stirred at 25°C for 12 h.
  • Example 78 4-Cyano-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-isobutylpiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to Example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4- isobutylpiperidine-4-carbonitrile.
  • Example 79 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-3-methylphenyl)boronic acid.
  • Example 80 N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-(hydroxymethyl)-4-isobutylpiperidine-1- carboxamide
  • Example 81 N-(1-(4-(((1H-Tetrazol-5-yl)methyl)carbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00428]
  • the target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 1H-tetrazol-5-ylmethanamine.
  • Example 82 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzamido)propanoic acid
  • the target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 3-aminopropanoate.
  • Example 83 4-(Cyanomethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-isobutylpiperidine-1- carboxamide
  • the target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 2-(4- isobutyl-1 ⁇ 2 -piperidin-4-yl)acetonitrile.
  • Example 84 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate
  • DCM 1,2,5,8,11,14,17,20-heptaoxadocosan-22-oyl
  • Example 85 N-(3-((1s,3s)-3-(4-((2,5,8,11,14,17,20-Heptaoxadocosan-22- yl)oxy)piperidine-1-carbonyl)cyclobutoxy)-5-(4-fluorophenoxy)phenyl)-4- hydroxy-4-isobutylpiperidine-1-carboxamide
  • Example 86 (1s,4s)-4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclohexane-1-carboxylic acid [00444]
  • the target compound was obtained in a similar manner to example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl (1r,4r)-4- hydroxycyclohexane-1-carboxylate.
  • Example 87 2-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid [00446]
  • the target compound was obtained in a similar manner to step D to I in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (2- (methoxycarbonyl)phenyl)boronic acid.
  • Example 88 3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid [00448]
  • the target compound was obtained in a similar manner to step D to I in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid.
  • Example 89 4-Hydroxy-N-(3-(4-(hydroxy( ⁇ 1 -oxidaneyl)methyl)phenoxy)-5- (trifluoromethoxy)phenyl)-4-isobutylpiperidine-1-carboxamide A) ((4-(3-Bromo-5-(trifluoromethoxy)phenoxy)phenyl)(methoxy)methyl)- ⁇ 1 - oxidane [00450] A mixture of methyl 4-hydroxybenzoate (300 mg), 2,2,6,6- tetramethylheptane-3,5-dione (101 uL), 1,3-dibromo-5- (trifluoromethoxy)benzene (946 mg), Cs 2 CO 3 (771 mg), CuCl (23.6 uL), and NMP (6.0 mL) was stirred at 120°C for 20 h.
  • Example 90 N-(1-(2,4-Dioxothiazolidin-5-yl)-4-(trifluoromethyl)-1H-indazol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(2-methoxy-2- oxoethyl)phenyl)boronic acid.
  • Example 91 4-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)-1H- benzo[d]imidazol-7-yl)oxy)benzoic acid
  • Ethyl 4-(3-amino-5-fluoro-2-nitrophenoxy)benzoate [00462] To a solution of 3,5-difluoro-2-nitro-aniline (2.0 g) in THF (30 mL) was added 60% NaH (689 mg) at 0°C. After stirred for 30 min, ethyl 4- hydroxybenzoate (2.3 g) was added to the mixture. The mixture was stirred at 25°C for 15.5 h.
  • Example 92 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (4-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 93 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)benzyl)azetidine-3-carboxylic acid A) Methyl 3-(4-fluorophenoxy)-5-nitrobenzoate [00474] To a mixture of methyl 3,5-dinitrobenzoate (5.0 g) in DMF (50 mL) was added K2CO3 (5.7 g) and 4-fluorophenol (2.5 g), and the mixture was stirred at 80°C for 20 h.
  • Example 94 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylcyclohexane-1- carboxamido)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 95 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 96 4-(3-(Difluoromethoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid
  • K2CO3 (16.3 g). The mixture was stirred at 120°C for 24 h.
  • Example 97 4-Hydroxy-4-isobutyl-N-(2-(4-(methylcarbamoyl)phenyl)-4- (trifluoromethyl)-2H-indazol-6-yl)piperidine-1-carboxamide
  • the target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4- (methoxycarbonyl)phenyl)boronic acid.
  • Example 98 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid
  • Example 99 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-2H- indazol-2-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 100 2-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid [00510]
  • the target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2- iodobenzoate.
  • Example 101 2-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)benzoic acid
  • the target compound was obtained in a similar manner to step A in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2- iodobenzoate.
  • Example 102 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid [00516]
  • the target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 103 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 104 3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid [00522]
  • the target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid.
  • Example 105 3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)benzoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid.
  • Example 106 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (4-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid.
  • Example 107 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5-(2,2,2- trifluoroethoxy)phenoxy)benzoic acid
  • Example 108 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)propanoic acid [00535]
  • the target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 3-(4- iodophenyl)propanoate.
  • Example 109 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)propanoic acid
  • the target compound was obtained in a similar manner to step A in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 3-(4- iodophenyl)propanoate.
  • Example 110 2-((4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzyl)oxy)acetic acid [00541]
  • the target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2-((4- iodobenzyl)oxy)acetate.
  • Example 111 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-bromo-4-(trifluoromethyl)-1H-benzo[d]imidazole and (4- (methoxycarbonyl)phenyl)boronic acid.
  • Example 112 N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H- benzo[d]imidazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00550]
  • the target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid and ethanamine hydrochloride.
  • Example 113 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenoxy)acetic acid [00552]
  • the target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2-(4- iodophenoxy)acetate.
  • Example 114 N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H-indol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00554]
  • the target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indol-1-yl)benzoic acid and ethanamine hydrochloride.
  • Example 115 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indol-1-yl)benzoic acid A) 5-Bromo-2-methyl-1-nitro-3-(trifluoromethyl)benzene [00556] 2-Methyl-1-nitro-3-(trifluoromethyl)benzene (8.9 g) was dissolved in H 2 SO 4 (90 mL).1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (7.4 g) was added in portions and the resulting mixture was stirred at 25°C for 3 h.
  • Example 116 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)indolin-1-yl)benzoic acid
  • To a stirred mixture of ethyl 4-(6-bromo-4-(trifluoromethyl)-1H- indol-1-yl)benzoate (1.0 g) in TFA (10 mL) was added NaBH3CN (1.2 g) in portions at 0°C. Then the mixture was allowed to warm to 25°C and stirred for 12 h.
  • Example 117 N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)indolin-6-yl)- 4-hydroxy-4-isobutylpiperidine-1-carboxamide
  • the target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)indolin-1-yl)benzoic acid and ethanamine hydrochloride.
  • Example 118 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)-3-methylphenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-2-methylphenyl)boronic acid.
  • Example 119 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)-3-methylphenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-2-methylphenyl)boronic acid.
  • Example 120 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-1H- indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-3-methylphenyl)boronic acid.
  • Example 121 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 4-(trifluoromethyl)-2H-indazol-2-yl)phenyl)butanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(3- (ethoxycarbonyl)pentan-3-yl)phenyl)boronic acid.
  • Example 122 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)butanoic acid
  • the target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(3- (ethoxycarbonyl)pentan-3-yl)phenyl)boronic acid.
  • Example 123 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanoic acid sodium salt
  • the target compound was obtained in a similar manner to step A to step D in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and ethyl 2- (5-iodopyridin-2-yl)-2-methylpropanoate.
  • Example 124 N-(1-(4-(2-(1H-Tetrazol-5-yl)propan-2-yl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) 2-(4-(6-Bromo-4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)-2- methylpropanenitrile [00593] The target compound was obtained in a similar manner to step A in Example 77 using 6-bromo-4-(trifluoromethyl)-1H-indazole and 2-(4- iodophenyl)-2-methylpropanenitrile.
  • Example 125 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)thiophen-2-yl)-2-methylpropanoic acid
  • the target compound was obtained in a similar manner to step A in Example 77 using 6-bromo-4-(trifluoromethyl)-1H-indazole and methyl 2-(5- iodothiophen-2-yl)-2-methylpropanoate.
  • Examples 126-127 Stroke and sepsis in vivo data Background and significance [00604] During inflammation, the vascular endothelium becomes activated, increasing permeability and coagulation. Increasing evidence indicates that sustained endothelial activation in numerous clinical settings including ischemia, sepsis and systemic inflammatory response syndrome, significantly contributes to tissue edema, perpetuates the inflammatory response, and exacerbates tissue injury ultimately resulting in organ failure and death. For instance, blood brain barrier (BBB) disruption exacerbates neuronal injury in stroke; severe endothelial dysfunction during sepsis; and systemic inflammatory response syndrome leads to increased vascular leakage and disseminated intravascular coagulation significantly contributing to multiorgan failure and death.
  • BBB blood brain barrier
  • S1PR2 is potently induced in cerebral microvessels during ischemia causing endothelial barrier dysfunction and exacerbation of brain injury. S1PR2 has also been demonstrated to play a critical role in vascular inflammation associated with sepsis. In the absence of S1PR2 or in the presence of JTE013-mediated inhibition of S1PR2 signaling, decreased vascular permeability is observed in response to endotoxin or polymicrobial sepsis challenge. [00605] Together these data suggest that antagonism of S1PR2 may be a useful approach for treating stroke, systemic inflammatory response syndrome, sepsis and other diseases characterized by vascular dysfunction.
  • Mouse stroke model [00606] The middle cerebral artery (MCA) and branches are the most commonly affected vessels in human ischemic stroke. Techniques that occlude these vessels are thus most similar to human ischemic infarcts.
  • MCA middle cerebral artery
  • tMCAO intra-arterial suture occlusion of the MCA
  • mice were subjected to several studies using the mouse tMCAO model. Animals were treated with either positive control S1PR2 antagonist JTE-013 or the compounds as described herein. All studies were conducted in a blinded fashion. As shown in FIG.1, treatment of animals with compound 39120 mg/kg b.i.d.
  • IP resulted in significant reduction of several stroke parameters including 60.7% reduction in infarct size (without edema correction), 66.7% reduction in infarct size (corrected for edema), 53.7% reduction in edema ratio, and 28.6% improvement in neurological outcomes.
  • AUC 3.69 ⁇ g*h/mL
  • mice were subjected to the cecal ligation and puncture (CLP) model of polymicrobial sepsis.
  • CLP cecal ligation and puncture
  • the CLP model for polymicrobial sepsis is the model which most closely resemble human sepsis.
  • Advantages of the CLP model include the polymicrobial flora used for development of sepsis, nonrequirement for growing microbes, and the similar cytokine profile to human sepsis.
  • CLP involves exposure and ligation of a portion of the cecum, followed by needle puncture and extrusion of fecal content into the body cavity. The severity of disease can be controlled by the size of needle puncture and length of cecal ligation. A rise in pro-inflammatory cytokines (including IL-6 and TNF-a) is observed after CLP.
  • pro-inflammatory cytokines including IL-6 and TNF-a
  • the CLP mouse model was conducted with male C57BL/6 mice treated with a single dose of vehicle (20% HPBCD/saline), JTE- 01330 mg/kg IP, or TDI-662160 mg/kg IP. The CLP surgery was conducted followed by compound administration.
  • S1pr2-/- mice were subjected to polymicrobial sepsis (CLP; see Example 128), S1pr2-/- mice exhibited significantly decreased vascular leakage in the lungs (FIG.4, left panel) and improved survival (FIG.4 right panel). Therefore, genetic deletion of S1PR2 in mice results in dramatic reduction of vascular leakage (in lungs and brain) and mortality after sepsis. [00614] Together these data demonstrate that antagonism of S1PR2 is efficacious in the treatment of vascular leakage associated with sepsis.
  • S1PR2 antagonists were administered after the onset of sepsis, thus, they could be used to prevent or mitigate tissue injury and multiple organ dysfunction, ultimately decreasing mortality and chronic morbidity and disabilities in sepsis survivors.
  • S1PR2 is expressed in the endothelium in human tissues and upregulated during inflammation, hypoxia and ischemia, the therapeutic potential of S1PR2 antagonists is very high.
  • Example 128 In vivo studies [00616] C57BL6 mice (Jax laboratories) male, 24-28g, were used for the study. Wild type and S1pr2 -/- mice were used. All animal experiments used randomization to treatment groups and blinded assessment.
  • tMCAO mouse model of stroke and treatments [00617] Transient focal cerebral ischemia was induced in mice by middle cerebral artery occlusion as we have previously described (tMCAO). Thirty-three mice (male, 24-28 g, C57BL6) were used in this study. Criteria for exclusion were development of subarachnoid hemorrhage, lack of reduction of cerebral blood flow or lack of recovery after reperfusion. Surgeries, as well as all behavioral and histological assessments were performed by an investigator blinded to the drug treatment. Mice were anesthetized with 3% isoflurane vaporized in O 2 for induction and 1.5% isoflurane for maintenance.
  • Temperature was maintained at 36.5 ⁇ 0.5oC, controlled by a thermostatic blanket (CMA 450 Temp Controller for mice, Harvard Apparatus, Holliston, MA) throughout the procedure.
  • CMA 450 Temp Controller for mice Harvard Apparatus, Holliston, MA
  • the left common carotid artery was exposed and the occipital artery branches of the external carotid artery (ECA) were isolated and coagulated.
  • ECA occipital artery branches of the external carotid artery
  • the ECA was dissected distally and coagulated along with the terminal lingual and maxillary artery branches.
  • the internal carotid artery (ICA) was isolated and the extracranial branch of the ICA was then dissected.
  • a rubber silicon-coated monofilament suture (Filament size 6-0, diameter 0.09-0.11 mm, length 20mm; diameter with coating 0.23 +/- 0.02 mm; coating length 5 mm, Doccol Corp., Sharon, MA) was introduced into the ECA lumen through an incision and then gently advanced approximately 9 to 9.5 mm in the ICA lumen to block MCA blood flow. For reperfusion, the suture was withdrawn 60 min after MCAO. 2-D laser speckle flowmetry (PeriCam PSI HR, Perimed, Jarfalla, Sweeden) was used to confirm MCA occlusion and reperfusion. After removal of the suture, animals randomly received an intraperitoneal injection of vehicle or compounds.
  • Physiological parameters (arterial O 2 saturation, heart rate, pulse distention and respiratory rate) were recorded before, during and after tMCAO using the Mouse Ox Plus (Starr Life Sciences Corp., Oakmon, PA). After the surgery, all animals were maintained in a small animal heated recovery chamber (IMS Vetcare Chamber Recovery Unit, Harvard Apparatus, Holliston, MA). After recovery, animals were returned to their cages with free access to food and water.
  • IMS Vetcare Chamber Recovery Unit Harvard Apparatus, Holliston, MA.
  • mice were returned to their cages with free access to food and water.
  • Neurobehavioral Testing [00619] Neurological function was evaluated at 24 h after reperfusion.
  • Neurological deficit was graded on a score of 0 to 4 as previously described: 0, no observable deficit; 1, weakness in right forelimb; 2, forelimb flexion and circling when held by tail; 3, forelimb flexion, decreased resistance to lateral push, and spontaneous circling; and 4, forelimb flexion and being unable or difficult to ambulate.
  • TTC staining and determination of infarct and edema ratios and infarct volumes [00620] Twenty-four hours after reperfusion, mice were anesthetized and decapitated. The brain was quickly removed from cranium, placed in -20 o C freezer for 20 min, and then cut into 1.5mm coronal slices using a rodent brain matrix.
  • Sections were stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC; Sigma Co., St. Louis, MO) at 37°C for 10 min and scanned. Infarct area on each slice was determined by using Image analysis software (Image J, the National Institutes of Health, Bethesda, MD) to obtain the infarct ratios, edema ratios and infarct volumes per brain (in millimeters 3 ).
  • TTC 2,3,5-triphenyltetrazolium chloride
  • cecal ligation and puncture model [00621] Under isoflurane anesthesia, a small incision was made in the peritoneal cavity (1.5 cm) to exteriorize the cecum, which was ligated at half the distance between the distal pole and the base of the cecum. Cecal puncture was conducted with a 18G needle and a small droplet of cecal content will be extruded from both holes to ensure patency. The cecum was relocated in the abdominal cavity and the incision sutured. Then, mice received pre-warmed normal saline (5mL/100g body weight) to avoid hypothermia.
  • vascular leakage Two percent Evans blue dye solution is injected into animals 3 hours (brain leakage) or 40 minute (lung leakage) prior to endpoint . At endpoint 7.5 hours after drug administration, the mice were transcardially perfused with cold PBS/5 mM EDTA, and organs were harvested, weighed, and frozen. Organs were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C. Fluorescence intensity was measured at Ex 620/ Em 680. Vascular permeability was calculated as RFU/g wet weight. Statistical analyses, randomization and blinding [00623] All values reported are mean ⁇ s.e.m. P values were calculated with GraphPad Prism software, using one-way non-parametric ANOVA (Kruskal Wallis) followed by Dunn’s test or t test. The criterion for statistical significance was set at P ⁇ 0.05. [00624]

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure provides a compound of the formula Het1-L1-Ar1-L2-G1, or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, that are useful for treating a variety of conditions. In such compounds, Het1, G1, Ar1, L1, and L2 are as defined herein. Pharmaceutical compositions of such compounds are also contemplated.

Description

SMALL MOLECULE INHIBITORS OF S1P2 RECEPTOR AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Appl. Ser. No.62/884,046, filed August 7, 2019, which is incorporated by reference as if fully set forth herein. BACKGROUND [0002] The sphingosine 1-phosphate receptor-2 (S1P2) is coupled preferentially to the heterotrimeric G13 and small GTPase Rho pathway. It is induced during pathological conditions in fibrogenic, immune and vascular cells. Activation of this pathway in fibroblasts induces the Rho/ Rho kinase (ROCK)- dependent fibrogenic factors, for example, connective tissue growth factor (CTGF) and the Hippo/ YAP signaling pathway are key downstream mediators that induce pathologic fibrosis. In vascular endothelial cells, the S1P2 receptor induces inflammatory responses, promotes vascular permeability and is induced during pathologic responses. Thus, it is thought to be one of the key drivers of tissue injury, fibrosis, and pathologic angiogenesis. [0003] The S1P signaling system is unique in that the ligand S1P is present abundantly in circulation during homeostatic conditions. Thus, receptor expression on the cell surface is critical for biological events such as cell migration and junction assembly. The first FDA-approved S1P receptor inhibitor, Fingolimod/Gilenya induces irreversible receptor internalization, followed by ubiquitinylation, and protesomal degradation. Fingolimod belongs to a class of S1P receptor inhibitors called functional antagonists and it appears that this class of compounds work better than competitive inhibitors against the receptor. However, Fingolimod and related molecules that were designed to block lymphocyte trafficking by targeting the S1P1 receptor do not interact with S1P2 receptor. Thus, there is a need to develop effective inhibitors of the S1P2 inhibitor. BRIEF DESCRIPTION OF THE FIGURES [0004] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein. [0005] FIG. 1 is plots showing, among other things, Infarct Volume, Edema Ratio, and Neurological Deficits After Intraperitoneal Administration of compound 39120 mg/kg Twice a Day in a tMCAO Model of Male C57BL/6 Mice. Male C57BL/6J mice, 10-11 weeks old, were subjected to intra-arterial suture occlusion of the middle cerebral artery (MCAO) for 60 minutes followed by reperfusion. Compounds (Vehicle [20% HPBCD], TDI-6621 120 mg/kg b.i.d.) were administered 1.3 and 9.3 hours after the onset of ischemia. Twenty-four hours after the start of tMCAO surgery, mice were assessed for infarct size, edema ratio, and neurological deficit scoring. Infarct size corrected for edema, infarct volume, and edema ratio was calculated from TTC staining images of brains. Neurological deficits were assigned as follows (4-unable to move, 3- spontaneous circling, 2-circling when held by tail, 1-weakness in right forelimb, 0- no deficit). (*P<0.05, **P<0.005, Mann-Whitney test). [0006] FIG.2 is plots of Infarct Volume, Edema Ratio, and Neurological Deficits After Delayed Intraperitoneal Administration of compound 39120 mg/kg Twice a Day in a tMCAO Model of Male C57BL/6 Mice. Male C57BL/6J mice, 10- 11 weeks old, were subjected to intra-arterial suture occlusion of the middle cerebral artery (MCAO) for 60 minutes followed by reperfusion. Compounds (Vehicle [20% HPBCD], TDI-6621120 mg/kg b.i.d.) were administered 4.5 h after the onset of ischemia. Twenty-four hours after the start of tMCAO surgery, mice were assessed for infarct size, edema ratio, and neurological deficit scoring. Infarct size corrected for edema, infarct volume, and edema ratio was calculated from TTC staining images of brains. Neurological deficits were assigned as follows (4-unable to move, 3-spontaneous circling, 2-circling when held by tail, 1-weakness in right forelimb, 0-no deficit). (*P<0.05, **P<0.005). [0007] FIG. 3 is plots showing that reatment with compound 39 significantly tprevented vascular permeability and blood brain barrier leakage in sepsis model. Male C57BL/6 mice (left) or S1PR2+/+ and S1PR2-/- mice (right) were subjected to CLP model of sepsis. The CLP surgery was performed on animals for 15 minutes followed by administration of compounds (vehicle, compound 3960 mg/kg IP, JTE-01330 mg/kg IP). Vascular permeability in the brain was calculated as RFU/g wet weight. Evans blue dye is injected into animals 3 hours prior to endpoint. At endpoint 7.5 hours after drug administration, the mice were transcardially perfused with cold PBS/5 mM EDTA, and the brains were harvested, weighed, and frozen. Brains were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C. Fluorescence intensity was measured at Ex 620/ Em 680. (*P<0.05, **P<0.005, ****P<0.00005). [0008] FIG. 4 is plots showing that genetic deletion of S1pr2 prevented vascular leakage in the lung and increased survival in the mouse sepsis model. S1pr2+/+ and S1pr2-/- mice were subjected to cecal ligation and puncture (CLP) model of sepsis. Left: Vascular permeability in the lungs was calculated as RFU/g wet weight. Evans blue dye was injected into animals 40 minutes prior to endpoint. At endpoint 7.5 hours after drug administration, the mice were transcardially perfused with cold PBS/5 mM EDTA, and lungs were harvested, weighed, and frozen. Lungs were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C. Fluorescence intensity was measured at Ex 620/ Em 680. (*P<0.05, **P<0.005, ****P<0.00005, unpaired t test). Right: Survival curves after CLP in wild type (S1pr2+/+) and S1pr2-/- mice. Survival rate at day 7 after CLP was 8.3% in wild type and 58.3% in S1pr2-/- mice. (*P < 0.05, Log-rank test). DESCRIPTION [0009] As described herein, medicinal chemistry efforts have been used to target the S1P2 receptor and associated pathological conditions. Various compounds described herein have been found to be much more effective than known compounds. Compounds disclosed herein demonstrate advantageous activity in modulating the S1P2 receptor corresponding to effective treatment of, among other diseases, fibrosis and vasoproliferative retinopathy. [0010] The present disclosure provides a compound of the Formula (1): Het1—L1—Ar1—L2—G1 Formula (1) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: Het1 is cycloalkyl or heterocyclyl; G1 is aryl, heterocyclyl, heterocyclyl alkyl, carboxyalkyl, carboxyalkyloxy (-O-alkyl- C(O)O-), carboxyalkyloxyalkyl (-alkyl-O-alkyl-C(O)O-), amidoalkyl, carboxy, alkoxycarbonyl or amido; Ar1 is a divalent aryl group or a divalent heteroaryl group; L1 is a bond, an acyl linker or an amido linker; L2 is a bond, heterocycloalkyl linker, cycloalkyloxy linker or an aryloxy linker; Het1 and G1 are different when Het1 and G1 are simultaneously heterocyclyl; provided that Ar1 is a divalent heteroaryl group when L2 is an aryloxy linker. [0011] Het1 can be a heterocycyclyl group, such as a four-, five- or six- membered heterocyclyl group. For example, Het1 can be a four-, five- or six- membered heterocyclyl group, wherein a heteroatom in Het1 is directly attached to L1. Het1 can be thiolane, thiane, thiophene, thiazole, thiazole, isothiazole, tetrahydrofuranyl, tetrahydropyranyl, indole, quinoline, isoquinoline, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, oxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, benzo[d][1,3]dioxole, pyridinyl or pyrimidinyl. For example, Het1 can be pyrrolidinyl, piperidinyl or azetidinyl. In addition, G1 can be pyrrolidinyl, piperidinyl or oxazolyl. [0012] Het1 can be substituted with one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is a counterion (e.g., Na+), hydrogen or alkyl, or combination thereof. [0013] For example, Het1 can be:
Figure imgf000006_0002
wherein: X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, aryl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; and Y is N or CH. An example of Het1 is:
Figure imgf000006_0003
[0014] Het1 can also be:
Figure imgf000006_0001
wherein: each m is independently 0 or 1, R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl; Y is N or CH; and Z is O, NR6, wherein R6 is H or alkyl, or CR2R3. [0015] Examples of Het1 include:
Figure imgf000007_0001
[0016] G1 can be aryl or G1 can be a heterocyclyl group, such as a four-, five- or six-membered heterocyclyl group. When G1 is heterocyclyl, G1 can be thiolane, thiane, thiophene, thiazole, thiazole, isothiazole, tetrahydrofuranyl, tetrahydropyranyl, indole, quinoline, isoquinoline, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, oxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzo[d][1,3]dioxole, pyridinyl or pyrimidinyl. For example, G1 can be pyrrolidinyl, piperidinyl or oxazolyl. [0017] G1, including when G1 is aryl or heterocycyclyl, can be substituted with one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl or combination thereof. [0018] For example, G1 can be:
Figure imgf000007_0002
wherein m is 0, 1 or 2; A1, A2, and A3 is independently CH, C-alkyl, N, NR5 or O, provided that at least one of A1, A2, and A3 is N or NR5; each R4 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R3 is independently H, alkyl or aryl. [0019] For example, G1 can be:
Figure imgf000008_0001
wherein m is 0, 1 or 2; and each R4 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido. [0020] G1 can also be carboxyalkyl, amidoalkyl, carboxy, alkoxycarbonyl or amido, such as a carboxyalkyl group having the formula -alkyl-C(O)O-R6, wherein R6 is H, alkyl or a counterion (e.g., Na+ or K+); a carboxy group having the formula C(O)OH, also known as a “carboxylic acid” group; an alkoxycarbonyl group of the formula C(O)O-R6; an amidoalkyl group having the formula -alkyl- C(O)NR7R8, wherein R7 and R8 are each, independently, hydrogen, alkyl, aryl or R7 and R8, together with the nitrogen atom to which they are attached, form a heterocyclyl group; and an amido group having the formula C(O)NR7R8. [0021] Ar1 can be a divalent aryl group. Examples of divalent aryl groups include groups of the formula:
Figure imgf000008_0002
wherein p is 0, 1, 2 or 3; and each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido or two R9 groups on adjacent carbon atoms to which they are attached, can form an aryl group, so as to form a napthyl, anthracenyl, fluorenyl, and the like. An example of R9 is aryl, aryloxy, alkoxy, trihaloalkyl (e.g., CF3), and SF5. [0022] Ar1 can be a divalent heteroaryl group. Examples of divalent heteroaryl groups include groups of the formula:
Figure imgf000008_0003
,
Figure imgf000009_0001
, wherein: each p is independently 0, 1, 2 or 3; each of A1 and A2 is independently, CR10 or N; A3 is NR10, O or S; A4 is CR10 or N; A5 is CR10 or N; A6 is NR10, O or S; A7 is CR10 or N; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl. An example of R9 is aryl, aryloxy, alkoxy, trihaloalkyl (e.g., CF3), and SF5. [0023] For example, Ar1 can be:
Figure imgf000010_0001
, wherein: the dashed line represents a single or a double bond; each p is independently 0, 1, 2 or 3; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl. [0024] For example, Ar1 can be:
Figure imgf000010_0002
,
Figure imgf000011_0001
wherein: each p is independently 0, 1, 2 or 3; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl. [0025] For example, Ar1 can be:
Figure imgf000011_0002
Figure imgf000012_0001
wherein each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl. [0026] L1 can be a bond or an acyl linker, such as an acyl linker having the formula -C(O)-R11-, wherein R11 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl. For example, R11 is alkyl. [0027] L1 can be amido linker, such as an amido linker having the formula -C(O)-N(R12)-, wherein R12 is H or alkyl. [0028] L2 can be a bond, heterocycloalkyl linker, cycloalkyloxy linker or an aryloxy linker. L2 can be, for example, a cycloalkyloxy linker having the formula -cycloalkyl-O-. L2 can be, for example, an aryloxy linker having the formula -aryl- O-. Examples of cycloalkyloxy linkers include:
Figure imgf000012_0002
, each of which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido. For example, cycloalkyloxy linkers can be:
Figure imgf000013_0001
[0029] Examples of aryloxy linkers include:
Figure imgf000013_0002
, which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido. [0030] Examples of heterocycloalkyl linkers include:
Figure imgf000013_0003
, which can be further substituted with at least one fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido. [0031] In compounds of the Formula (1), Het1 can be a four-, five- or six- membered heterocyclyl group, wherein a heteroatom in Het1 is directly attached to L1. For example, Het1—L1 can have the formula:
Figure imgf000014_0001
wherein X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; and R12 is H or alkyl. [0032] In compounds of the Formula (1), L2—G1 can have the formula:
Figure imgf000014_0002
wherein d is 0, 1, 2, 3, 4, or 5; R13 and R14 are each independently H, alkyl or aryl, wherein each repeating CR13R14 unit can be the same or different; and G2 is OR15 or NR16R17, wherein R15 is H or alkyl and R16 and R17 are each independently H or alkyl or R16 and R17 together with the nitrogen atom to which they are attached, form a heterocyclyl group. [0033] Compounds of the Formula (1) include compounds of the Formula (A) and Formula (B):
Figure imgf000014_0003
wherein: X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; Q and Q1 are each independently N or CH; T is N or CR18, wherein R18 is alkyl, alkoxy, aryloxy, arylamino, SF5, trihaloalkyl, dihaloalkyl, trihaloalkoxy, or dihaloalkoxy; provided that Q, Q1, and T are not N at the same time. [0034] Examples of compounds of the Formula (A) and Formula (B) include:
Figure imgf000015_0001
[0035] Examples of compounds of the Formula (A) and Formula (B) also include:
Figure imgf000015_0002
[0036] Examples of compounds of the Formula (A) and Formula (B) also include:
Figure imgf000016_0001
[0037] Examples of compounds of the Formula (A) and Formula (B) also include:
Figure imgf000016_0002
wherein X3 is O or NR20, wherein R20 is H or alkyl; and R19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy. [0038] Examples of compounds of the Formula (A) and Formula (B) also include:
Figure imgf000016_0003
,
Figure imgf000017_0001
Figure imgf000018_0001
. [0039] Compounds of the Formula (1) include compounds of the Formula (C) and Formula (D):
Figure imgf000018_0002
wherein: each m is independently 0, 1 or 2, R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl; Y is N or CH; and Z is O, NR6, wherein R6 is H or alkyl, or CR2R3; Q and Q1 are each independently N or CH; T is N or CR18, wherein R18 is alkyl, alkoxy, aryloxy, arylamino, SF5, trihaloalkyl, dihaloalkyl, trihaloalkoxy, or dihaloalyoxy; provided that Q, Q1, and T are not N at the same time. [0040] Examples of compounds of the Formula (C) and Formula (D) include: , ,
Figure imgf000019_0001
[0041] Examples of compounds of the Formula (C) and Formula (D) also include:
Figure imgf000020_0001
[0042] Examples of compounds of the Formula (C) and Formula (D) also include:
Figure imgf000020_0002
wherein X3 is O or NR20, wherein R20 is H or alkyl; and R19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy. [0043] Examples of compounds of the Formula (C) and Formula (D) also include:
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
[0044] X3 can be O in any of the foregoing examples of compounds of the Formula (C) and Formula (D). [0045] Compounds of the Formula (1) also include compounds of the Formula (E)-(M):
Figure imgf000023_0002
Figure imgf000024_0001
wherein: X is -(CH2)nC(R2)(R3)(CH2)n -, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; p is 0, 1, 2 or 3; A6 is NR10, O or S; A7 is CR10 or N; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl [0046] Examples of compounds of the formulae (E)-(M) include:
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
[0047] In any of the foregoing examles of compounds of the Formulae (E)-(M), Y can be N. [0048] The present disclosure also provides a compound of the Formula (2) and (3):
Figure imgf000029_0002
( ) ( ) wherein Z, X, L1, R8, d, R13 and R14 are defined herein; G3 is selected from:
Figure imgf000030_0002
, wherein q is 1 to 25 (e.g., 1 to 3, 1 to 5 or 1 to 10); X1 is O or NH; and X2 is alkyl, OR21 or N(R21)2, wherein each R21 is H, alkyl, aryl or OP(O)(OR1)2, wherein each R1 is a counterion (e.g., Na+), hydrogen or alkyl, or combination thereof, or wherein the two R21 groups, together with the nitrogen atoms to which they are attached, form a heterocyclyl group; N(R22)2, wherein the R22 groups, along with the nitrogen atom to which they are attached, form a heterocyclyl group; N(R23)2, wherein each R23 group is, independently, H or , provided that at least one R23 groups is
Figure imgf000030_0003
; and G4 is selected from: X3, wherein X3 is OR24 or N(R24)2, wherein each R24 is, independently, H and alkyl;
Figure imgf000030_0001
, wherein q is 1 to 25 (e.g., 1 to 3, 1 to 5 or 1 to 10); X1 is O or NH; and X2 is alkyl, OR21 or N(R21)2, wherein each R21 is H, alkyl, aryl or OP(O)(OR1)2, wherein each R1 is a counterion (e.g., Na+), hydrogen or alkyl, or combination thereof, or wherein the two R21 groups, together with the nitrogen atoms to which they are attached, form a heterocyclyl group; N(R22)2, wherein the R22 groups, along with the nitrogen atom to which they are attached, form a heterocyclyl group; N(R23)2, wherein each R23 group is, independently, H or
Figure imgf000030_0005
, provided that at least one R23 groups is
Figure imgf000030_0004
[0049] Compounds encompassed by one or more of the foregoing formulae include:
, ,
Figure imgf000031_0001
, , ,
Figure imgf000032_0001
Figure imgf000033_0001
,
Figure imgf000034_0001
,
Figure imgf000035_0001
,
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
,
Figure imgf000039_0001
,
Figure imgf000040_0001
,
Figure imgf000041_0001
Figure imgf000042_0001
,
Figure imgf000043_0001
,
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
,
Figure imgf000047_0001
,
Figure imgf000048_0001
[0050] The compound of any of the preceding formulae, wherein the compound is other than
Figure imgf000049_0001
. [0051] In various embodiments of the compound, the compound can meet the requirements of more than one of Formula (1) and (A)-(M). For example, the compound can have the structure of Formula (1) and Formula (A) or the compound can have the structure of Formula (1) and Formula (M). [0052] Compounds of the Formulae (1)-(3) and (A)-(M) exhibit sphingosine 1-phosphate receptor 2 (S1P2) agonisitc activity. In some examples, compounds of the Formulae (1)-(3) and (A)-(M) exhibit S1P2 agonistic activity at concentrations of from about 100 nM to about 100 mM (e.g., from about 100 nM to about 10 mM; about 100 nM to about 900 nM; about 250 nM to about 1 mM; or about 750 nM to about 100 mM). [0053] The present invention also provides a pharmaceutical composition comprising a compound of any of the preceding formulae and a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of one of Formulae (1)-(3) and (A)-(M), and a pharmaceutically acceptable carrier. [0054] Pharmaceutical compositions contemplated herein are those comprising one or more compounds of the various embodiments of the present invention and one or more pharmaceutically acceptable excipients. A “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal). Such compositions can be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration. [0055] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and/or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety. [0056] As used herein “pharmaceutically acceptable carrier” or “excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions. [0057] Pharmaceutical compositions can be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. [0058] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art. [0059] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present invention can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations can be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present invention can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers. [0060] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms as known in the art. Any biologically- acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof. [0061] Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrose-saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations. [0062] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. The suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. [0063] The amount of active compound in a therapeutic composition according to various embodiments of the present invention can vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation. [0064] A “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the present invention or an appropriate pharmaceutical composition thereof are effective, the compounds of the present invention can be administered in an effective amount. The dosages as suitable for this invention can be a composition, a pharmaceutical composition or any other compositions described herein. [0065] For each of the recited embodiments, the dosage is typically administered once, twice, or thrice a day, although more frequent dosing intervals are possible. The dosage can be administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and/or every 7 days (once a week). In one embodiment, the dosage can be administered daily for up to and including 30 days, preferably between 7-10 days. In another embodiment, the dosage can be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage can be administered for as long as signs and/or symptoms persist. The patient can require "maintenance treatment" where the patient is receiving dosages every day for months, years, or the remainder of their lives. In addition, the composition of this invention can be to effect prophylaxis of recurring symptoms. For example, the dosage can be administered once or twice a day to prevent the onset of symptoms in patients at risk, especially for asymptomatic patients. [0066] The compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. The preferred routes of administration are buccal and oral. The administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease. Local administration can be administration to, for example, tissue, organ, and/or organ system, which encompasses and/or is affected by the disease, and/or where the disease signs and/or symptoms are active or are likely to occur. Administration can be topical with a local effect, composition is applied directly where its action is desired. Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract. Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract. [0067] The present disclosure also provides a method for treating a fibrotic disease, abnormal vascular leak and pathological angiogenesis, and tumor-associated angiogenesis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. In various embodiments, the abnormal vascular leak and pathological angiogenesis is associated with the wet form of age-related macular degeneration. In various embodiments, the fibrotic disease is fibrosis of the lung, liver, kidney, retina, skin or heart. [0068] The present disclosure also provides a method for treating multiple sclerosis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0069] The present disclosure also provides a method for treating highly vascular tumors comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. In various embodiments, the highly vascular tumors are renal carcinoma, glioblastoma, and neuroblastoma. The tumors can be highly fibrotic such as in the case of pancreatic cancer. [0070] The present disclosure also provides a method for chimeric antigen receptor T-cell (CAR-T) therapy, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject. CAR-T therapy represents an emerging breakthrough in oncology with rapidly increasing uptake by clinicians due to its promise for patients. Unfortunately, CAR-T can be associated with significant toxicity, sequelae from treatment-related inflammation and leaky vessels, including cytokine release syndrome (CRS; 50%-100% of patients) and/or neurologic side effects (10%-50% of patients). These side effects often prove fatal, limiting the potential utility of CAR-T and many of the drugs currently used to manage the CRS side effects significantly reduce CAR-T efficacy. Compounds described herein may have an advantage of abrogating this significant CAR-T risk without eliminating its effectiveness. Without being limited by theory, compounds described herein may provide such advantages by merit of protecting the blood-brain barrier from vascular leakage. [0071] The present disclosure also provides a method for treating cytokine release syndrome, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject. [0072] The present disclosure also provides a method for treating pathological angiogenesis in a subject, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to the subject. [0073] The present disclosure also provides a method for treating atherosclerosis comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0074] The present disclosure also provides a method for treating diabetes comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0075] The present disclosure also provides a method for treating stroke (e.g., ischemic stroke and stroke related conditions, such as cerebral vasogenic edema) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. Antagonism of S1PR2 may be a useful approach to ameliorate the brain damage associated with stroke and reperfusion by preserving neurovascular integrity, thereby reducing the entry of toxic plasma proteins and blood cells into the brain parenchyma and diminishing downstream inflammatory and mechanical injury. [0076] The present disclosure also provides a method for preventing or treating sepsis-induced changes in blood-brain barrier permeability (e.g., decreasing BBB permeability during septic infenctions) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0077] The present disclosure also provides a method for treating nonalcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0078] The present disclosure also provides a method for treating nonalcoholic fatty liver disease (NAFLD) comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0079] The present disclosure also provides a method for treating hepatobiliary conditions, including cholangiocarcinoma, as well as glucose and lipid management, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0080] The present disclosure also provides a method for at least one of regulating proliferation of cholangiocytes and promoting ductular reaction comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0081] The present disclosure also provides a method for ameliorating blood brain barrier dysfunction and brain damage associated with chronic traumatic encephalopathy; and at least one of traumatic brain injury, hypertensive encephalopathy, neurodegenerative diseases, vascular dementias, and multiple sclerosis, comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)- (M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0082] The present disclosure also provides a method for at least one of treating and preventing at least one of inflammatory response syndrome and sepsis; restoring endothelial function, preventing vascular leak, disseminated intravascular coagulation, systemic vascular failure, ischemia and acute multiple organ dysfunction, including acute respiratory distress syndrome, kidney, heart, liver and brain injury (delirium and coma) and death; treating or preventing vascular complications of diabetes, such as cardiovascular disease, coronary artery disease, stroke, retinopathy, nephropathy and neuropathy, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. Causes of sepsis and systemic inflammatory response syndrome include, but are not limited to systemic trauma, burns, viral infections, surgery, cancer and cancer treatments, among others. [0083] The present disclosure also provides a method of treating and preventing chronic complications of systemic inflammatory response syndrome and sepsis, including lung, kidney, heart and liver chronic dysfunction, and central nervous system pathologies such as depression, anxiety, cognitive decline and accelerated dementia, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0084] Three coronaviruses have crossed the species barrier to cause deadly pneumonia in humans since the beginning of the 21st century: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus, and SARS-CoV-2. SARS-CoV emerged in the Guangdong province of China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. In 2012, MERS- CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of 2,494 individuals and claiming 858 lives. A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 SARSCoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 400,000 people and killed more than 10,000 of those affected in >60 countries as of March 26, 2020. [0085] On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern. MERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels. Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses. Whereas palm civets and racoon dogs have been recognized as intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans, the SARS-CoV-2 intermediate host remains unknown. The recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs), suggest that future zoonotic transmission events may continue . In addition to the highly pathogenic zoonotic pathogens SARS- CoV, MERS-CoV, and SARS-CoV-2, all belonging to the b-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoVHKU1, HCoV-NL63, and HCoV-229E. [0086] Accordingly, the present disclosure also provides a method of treating and preventing conditions caused by one or more coronaviruses, including SARS-CoV-2 (COVID-19), characterized by at least one of acute lung injury, vascular leakage, endothelial inflammation (endotheliitis), disseminated intravascular coagulation and systemic vascular dysfunction leading to at least one of hypoxia, ischemia, multiple organ failure (kidney, heart, liver and brain injury), coma, and death, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0087] The present disclosure also provides a method of treating and preventing chronic complications of coronavirus-associated dieseases (e.g., COVID-19), including lung, kidney, heart and liver chronic dysfunction and central nervous system pathologies such as depression, anxiety, cognitive decline and accelerated dementia, the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. [0088] The present disclosure also provides a method of treating and preventing conditions caused by one or more viruses characterized by at least one of vascular leakage and endothelial inflammation (endotheliitis), the method comprising administering a therapeutically effective amount of any of the preceding compounds, e.g., a compound of any of Formulae (1)-(3) and (A)-(M), or a pharmaceutical composition comprising said compound, to a subject in need thereof. Such viruses include, but are not limited to the Filoviridae family of viruses and the Flaviviridae family of viruses. [0089] Two members of the Filoviridae family have been identified: EBOV and MARV. Two key pathogenic types of the Filoviridae family have been identified: Ebolavirus and MARV. There is one identified variant of MARV and five identified species of ebolavirus: Zaire (e.g., Ebola virus, EBOV), Sudan, Tai Forest, Bundibugyo, and Reston. The exact origin, locations, and natural habitat of Filoviridae are unknown. However, because of available evidence and the nature of similar viruses, it is postulated that Filoviridae are zoonotic (i.e., animal- borne) and are normally maintained in an animal host that is native to the African continent. [0090] The Ebola virus genus includes five known species: (1) Bundibugyo ebolavirus, also known as Bundibugyo virus (BDBV, previously BEBOV); (2) Reston ebolavirus, also known as Reston virus or Ebola-Reston (RESTV, previously REBOV); (3) Sudan ebolavirus, also known as Sudan virus or Ebola-Sudan (SUDV, previously SEBOV); (4) Tai Forest ebolavirus, also known as Tai Forest virus or Ebola-Tai (TAFV, previously CIEBOV); and (5) Zaire ebolavirus, also known as Ebola virus or Ebola-Zaire (EBOV, previously ZEBOV). [0091] The Marburg virus genus includes the species Marburg marburgvirus, also known as Marburg virus (MARV) or Ravn virus (RAVV). The Cuevavirus genus includes the species Lloviu cuevavirus, also known as the Lloviu virus (LLOV). [0092] Viruses included in the Flaviviridae family include at least three distinguishable genera including pestiviruses, flaviviruses, and hepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43). While pestiviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, hog cholera) and border disease of sheep (BDV), their importance in human disease is less well characterized (Moennig, V., et al., Adv. Vir. Res.1992, 48, 53-98). Flaviviruses are responsible for important human diseases such as dengue fever and yellow fever while hepaciviruses cause hepatitis C virus infections in humans. Other important viral infections caused by the Flaviviridae family include West Nile virus (WNV) Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis, St Louis enchaplitis, Omsk hemorrhagic fever virus and Zika virus. Combined, infections from the Flaviviridae virus family cause significant mortality, morbidity and economic losses throughout the world. Therefore, there is a need to develop effective treatments for Flaviviridae virus infections. [0093] The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol.32:98-112, 2000) so a significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85, (1999); Gordon, C. P., et al., J. Med. Chem.2005, 48, 1-20; Maradpour, D.; et al., Nat. Rev. Micro.2007, 5(6), 453-463). A number of HCV treatments are reviewed by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000). [0094] Various compounds disclosed herein have ^-arrestin-determined IC50 values of less than 1 mM, less than 500 nM, less than 200 nM, less than 100 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM or less than 10 nM; for example, ^-arrestin-determined IC50 values IC50 values of from about 1 nM to about 100 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 100 nM to about 1 mM, about 1 mM to about 5 mM or between about 5 mM and 10 mM. [0095] The term “therapeutically effective amount” as used herein, refers to that amount of one or more compounds of the various examples of the present invention that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some examples, the therapeutically effective amount is that which can treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein. [0096] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having from 1 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 1 to 10 carbons atoms, 1 to 8 carbon atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 1 to 3 carbon atoms. Examples of straight chain mono-valent (C1-C20)-alkyl groups include those with from 1 to 8 carbon atoms such as methyl (i.e., CH3), ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl groups. Examples of branched mono-valent (C1-C20)-alkyl groups include isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, and isopentyl. Examples of straight chain bi-valent (C1-C20)alkyl groups include those with from 1 to 6 carbon atoms such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-. Examples of branched bi-valent alkyl groups include –CH(CH3)CH2- and –CH2CH(CH3)CH2-. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and bicyclo[2.2.1]heptyl. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. In some embodiments, alkyl includes a combination of substituted and unsubstituted alkyl. As an example, alkyl, and also (C1)alkyl, includes methyl and substituted methyl. As a particular example, (C1)alkyl includes benzyl. As a further example, alkyl can include methyl and substituted (C2-C8)alkyl. Alkyl can also include substituted methyl and unsubstituted (C2-C8)alkyl. In some embodiments, alkyl can be methyl and C2-C8 linear alkyl. In some embodiments, alkyl can be methyl and C2-C8 branched alkyl. The term methyl is understood to be -CH3, which is not substituted. The term methylene is understood to be -CH2-, which is not substituted. For comparison, the term (C1)alkyl is understood to be a substituted or an unsubstituted -CH3 or a substituted or an unsubstituted -CH2-. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, cycloalkyl, heterocyclyl, aryl, amino, haloalkyl, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. As further example, representative substituted alkyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. In some embodiments, representative substituted alkyl groups can be substituted from a set of groups including amino, hydroxy, cyano, carboxy, nitro, thio and alkoxy, but not including halogen groups. Thus, in some embodiments alkyl can be substituted with a non-halogen group. For example, representative substituted alkyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. In some embodiments, representative substituted alkyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups. For example, alkyl can be trifluoromethyl, difluoromethyl, or fluoromethyl, or alkyl can be substituted alkyl other than trifluoromethyl, difluoromethyl or fluoromethyl. Alkyl can be haloalkyl or alkyl can be substituted alkyl other than haloalkyl. The term “alkyl” also generally refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain. Thus, for example, “alkyl” also encompasses groups such as –[(CH2)pO]qH and the like. [0097] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having at least one carbon-carbon double bond and from 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. The double bonds can be be trans or cis orientation. The double bonds can be terminal or internal. The alkenyl group can be attached via the portion of the alkenyl group containing the double bond, e.g., vinyl, propen-1-yl and buten-1-yl, or the alkenyl group can be attached via a portion of the alkenyl group that does not contain the double bond, e.g., penten-4-yl. Examples of mono-valent (C2-C20)-alkenyl groups include those with from 1 to 8 carbon atoms such as vinyl, propenyl, propen-1-yl, propen-2-yl, butenyl, buten-1-yl, buten-2-yl, sec-buten-1-yl, sec-buten-3-yl, pentenyl, hexenyl, heptenyl and octenyl groups. Examples of branched mono- valent (C2-C20)-alkenyl groups include isopropenyl, iso-butenyl, sec-butenyl, t- butenyl, neopentenyl, and isopentenyl. Examples of straight chain bi-valent (C2- C20)alkenyl groups include those with from 2 to 6 carbon atoms such as -CHCH- , -CHCHCH2-, -CHCHCH2CH2-, and -CHCHCH2CH2CH2-. Examples of branched bi-valent alkyl groups include –C(CH3)CH- and –CHC(CH3)CH2-. Examples of cyclic alkenyl groups include cyclopentenyl, cyclohexenyl and cyclooctenyl. It is envisaged that alkenyl can also include masked alkenyl groups, precursors of alkenyl groups or other related groups. As such, where alkenyl groups are described it, compounds are also envisaged where a carbon-carbon double bond of an alkenyl is replaced by an epoxide or aziridine ring. Substituted alkenyl also includes alkenyl groups which are substantially tautomeric with a non-alkenyl group. For example, substituted alkenyl can be 2-aminoalkenyl, 2-alkylaminoalkenyl, 2-hydroxyalkenyl, 2- hydroxyvinyl, 2-hydroxypropenyl, but substituted alkenyl is also understood to include the group of substituted alkenyl groups other than alkenyl which are tautomeric with non-alkenyl containing groups. In some embodiments, alkenyl can be understood to include a combination of substituted and unsubstituted alkenyl. For example, alkenyl can be vinyl and substituted vinyl. For example, alkenyl can be vinyl and substituted (C3-C8)alkenyl. Alkenyl can also include substituted vinyl and unsubstituted (C3-C8)alkenyl. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio, alkoxy, and halogen groups. As further example, representative substituted alkenyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. In some embodiments, representative substituted alkenyl groups can be substituted from a set of groups including monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio and alkoxy, but not including halogen groups. Thus, in some embodiments alkenyl can be substituted with a non-halogen group. In some embodiments, representative substituted alkenyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. For example, alkenyl can be 1-fluorovinyl, 2-fluorovinyl, 1,2-difluorovinyl, 1,2,2-trifluorovinyl, 2,2- difluorovinyl, trifluoropropen-2-yl, 3,3,3-trifluoropropenyl, 1-fluoropropenyl, 1- chlorovinyl, 2-chlorovinyl, 1,2-dichlorovinyl, 1,2,2-trichlorovinyl or 2,2- dichlorovinyl. In some embodiments, representative substituted alkenyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups. [0098] The term “alkynyl” as used herein, refers to substituted or unsubstituted straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 50 carbon atoms, 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. Examples include, but are not limited to ethynyl, propynyl, propyn- 1-yl, propyn-2-yl, butynyl, butyn-1-yl, butyn-2-yl, butyn-3-yl, butyn-4-yl, pentynyl, pentyn-1-yl, hexynyl, Examples include, but are not limited to –CºCH, -CºC(CH3), -CºC(CH2CH3), -CH2CºCH, -CH2CºC(CH3), and -CH2CºC(CH2CH3) among others. [0099] The term “aryl” as used herein refers to substituted or unsubstituted univalent groups that are derived by removing a hydrogen atom from an arene, which is a cyclic aromatic hydrocarbon, having from 6 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 20 carbon atoms, 6 to about 10 carbon atoms or 6 to 8 carbon atoms. Examples of (C6-C20)aryl groups include phenyl, napthalenyl, azulenyl, biphenylyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, anthracenyl groups. Examples include substituted phenyl, substituted napthalenyl, substituted azulenyl, substituted biphenylyl, substituted indacenyl, substituted fluorenyl, substituted phenanthrenyl, substituted triphenylenyl, substituted pyrenyl, substituted naphthacenyl, substituted chrysenyl, and substituted anthracenyl groups. Examples also include unsubstituted phenyl, unsubstituted napthalenyl, unsubstituted azulenyl, unsubstituted biphenylyl, unsubstituted indacenyl, unsubstituted fluorenyl, unsubstituted phenanthrenyl, unsubstituted triphenylenyl, unsubstituted pyrenyl, unsubstituted naphthacenyl, unsubstituted chrysenyl, and unsubstituted anthracenyl groups. Aryl includes phenyl groups and also non- phenyl aryl groups. From these examples, it is clear that the term (C6-C20)aryl encompasses mono- and polycyclic (C6-C20)aryl groups, including fused and non- fused polycyclic (C6-C20)aryl groups. [00100] The term “heterocyclyl” as used herein refers to substituted aromatic, unsubstituted aromatic, substituted non-aromatic, and unsubstituted non-aromatic rings containing 3 or more atoms in the ring, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6) or 6 to 8 carbon atoms (C6-C8). A heterocyclyl group designated as a C2-heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to piperidynyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups. For example, heterocyclyl groups include, without limitation:
Figure imgf000065_0001
wherein X1 represents H, (C1- C20)alkyl, (C6-C20)aryl or an amine protecting group (e.g., a t-butyloxycarbonyl group) and wherein the heterocyclyl group can be substituted or unsubstituted. A nitrogen-containing heterocyclyl group is a heterocyclyl group containing a nitrogen atom as an atom in the ring. In some embodiments, the heterocyclyl is other than thiophene or substituted thiophene. In some embodiments, the heterocyclyl is other than furan or substituted furan. [00101] The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. Thus, alkyoxy also includes an oxygen atom connected to an alkyenyl group and oxygen atom connected to an alkynyl group. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. [00102] The term “aryloxy” as used herein refers to an oxygen atom connected to an aryl group as are defined herein. [00103] The term “aralkyl” and “arylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl, biphenylmethyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. [00104] The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. [00105] The term “amine” and “amino” as used herein refers to a substituent of the form -NH2, -NHR, -NR2, -NR3 +, wherein each R is independently selected, and protonated forms of each, except for -NR3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. [00106] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, group or the like. [00107] The term “formyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to a hydrogen atom. [00108] The term “alkoxycarbonyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyl group. Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyenyl group. Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkynyl group. In a further case, which is included in the definition of alkoxycarbonyl as the term is defined herein, and is also included in the term “aryloxycarbonyl,” the carbonyl carbon atom is bonded to an oxygen atom which is bonded to an aryl group instead of an alkyl group. [00109] The term “arylcarbonyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to an aryl group. [00110] The term “alkylamido” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to a nitrogen group which is bonded to one or more alkyl groups. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more aryl group instead of, or in addition to, the one or more alkyl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to an nitrogen atom which is bonded to one or more alkenyl group instead of, or in addition to, the one or more alkyl and or/aryl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more alkynyl group instead of, or in addition to, the one or more alkyl, alkenyl and/or aryl group. [00111] The term “carboxy” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to a hydroxy group or oxygen anion so as to result in a carboxylic acid or carboxylate. Carboxy also includes both the protonated form of the carboxylic acid and the salt form. For example, carboxy can be understood as COOH or CO2H. [00112] The term “amido” as used herein refers to a group having the formula C(O)NRR, wherein R is defined herein and can each independently be, e.g., hydrogen, alkyl, aryl or each R, together with the nitrogen atom to which they are attached, form a heterocyclyl group. [00113] The term “alkylthio” as used herein refers to a sulfur atom connected to an alkyl, alkenyl,or alkynyl group as defined herein. [00114] The term “arylthio” as used herein refers to a sulfur atom connected to an aryl group as defined herein. [00115] The term “alkylsulfonyl” as used herein refers to a sulfonyl group connected to an alkyl, alkenyl,or alkynyl group as defined herein. [00116] The term “alkylsulfinyl” as used herein refers to a sulfinyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein. [00117] The term “dialkylaminosulfonyl” as used herein refers to a sulfonyl group connected to a nitrogen further connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups. [00118] The term “dialkylamino” as used herein refers to an amino group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups. [00119] The term “dialkylamido” as used herein refers to an amido group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups. [00120] The term “substituted” as used herein refers to a group that is substituted with one or more groups including, but not limited to, the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CH2OH), OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, methylenedioxy, ethylenedioxy, (C3- C20)heteroaryl, N(R)2, Si(R)3, SR, SOR, SO2R, SO2N(R)2, SO3R, P(O)(OR)2, OP(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, C(O)N(R)OH, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0- 2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, or C(=NOR)R wherein R can be hydrogen, (C1-C20)alkyl, (C6-C20)aryl, heterocyclyl or polyalkylene oxide groups, such as polyalkylene oxide groups of the formula -(CH2CH2O)f-R-OR, -(CH2CH2CH2O)g-R-OR, -(CH2CH2O)f(CH2CH2CH2O)g-R-OR each of which can, in turn, be substituted or unsubstituted and wherein f and g are each independently an integer from 1 to 50 (e.g., 1 to 10, 1 to 5, 1 to 3 or 2 to 5). Substituted also includes a group that is substituted with one or more groups including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. Where there are two or more adjacent substituents, the substituents can be linked to form a carbocyclic or heterocyclic ring. Such adjacent groups can have a vicinal or germinal relationship, or they can be adjacent on a ring in, e.g., an ortho-arrangement. Each instance of substituted is understood to be independent. For example, a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl. It is envisaged that a substituted group can be substituted with one or more non-fluoro groups. As another example, a substituted group can be substituted with one or more non-cyano groups. As another example, a substituted group can be substituted with one or more groups other than haloalkyl. As yet another example, a substituted group can be substituted with one or more groups other than tert-butyl. As yet a further example, a substituted group can be substituted with one or more groups other than trifluoromethyl. As yet even further examples, a substituted group can be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than thiophenyl, or other than nitrophenyl, or groups meeting a combination of such descriptions. Further, substituted is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups. [00121] In some instances, the compounds described herein (e.g., the compounds of the Formulae (1)-(3) and (A)-(M) can contain chiral centers. All diastereomers of the compounds described herein are contemplated herein, as well as racemates. [00122] As used herein, the term “salts” and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. [00123] Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference. [00124] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. [00125] The term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH). [00126] As used herein, the term “subject” or “patient” refers to any organism to which a composition described herein can be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Subject refers to a mammal receiving the compositions disclosed herein or subject to disclosed methods. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs. [00127] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. [00128] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading can occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. [00129] In the methods described herein, the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. [00130] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. [00131] Each embodiment described above is envisaged to be applicable in each combination with other embodiments described herein. For example, embodiments corresponding to Formula (I) are equally envisaged as being applicable to Formulae (A)-(M). [00132] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present disclosure. Thus, it should be understood that although the present disclosure has been specifically disclosed by specific embodiments and optional features, modification and variation of the concepts herein disclosed can be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present disclosure [00133] The invention is now described with reference to the following Examples. The following working examples therefore, are provided for the purpose of illustration only and specifically point out certain embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. Therefore, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Examples [00134] The present invention can be better understood by reference to the following examples which are offered by way of illustration. The present invention is not limited to the examples given herein. Biological methods b-Arrestin assay [00135] CHO (Chinese Hamster Ovary) cells stably expressing mEDG5 (mouse-S1PR2) receptor based on enzyme fragment complementation technology were purchased from Discover X, USA and cultured according to the manufacturer’s instruction. b-Arrestin assay was performed using this stable cell line to determine the IC50 value of the compounds with minor modifications in manufacturer’s instruction. Briefly, 1 x 104 cells/well reconstituted in a final volume of 100µl of cell plating reagent were plated into a 96 well white clear bottom plate (CorningTM CostarTM , USA) and incubated 16 h at 37 °C in a humidified 95 % air and 5 % CO2 incubator. Compounds were diluted in 0.4 % fatty acid free BSA (Sigma Aldrich, USA) prepared in 1XPBS, pH7.4 (GIBCO). Plated cells were first pretreated with the compounds for 30 min. Thereafter, pretreated cells were exposed to 5µl of agonist treatment i.e, Sphingosine1- phosphate(S1P) (Enzo Lifescience, USA) at EC80 concentration and incubated for 90 min under normal incubation conditions. Then, 55 µL of substrate solution was added to each well of the assay plate and incubated further for 60 min in dark at room temperature. Thereafter, the intensity of luminescence was measured using a luminometer (Promega,USA). The IC50 value for each of the compounds with antagonist activity was calculated using the appropriate statistical parameters in Prism/Graphpad7. Functional assay: E-Selectin assay and Dextran leakage assay 1) E-Selectin assay Cell culture and treatment [00136] The mouse brain endothelial cell line, bEnd.3 was obtained from ATCC and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10 % fetal bovine serum (ATCC), 1x GlutaMax (GIBCO, USA), and 100 U/ml penicillin/streptomycin (GIBCO, USA) at 37 °C in a humidified 95 % air and 5 % CO2 incubator. For the assay, 5X104 cells were seeded in a final volume of 250µl of complete DMEM in each well of a 48 well plate and allowed to grow until 80% confluency. Then complete media was replenished with serum-deprived DMEM culture media and allowed to equilibrate for 3hours prior to treatments. Then cells (in serum starved condition) were first pre-treated with indicated concentrations of JTE-013 (Cayman Chemical Co., USA):
Figure imgf000073_0001
or, synthesized compounds diluted in 0.4 % fatty acid free BSA (Millipore-Sigma) prepared in 1XPBS, pH7.4 (GIBCO, USA) independently for 30 min and incubated under normal culture conditions. Thereafter, pre-treated cells were exposed to 2 ng/ml of recombinant muTNF-a (R&D Systems, USA) for 6 h under normal culture conditions. Finally, cells were harvested for total RNA isolation. RNA isolation [00137] First, cells were gently rinsed with ice-cold PBS on ice twice after the treatment to remove media and debris. Then 100µl of lysis buffer reagent (Qiagen, Germany) was added to each well and incubated for 3 min at room temperature. Thereafter, RNA was extracted from the total cell lysate with RNeasy Kit (QIAGEN, Germany) constituting on-column DNAseI digestion according to the manufacturer’s instruction. Finally, the concentration of extracted total RNA from respective samples were measured with VarioskanTM Multimode plate reader (Thermo Scientific, USA) and RNA preps were processed for cDNA synthesis. Reverse transcription of RNA and quantitative real-time (qRT) PCR 100 ng of total RNA was used as template to prepare cDNA for each sample in the presence of Verso-Reverse Transcriptase and Random Hexamer Primers (Thermo Scientific, USA) at 42 °C for 30 min in a final reaction volume of 20µl. Then, the cDNA prep was diluted 5-fold with nuclease free water to obtain a final volume of 100µl. SYBR Green chemistry with Rox dye signal normalization (Quanta bio, MA, USA) -based quantitative PCR was performed to quantify the expression of mouse specific pro-inflammatory gene E-selectin with primers (Forward: CCGTCCCTTGGTAGTTGCA, Reverse: CAAGTAGAGCAATGAGGACGATGT) and housekeeping control 18srRNA using primers (Forward: ACCTCTCGAAGTGTTGGATACAG, Reverse: TTCACTAATGACACAAACGTGATTC). qPCR reactions were run in triplicates on a 96 well plate with 2µl of cDNA as template in a final reaction volume of 10µl per well for each sample. Finally, the plate was loaded on to the ABI-7500 Sequence Detection System PCR machine (Applied Biosystems, USA) as per manufacturer’s instructions. The expression levels (Ct values) of E-selectin were normalized to expression levels of 18s rRNA as DCt values. For samples and controls, the relative expression levels of E-selectin were expressed as 2-D Ct values by comparing the DCt values of TNF-alpha treated control to the compound+TNF-alpha treated samples. Fold change in E-selectin expression was calculated by comparing the 2-D Ct values of the treated sample with that of respective experimental control. 2) Dextran leakage assay [00138] bEND3 cells were grown on the Transwell Multiple Well Plate with Permeable Polyester Membrane Inserts, pore size 0.4 mM, culture area 0.33cm2 (Corning, USA) coated with 50 ^g/ml of fibronectin (EMD Millipore, USA). Upon confluency, cells plated in the insert (upper chamber) were treated with appropriate concentrations of the compounds (at a final volume of 5 ml) prepared in 0.4% fatty acid free BSA (Sigma Aldrich, USA) or, complete DMEM media. Thereafter, cells were incubated for 30 min followed by treatment of 10 ng/ml of recombinant muTNF-a (R&D Systems) for 6hrs. To assess the leakage of the endothelial cells, of conjugated 4.4 kDa Tetramethylrhodamine Isothiocyanate (TMR)-Dextran (Sigma Aldrich, USA) dissolved in 5 ml of serum free medium to give a final concentration of 100mg/ml was added to each insert with compound treated cells and incubated for 1 hr at 37 °C in dark. The protective effects of the compounds were assessed based on the leakage of dextran from the upper chamber to the lower chamber containing complete media of each well. The fluorescence intensity was measured at Ex550nm/Em570nm with a fluorescence reader (SpectraMax M2, Molecular Devices) by taking 100 ml of medium from the lower chamber. Biological data
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
[00139] The compounds described herein can be synthesized via general Schemes 1-7 and the synthetic protocols provided herein.
Figure imgf000101_0002
Figure imgf000101_0001
Scheme 1 – General scheme for Formula I-I [00140] As described in Scheme 1, amine A was acylated with 2,2,2- trichloroethoxycarbocyl chloride to give carbamate B. Coupling of B with corresponding amine C4 gave formula I-I.
. V I-I o t I I- I al u mr oF r of e m 0 eh 0 1 c sl a re ne G – 2 e m eh c S
Figure imgf000102_0001
[00141] As described in Scheme 2, dichloropyridine D was subject to SNAr reaction to give mono-chlorobenzene E. Mono-chloropyridine E was subject to SNAr reaction to give pyridine F. Pyridine F was reacted with DPPA then amine C to give urea I-II. Urea I-II was hydrolyzed to give carboxylic acid I-III. Subsequent amination gives I-IV.
Figure imgf000103_0001
Scheme 3 – Synthesis for intermediate A1-1 [00142] As described in Scheme 3, phenol 1 was subject to Mitsunobu reaction to give 2. Subsequent reduction gives intermediate A1-1.
Figure imgf000104_0001
[00143] As described in Scheme 4, difluorobenzene 3 was subject to SNAr reaction to give mono-fluorobenzene 4. Mono-fluorobenzene was subject to SNAr reaction to give 5. Subsequent reduction gives intermediate A-2.
4 0 1
Figure imgf000106_0001
[00144] As described in Scheme 5, dinitrobenzene 6 was subject to SNAr reaction to give mono-nitrobenzene 7. Subsequent reduction gives intermediate A-3.
Figure imgf000108_0001
[00145] As described in Scheme 6 trichloropyridine 8 was subject to SNAr reaction to give di-chlorobenzene 9 and 11. Di-chloropyridine 9 and 11 were subject to SNAr reaction to give mono-chloropyridine 10 and 12. Mono- chloropyridine 10 and 12 was subject to coupling reaction with BocNH2 followed by deprotection to give A-4 and A-5.
8 0 1
Figure imgf000110_0001
[00146] As described in Scheme 7, bromide G was subject to cupper mediated coupling reaction to give adduct H. Palladium-catalyzed coupling using NHBoc gives I. Subsequent deprotection of Boc gives A-6. Alternatively, nitro J was subject to cupper mediated coupling reaction to give adduct K. Subsequent reduction gives A-6.
0 11
Figure imgf000112_0001
[00147] As described in Scheme 8, bromide G-1 was subject to cupper mediated coupling reaction to give adduct H-1. Palladium-catalyzed coupling using NHBoc gives I-1. Subsequent deprotection of Boc gives A-7. Alternatively, nitro J-1 was subject to cupper mediated coupling reaction to give adduct K-1. Subsequent reduction gives A-6. Experimental procedure Example 1: 2-(4-(3-(4-Fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid [00148] The target compound was obtained in a similar manner to step G to I of Example 63 using methyl 2-(4-(3-amino-5-(4- fluorophenoxy)phenoxy)phenyl)-2-methylpropanoate. MS: (M+H+): 551.4. Example 2: N-(3-(4-(1-(Ethylamino)-2-methyl-1-oxopropan-2-yl)phenoxy)-5-(4- fluorophenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1-carboxamide [00149] DIPEA (95.2 uL) was added to the solution of 2-(4-(3-(4- fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid (100 mg), 2 M EtNH2 (454 uL) and COMU (91.9 mg) in DMF (4.0 mL) at rt, and the mixture was stirred at rt for 1 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (hexane/EtOAc = 3/2 to 1/9) to give the target compound (76.2 mg) as a solid. [00150] 1H NMR (500 MHz, CDCl3) d: 7.36–7.31 (m, 2H), 7.06–6.99 (m, 6H), 6.91 (t, J = 2.0 Hz, 1H), 6.79 (t, J = 2.1 Hz, 1H), 6.35 (t, J = 2.2 Hz, 1H), 6.15 (s, 1H), 5.24 (s, 1H), 3.64–3.50 (m, 3H), 3.34 (d, J = 10.9 Hz, 1H), 3.24 (qd, J = 7.3, 5.7 Hz, 2H), 2.09–1.99 (m, 1H), 1.99–1.85 (m, 2H), 1.57 (s, 8H), 1.04 (dt, J = 17.6, 7.0 Hz, 9H). Example 3: Ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine- 1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00151] The target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and ethanol. [00152] 1H NMR (500 MHz, CDCl3) d: 7.35–7.29 (m, 2H), 7.06–6.96 (m, 5H), 6.90 (t, J = 2.1 Hz, 1H), 6.77 (t, J = 2.1 Hz, 1H), 6.33 (t, J = 2.2 Hz, 1H), 6.12 (s, 1H), 5.87–5.77 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.65–3.51 (m, 2H), 3.34 (d, J = 10.9 Hz, 1H), 1.90 (s, 2H), 1.59 (d, J = 9.1 Hz, 11H), 1.22 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 6.6 Hz, 6H). Example 4: Isopropyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00153] To a mixture of 2-methyl-6-nitrobenzoic anhydride (125 mg), DMAP (11.1 mg), and DMF (3.0 mL) was added Et3N (25.2 uL). Then 2-(4-(3-(4- fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid (100 mg) and iPrOH (5.0 mL) were added, and the mixture was stirred at 70°C overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purified by silica gel column chromatography (hexane/EtOAc = 4/1 to 2/3) to give the target compound (101 mg) as a solid. [00154] 1H NMR (500 MHz, CDCl3) d: 7.33–7.30 (m, 2H), 7.08–6.95 (m, 6H), 6.90 (t, J = 2.1 Hz, 1H), 6.76 (t, J = 2.1 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 6.13 (s, 1H), 5.01 (p, J = 6.2 Hz, 1H), 3.71–3.50 (m, 4H), 3.34 (d, J = 10.9 Hz, 1H), 2.07–2.00 (m, 1H), 1.97–1.87 (m, 2H), 1.62 (dd, J = 8.1, 6.3 Hz, 3H), 1.17 (dd, J = 15.1, 6.2 Hz, 10H), 1.02 (t, J = 6.7 Hz, 6H). Example 5: 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid [00155] The target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and (2R)-2-amino-2- phenyl-ethanol. [00156] 1H NMR (500 MHz, CDCl3) d: 7.46 (d, J = 8.7 Hz, 4H), 7.32–7.28 (m, 4H), 7.25–7.00 (m, 20H), 6.43 (q, J = 2.1 Hz, 2H), 6.38 (dt, J = 10.9, 2.1 Hz, 2H), 6.15 (d, J = 9.5 Hz, 4H), 4.95 (d, J = 4.1 Hz, 2H), 3.79–3.68 (m, 3H), 3.53– 3.31 (m, 4H), 3.13 (dd, J = 47.5, 10.8 Hz, 2H), 1.99–1.77 (m, 5H), 1.63 (d, J = 1.9 Hz, 13H), 1.60–1.48 (m, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.02–0.87 (m, 15H). Example 6: 2-Hydroxyethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00157] The target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and ethylene glycol. [00158] 1H NMR (500 MHz, CDCl3) d: 7.39–7.33 (m, 2H), 7.29 (s, 1H), 7.23–7.16 (m, 2H), 7.08–7.00 (m, 3H), 6.77 (t, J = 2.1 Hz, 1H), 6.70 (t, J = 2.1 Hz, 1H), 6.37 (t, J = 2.2 Hz, 1H), 6.16 (s, 1H), 4.25–4.19 (m, 2H), 3.74–3.68 (m, 2H), 3.61–3.49 (m, 3H), 3.30 (d, J = 10.9 Hz, 1H), 2.38 (s, 2H), 2.04–1.84 (m, 2H), 1.65–1.56 (m, 7H), 1.01 (t, J = 6.6 Hz, 6H). Example 7: Methyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine- 1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00159] The target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and methanol. [00160] 1H NMR (500 MHz, CDCl3) d: 7.34–7.29 (m, 2H), 7.09–6.96 (m, 6H), 6.90 (t, J = 2.1 Hz, 1H), 6.77 (t, J = 2.1 Hz, 1H), 6.33 (t, J = 2.2 Hz, 1H), 6.11 (s, 1H), 3.69 (s, 3H), 3.56 (dd, J = 19.7, 11.7 Hz, 3H), 3.35 (d, J = 10.9 Hz, 1H), 2.08–1.85 (m, 1H), 1.59 (d, J = 5.1 Hz, 10H), 1.02 (t, J = 6.6 Hz, 6H). Example 8: N-(3-(4-Fluorophenoxy)-5-(4-(1-(4-hydroxypiperidin-1-yl)-2-methyl- 1-oxopropan-2-yl)phenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1- carboxamide [00161] The target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and piperidin-4-ol. [00162] 1H NMR (500 MHz, CDCl3) d: 7.27–7.22 (m, 2H), 7.09–7.00 (m, 7H), 6.44 (t, J = 2.1 Hz, 1H), 6.39 (t, J = 2.2 Hz, 1H), 6.10 (s, 1H), 4.43 (s, 1H), 3.76–3.46 (m, 7H), 3.31–3.22 (m, 1H), 2.86 (s, 1H), 2.05–1.84 (m, 5H), 1.58 (s, 11H), 1.01 (dd, J = 6.6, 5.1 Hz, 6H). Example 9: Isopentyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate [00163] The target compound was obtained in a similar manner to Example 4 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and 3-methyl-1-butanol. [00164] 1H NMR (500 MHz, CDCl3) d: 7.34–7.30 (m, 2H), 7.08–6.96 (m, 6H), 6.90 (t, J = 2.0 Hz, 1H), 6.76 (t, J = 2.0 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 6.11 (s, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.66–3.51 (m, 3H), 3.34 (d, J = 10.8 Hz, 1H), 2.06–1.85 (m, 2H), 1.67–1.60 (m, 10H), 1.48 (q, J = 6.8 Hz, 2H), 1.02 (t, J = 6.6 Hz, 6H), 0.88 (d, J = 6.6 Hz, 6H). Example 10: 2-(Phosphonooxy)ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate sodium salt A) 2-((Bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3- hydroxy-3-isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2- methylpropanoate [00165] To a solution of tetrabenzyl diphosphate (271 mg), 2-hydroxyethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoate (120 mg) and Ag2O (19.7 uL) in CH2Cl2 (10 mL) was added Bu4NI (149 mg), and the mixture was stirred at rt for 48 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purifed by sílica gel chromatography to give the target compound (100 mg) as an oil. [00166] 1H NMR (500 MHz, CDCl3) d: 7.38–7.34 (m, 5H), 7.28 (s, 3H), 7.04 (td, J = 7.2, 6.7, 3.5 Hz, 8H), 6.94 (d, J = 8.7 Hz, 1H), 6.77 (t, J = 2.1 Hz, 1H), 6.72–6.56 (m, 2H), 6.39–6.32 (m, 1H), 6.17 (s, 1H), 4.93 (d, J = 8.0 Hz, 2H), 4.25– 4.19 (m, 3H), 3.74–3.68 (m, 2H), 3.52 (d, J = 10.8 Hz, 4H), 3.30 (dd, J = 10.9, 5.9 Hz, 1H), 2.07 (d, J = 6.6 Hz, 2H), 1.89 (pd, J = 11.8, 10.8, 6.7 Hz, 3H), 1.57 (s, 3H), 1.00 (dt, J = 8.2, 6.6 Hz, 9H). B) 2-(Phosphonooxy)ethyl 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoate sodium salt [00167] To a mixture of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-(3-(4- fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoate (100 mg) and MeOH (10 mL) was added Pd/C (14.2 mg), and the mixture was stirred at rt under H2 atmosphere overnight. The solution was filtrated by Celite and concentrarted. The residue was dissolved in MeOH (10 mL) and 1 M NaOH (117 uL) was added. The mixture was stirred at 0°C for 30 min. The mixture was concentrated and the resulting precipitate was collected to give the target compound (21 mg) as a solid. [00168] 1H NMR (500 MHz, CD3OD) d: 7.46–7.34 (m, 3H), 7.13–6.97 (m, 7H), 6.94–6.77 (m, 2H), 6.26–6.19 (m, 1H), 4.27 (t, J = 5.6 Hz, 1H), 4.15 (t, J = 5.0 Hz, 1H), 3.99 (d, J = 5.8 Hz, 1H), 3.70 (t, J = 5.0 Hz, 1H), 3.58–3.47 (m, 4H), 1.58 (d, J = 11.1 Hz, 9H), 1.01 (t, J = 6.0 Hz, 8H). Example 11: N-(3-(4-Fluorophenoxy)-5-(4-(1-(4-hydroxypiperidin-1-yl)-2- methyl-1-oxopropan-2-yl)phenoxy)phenyl)-3-hydroxy-3-isobutylpyrrolidine-1- carboxamide [00169] The target compound was obtained in a similar manner to Example 2 using 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid and 2-aminoethan-1-ol. [00170] 1H NMR (500 MHz, CD3OD) d: 7.38 (d, J = 8.7 Hz, 2H), 7.13–7.00 (m, 6H), 6.95–6.88 (m, 2H), 6.23 (s, 1H), 3.56 (dt, J = 9.1, 3.7 Hz, 5H), 3.32–3.28 (m, 3H), 1.61–1.52 (m, 8H), 1.01 (t, J = 6.6 Hz, 9H). Example 12: 2-(4-(3-(4-Fluorophenoxy)-5-(3-hydroxy-3-isobutylpyrrolidine-1- carboxamido)phenoxy)phenyl)-2-methylpropanoic acid sodium salt [00171] A mixture of 2-(4-(3-(4-fluorophenoxy)-5-(3-hydroxy-3- isobutylpyrrolidine-1-carboxamido)phenoxy)phenyl)-2-methylpropanoic acid (225 mg), NaOH (16.4 mg), and EtOH (2.0 mL) was stirred at 25°C for 0.25 h . The mixture was concentrated, and the residue was collected to give the target compound (220 mg) as a solid. [00172] 1H NMR (500 MHz, DMSO-d6) d: 8.26 (s, 1H), 7.47–7.33 (m, 2H), 7.24 (t, J = 8.7 Hz, 2H), 7.15–7.00 (m, 3H), 7.00–6.83 (m, 4H), 6.17 (t, J = 2.3 Hz, 1H), 4.58 (s, 1H), 3.62 (t, J = 6.1 Hz, 1H), 3.47–3.36 (m, 4H), 3.12 (d, J = 10.9 Hz, 1H), 1.93–1.63 (m, 3H), 1.45 (dq, J = 14.0, 7.2, 6.5 Hz, 2H), 1.35 (s, 8H), 1.05 (d, J = 6.0 Hz, 6H), 0.93 (t, J = 6.5 Hz, 8H). Example 13: Methyl 4-((6-(4-fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)pyridin-2-yl)oxy)benzoate A) tert-Butyl 2-chloro-6-(4-(methoxycarbonyl)phenoxy)isonicotinate [00173] A solution of methyl 4-hydroxybenzoate (307 mg), tert-butyl 2,6- dichloropyridine-4-carboxylate (500 mg), and Cs2CO3 (658 mg) in DMF was stirred at rt for 24 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purified by silica gel column chromatography to give the target compound (635 mg) as an oil. 1H NMR (500 MHz, CDCl3) d: 8.17–8.07 (m, 2H), 7.58 (d, J = 1.0 Hz, 1H), 7.38 (d, J = 1.0 Hz, 1H), 7.25–7.19 (m, 2H), 3.95 (s, 4H), 1.58 (d, J = 0.9 Hz, 9H). B) tert-Butyl 2-(4-fluorophenoxy)-6-(4-(methoxycarbonyl)phenoxy)isonicotinate [00174] A mixture of tert-butyl 2-chloro-6-(4- (methoxycarbonyl)phenoxy)isonicotinate (635 mg), 4-fluorophenol (196 mg), and Cs2CO3 (570 mg) in DMSO (5.0 mL) was stirred at 100°C for 16 h . The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purified by silica gel column chromatography to give the target compound (351 mg) as a solid. MS: (M+H+): 440.3. C) 2-(4-Fluorophenoxy)-6-(4-(methoxycarbonyl)phenoxy)isonicotinic acid [00175] The target compound was obtained in a similar manner to step F in Example 63 using tert-butyl 2-(4-fluorophenoxy)-6-(4- (methoxycarbonyl)phenoxy)isonicotinate. [00176] 1H NMR (500 MHz, DMSO-d6) d: 13.94 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 6.5 Hz, 4H), 7.12–7.04 (m, 2H), 3.87 (s, 3H). D) Methyl 4-((6-(4-fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoate [00177] A mixture of 4-isobutylpiperidin-4-ol (37.4 mg), 2-(4- fluorophenoxy)-6-(4-(methoxycarbonyl)phenoxy)isonicotinic acid (83 mg), and triethylamine (60 uL) in toluene (2.0 mL) was stirred at 100°C for 1 h. To the mixture was added a solution of 4-isobutylpiperidin-4-ol (37.5 mg) in THF (2.0 mL), and the mixture was stirred at 100°C for 1 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, concentrated, and purified by sílica gel column chromatography to give the target compound (71.0 mg) as a solid. [00178] 1H NMR (500 MHz, CDCl3) d: 8.06–7.95 (m, 2H), 7.16–7.09 (m, 2H), 7.07–6.95 (m, 5H), 6.61–6.48 (m, 2H), 4.44 (dt, J = 13.4, 3.8 Hz, 1H), 3.94 (s, 4H), 3.57–3.43 (m, 2H), 3.25 (td, J = 12.6, 3.6 Hz, 1H), 1.86 (dt, J = 12.9, 6.5 Hz, 1H), 1.80–1.54 (m, 6H), 1.55–1.47 (m, 2H). Example 14: 4-((6-(4-Fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid [00179] The target compound was obtained in a similar manner to step I in Example 63 using methyl 4-((6-(4-fluorophenoxy)-4-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)pyridin-2-yl)oxy)benzoate. [00180] 1H NMR (500 MHz, DMSO-d6) d: 12.92 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.19 (dq, J = 16.5, 8.7 Hz, 7H), 6.73 (d, J = 16.2 Hz, 2H), 4.24 (s, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.12 (t, J = 11.6 Hz, 1H), 1.83 (dq, J = 13.5, 6.7 Hz, 1H), 1.57 (d, J = 13.3 Hz, 1H), 1.46 (d, J = 9.3 Hz, 3H), 1.05 (d, J = 6.1 Hz, 2H), 0.93 (d, J = 6.5 Hz, 6H). Example 15: 4-((6-Butoxy-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid A) Methyl 4-((6-butoxy-4-((tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)benzoate [00181] The target compound was obtained in a similar manner to step B in Example 13 using methyl 4-((4-((tert-butoxycarbonyl)amino)-6-chloropyridin-2- yl)oxy)benzoate and butan-1-ol. [00182] 1H NMR (500 MHz, DMSO-d6) d: 8.18–7.94 (m, 2H), 7.32 (dd, J = 8.7, 2.1 Hz, 2H), 6.94 (d, J = 1.7 Hz, 2H), 4.06 (d, J = 6.1 Hz, 3H), 3.87 (s, 3H), 1.56 (s, 11H), 1.29 (q, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). B) 4-((6-Butoxy-4-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)pyridin-2- yl)oxy)benzoic acid [00183] The target compound was obtained in a similar manner to step C to D in Example 13 using methyl 4-((6-butoxy-4-((tert- butoxycarbonyl)amino)pyridin-2-yl)oxy)benzoate. MS: (M+H+): 486.4. Example 16: 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid A) Methyl 4-(3-nitro-5-(trifluoromethyl)phenoxy)benzoate [00184] A mixture of methyl 4-hydroxybenzoate (3.3 g), 1,3-dinitro-5- (trifluoromethyl)benzene (5.1 g), K2CO3 (3.3 g), and DMF (30 mL) was stirred at 80°C for 4 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified by silica gel column to give the target compound (6.8 g) as a solid. MS: (M+H+): 365.3. B) 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid [00185] The target compound was obtained in a similar manner to Step F to I in Example 63 using (1s,3s)-3-(3-(4-(cyclopropylmethyl)-4-hydroxypiperidine- 1-carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylic acid and piperidin-4-ol. [00186] 1H NMR (500 MHz, DMSO-d6) d: 12.89 (s, 1H), 8.87 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 2.2 Hz, 1H), 4.14 (s, 1H), 3.78 (dt, J = 13.3, 3.8 Hz, 2H), 3.23–3.07 (m, 2H), 1.89–1.77 (m, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.40 (td, J = 12.6, 4.3 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). Example 17: 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid [00187] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and piperidin-4-ol. [00188] 1H NMR (500 MHz, DMSO-d6) d: 8.88 (s, 1H), 7.78 (s, 1H), 7.62– 7.38 (m, 3H), 7.11 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 4.81 (s, 1H), 4.15 (s, 1H), 4.00 (s, 1H), 3.77 (t, J = 12.8 Hz, 3H), 3.67–3.49 (m, 1H), 3.17 (q, J = 13.8, 12.4 Hz, 4H), 1.87–1.66 (m, 3H), 1.58–1.35 (m, 5H), 1.05 (d, J = 6.1 Hz, 4H), 0.93 (d, J = 6.7 Hz, 6H). Example 18: N-(3-(4-Fluorophenoxy)-5-(4-(4-hydroxypiperidine-1- carbonyl)phenoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00189] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid and piperidin-4-ol. [00190] 1H NMR (500 MHz, DMSO-d6) d: 8.58 (s, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 8.7 Hz, 2H), 7.19–6.94 (m, 6H), 6.27 (d, J = 2.4 Hz, 1H), 4.80 (d, J = 4.0 Hz, 1H), 4.11 (s, 1H), 3.73 (tt, J = 12.8, 4.0 Hz, 3H), 3.27–3.02 (m, 4H), 1.80 (ddd, J = 22.1, 14.3, 7.8 Hz, 3H), 1.56–1.10 (m, 10H), 0.92 (d, J = 6.6 Hz, 6H). Example 19: 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid The target compound was obtained in a similar manner to step G to I of Example 63 using methyl 4-(3-amino-5-(4-fluorophenoxy)phenoxy)benzoate. 1H NMR (500 MHz, DMSO-d6) d: 12.86 (s, 1H), 8.59 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 8.7 Hz, 2H), 7.15 (dd, J = 9.0, 4.5 Hz, 2H), 7.13–7.05 (m, 3H), 7.03 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 4.11 (s, 1H), 3.73 (dd, J = 13.4, 4.0 Hz, 2H), 3.20–2.99 (m, 2H), 1.81 (dp, J = 12.8, 6.4 Hz, 1H), 1.52–1.17 (m, 6H), 0.91 (d, J = 6.6 Hz, 6H). Example 20: 4-Hydroxy-N-(3-(4-((2-(2- hydroxyethoxy)ethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide [00191] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-aminoethoxy)ethanol. [00192] 1H NMR (500 MHz, DMSO-d6) d: 8.85 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.51 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.94 (s, 1H), 4.61 (t, J = 5.5 Hz, 1H), 3.78 (dt, J = 13.7, 3.9 Hz, 2H), 3.53 (dt, J = 16.9, 5.7 Hz, 4H), 3.45 (dt, J = 16.6, 5.4 Hz, 4H), 3.15 (t, J = 12.5 Hz, 2H), 1.82 (q, J = 6.2 Hz, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.39 (td, J = 12.7, 4.2 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 1.05 (d, J = 6.1 Hz, 1H), 0.92 (d, J = 6.6 Hz, 6H). Example 21: 4-Hydroxy-N-(3-(4-((2-(2-(2- hydroxyethoxy)ethoxy)ethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide [00193] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-(2-aminoethoxy)ethoxy)ethanol. [00194] 1H NMR (500 MHz, DMSO-d6) d: 8.85 (s, 1H), 8.53 (t, J = 5.7 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.51 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 4.59 (t, J = 5.5 Hz, 1H), 6.94 (s, 1H), 4.15 (s, 1H), 3.78 (d, J = 13.2 Hz, 2H), 3.66– 3.39 (m, 12H), 3.15 (t, J = 12.3 Hz, 2H), 1.82 (dq, J = 13.1, 6.5 Hz, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.39 (td, J = 13.2, 12.8, 4.2 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 22: 4-Hydroxy-N-(3-(4-((2-hydroxyethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-isobutylpiperidine-1-carboxamide [00195] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-aminoethanol. [00196] 1H NMR (500 MHz, DMSO-d6) d: 8.88 (s, 1H), 7.78 (s, 1H), 7.62– 7.38 (m, 3H), 7.11 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 4.81 (s, 1H), 4.15 (s, 1H), 4.00 (s, 1H), 3.77 (t, J = 12.8 Hz, 3H), 3.67–3.49 (m, 1H), 3.17 (q, J = 13.8, 12.4 Hz, 4H), 1.87–1.66 (m, 3H), 1.58–1.35 (m, 5H), 1.05 (d, J = 6.1 Hz, 4H), 0.93 (d, J = 6.7 Hz, 6H). Example 23: N-(3-(4-(Bis(2-hydroxyethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00197] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(2-hydroxyethylamino)ethanol. [00198] 1H NMR (500 MHz, DMSO-d6) d: 8.87 (s, 1H), 7.77 (s, 1H), 7.54– 7.45 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 6.93 (s, 1H), 4.82 (q, J = 4.6 Hz, 2H), 4.15 (s, 1H), 3.78 (dt, J = 13.4, 3.8 Hz, 2H), 3.62 (s, 2H), 3.50 (ddt, J = 17.4, 11.8, 5.7 Hz, 4H), 3.39 (td, J = 12.1, 10.1, 5.9 Hz, 2H), 3.21–3.11 (m, 2H), 1.89–1.77 (m, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.40 (td, J = 12.0, 3.8 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). Example 24: N-(3-(4-((2-(Dimethylamino)ethyl)carbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00199] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and N',N'-dimethylethane-1,2-diamine. [00200] 1H NMR (500 MHz, DMSO-d6) d: 8.85 (s, 1H), 8.39 (t, J = 5.7 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.50 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.94 (s, 1H), 4.15 (s, 1H), 3.78 (dt, J = 13.3, 3.8 Hz, 2H), 3.40–3.34 (m, 2H), 3.21– 3.10 (m, 2H), 2.40 (t, J = 6.9 Hz, 2H), 2.19 (s, 6H), 1.83 (dt, J = 13.4, 6.7 Hz, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.39 (td, J = 13.1, 12.7, 4.3 Hz, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 25: 4-Hydroxy-4-isobutyl-N-(3-(4-((2- methoxyethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1- carboxamide [00201] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-methoxyethanamine. [00202] 1H NMR (500 MHz, DMSO-d6) d: 8.85 (s, 1H), 8.53 (t, J = 5.3 Hz, 1H), 8.02–7.89 (m, 2H), 7.77 (s, 1H), 7.51 (t, J = 2.1 Hz, 1H), 7.22–7.07 (m, 2H), 6.94 (d, J = 1.9 Hz, 1H), 4.14 (s, 1H), 3.78 (dt, J = 13.7, 3.8 Hz, 2H), 3.45 (dq, J = 15.6, 5.4 Hz, 4H), 3.28 (s, 3H), 3.23–3.09 (m, 2H), 1.83 (hept, J = 6.4 Hz, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.44–1.34 (m, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). Example 26: 4-Hydroxy-4-isobutyl-N-(3-(4-((2- morpholinoethyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1- carboxamide [00203] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-morpholinoethanamine^ MS: (M+H+): 593.3. Example 27: 4-Hydroxy-N-(3-(4-((2-hydroxy-2- methylpropyl)carbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)-4- isobutylpiperidine-1-carboxamide [00204] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 1-amino-2-methyl-propan-2-ol. [00205] 1H NMR (500 MHz, DMSO-d6) d: 8.86 (s, 1H), 8.27 (t, J = 6.1 Hz, 1H), 7.99–7.92 (m, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 2.0 Hz, 1H), 7.29– 7.14 (m, 2H), 6.94 (t, J = 1.8 Hz, 1H), 4.57 (s, 1H), 4.14 (s, 1H), 3.78 (dt, J = 13.4, 3.8 Hz, 2H), 3.27 (d, J = 6.1 Hz, 2H), 3.21–3.08 (m, 2H), 1.83 (dt, J = 12.8, 6.3 Hz, 1H), 1.50 (d, J = 13.1 Hz, 2H), 1.40 (td, J = 12.9, 12.3, 4.3 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 1.12 (s, 6H), 0.93 (d, J = 6.6 Hz, 6H). Example 28: 4-Hydroxy-4-isobutyl-N-(3-(4-(3-(methylsulfonyl)pyrrolidine-1- carbonyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1-carboxamide [00206] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 3-methylsulfonylpyrrolidine. [00207] 1H NMR (500 MHz, DMSO-d6) d: 8.87 (s, 1H), 7.79 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 4.14 (s, 1H), 4.09–3.84 (m, 2H), 3.82–3.54 (m, 4H), 3.22–3.12 (m, 2H), 3.06 (d, J = 31.9 Hz, 3H), 2.31 (s, 2H), 1.83 (dt, J = 12.8, 6.4 Hz, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.40 (td, J = 12.0, 3.8 Hz, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). Example 29: 4-Hydroxy-4-isobutyl-N-(3-(4-(methylcarbamoyl)phenoxy)-5- (trifluoromethyl)phenyl)piperidine-1-carboxamide [00208] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and methanamine. MS: (M+H+): 476.4. Example 30: 4-Hydroxy-N-(3-(4-(3-hydroxypyrrolidine-1-carbonyl)phenoxy)-5- (trifluoromethyl)phenyl)-4-isobutylpiperidine-1-carboxamide [00209] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and pyrrolidin-3-ol. [00210] 1H NMR (500 MHz, DMSO-d6) d: 8.87 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.66–7.58 (m, 2H), 7.52 (t, J = 2.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 1.9 Hz, 1H), 5.06–4.93 (m, 1H), 4.39–4.23 (m, 1H), 3.78 (dt, J = 13.4, 3.8 Hz, 2H), 3.66–0.87 (m, 22H). Example 31: N-(3-(4-Fluorophenoxy)-5-(4-((2- hydroxyethyl)carbamoyl)phenoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00211] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid and 2-aminoethanol. [00212] 1H NMR (500 MHz, DMSO-d6) d: 8.56 (s, 1H), 8.40 (t, J = 5.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.31–7.23 (m, 2H), 7.18–6.97 (m, 6H), 6.32–6.25 (m, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.11 (s, 1H), 3.72 (dt, J = 13.2, 3.8 Hz, 2H), 3.52 (q, J = 6.1 Hz, 2H), 3.37–3.30 (m, 2H), 3.16–3.03 (m, 2H), 1.88–1.75 (m, J = 6.4 Hz, 1H), 1.53–1.42 (m, 2H), 1.40–1.21 (m, 4H), 0.92 (d, J = 6.6 Hz, 6H). Example 32: N-(3-(4-((2-(1,1-Dioxidothiomorpholino)ethyl)carbamoyl)phenoxy)- 5-(trifluoromethyl)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00213] The target compound was obtained in a similar manner to Example 37 using 4-(3-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-5- (trifluoromethyl)phenoxy)benzoic acid and 2-(1,1-dioxo-1,4-thiazinan-4- yl)ethanamine. MS: (M+H+): 641.4. Example 33: 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid potassium salt [00214] To a mixture of 4-(3-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-5-(trifluoromethyl)phenoxy)benzoic acid (400 mg) and iPrOH (7.0 mL) was added 6 M KOH (43.0 mg). After stirring at rt for 5 min, the solvent was concentrated to give the target compound (320 mg) as a solid. [00215] 1H NMR (500 MHz, DMSO-d6) d: 8.54 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.28–7.20 (m, 2H), 7.18–7.08 (m, 2H), 6.99 (t, J = 2.0 Hz, 1H), 6.95–6.84 (m, 3H), 6.21 (t, J = 2.2 Hz, 1H), 4.10 (s, 1H), 3.71 (d, J = 13.2 Hz, 1H), 3.10 (ddd, J = 13.5, 11.5, 2.9 Hz, 2H), 1.81 (dt, J = 12.8, 6.4 Hz, 1H), 1.46 (d, J = 13.3 Hz, 2H), 1.39–1.30 (m, 2H), 1.29 (d, J = 5.8 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 34: (1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid A) Methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-nitrophenoxy)cyclobutane-1- carboxylate [00216] To a solution of 3-(4-fluorophenoxy)-5-nitrophenol (32.8 g), methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate (20.6 g) and PPh3 (69.1 g) in THF (160 mL) was added DEAD (45.9 g) at 0°C dropwise, and the reaction mixture was stirred at 40°C for 16 h. The reaction mixture was concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to afford the target compound (28 g) as an oil. [00217] 1H NMR (400 MHz, DMSO-d6) d: 7.36-7.33 (m, 2H), 7.11-7.09 (m, 2H), 7.06-7.05 (m, 2H), 6.71 (s, 1H), 4.66-4.59 (m, 1H), 2.86-2.79 (m, 1H), 2.78- 2.76 (m, 2H), 2.49-2.45 (m, 2H). B) Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)phenoxy)cyclobutane-1- carboxylate [00218] To a solution of methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5- nitrophenoxy)cyclobutane-1-carboxylate (28.0 g) in MeOH (500 mL) was added 10% Pd/C (3.0 g), and the mixture was stirred under H2 atmosphere (40 psi) at 25°C for 16 h. The mixture was filtered and the filtrate was concentrated to afford the target compound (21.1 g) as a solid. [00219] 1H NMR (400 MHz, CDCl3) d: 7.04-6.99 (m, 4H), 5.88 (m, 2H), 5.83-5.82 (m, 1H), 4.50-4.47 (m, 1H), 3.72 (s, 3H), 2.77-2.68 (m, 1H), 2.67-2.66 (m, 2H), 2.43-2.40 (m, 2H). C) Methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate [00220] To a mixture of methyl (1s,3s)-3-(3-amino-5-(4- fluorophenoxy)phenoxy)cyclobutane-1-carboxylate (21.0 g), NaHCO3 (10.7 g), and EtOAc (120 mL) was added 2,2,2-trichloroethyl carbonochloridate (14.8 g) drop-wise at 0°C under N2. The mixture was stirred at 20°C for 17 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (32.9 g) as an oil. [00221] 1H NMR (400 MHz, CDCl3) d: 7.07-7.00 (m, 4H), 6.85 (d, J = 13.2 Hz, 2H), 6.54 (t, J = 2.0 Hz, 1H), 6.16 (t, J = 2.0 Hz, 1H), 4.80 (s, 2 H), 4.56-4.52 (m, 1H), 3.71 (s, 3H), 2.78-2.72 (m, 1H), 2.71-2.70 (m, 2H), 2.45-2.42 (m, 2H). D) Methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylate [00222] To a solution of methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate (25.0 g) and 4-isobutylpiperidin-4-ol (15.5 g) in DMF (300 mL) was added DBU (7.51 g) at 20°C. The mixture was stirred at 60°C for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 3/1) to give the target compound (19.5 g) as an oil. [00223] 1H NMR (400 MHz, CDCl3) d: 7.05-6.98 (m, 4H), 6.86 (t, J = 2.0 Hz, 1H), 6.44 (t, J = 2.0 Hz, 1H), 6.40 (s, 1H), 6.10 (t, J = 2.0 Hz, 1H), 4.57-4.55 (m, 1H), 3.78-3.75 (m, 2H), 3.70 (s, 3H), 3.32-3.27 (m, 2H), 2.72-2.70 (m, 3H), 2.42-2.40 (m, 2H), 1.89-1.82 (m, 1H), 1.64-1.61 (m, 5H), 1.42 (d, J = 6.0 Hz, 2H), 0.98 (d, J = 6.4 Hz, 6H). E) (1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid [00224] To a solution of methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- hydroxy-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carboxylate (19.5 g) in MeOH (80 mL) was added a solution of NaOH (7.6 g) in H2O (40 mL) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was concentrated and pH was adjusted to 4 with 1 M HCl. The aqueous phase was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the target compound (16.3 g) as an oil. [00225] 1H NMR (400 MHz, CDCl3) d: 7.04-6.97 (m, 4H), 6.82 (s, 1H), 6.54 (s, 1H), 6.40 (d, J = 2.0 Hz, 2H), 6.11 (s 1H), 4.56-4.52 (m, 1H), 3.78-3.74 (m, 2H), 3.32-3.29 (m, 2H), 2.77-2.73 (m, 3H), 2.43-2.40 (m, 2H), 1.87-1.84 (m, 1H), 1.62-1.59 (m, 4H), 1.41 (d, J = 5.6 Hz, 2H), 0.98 (d, J = 6.4 Hz, 6H). Example 35: 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylic acid A) Methyl 4-bromo-2-(3-(4-fluorophenoxy)-5-nitrophenoxy)butanoate [00226] To a solution of methyl 2,4-dibromobutanoate (5.0 g) and 3-(4- fluorophenoxy)-5-nitrophenol (5.0 g) in DMF (100 mL) was added potassium carbonate (5.3 g) in one portion. The mixture was stirred at 20°C for 5 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give the target compound (5 g) as an oil. [00227] 1H NMR (400 MHz, DMSO-d6) d: 7.50 (s, 1H), 7.32-7.23 (m, 5H), 7.04 (s, 1H), 5.20-5.14 (m, 1H), 3.69-3.35 (m, 5H), 2.43 (q, J = 6.4 Hz, 2H). B) Methyl 1-(3-(4-fluorophenoxy)-5-nitrophenoxy)cyclopropane-1-carboxylate [00228] To a solution of methyl 4-bromo-2-(3-(4-fluorophenoxy)-5- nitrophenoxy)butanoate (2.0 g) in THF (50 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 100°C for 5 h. The mixture was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1 to 30/1) to afford the target compound (1.0 g) as an oil. [00229] 1H NMR (300 MHz, CDCl3) d: 7.47 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.11-7.06 (m, 4H), 6.84 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 1.70-1.67 (m, 2H), 1.38-1.34 (m, 2H). C) Methyl 1-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclopropane-1-carboxylate [00230] To a solution of methyl 1-(3-(4-fluorophenoxy)-5- nitrophenoxy)cyclopropane-1-carboxylate (1.0 g) in methanol (10 mL) was added 10% Pd/C (0.5 g), and he mixture was stirred under H2 atmosphere (15 psi) at 20°C for 2 h. The mixture was filtered and concentrated in vacuum to afford the intermediate aniline (0.80 g) as an oil. To a mixture of the aniline (0.80 g) in EtOAc (8.0 mL) was added sodium bicarbonate (424 mg) and 2,2,2-trichloroethyl carbonochloridate (588 mg). The mixture was stirred at 20°C for 1 h. The mixture was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to afford the target compound (1.0 g) as a solid. [00231] 1H NMR (400 MHz, DMSO) d: 10.12 (br s, 1H), 7.25 (t, J = 8.8 Hz, 2H), 7.12-7.10 (m, 2H), 6.91 (s, 1H), 6.84 (s, 1H), 6.16 (t, J = 2.0 Hz, 1H), 4.86 (s, 2H), 3.64 (s, 3H), 1.52-1.49 (m, 2H), 1.33-1.29 (m, 2H). D) Methyl 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylate [00232] To a mixture of methyl 1-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclopropane-1-carboxylate (1.0 g) and 4-isobutylpiperidin-4-ol (638 mg) in DMF (15 mL) was added DBU (309 mg), and the mixture was stirred at 60°C for 1 h. The mixture was concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to afford the target compound (0.80 g) as colorless oil. MS: (M+H+): 501.0. D) 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylic acid [00233] To a mixture of methyl 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylate (800 mg), water (5.0 mL), and methanol (10 mL) was added sodium hydroxide (302 mg), and the mixture was stirred at 20°C for 1 h then at 50°C for 1 h. The mixture was concentrated and adjusted pH to 5 with 1 M HCl. The resulting precipitate was collected to give the target compound (750 mg) as a solid. [00234] 1H NMR (400 MHz, DMSO-d6) d: 8.46 (s, 1H), 7.22 (t, J = 8.8 Hz, 2H), 7.07-7.04 (m, 2H), 6.96 (s, 1H), 6.80 (s, 1H), 6.05 (t, J = 2.0 Hz, 1H), 4.11 (br s, 1H), 3.72 (d, J = 14.4 Hz, 2H), 3.11 (t, J = 11.2 Hz, 2H), 1.84-1.79 (m, 1H), 1.48-1.36 (m, 6H), 1.29 (d, J = 6.0 Hz, 2H), 1.18 (s, 2H), 0.91 (d, J = 6.8 Hz, 6H). Example 36: N-(3-(4-Fluorophenoxy)-5-(1-((2- hydroxyethyl)carbamoyl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00235] To a mixture of 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylic acid (100 mg), 2-aminoethan-1-ol (14.6 mg) in DCM (5.0 mL) was added diisopropylethylamine (51.6 mg) and HATU (114 mg), and the mixture was stirred at 20°C for 1 h. The mixture was concentrated, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to afford the target compound (80 mg) as a solid. [00236] 1H NMR (400 MHz, CD3OD) d: 7.10-7.03 (m, 4H), 6.84 (t, J = 2.0 Hz, 1H), 6.72 (t, J = 2.0 Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 3.83 (d, J = 5.2 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.35-3.33 (m, 2H), 3.29-3.26 (m, 2H), 1.91-1.88 (m, 1H), 1.64-1.48 (m, 6H), 1.40 (d, J = 6.0 Hz, 2H), 1.18-1.16 (m, 2H), 0.98 (d, J = 6.4 Hz, 6H). Example 37: N-(3-(4-Fluorophenoxy)-5-(1-(4-hydroxypiperidine-1- carbonyl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00237] To a mixture of 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylic acid (100 mg), piperidin-4-ol (24.2 mg) and DCM (5 mL) was added diisopropylethylamine (51.6 mg) and HATU (114 mg), and the mixture was stirred at 20°C for 1 h. The mixture was concentrated, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to afford the target compound (64.6 mg) as a solid. [00238] 1H NMR (400 MHz, CD3OD) d: 7.11-7.01 (m, 4H), 6.81 (t, J = 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.29 (br s, 1H), 3.98 (br s, 1H), 3.81-3.78 (m, 3H), 3.49-3.48 (m, 1H), 3.29-3.22 (m, 2H), 3.14-2.96 (m, 1H), 1.91-1.88 (m, 3H), 1.64-1.56 (m, 4H), 1.41-1.38 (m, 6H), 1.15 (s, 2H), 0.98 (d, J = 6.8 Hz, 6H). Example 38: N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-((2- hydroxyethyl)carbamoyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00239] To a mixture of (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid (100 mg), HATU (114 mg) and DMF (2.0 mL) was added DIPEA (65 mg), and the mixture was stirred at 20°C for 10 minutes. Then 2-aminoethan-1-ol (15 mg) was added and the mixture was stirred at 20°C for 20 minutes. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by HPLC to give the target compound (26 mg) as a solid. [00240] 1H NMR (CDCl3, 400 MHz) d: 7.04-6.95 (m, 4H), 6.83 (s, 1H), 6.72 (s, 1H), 6.41 (t, J = 2.0 Hz, 1H), 6.36 (br s, 1H), 6.08 (t, J = 2.4 Hz, 1H), 4.53-4.46 (m, 1H), 3.78-3.71 (m, 4H), 3.42-3.41 (m, 2H), 3.32-3.25 (m ,2H), 2.67-2.59 (m, 3H), 2.38-2.31 (m, 2H), 1.87-1.80 (m, 1H), 1.64-1.55 (m, 4H), 1.41 (d, J = 6.4 Hz, 2H), 0.97 (d, J = 6.4 Hz, 6H). Example 39: N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00241] To a mixture of (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid (16.3 g), HATU (18.6 g) and DMF (75 mL) was added DIPEA (10.5 g) at 0°C, and the mixture was stirred at 20°C for 30 minutes. Then piperidin-4-ol (4.0 g) was added and the mixture was stirred at 20°C for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 5/1) to give the residue. Recrystallization from MeCN to give the target compound (7.3 g) as a solid. [00242] 1H NMR (400 MHz, CDCl3) d: 7.04-6.97 (m, 4H), 6.86 (s, 1 H), 6.50 (s, 1H), 6.45 (s, 1H), 6.10 (s, 1H), 4.61-4.55 (m, 1H), 4.07 (m, 1H), 3.92 (m, 1H), 3.79-3.75 (m, 2H), 3.62 (m, 1H), 3.32-3.29 (m, 2H), 3.17 (m, 2H), 2.86 (m, 1H), 2.67-2.64 (m, 2H), 2.46-2.34 (m, 2H), 1.87-1.84 (m, 3H), 1.74-1.73 (m, 1H), 1.62- 1.59 (m, 4H), 1.58-1.42 (m, 2H), 1.41 (d, J = 5.6 Hz, 2H), 1.21 (s, 1H), 0.98 (d, J = 6.4 Hz, 6H). Example 40: N-(3-(4-Fluorophenoxy)-5-(1-(5-(hydroxymethyl)-4-methyloxazol- 2-yl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) 1-Ethoxy-1,3-dioxobutan-2-yl 1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropane-1-carboxylate [00243] To a mixture of ethyl 2-chloro-3-oxobutanoate (181 mg), 1-(3-(4- fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylic acid (0.50 g) and DMF (5.0 mL) was added potassium carbonate (276 mg), and the mixture was stirred at 20°C for 12 h. Then another batch of 2-chloro-3-oxobutanoate (0.20 g) was added, and the mixture was stirred at 20°C for 2 h. The mixture was poured into water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to give the target compound (0.50 g) as an oil. [00244] 1H NMR (400 MHz, CDCl3) d: 7.03-6.89 (m, 4H), 6.91 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 1.6 Hz, 1H), 5.48 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.81-3.78 (m, 2H), 3.32-3.25 (m, 2H), 2.26 (s, 3H), 1.85-1.83 (m, 1H), 1.74 (d, J = 4.4 Hz, 2H), 1.75-1.70 (m, 2H), 1.62-1.56 (m, 2H), 1.45-1.41 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H), 0.98 (d, J = 6.4 Hz, 6H). B) Ethyl 2-(1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropyl)-4-methyloxazole-5-carboxylate [00245] To a mixture of 1-ethoxy-1,3-dioxobutan-2-yl 1-(3-(4- fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclopropane-1-carboxylate (0.80 g) in AcOH (16 mL) was added ammonium acetate (502 mg), and the mixture was stirred at 100°C for 15 minutes under microwave irradiation. The mixture was poured into water, extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, and concentrated to give the target compound (0.20 g) as an oil. MS: (M+H+): 596.3. C) N-(3-(4-Fluorophenoxy)-5-(1-(5-(hydroxymethyl)-4-methyloxazol-2- yl)cyclopropoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00246] To a solution of ethyl 2-(1-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclopropyl)-4-methyloxazole-5- carboxylate (0.20 g) in THF (5 mL) was added LAH (3.5 mg) in one portion at 0°C, and the mixture was stirred at 10°C for 3.5 h. The reaction mixture was quenched 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 1/2) followed by HPLC to give the target compound (11 mg) as a solid. [00247] 1H NMR (400 MHz, CD3OD) d: 7.08-7.04 (m, 2H), 6.99-6.98 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 6.18 (s, 1H), 4.48 (s, 2H), 3.82-3.77 (m, 2H), 3.27-3.20 (m, 2H), 2.10 (s, 3H), 1.90-1.85 (m, 1H), 1.63-1.56 (m, 6H), 1.43-1.38 (m, 4H), 0.97 (d, J = 6.8 Hz, 6H). Example 41: N-(3-(4-Fluorophenoxy)-5-(3-(5-(hydroxymethyl)-4-methyloxazol- 2-yl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00248] The target compound was obtained in a similar manner to Example 40 using 3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 2-chloro-3- oxobutanoate. [00249] 1H NMR (400 MHz, CD3OD) d: 7.09 (t, J = 8.4 Hz, 2H), 7.02 (t, J = 4.4 Hz, 2H), 6.76 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.11 (t, J = 2.0 Hz, 1H), 4.71-4.65 (m, 1H), 4.52 (s, 2H), 3.84-3.81 (m, 2H), 3.31-3.23 (m, 2H), 2.89- 2.87 (m, 2H), 2.44-2.42 (m ,2H), 2.13 (s, 3H), 1.90-1.82 (m, 1H), 1.64-1.54 (m, 4H), 1.40 (d, J = 5.6 Hz, 2H), 0.97 (d, J = 6.8 Hz, 6H). Example 42: (1r,3r)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid [00250] The target compound was obtained in a similar manner to Example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl 3- hydroxycyclobutane-1-carboxylate [00251] 1H NMR (400 MHz, CD3OD) d: 7.08-7.01 (m, 4H), 6.68-6.66 (m, 2H), 6.06 (t, J = 2.0 Hz, 1H), 4.82-4.77 (m, 1H), 3.82 (d, J = 13.6 Hz, 2H), 3.28- 3.25 (m, 2H), 3.15-3.05 (m, 1H), 2.68-2.66 (m, 2H), 2.41-2.38 (m, 2H), 1.90-1.82 (m, 1H), 1.60-1.55 (m, 4H), 1.40 (d, J = 6.0 Hz, 2H), 0.97 (d, J = 6.8 Hz, 6H). Example 43: 4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylazepane-1- carboxamido)phenoxy)benzoic acid [00252] The target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 4-isobutyl-1^2-azepan-4- ol. [00253] 1H NMR (400 MHz, CDCl3) d: 8.03 (d, J = 8.8 Hz, 2H), 7.05-7.01 (m, 5H), 6.98 (s, 1H), 6.83 (t, J = 2.0 Hz, 1H), 6.37 (t, J = 2.2 Hz, 1H), 6.34 (s, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.55-3.48 (m, 1H), 3.44 (td, J = 5.5, 11.0 Hz, 1H), 3.37 (d, J = 14.5 Hz, 1H), 2.15 (d, J = 10.5 Hz, 1H), 1.85-1.77 (m, 3H), 1.76-1.70 (m, 2H), 1.59-1.50 (m, 1H), 1.47-1.35 (m, 2H), 0.96 (t, J = 6.4 Hz, 6H). Example 44: 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-isobutyl-2- azaspiro[3.3]heptane-2-carboxamido)phenoxy)benzoic acid [00254] The target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 6-isobutyl-2L2- azaspiro[3.3]heptan-6-ol. [00255] 1H NMR (400 MHz, DMSO-d6) d: 8.48 (s, 1H), 7.98-7.92 (m, 2H), 7.27-7.22 (m, 2H), 7.14-7.05 (m, 5H), 7.00 (t, J = 2.0 Hz, 1H), 6.30 (t, J = 2.2 Hz, 1H), 3.85 (d, J = 3.2 Hz, 4H), 2.20-2.06 (m, 4H), 1.78 (td, J = 6.5, 13.2 Hz, 1H), 1.29 (d, J = 6.4 Hz, 2H), 0.87 (d, J = 6.7 Hz, 6H). Example 45: 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-isobutyl-3- azabicyclo[3.1.1]heptane-3-carboxamido)phenoxy)benzoic acid [00256] The target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 6-isobutyl-3L2- azabicyclo[3.1.1]heptan-6-ol. [00257] 1H NMR (400 MHz, CD3OD) d: 8.00 (d, J = 8.8 Hz, 2H), 7.14-6.97 (m, 8H), 6.30 (t, J = 2.2 Hz, 1H), 3.71-3.58 (m, 4H), 2.36 (d, J = 5.3 Hz, 2H), 1.98- 1.80 (m, 2H), 1.68 (d, J = 6.6 Hz, 2H), 1.30 (d, J = 10.1 Hz, 1H), 0.98 (d, J = 6.6 Hz, 6H). Example 46: 4-(3-(4-Fluoro-4-isobutylpiperidine-1-carboxamido)-5-(4- fluorophenoxy)phenoxy)benzoic acid A) Methyl 4-(3-(4-fluorophenoxy)-5-nitro-phenoxy)benzoate [00258] To a solution of 1-fluoro-3-(4-fluorophenoxy)-5-nitro-benzene (7.0 g), methyl 4-hydroxybenzoate (4.2 g) in DMA (40 mL) was added Cs2CO3 (27.24 g). The mixture was stirred at 100oC for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 5/1) to afford the target compound (6.0 g) as a solid. [00259] 1H NMR (400 MHz, CDCl3) d: 8.13-8.05 (m, 2H), 7.51 (td, J = 2.1, 10.3 Hz, 2H), 7.16-7.03 (m, 6H), 6.97 (t, J =2.2 Hz, 1H), 3.93 (s, 3H). B) Methyl 4-(3-amino-5-(4-fluorophenoxy)phenoxy)benzoate To a solution of methyl 4-(3-(4-fluorophenoxy)-5-nitro-phenoxy)benzoate (5.5 g) in MeOH (70 mL) was added 10% Pd/C (8.0 g), and the mixture was stirred under H2 atmosphere (50 psi) at 50oC for 12 h. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford the target compound (4.6 g) as a solid. MS: (M+H+): 528.1. C) 4-(3-(4-Fluorophenoxy)-5-(2,2,2-trichloroethoxycarbonylamino) phenoxy)benzoate [00260] To a mixture of methyl 4-(3-amino-5-(4- fluorophenoxy)phenoxy)benzoate (1.5 g), NaHCO3 (713 mg) and EtOAc (30 mL) was added 2,2,2-trichloroethyl carbonochloridate (1.1 g), and the mixture was stirred at 20oC for 12 h. The reaction was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1 to 5/1) to afford the target compound (1.3 g) as a solid. D) Methyl 4-(3-((4-fluoro-4-isobutyl-piperidine-1-carbonyl)amino)-5-(4- fluorophenoxy)phenoxy)benzoate [00261] To a solution of methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate (500 mg) and 4-fluoro-4- isobutylpiperidine hydrochloride (463 mg) in DMF (1.0 mL) was added DBU (432 mg), and the mixture was stirred at 60°C for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 15/1) to give the target compound (320 mg) as an oil. [00262] 1H NMR (400 MHz, CD3OD) d: 8.01 (d, J = 9.0 Hz, 2H), 7.11 (s, 1H), 7.10-7.04 (m, 5H), 6.91 (td, J = 2.0, 13.5 Hz, 2H), 6.30 (t, J = 2.1 Hz, 1H), 3.92 (d, J = 13.5 Hz, 2H), 3.88 (s, 3H), 3.20-3.11 (m, 2H), 1.94-1.82 (m, 3H), 1.59- 1.47 (m, 3H), 0.95 (d, J = 6.6 Hz, 6H), 0.88 (dd, J = 6.6, 7.9 Hz, 1H). E) 4-(3-(4-Fluoro-4-isobutylpiperidine-1-carboxamido)-5-(4- fluorophenoxy)phenoxy)benzoic acid [00263] To a solution of methyl 4-(3-((4-fluoro-4-isobutyl-piperidine-1- carbonyl)amino)-5-(4-fluorophenoxy)phenoxy)benzoate (300 mg) in dioxane (3.0 mL) was added a solution of NaOH (223 mg) in H2O (3.0 mL), and the mixture was stirred at 60°C for 2 h. The mixture was acidified to pH = 10 with concentrated HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified by HPLC to give the target compound (70 mg) as a solid. [00264] 1H NMR (400 MHz, CD3OD) d: 8.00 (d, J = 8.7 Hz, 2H), 7.15-7.01 (m, 6H), 6.90 (d, J = 2.1 Hz, 2H), 6.29 (t, J = 2.1 Hz, 1H), 3.92 (br d, J = 13.4 Hz, 2H), 3.20-3.10 (m, 2H), 1.95-1.81 (m, 3H), 1.72-1.48 (m, 4H), 0.95 (d, J = 6.6 Hz, 6H). Example 47: 4-(3-(4-Fluorophenoxy)-5-(6-hydroxy-6-(2-methylallyl)-2- azaspiro[3.3]heptane-2-carboxamido)phenoxy)benzoic acid [00265] The target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate (500 mg) and 6-(2-methylallyl)- 2L2-azaspiro[3.3]heptan-6-ol. [00266] 1H NMR (400 MHz, DMSO-d6) d: 8.50 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.28-7.21 (m, 2H), 7.16-7.10 (m, 2H), 7.09-7.03 (m, 3H), 7.00 (t, J = 1.9 Hz, 1H), 6.30 (t, J = 2.2 Hz, 1H), 4.83 (br s, 1H), 4.77 (d, J = 1.1 Hz, 1H), 4.66 (s, 1H), 3.86 (d, J = 6.4 Hz, 4H), 2.24 (d, J = 12.8 Hz, 2H), 2.12-2.05 (m, 4H), 1.71 (s, 3H). Example 48: 4-(Cyclopropylmethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide A) (1s,3s)-3-(3-(4-(Cyclopropylmethyl)-4-hydroxypiperidine-1-carboxamido)-5- (4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylic acid [00267] The target compound was obtained in a similar manner to step H to I in example 63 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4- (cyclopropylmethyl)-1L2-piperidin-4-ol. MS: (M+H+): 513.3. B) 4-(Cyclopropylmethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide [00268] The target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-(3-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1- carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylic acid and piperidin-4-ol. [00269] 1H NMR (400 MHz, CD3OD) d: 7.12-7.05 (m, 2H), 7.04-6.98 (m, 2H), 6.76 (t, J = 2.0 Hz, 1H), 6.62 (t, J = 2.0 Hz, 1H), 6.09 (t, J = 2.1 Hz, 1H), 4.58 (quin, J = 7.2 Hz, 2H), 4.08-4.00 (m, 1H), 3.89-3.80 (m, 3H), 3.77-3.70 (m, 1H), 3.29-3.02 (m, 6H), 2.68 (td, J = 6.1, 12.6 Hz, 2H), 2.34-2.22 (m, 2H), 1.92-1.77 (m, 2H), 1.67-1.64 (m, 3H), 1.41 (d, J = 6.8 Hz, 3H), 0.80 (tt, J = 6.6, 13.0 Hz, 1H), 0.51-0.44 (m, 2H), 0.06 (q, J = 4.9 Hz, 2H). Example 49: 4-Hydroxy-N-(3-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-5-(pentafluoro-L6-sulfaneyl)phenyl)-4-isobutylpiperidine- 1-carboxamide A) (3-Bromo-5-nitrophenyl)pentafluoro-L6-sulfane [00270] To a solution of pentafluoro-(3-nitrophenyl)-sulfane (7.8 g) in TFA (15 mL) and H2SO4 (80 mL) was added NBS (8.3 g). The mixture was stirred at 25°C for 7 h. The reaction mixture was added to water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (10 g) as a solid. [00271] 1H NMR (400 MHz, CD3OD) d: 8.68 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H). B) 3-Nitro-5-(pentafluoro-L6-sulfaneyl)phenol [00272] A mixture of (3-bromo-5-nitrophenyl)pentafluoro-^6-sulfane (10 g), KOH (6.8 g), Pd2(dba)3 (558 mg), t-BuXphos (647 mg), water (100 mL), and dioxane (100 mL) was stirred at 100°C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 20/1) to give the target compound (7.0 g) as an oil. [00273] 1H NMR (400 MHz, CD3OD) d: 8.07 (t, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.58 (t, J = 2.0 Hz, 1H). C) Methyl (1s,3s)-3-(3-nitro-5-(pentafluoro-L6-sulfaneyl)phenoxy)cyclobutane-1- carboxylate [00274] To a solution of 3-nitro-5-(pentafluoro-L6-sulfaneyl)phenol (2.0 g), methyl 3-hydroxycyclobutanecarboxylate (1.2 g) and PPh3 (4.0 g) in THF (20 mL) was added DEAD (2.74 mL) at 0°C, and the mixture was stirred at 40°C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give the target compound (1.5 g) as an oil. [00275] 1H NMR (400 MHz, CD3OD) d: 8.22 (t, J = 1.8 Hz, 1H), 7.90 (t, J = 2.0 Hz, 1H), 7.70 (t, J = 2.1 Hz, 1H), 4.94-4.88 (m, 1H), 3.70 (s, 3H), 2.90-2.90 (m, 1H), 3.01-2.90 (m, 1H), 2.88-2.77 (m, 2H), 2.47-2.35 (m, 2H). D) 4-Hydroxy-N-(3-((1s,3s)-3-(4-hydroxypiperidine-1-carbonyl)cyclobutoxy)-5- (pentafluoro-L6-sulfaneyl)phenyl)-4-isobutylpiperidine-1-carboxylic acid [00276] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl (1s,3s)-3-(3-nitro-5-(pentafluoro-L6- sulfaneyl)phenoxy)cyclobutane-1-carboxylate. E) 4-Hydroxy-N-(3-((1s,3s)-3-(4-hydroxypiperidine-1-carbonyl)cyclobutoxy)-5- (pentafluoro-L6-sulfaneyl)phenyl)-4-isobutylpiperidine-1-carboxamide [00277] The target compound was obtained in a similar manner to Example 39 using 4-hydroxy-N-(3-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-5-(pentafluoro-L6-sulfaneyl)phenyl)-4-isobutylpiperidine- 1-carboxylic acid and piperidin-4-ol. [00278] 1H NMR (400 MHz, CD3OD) d: 7.51 (t, J = 2.0 Hz, 1H), 7.27 (s, 1H), 6.87 (t, J = 2.2 Hz, 1H), 4.69 (quin, J = 7.2 Hz, 1H), 4.61 (s, 1H), 4.10-4.02 (m, 1H), 3.91-3.81 (m, 3H), 3.76 (d, J = 14.0 Hz, 1H), 3.33 (br s, 1H), 3.28-3.22 (m, 1H), 3.22-3.08 (m, 2H), 2.81-2.70 (m, 2H), 2.38-2.29 (m, 2H), 1.93-1.81 (m, 3H), 1.68-1.54 (m, 4H), 1.50-1.36 (m, 4H), 0.99 (d, J = 7.0 Hz, 6H). Example 50: 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl methyl hydrogen phosphate [00279] To a suspension of 1-((1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- hydroxy-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carbonyl)piperidin-4-yl dimethyl phosphate (0.3 g) in DCM (6.0 mL) was added TMSBr (169 uL), and the mixture was stirred at 25oC for 6 h. The reaction mixture was quenched with sat. NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, concentrated, and purified by neutral prep-HPLC to give the target compound (22.1 mg) as a solid. [00280] 1H NMR (400 MHz, CD3OD) d: 7.12-7.06 (m, 2H), 7.05-6.98 (m, 2H), 6.76-6.72 (m, 1H), 6.65 (t, J = 2.0 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 4.63-4.54 (m, 1H), 4.48-4.40 (m, 1H), 3.86-3.76 (m, 3H), 3.63 (d, J = 11.0 Hz, 4H), 3.52- 3.46 (m, 1H), 3.44-3.34 (m, 1H), 3.28-3.21 (m, 2H), 3.15-3.05 (m, 1H), 2.68 (d, J = 6.2 Hz, 2H), 2.28 (br s, 2H), 1.96-1.82 (m, 3H), 1.77-1.66 (m, 2H), 1.66-1.51 (m, 4H), 1.40 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 51: 4-(2-Fluoro-2-methylpropyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3- (4-hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide [00281] The target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(2- fluoro-2-methylpropyl)piperidin-4-ol. [00282] 1H NMR (400 MHz, CD3OD) d: 7.12-7.05 (m, 2H), 7.05-6.98 (m, 2H), 6.76 (s, 1H), 6.63 (s, 1H), 6.10 (s, 1H), 4.61-4.56 (m, 1H), 4.08-4.01 (m, 1H), 3.88-3.70 (m, 4H), 3.33 (br s, 1H), 3.29-3.01 (m, 4H), 2.68 (td, J = 6.4, 12.2 Hz, 2H), 2.33 -2.23 (m, 2H), 1.91-1.80 (m, 4H), 1.77-1.62 (m, 4H), 1.51-1.38 (m, 8H). Example 52: 4-(Cyclopropylmethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxy-4-methylpiperidine-1-carbonyl)cyclobutoxy)phenyl)-4- hydroxypiperidine-1-carboxamide [00283] The target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1- carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylic acid and 4- methylpiperidin-4-ol. [00284] 1H NMR (400 MHz, CD3OD) d: 7.14-7.01 (m, 4H), 6.78 (t, J = 2.0 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 6.12 (t, J = 2.1 Hz, 1H), 4.60 (quin, J = 7.2 Hz, 1H), 4.12-4.03 (m, 1H), 3.84 (d, J = 13.3 Hz, 2H), 3.60 (d, J = 13.3 Hz, 1H), 3.49- 3.40 (m, 1H), 3.31-3.04 (m, 4H), 2.70 (td, J = 7.6, 11.3 Hz, 2H), 2.35-2.24 (m, 2H), 1.89 (td, J = 6.3, 12.9 Hz, 1H), 1.68-1.47 (m, 8H), 1.42 (d, J = 5.7 Hz, 2H), 1.25 (s, 3H), 0.99 (d, J = 6.6 Hz, 6H). Example 53: N-(3-(4-Fluorophenoxy)-5-((1r,3r)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) (1r,3r)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid [00285] The target compound was obtained in a similar manner to Example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl (1s,3s)-3- hydroxycyclobutane-1-carboxylate. MS: (M+H+): 501.2. B) N-(3-(4-Fluorophenoxy)-5-((1r,3r)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00286] The target compound was obtained in a similar manner to example 39 using (1r,3r)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 4-isobutylpiperidin-4- ol. [00287] 1H NMR (400 MHz, CD3OD) d: 6.98-7.12 (m, 4H), 6.66 (d, J = 2.2 Hz, 2H), 6.07 (t, J = 2.2 Hz, 1H), 4.69 (quin, J = 6.1 Hz, 1H), 4.04-4.13 (m, 1H), 3.77-3.88 (m, 3H), 3.63-3.72 (m, 1H), 3.47 (tt, J = 4.8, 9.8 Hz, 1H), 3.12-3.29 (m, 4H), 2.62-2.73 (m, 2H), 2.40 (tt, J = 5.1, 10.1 Hz, 2H), 1.81-1.93 (m, 3H), 1.36- 1.66 (m, 8H), 0.97 (d, J = 6.7 Hz, 6H). Example 54: N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxy-4- methylpiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxy-4-isobutylpiperidine- 1-carboxamide [00288] The target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 4-methylpiperidin-4-ol. [00289] 1H NMR (400 MHz, CD3OD) d: 7.14-7.01 (m, 4H), 6.78 (t, J = 2.0 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 6.12 (t, J = 2.1 Hz, 1H), 4.60 (quin, J = 7.2 Hz, 1H), 4.12-4.03 (m, 1H), 3.84 (d, J = 13.3 Hz, 2H), 3.60 (d, J = 13.3 Hz, 1H), 3.49- 3.40 (m, 1H), 3.31-3.04 (m, 4H), 2.70 (td, J = 7.6, 11.3 Hz, 2H), 2.35-2.24 (m, 2H), 1.89 (td, J = 6.3, 12.9 Hz, 1H), 1.68-1.47 (m, 8H), 1.42 (d, J = 5.7 Hz, 2H), 1.25 (s, 3H), 0.99 (d, J = 6.6 Hz, 6H). Example 55: 4-(4-Bromophenyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide [00290] The target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(4- bromophenyl)piperidin-4-ol. [00291] 1H NMR (400 MHz, CD3OD) d: 7.50-7.45 (m, 2H), 7.44-7.40 (m, 2H), 7.12-6.99 (m, 4H), 6.79 (t, J = 1.9 Hz, 1H), 6.65 (t, J = 1.9 Hz, 1H), 6.11 (t, J = 2.1 Hz, 1H), 4.59 (quin, J = 7.2 Hz, 1H), 4.09-4.00 (m, 3H), 3.84 (tt, J = 4.0, 8.4 Hz, 1H), 3.78-3.70 (m, 1H), 3.40-3.32 (m, 2H), 3.26-3.03 (m, 3H), 2.69 (td, J = 6.3, 12.5 Hz, 2H), 2.33-2.25 (m, 2H), 2.04-1.95 (m, 2H), 1.91-1.80 (m, 2H), 1.72 (d, J = 13.0 Hz, 2H), 1.48-1.36 (m, 2H). Example 56: 4-(4-Chlorophenyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-hydroxypiperidine-1- carboxamide [00292] The target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4-(4- chlorophenyl)piperidin-4-ol. [00293] 1H NMR (400 MHz, CD3OD) d: 7.48 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.11-7.00 (m, 4H), 6.79 (t, J = 1.9 Hz, 1H), 6.65 (t, J = 1.9 Hz, 1H), 6.11 (t, J = 2.1 Hz, 1H), 4.59 (quin, J = 7.2 Hz, 1H), 4.04 (d, J = 10.8 Hz, 3H), 3.84 (tt, J = 3.9, 8.3 Hz, 1H), 3.78-3.71 (m, 1H), 3.40-3.34 (m, 2H), 3.26-3.02 (m, 3H), 2.69 (td, J = 6.1, 12.4 Hz, 2H), 2.34-2.24 (m, 2H), 2.06-1.96 (m, 2H), 1.91- 1.80 (m, 2H), 1.73 (d, J = 13.0 Hz, 2H), 1.48-1.36 (m, 2H). Example 57: 4-(3-(3-Fluoro-3-isobutylpyrrolidine-1-carboxamido)-5-(4- fluorophenoxy)phenoxy)benzoic acid [00294] The target compound was obtained in a similar manner to step D to E in Example 46 using methyl 4-(3-(4-fluorophenoxy)-5-(2,2,2- trichloroethoxycarbonylamino) phenoxy)benzoate and 3-fluoro-3- isobutylpyrrolidine. [00295] 1H NMR (400 MHz, DMSO-d6) d: 8.37 (s, 1H), 7.99-7.96 (m, 1H), 7.96-7.93 (m, 1H), 7.30-7.22 (m, 2H), 7.18-7.15 (m, 1H), 7.14-7.12 (m, 1H), 7.11 (s, 2H), 7.09 (s, 1H), 7.08-7.05 (m, 1H), 6.34 (t, J = 2.2 Hz, 1H), 3.72-3.61 (m, 1H), 3.57 (t, J = 10.0 Hz, 1H), 3.44-3.35 (m, 2H), 2.14 (dt, J = 6.8, 14.4 Hz, 1H), 2.07-1.89 (m, 1H), 1.83 (quind, J = 6.7, 13.1 Hz, 1H), 1.74-1.70 (m, 1H), 1.66 (d, J = 6.0 Hz, 1H), 0.94 (dd, J = 4.4, 6.5 Hz, 6H). Example 58: 4-((4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid A) Methyl 4-((6-amino-4-(4-fluorophenoxy)pyridin-2-yl)oxy)benzoate [00296] The target compound was obtained in a similar manner to step D in Example 59 using methyl 4-((6-((tert-butoxycarbonyl)amino)-4-(4- fluorophenoxy)pyridin-2-yl)oxy)benzoate. [00297] 1H NMR (400 MHz, DMSO-d6) d: 7.99-7.93 (m, 2H), 7.34-7.21 (m, 4H), 7.19-7.13 (m, 2H), 6.15 (s, 2H), 5.76 (d, J = 1.8 Hz, 1H), 5.61 (d, J = 1.7 Hz, 1H), 3.84 (s, 3H). B) 4-((4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-2-yl)oxy)benzoic acid [00298] The target compound was obtained in a similar manner to step G to I in Example 63 using methyl 4-((6-amino-4-(4-fluorophenoxy)pyridin-2- yl)oxy)benzoate. [00299] 1H NMR (400 MHz, CD3OD) d: 8.06 (d, J = 8.4 Hz, 2H), 7.27-7.11 (m, 7H), 6.10 (d, J = 1.8 Hz, 1H), 3.76 (d, J = 13.7 Hz, 2H), 3.27-3.16 (m, 2H), 1.91-1.77 (m, 1H), 1.63-1.45 (m, 4H), 1.37 (d, J = 5.7 Hz, 2H), 0.96 (d, J = 6.7 Hz, 6H). Example 59: 4-((2-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-4-yl)oxy)benzoic acid A) Methyl 4-((2,6-dichloropyridin-4-yl)oxy)benzoate [00300] To a mixture of 2,4,6-trichloropyridine (10 g), methyl 4- hydroxybenzoate (8.3 g), and DMF (240 mL) was added K2CO3 (22.7 g), and the mixture was stirred at 50°C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 50/1) to give the target compound (6.5 g) as a mixture with methyl 4-((4,6-dichloropyridin-2-yl)oxy)benzoate. [00301] 1H NMR (400 MHz, CD3OD) d: 8.18-8.12 (m, 2H), 7.31-7.26 (m, 2H), 7.00 (s, 2H), 3.92 (s, 3H). B) Methyl 4-((2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)oxy)benzoate [00302] To a mixture of methyl 4-((2,6-dichloropyridin-4-yl)oxy)benzoate (6.7 g) and 4-fluorophenol (2.5 g) in DMF (80 mL) was added K2CO3 (6.3 g), and the mixture was stirred at 120°C for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 20/1) to give the target compound (3.5 g) as a mixture with methyl 4- ((6-chloro-4-(4-fluorophenoxy)pyridin-2-yl)oxy)benzoate. [00303] 1H NMR (400 MHz, DMSO-d6) d: 8.10-7.99 (m, 2H), 7.40-7.17 (m, 6H), 6.84 (dd, J = 1.8, 17.9 Hz, 1H), 6.53 (dd, J = 1.7, 4.7 Hz, 1H), 3.88 (d, J = 5.1 Hz, 3H). C) Methyl 4-((2-((tert-butoxycarbonyl)amino)-6-(4-fluorophenoxy)pyridin-4- yl)oxy)benzoate [00304] A mixture of methyl 4-((2-chloro-6-(4-fluorophenoxy)pyridin-4- yl)oxy)benzoate (3.5 g), NH2Boc (2.0 g) , Cs2CO3 (5.5 g), Pd2(dba)3 (306 mg), Xantphos (580 mg) and dioxane (50 mL) was stirred at 110°C for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to give the target compound (2.3 g) as a mixture with methyl 4-((6-((tert-butoxycarbonyl)amino)-4- (4-fluorophenoxy)pyridin-2-yl)oxy)benzoate. D) Methyl 4-((2-amino-6-(4-fluorophenoxy)pyridin-4-yl)oxy)benzoate [00305] To a mixture of methyl 4-((2-((tert-butoxycarbonyl)amino)-6-(4- fluorophenoxy)pyridin-4-yl)oxy)benzoate (2.3 g) in DCM (25 mL) was added TFA (25 mL), and the mixture was stirred at 15°C for 12 h. The reaction mixture was concentrated and purified by prep-HPLC to give the target compound (0.2 g). [00306] 1H NMR (400 MHz, DMSO-d6) d: 8.06-7.99 (m, 2H), 7.29-7.09 (m, 6H), 6.12 (s, 2H), 5.67 (dd, J = 1.8, 11.0 Hz, 2H), 3.85 (s, 3H). E) 4-((2-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-4-yl)oxy)benzoic acid [00307] The target compound was obtained in a similar manner to step G to I in Example 63 using methyl 4-((2-amino-6-(4-fluorophenoxy)pyridin-4- yl)oxy)benzoate. [00308] 1H NMR (400 MHz, CD3OD) d: 8.11 (d, J = 8.7 Hz, 2H), 7.24-7.19 (m, 3H), 7.18-7.11 (m, 4H), 6.11 (d, J = 1.7 Hz, 1H), 3.76 (d, J = 13.3 Hz, 2H), 3.26-3.17 (m, 2H), 1.89-1.79 (m, 1H), 1.63-1.46 (m, 4H), 1.37 (d, J = 5.7 Hz, 2H), 0.96 (d, J = 6.7 Hz, 6H). Example 60: 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl dihydrogen phosphate A) 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4-yl dimethyl phosphate [00309] The target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carboxylic acid and dimethyl (1L2-piperidin-4-yl) phosphate. B) 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4-yl dihydrogen phosphate [00310] To a suspension of 1-((1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- hydroxy-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carbonyl)piperidin-4-yl dimethyl phosphate (0.3 g) in DCM (6.0 mL) was added TMSBr (169 uL), and the mixture was stirred at 25oC for 6 h. The reaction mixture was quenched with sat. NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, concentrated, and purified by neutral prep-HPLC to give the target compound (65.4 mg) as a solid. [00311] 1H NMR (400 MHz, CD3OD) d: 7.12-7.06 (m, 1H), 7.12-7.05 (m, 1H), 7.05-6.99 (m, 2H), 6.74 (t, J = 2.0 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 4.65-4.53 (m, 1H), 4.45 (br s, 1H), 3.88-3.63 (m, 4H), 3.57-3.48 (m, 1H), 3.40 (br s, 1H), 3.28-3.21 (m, 2H), 3.09 (t, J = 8.4 Hz, 1H), 2.69 (d, J = 9.3 Hz, 2H), 2.29 (d, J = 9.5 Hz, 2H), 1.96-1.82 (m, 3H), 1.73 (br s, 2H), 1.66-1.50 (m, 4H), 1.40 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 61: N-(6-(4-Fluorophenoxy)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)pyridin-2-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide A) Methyl (1s,3s)-3-((2,6-dichloropyridin-4-yl)oxy)cyclobutane-1-carboxylate [00312] To a solution of 2,6-dichloropyridin-4-ol (2.0 g), methyl 3- hydroxycyclobutanecarboxylate (1.9 g) and PPh3 (6.4 g) in THF (50 mL) was added DEAD (4.3 g) at 0°C, and the reaction mixture was stirred at 40°C for 12 h. The reaction mixture was concentrated and purified by silica gel column (petroleum ether/ethyl acetate = 6/1 to 4/1) to give the target compound (2.6 g) as an oil. [00313] 1H NMR (400 MHz, CD3OD) d: 6.93 (s, 2H), 4.80 (quin, J = 7.2 Hz, 1H), 3.69 (s, 3H), 2.98-2.84 (m, 1H), 2.79 (dtd, J = 2.8, 7.2, 9.8 Hz, 2H), 2.42- 2.30 (m, 2H). B) Methyl (1s,3s)-3-((2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)oxy)cyclobutane- 1-carboxylate [00314] To a mixture of methyl (1s,3s)-3-((2,6-dichloropyridin-4- yl)oxy)cyclobutane-1-carboxylate (2.6 g) and 4-fluorophenol (1.1 g) in DMF (50 mL) was added K2CO3 (2.6 g), and the reaction mixture was stirred at 120°C for 12 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to give the target compound (2.5 g) as an oil. C) Methyl (1s,3s)-3-((2-((tert-butoxycarbonyl)amino)-6-(4-fluorophenoxy)pyridin- 4-yl)oxy)cyclobutane-1-carboxylate [00315] To a solution of tert-butyl carbamate (2.1 g) and methyl (1s,3s)-3- ((2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)oxy)cyclobutane-1-carboxylate (2.5 g) in dioxane (40 mL) was added Cs2CO3 (5.8 g), Pd2(dba)3 (325 mg) and Xantphos (617 mg), and the mixture was stirred at 110°C for 12 h. The mixture was concentrated and purified by silica gel column (petroleum ether/ethyl acetate = 30/1 to 10/1) to give the target compound (1.1 g) as a solid. D) Methyl (1s,3s)-3-((2-amino-6-(4-fluorophenoxy)pyridin-4-yl)oxy)cyclobutane- 1-carboxylate [00316] To a solution of methyl (1s,3s)-3-((2-((tert-butoxycarbonyl)amino)- 6-(4-fluorophenoxy)pyridin-4-yl)oxy)cyclobutane-1-carboxylate (1.1 g) in DCM (10 mL) was added TFA (9.0 mL) at 15°C, and the mixture was stirred at the same temperature for 6 h. The mixture was diluted with water, basified to pH = 9 with 3 M NaOH solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1 to 4/1) to afford the target compound (0.2 g) as a solid. [00317] 1H NMR (400 MHz, DMSO-d6) d: 7.24-7.15 (m, 2H), 7.13-7.02 (m, 2H), 5.91 (s, 2H), 5.67-5.51 (m, 2H), 4.67-4.56 (m, 1H), 3.62 (s, 3H), 2.86 (quin, J = 8.8 Hz, 1H), 2.73-2.61 (m, 2H), 2.23-2.11 (m, 2H). E) (1s,3s)-3-((2-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)pyridin-4-yl)oxy)cyclobutane-1-carboxylic acid [00318] The target compound was obtained in a similar manner to step G to I in Example 63 using methyl (1s,3s)-3-((2-amino-6-(4-fluorophenoxy)pyridin- 4-yl)oxy)cyclobutane-1-carboxylate. F) N-(6-(4-Fluorophenoxy)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)pyridin-2-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00319] The target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-((2-(4-fluorophenoxy)-6-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)pyridin-4-yl)oxy)cyclobutane-1-carboxylic acid and 1^2-piperidin-4-ol. [00320] 1H NMR (400 MHz, CD3OD) d: 7.22-7.05 (m, 5H), 5.98 (d, J = 1.7 Hz, 1H), 4.85-4.78 (m, 1H), 4.09 (d, J = 12.6 Hz, 1H), 3.89-3.76 (m, 3H), 3.68 (d, J = 12.8 Hz, 1H), 3.55-3.46 (m, 1H), 3.26-3.10 (m, 4H), 2.74 (br s, 2H), 2.51-2.39 (m, 2H), 1.93-1.81 (m, 3H), 1.65-1.35 (m, 8H), 0.97 (d, J = 6.6 Hz, 6H). Example 62: 4-((1-(4-Fluorophenyl)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-6-yl)oxy)benzoic acid A) 4-Bromo-1-(4-fluorophenyl)-6-methoxy-1H-indazole [00321] The target compound was obtained in a similar manner to step D in Example 63 using 4-bromo-6-methoxy-1H-indazole and (4- fluorophenyl)boronic acid. [00322] 1H NMR (400 MHz, DMSO-d6) d: 8.20 (s, 1H), 7.83-7.75 (m, 2H), 7.48-7.40 (m, 2H), 7.20-7.10 (m, 2H), 3.86 (s, 3H). B) 4-Bromo-1-(4-fluorophenyl)-1H-indazol-6-ol [00323] To a mixture of 4-bromo-1-(4-fluorophenyl)-6-methoxy-1H- indazole (3.0 g) in DCM (10 mL) was added BBr3 (4.5 mL) at 0°C, and the mixture was stirred at 25°C for 12 h. The mixture was poured into cold water and the resulting precipitate was collected by filtration. The filter cake was collected and dried under reduced pressure to the target compound (2.5 g) as a solid. [00324] 1H NMR (400 MHz, DMSO-d6) d: 10.28 (br s, 1H), 8.14 (s, 1H), 7.72 (dd, J = 5.0, 8.1 Hz, 2H), 7.44 (t, J = 8.6 Hz, 2H), 7.01 (d, J = 12.7 Hz, 2H). C) Methyl 4-((4-bromo-1-(4-fluorophenyl)-1H-indazol-6-yl)oxy)benzoate [00325] To a mixture of 4-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (500 mg) in DMSO (5 mL) was added methyl 4-fluorobenzoate (316 uL) and Cs2CO3 (1.1 g), and the mixture was stirred at 120°C for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 100/1 to 50/1 to 30/1 to 10/1) to give the target compound (350 mg) as a solid. D) 4-((1-(4-Fluorophenyl)-4-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-1H- indazol-6-yl)oxy)benzoic acid [00326] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 4-((4-bromo-1-(4-fluorophenyl)-1H-indazol-6- yl)oxy)benzoate. [00327] 1H NMR (400 MHz, CD3OD) d: 8.27 (d, J = 0.61 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.68-7.61 (m, 2H), 7.32-7.24 (m, 2H), 7.09-6.97 (m, 4H), 3.93 (d, J = 13.3 Hz, 2H), 3.41-3.33 (m, 2H), 1.94-1.84 (m, 1H), 1.71-1.59 (m, 4H), 1.43 (d, J = 5.8 Hz, 2H), 0.99 (d, J = 6.7 Hz, 6H). Example 63: 4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid A) 5-Bromo-1-(4-fluorophenoxy)-2-methyl-3-nitro-benzene [00328] A mixture of 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (4.0 g), 4- fluorophenol (2.3 g), K2CO3 (2.8 g) and DMF (60 mL) was stirred at 120°C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0) to give the target compound (5.1 g) as an oil. [00329] 1HNMR (400 MHz CDCl3) d: 7.74 (d, J = 1.8 Hz, 1H), 7.16-7.04 (m, 3H), 7.01-6.93 (m, 2H), 2.43 (s, 3H). B) 5-Bromo-3-(4-fluorophenoxy)-2-methyl-aniline [00330] To a solution of 5-bromo-1-(4-fluorophenoxy)-2-methyl-3-nitro- benzene (5.5 g) in THF (55 mL) was added AcOH (11 mL) and Fe (4.71 g), and the mixture was stirred at 80°C for 10 h. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0) to give the target compound (6.2 g) as an oil. [00331] 1H NMR (400 MHz, CD3OD) d: 7.06 (t, J = 8.7 Hz, 2H), 6.89 (dd, J = 9.0, 4.3 Hz, 2H), 6.69 (s, 1H), 6.25 (s, 1H), 1.97 (s, 3 H). C) 6-Bromo-4-(4-fluorophenoxy)-1H-indazole [00332] To a solution of 5-bromo-3-(4-fluorophenoxy)-2-methyl-aniline (5.2 g) in AcOH (50 mL) was added sodium nitrite (1.3 g), and the mixture was stirred at 120°C for 10 h. The reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give the target compound (3.9 g) as a solid. [00333] 1H NMR (400 MHz, CDCl3) d: 7.97 (s, 1H), 7.38 (s, 1H), 7.13 (d, J = 6.36 Hz, 4H), 6.56 (d, J = 1.10 Hz, 1H). D) Methyl 4-(6-bromo-4-(4-fluorophenoxy)indazol-1-yl)benzoate [00334] To a solution of 6-bromo-4-(4-fluorophenoxy)-1H-indazole (500 mg) and (4-methoxycarbonylphenyl)boronic acid (586 mg) in DCM (10 mL) was added TEA (329 mg) and Cu(OAc)2 (444 mg), and the mixture was stirred at 25°C for 18 h under O2 atmosphere (14 psi). The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give the target compound (400 mg) as a solid. [00335] 1H NMR (400 MHz, CDCl3) d: 8.25 (d, J = 8.6 Hz, 2H), 8.18 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.16 (d, J = 6.2 Hz, 4H), 6.63 (s, 1H), 3.98 (s, 3H). E) Methyl 4-(6-(tert-butoxycarbonylamino)-4-(4-fluorophenoxy)indazol-1- yl)benzoate [00336] A mixture of methyl 4-(6-bromo-4-(4-fluorophenoxy)indazol-1- yl)benzoate (200 mg) , NH2Boc (133 mg), Cs2CO3 (369 mg), Xantphos (39.3 mg), Pd2(dba)3 (20.8 mg) and dioxane (12 mL) was stirred at 110°C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give the target compound (170 mg) as a solid. [00337] 1H NMR (400 MHz, CDCl3) d: 8.23 (d, J = 8.8 Hz, 2H), 8.05 (s, 1H), 7.92 (br s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.10-7.15 (m, 4H), 6.54 (s, 1H), 6.29 (s, 1H), 3.97 (s, 3H), 1.50 (s, 9H). F) Methyl 4-(6-amino-4-(4-fluorophenoxy)indazol-1-yl)benzoate [00338] To a solution of methyl 4-(6-(tert-butoxycarbonylamino)-4-(4- fluorophenoxy)indazol-1-yl)benzoate (170 mg) in EtOAc (2.0 mL) was added 4 M HCl/EtOAc (5.0 mL), and the mixture was stirred at 15°C for 4 h. The residue was diluted with sat. NaHCO3 solution (15 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (140 mg) as an oil. MS: (M+H+): 378.2. G) Methyl 4-(4-(4-fluorophenoxy)-6-(2,2,2- trichloroethoxycarbonylamino)indazol-1-yl) benzoate [00339] To a solution of methyl 4-(6-amino-4-(4-fluorophenoxy)indazol-1- yl)benzoate (100 mg) and 2,2,2-trichloroethyl carbonochloridate (67.4 mg) in EtOAc (10 mL) was added NaHCO3 (44.5 mg), and the mixture was stirred at 15°C for 15 h. The reaction mixture was filtered and concentrated to give the target compound (145 mg) as an oil. MS: (M+H+): 554.0. H) Methyl 4-(4-(4-fluorophenoxy)-6-((4-hydroxy-4-isobutyl-piperidine-1- carbonyl)amino) indazol-1-yl)benzoate [00340] A mixture of methyl 4-(4-(4-fluorophenoxy)-6-(2,2,2- trichloroethoxycarbonylamino)indazol-1-yl) benzoate (145 mg), 4- isobutylpiperidin-4-ol (49.5 mg), DBU (200 mg), and DMF (5.0 mL) was stirred at 60°C for 1 h. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to give the target compound (50 mg) as a solid. MS: (M+H+): 561.3. I) 4-(4-(4-Fluorophenoxy)-6-((4-hydroxyl-4-isobutyl-piperidine-1- carbonyl)amino)indazol-1-yl)benzoic acid [00341] To a solution of methyl 4-(4-(4-fluorophenoxy)-6-((4-hydroxy-4- isobutyl-piperidine-1-carbonyl)amino)indazol-1-yl)benzoate (20 mg) in dioxane (1.0 mL) and H2O (1.0 mL) was added LiOH.H2O (4.49 mg), and the mixture was stirred at 15 °C for 4 h. The reaction mixture was concentrated and purified by HPLC to give the target compound (15 mg) as a solid. [00342] 1H NMR (400 MHz, CD3OD) d: 8.19 (d, J = 8.6 Hz, 2H), 8.02 (s, 1H), 7.73-7.82 (m, 3H), 7.13-7.24 (m, 4H), 6.76 (d, J = 0.98 Hz, 1H), 3.83 (br d, J = 13.2 Hz, 2H), 3.21-3.29 (m, 2H), 1.86 (dquin, J = 12.8, 6.3 Hz, 1H), 1.48-1.66 (m, 4H), 1.39 (d, J = 5.8 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). Example 64: 4-((1-(4-Fluorophenyl)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-4-yl)oxy)benzoic acid A) 6-Bromo-1-(4-fluorophenyl)-4-methoxy-1H-indazole [00343] The target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-methoxy-1H-indazole and (4- fluorophenyl)boronic acid. [00344] 1H NMR (400 MHz, CDCl3) d: 8.13 (s, 1H), 7.51-7.60 (m, 2H), 7.33 (s, 1H), 7.14-7.18 (m, 1H), 6.61 (s, 1H), 3.92 (s, 3H). B) 6-Bromo-1-(4-fluorophenyl)-1H-indazol-4-ol [00345] The target compound was obtained in a similar manner to step B in Example 62 using 6-bromo-1-(4-fluorophenyl)-4-methoxy-1H-indazole. [00346] 1H NMR (400 MHz, CDCl3) d: 8.34 (s, 1H), 7.76 (dd, J = 8.8, 4.9 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H), 7.34 (s, 1H), 6.70 (s, 1H). C) Methyl 4-((6-bromo-1-(4-fluorophenyl)-1H-indazol-4-yl)oxy)benzoate [00347] To a solution of 6-bromo-1-(4-fluorophenyl)-1H-indazol-4-ol (0.15 g) and (4-methoxy carbonylphenyl) boronic acid (264 mg) in DCM (10 mL) was added TEA (136 uL) and Cu(OAc)2 (222 mg), and the mixture was stirred at 35°C for 12 h under O2 atmosphere. The reaction mixture was filtered, concentrated, and purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give the target compound (0.084 g) as a solid. [00348] 1H NMR (400 MHz, DMSO-d6): d 8.08-8.13 (m, 2H), 8.02 (d, J = 0.88 Hz, 1H), 7.61-7.68 (m, 2H), 7.58 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.17 (d, J = 9.2 Hz, 2H), 6.82 (d, J = 1.3 Hz, 1H), 3.91-3.96 (m, 3H). D) 4-((1-(4-Fluorophenyl)-6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-1H- indazol-4-yl)oxy)benzoic acid [00349] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 4-((6-bromo-1-(4-fluorophenyl)-1H-indazol-4- yl)oxy)benzoate. [00350] 1H NMR (400 MHz, DMSO-d6) d: 8.10 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H), 7.68-7.79 (m, 3H), 7.35 (t, J = 8.7 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 1.5 Hz, 1H), 3.87 (d, J = 13.5 Hz, 2H), 3.27 (br s, 2H), 1.80-1.93 (m, 1H), 1.52- 1.71 (m, 4H), 1.42 (d, J = 5.9 Hz, 2H), 0.99 (d, J = 6.7 Hz, 6H). Example 65: 4-(6-(4-Fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid A) 1-Bromo-5-(4-fluorophenoxy)-2-methyl-3-nitrobenzene [00351] A mixture of 4-fluorophenol (6.7 g), 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (10 g), K2CO3 (6.5 g), and DMA (70 mL) was stirred at 120°C for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was diluted with water, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether) to give the target compound (12 g) as an oil. B) 3-Bromo-5-(4-fluorophenoxy)-2-methylaniline [00352] To a mixture of 1-bromo-5-(4-fluorophenoxy)-2-methyl-3- nitrobenzene (12 g), EtOH (80 mL) and water (20 mL) was added Fe (6.2 g) and NH4Cl (6.3 g), and the mixture was stirred at 70°C for 3 h. The reaction mixture was diluted with EtOAc, filtered through a pad of Celite, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/EtOAc = 1/0 to 97/3 to 19/1) to give the target compound (9.3 g) as an oil. [00353] 1H NMR (400 MHz, CDCl3) d: 7.08-6.97 (m, 4H), 6.63 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 3.79 (br s, 2H), 2.24 (s, 3H). C) 4-Bromo-6-(4-fluorophenoxy)-1H-indazole [00354] A mixture of 3-bromo-5-(4-fluorophenoxy)-2-methylaniline (5.0 g), Ac2O (4.8 mL), KOAc (1.7 g), and toluene (60 mL) was stirred at 80°C for 40 min, then a solution of isopentyl nitrite (3.4 mL) in toluene (5.0 mL) was added dropwise over 20 min at 80°C. After stirred at 80°C for 12 h, the mixture was filtrated and concentrated. Water (15 mL) and 6 M HCl (30 mL) were added to the residue, and the mixture was heated to 55°C for 10 min. Then MeOH (100 mL) was added and the mixture was heated at 80°C for 0.5 h. The resulting solution was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 6/1) to give the target compound (3.5 g) as a solid. [00355] 1H NMR (400 MHz, CDCl3) d: 10.46 (br s, 1H), 8.03 (s, 1H), 7.13- 6.99 (m, 5H), 6.88 (s, 1H). D) Methyl 4-(4-bromo-6-(4-fluorophenoxy)-1H-indazol-1-yl)benzoate [00356] The target compound was obtained in a similar manner to step A in Example 77 using 4-bromo-6-(4-fluorophenoxy)-1H-indazole and methyl 4- iodobenzoate. [00357] 1H NMR (400 MHz, DMSO-d6) d: 8.42 (d, J = 0.7 Hz, 1H), 8.15- 8.11 (m, 2H), 7.93-7.87 (m, 2H), 7.50 (d, J = 0.6 Hz, 1H), 7.30-7.16 (m, 5H), 3.89 (s, 3H). E) 4-(6-(4-Fluorophenoxy)-4-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 1H-indazol-1-yl)benzoic acid [00358] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 4-(4-bromo-6-(4-fluorophenoxy)-1H-indazol-1- yl)benzoate. [00359] 1H NMR (400 MHz, DMSO-d6) d: 8.87 (s, 1H), 8.45 (s, 1H), 8.09 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.27-7.20 (m, 2H), 7.14-7.10 (m, 4H), 4.17 (br s, 1H), 3.82 (d, J = 13.1 Hz, 2H), 3.22 (t, J = 10.9 Hz, 2H), 1.88-1.77 (m, 1H), 1.56-1.41 (m, 4H), 1.32 (d, J = 5.7 Hz, 2H), 0.93 (s, 3H), 0.92 (s, 3H). Example 66: N-(1-(4-Fluorophenyl)-6-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-4-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide A) Methyl (1s,3s)-3-((4-bromo-1-(4-fluorophenyl)-1H-indazol-6- yl)oxy)cyclobutane-1-carboxylate [00360] To a mixture of 4-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (1.0 g) in THF (15 mL) was added methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate (848 mg) and PPh3 (1.7 g). Then a solution of tert-butyl (NE)-N-tert- butoxycarbonyliminocarbamate (1.5 g) in THF (3.0 mL) was added to the mixture dropwise at 0°C, and the mixture was heated to 40°C and stirred for 12 h. The reaction mixture was concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 15/1 to 20/1) to give the target compound (0.8 g) was as an oil. [00361] 1H NMR (400 MHz, CDCl3) d: 8.00 (d, J = 0.6 Hz, 1H), 7.56-7.49 (m, 2H), 7.21-7.12 (m, 2H), 6.93 (d, J = 1.7 Hz, 1H), 6.73 (d, J = 0.7 Hz, 1H), 4.54 (quin, J = 7.2 Hz, 1H), 3.64 (s, 3H), 2.82-2.62 (m, 3H), 2.47-2.35 (m, 2H). B) (1s,3s)-3-((1-(4-Fluorophenyl)-4-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-6-yl)oxy)cyclobutane-1-carboxylic acid [00362] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl (1s,3s)-3-((4-bromo-1-(4-fluorophenyl)-1H- indazol-6-yl)oxy)cyclobutane-1-carboxylate. MS: (M+H+): 525.4. C) N-(1-(4-Fluorophenyl)-6-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-4-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00363] The target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-((1-(4-fluorophenyl)-4-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)-1H-indazol-6-yl)oxy)cyclobutane-1-carboxylic acid and 1^2-piperidin-4-ol. [00364] 1H NMR (400 MHz, CD3OD) d: 8.13 (s, 1H), 7.69-7.61 (m, 2H), 7.35-7.27 (m, 2H), 6.88 (d, J = 1.7 Hz, 1H), 6.63 (s, 1H), 4.75-4.61 (m, 1H), 4.01- 4.10 (m, 1H), 3.94 (d, J = 13.5 Hz, 2H), 3.83 (tt, J = 3.9, 8.3 Hz, 1H), 3.73 (d, J = 13.8 Hz, 1H), 3.42-3.34 (m, 2H), 3.26-3.01 (m, 3H), 2.77-2.64 (m, 2H), 2.40-2.26 (m, 2H), 1.97-1.78 (m, 3H), 1.74-1.59 (m, 4H), 1.48-1.32 (m, 4H), 1.00 (d, J = 6.7 Hz, 6H). Example 67: N-(1-(4-Fluorophenyl)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide A) Methyl (1s,3s)-3-((6-bromo-1-(4-fluorophenyl)-1H-indazol-4- yl)oxy)cyclobutane-1-carboxylate [00365] The target compound was obtained in a similar manner to step A in Example 66 using 6-bromo-1-(4-fluorophenyl)-1H-indazol-4-ol and methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate. [00366] 1H NMR (400 MHz, CDCl3) d: 8.20 (s, 1 H), 7.65-7.61 (m, 2 H), 7.40 (s, 1 H), 7.27-7.21 (m, 2 H), 6.51 (d, J = 0.88 Hz, 1 H), 4.83-4.73 (m, 1 H), 3.74 (s, 3 H), 2.92-2.81 (m, 3 H), 2.64-2.55 (m, 2 H). B) (1s,3s)-3-((1-(4-Fluorophenyl)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-4-yl)oxy)cyclobutane-1-carboxylic acid [00367] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl (1s,3s)-3-((6-bromo-1-(4-fluorophenyl)-1H- indazol-4-yl)oxy)cyclobutane-1-carboxylate. MS: (M+H+): 525.2. C) N-(1-(4-Fluorophenyl)-4-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1- carboxamide [00368] The target compound was obtained in a similar manner to Example 39 using (1s,3s)-3-((1-(4-Fluorophenyl)-6-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)-1H-indazol-4-yl)oxy)cyclobutane-1-carboxylic acid and 1L2-piperidin-4-ol. [00369] 1H NMR (400 MHz, CD3OD) d: 8.11 (s, 1 H), 7.66-7.72 (m, 2 H), 7.43 (s, 1 H), 7.30 (t, J = 8.2 Hz, 2 H), 6.73 (d, J = 1.2 Hz, 1 H), 4.80-4.86 (m, 1 H), 4.04-4.11 (m, 1 H), 3.76-3.93 (m, 4 H), 3.33-3.37 (m, 1 H), 3.13-3.22 (m, 2 H), 2.81-2.91 (m, 2 H), 2.40-2.49 (m, 2 H), 1.88 (td, J = 12.9, 6.3 Hz, 3 H), 1.55-1.68 (m, 4 H), 1.44-1.52 (m, 1 H), 1.42 (d, J = 5.8 Hz, 2 H), 0.99 (d, J = 6.6 Hz, 6 H). Example 68: ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1s,4S)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone A) Methyl (1s,3s)-3-(3-bromo-5-fluoro-2-nitrophenoxy)cyclobutane-1- carboxylate [00370] To a mixture of methyl 3-hydroxycyclobutanecarboxylate (3.6 g) in THF (20 mL) was added 1 M LiHMDS (32.8 mL) at 0°C and the reaction mixture was stirred for 0.5 h. Then 1-bromo-3,5-difluoro-2-nitrobenzene (6.5 g) was added and the mixture was stirred for further 12 h. The reaction mixture was quenched by saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1 to 10/1) to give the target compound (4.0 g) as a white solid. [00371] 1H NMR (400 MHz, CDCl3) d: 6.98 (dd, J = 2.4, 7.6 Hz, 1H), 6.56 (dd, J = 2.4, 9.7 Hz, 1H), 4.68-4.57 (m, 1H), 3.72 (s, 3H), 2.90-2.69 (m, 3H), 2.57- 2.45 (m, 2H). B) Methyl (1s,3s)-3-(3-bromo-5-(4-fluorophenoxy)-2-nitrophenoxy)cyclobutane- 1-carboxylate [00372] A mixture of methyl (1s,3s)-3-(3-bromo-5-fluoro-2- nitrophenoxy)cyclobutane-1-carboxylate (3.0 g), 4-fluorophenol (966 mg), Cs2CO3 (4.2 g), and DMF (40 mL) was stirred at 50°C for 12 h. Another batch with 1.0 g of the starting material was combined. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1 to 10/1) to give the target compound (4.1 g) as a solid. [00373] 1H NMR (400 MHz, CDCl3) d: 7.16-7.09 (m, 2H), 7.07-7.02 (m, 2H), 6.66 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 4.55 (quin, J = 7.2 Hz, 1H), 3.71 (s, 3H), 2.81-2.74 (m, 1H), 2.66 (dtd, J = 2.7, 7.3, 9.9 Hz, 2H), 2.52-2.44 (m, 2H). C) Methyl (1s,3s)-3-(3-((tert-butoxycarbonyl)amino)-5-(4-fluorophenoxy)-2- nitrophenoxy)cyclobutane-1-carboxylate [00374] A mixture of methyl (1s,3s)-3-(3-bromo-5-(4-fluorophenoxy)-2- nitrophenoxy)cyclobutane-1-carboxylate (3.1 g), tert-butyl carbamate (2.5 g), Pd2(dba)3 (645 mg), Xantphos (1.2 g), Cs2CO3 (5.7 g) and dioxane (50 mL) was stirred at 110°C for 12 h. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1 to 10/1) to give the target compound (3.0 g) as a solid. [00375] 1H NMR (400 MHz, CDCl3) d: 8.02 (s, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.06-7.00 (m, 2H), 6.99-6.93 (m, 2H), 5.92 (d, J = 2.3 Hz, 1H), 4.44 (quin, J = 7.2 Hz, 1H), 3.63 (s, 3H), 2.75-2.63 (m, 1H), 2.61-2.50 (m, 2H), 2.46-2.33 (m, 2H), 1.40 (s, 9H). D) Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2-nitrophenoxy)cyclobutane- 1-carboxylate [00376] To a mixture of methyl (1s,3s)-3-(3-((tert-butoxycarbonyl)amino)- 5-(4-fluorophenoxy)-2-nitrophenoxy)cyclobutane-1-carboxylate (2.4 g) in EtOAc (5 mL) was added 4 M HCl/EtOAc (60 mL), and the mixture was stirred at 20°C for 4 h. The reaction mixture was concentrated under the reduced pressure to afford the target compound (1.8 g) as a solid. E) Methyl (1s,3s)-3-(2,3-diamino-5-(4-fluorophenoxy)phenoxy)cyclobutane-1- carboxylate [00377] Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2- nitrophenoxy)cyclobutane-1-carboxylate (1.0 g) in MeOH (20 mL) and EtOAc (10 mL) was added into 10% Pd/C (1.0 g) in EtOAc (20 mL) at 20°C. Then the mixture was stirred at 20°C for 24 h under H2 atmosphere (15 psi). The reaction mixture was diluted with EtOAc, filtered through Celite, and concentrated under the reduced pressure. The residue purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/7) to give the target compound (570 mg) as a solid. [00378] 1H NMR (400 MHz, DMSO-d6) d: 7.19-7.10 (m, 2H), 6.94-6.88 (m, 2H), 5.93 (d, J = 2.4 Hz, 1H), 5.83 (d, J = 2.4 Hz, 1H), 4.73 (br s, 2H), 4.52 (quin, J = 7.2 Hz, 1H), 3.92 (br s, 2H), 3.65-3.60 (m, 3H), 2.86-2.74 (m, 1H), 2.68-2.56 (m, 2H), 2.27-2.15 (m, 2H). F) Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2-(4-hydroxy-4- isobutylcyclohexane-1-carboxamido)phenoxy)cyclobutane-1-carboxylate [00379] To a mixture of methyl (1s,3s)-3-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)cyclobutane-1-carboxylate (970 mg) and 4-hydroxy-4- isobutyl-cyclohexanecarboxylic acid (841 mg) in DMF (10 mL) was added PYAOP (2.2 g). Then DIPEA (1.22 mL) was added to the mixture at 20°C, and the mixture was stirred at 80°C for 12 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2/3) to afford the target compound (1 g) as a mixture with methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- hydroxy-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carboxylate. G) Methyl (1S,3s)-3-((6-(4-fluorophenoxy)-2-((1s,4S)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylate [00380] Methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2-(4-hydroxy-4- isobutylcyclohexane-1-carboxamido)phenoxy)cyclobutane-1-carboxylate (1.0 g) in acetic acid (10 mL) was stirred at 60°C for 2 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1 to 0/1) to afford the target compound (250 mg) as an oil. [00381] 1H NMR (400 MHz, CD3OD) d: 7.20-7.13 (m, 2H), 7.12-7.06 (m, 2H), 6.69 (d, J = 1.8 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 4.90 (br s, 1H), 3.70 (s, 3H), 3.10 (tt, J = 3.4, 12.4 Hz, 1H), 3.00-2.90 (m, 1H), 2.86-2.76 (m, 2H), 2.51- 2.41 (m, 2H), 2.17-2.05 (m, 2H), 1.98-1.85 (m, 5H), 1.56 (dt, J = 3.9, 13.5 Hz, 2H), 1.43 (d, J = 5.6 Hz, 2H), 1.00 (d, J = 6.7 Hz, 6H). H) (1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1s,4S)-4-hydroxy-4-isobutylcyclohexyl)- 1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylic acid [00382] To a stirred mixture of methyl (1S,3s)-3-((6-(4-fluorophenoxy)-2- ((1s,4S)-4-hydroxy-4-isobutylcyclohexyl)-1H-benzo[d]imidazol-4- yl)oxy)cyclobutane-1-carboxylate (250 mg) in dioxane (0.5 mL) and water (0.5 mL) was added LiOH.H2O (61.6 mg) at 25°C. The mixture was stirred at 25°C for 3 h. The reaction mixture was diluted with water and adjusted to pH = 5 with 4 M HCl. Then the solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under the reduced pressure to afford the target compound (230 mg) as an oil. I) ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1s,4S)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone [00383] To a stirred mixture of (1S,3s)-3-((6-(4-fluorophenoxy)-2-((1s,4S)- 4-hydroxy-4-isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1- carboxylic acid (230 mg) in DMF (2.5 mL) were added piperidin-4-ol (93.7 mg), HOBt (93.9 mg), EDCI (133 mg), and DIPEA (242 uL) at 25°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under the reduced pressure. The residue was purified by neutral HPLC to give the target compound (54.3 mg) as a solid. 1H NMR (400 MHz, CD3OD) d: 7.10-7.02 (m, 2H), 7.01-6.94 (m, 2H), 6.67 (s, 1H), 6.35 (d, J = 1.8 Hz, 1H), 4.77 (quin, J = 7.2 Hz, 1H), 4.13-4.00 (m, 1H), 3.84 (tt, J = 4.0, 8.3 Hz, 1H), 3.80-3.70 (m, 1H), 3.27-3.05 (m, 3H), 2.90-2.79 (m, 1H), 2.73 (td, J = 6.2, 12.5 Hz, 2H), 2.50-2.37 (m, 2H), 2.05 (dq, J = 3.3, 13.0 Hz, 2H), 1.96-1.78 (m, 7H), 1.51 (dt, J = 4.1, 13.6 Hz, 2H), 1.46-1.35 (m, 4H), 0.99 (d, J = 6.7 Hz, 6H). Example 69: ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1r,4R)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone A) Methyl (1S,3s)-3-((6-(4-fluorophenoxy)-2-((1r,4R)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylate [00384] The target compound was obtained in a similar manner to step G in Example 68 using methyl (1s,3s)-3-(3-amino-5-(4-fluorophenoxy)-2-(4- hydroxy-4-isobutylcyclohexane-1-carboxamido)phenoxy)cyclobutane-1- carboxylate. [00385] 1H NMR (400 MHz, CD3OD) d: 7.20-7.13 (m, 2H), 7.13-7.06 (m, 2H), 6.70 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.91 (br s, 1H), 3.70 (s, 3H), 3.20 (tt, J = 3.9, 10.9 Hz, 1H), 3.01-2.90 (m, 1H), 2.86-2.77 (m, 2H), 2.51- 2.42 (m, 2H), 2.16-2.08 (m, 2H), 1.96-1.83 (m, 5H), 1.65-1.58 (m, 2H), 1.56 (d, J = 6.0 Hz, 2H), 1.02 (d, J = 6.6 Hz, 6H). B) (1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1r,4R)-4-hydroxy-4-isobutylcyclohexyl)- 1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylic acid [00386] The target compound was obtained in a similar manner to step H in Example 68 using methyl (1S,3s)-3-((6-(4-fluorophenoxy)-2-((1r,4R)-4- hydroxy-4-isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1- carboxylate. C) ((1S,3s)-3-((6-(4-Fluorophenoxy)-2-((1r,4R)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutyl)(4- hydroxypiperidin-1-yl)methanone [00387] The target compound was obtained in a similar manner to step I in Example 68 using (1S,3s)-3-((6-(4-fluorophenoxy)-2-((1r,4R)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylic acid 1H NMR (400 MHz, CD3OD) d: 7.11-7.02 (m, 2H), 7.01-6.94 (m, 2H), 6.66 (br s, 1H), 6.35 (br s, 1H), 4.78 (quin, J = 7.2 Hz, 1H), 4.10-4.02 (m, 1H), 3.84 (tt, J = 3.9, 8.3 Hz, 1H), 3.80-3.71 (m, 1H), 3.22 (ddd, J = 3.2, 10.0, 13.6 Hz, 1H), 3.17- 3.07 (m, 2H), 2.96-2.86 (m, 1H), 2.73 (td, J = 6.2, 12.7 Hz, 2H), 2.49-2.38 (m, 2H), 2.03-1.94 (m, 2H), 1.93-1.79 (m, 7H), 1.63-1.51 (m, 4H), 1.49-1.33 (m, 2H), 1.01 (d, J = 6.6 Hz, 6H). Example 70: 4-((6-(4-Fluorophenoxy)-2-((1r,4r)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)benzoic acid [00388] The target compound was obtained in a similar manner to step F to H in Example 68 using ethyl 4-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)benzoate and 4-hydroxy-4-isobutyl- cyclohexanecarboxylic acid. [00389] 1H NMR (400 MHz, CD3OD) d: 8.02-7.97 (m, 2H), 7.12-6.97 (m, 6H), 6.91 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 2.98-2.87 (m, 1H), 1.98 (dd, J = 3.9, 13.6 Hz, 2H), 1.91-1.78 (m, 5H), 1.58-1.48 (m, 4H), 0.98 (d, J = 6.7 Hz, 6H). Example 71: 4-((6-(4-Fluorophenoxy)-2-((1s,4s)-4-hydroxy-4- isobutylcyclohexyl)-1H-benzo[d]imidazol-4-yl)oxy)benzoic acid [00390] The target compound was obtained in a similar manner to step F to H in Example 68 using ethyl 4-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)benzoate and 4-hydroxy-4-isobutyl- cyclohexanecarboxylic acid. [00391] 1H NMR (400 MHz, CD3OD) d: 8.03-7.97 (m, 2H), 7.10-6.97 (m, 6H), 6.93 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 2.89-2.78 (m, 1H), 2.05 (dq, J = 3.6, 13.0 Hz, 2H), 1.93-1.77 (m, 5H), 1.49 (dt, J = 4.2, 13.7 Hz, 2H), 1.39 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 72: ((1s,3s)-3-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin- 1-yl)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutyl)(4-hydroxypiperidin-1- yl)methanone A) Methyl (1s,3s)-3-((6-(4-fluorophenoxy)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylate [00392] To a stirred mixture of methyl (1s,3s)-3-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)cyclobutane-1-carboxylate (370 mg) in THF (4.0 mL) was added bis(1,2,4-triazol-1-yl)methanone (263 mg). The mixture was stirred at 70°C for 12 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/EtOAc = 72:28) to give the target compound (150 mg) as a solid. [00393] 1H NMR (400 MHz, DMSO-d6) d: 10.66 (s, 1H), 10.55 (s, 1H), 7.22- 7.14 (m, 2H), 7.03-6.96 (m, 2H), 6.24 (d, J = 1.8 Hz, 1H), 6.17 (d, J = 1.7 Hz, 1H), 4.68 (quin, J = 7.2 Hz, 1H), 3.62 (s, 3H), 2.86-2.76 (m, 1H), 2.69-2.61 (m, 2H), 2.28-2.18 (m, 2H). B) Methyl (1s,3s)-3-((2-chloro-5-(4-fluorophenoxy)-1H-benzo[d]imidazol-7- yl)oxy)cyclobutane-1-carboxylate [00394] To a stirred mixture of methyl (1s,3s)-3-((6-(4-fluorophenoxy)-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)cyclobutane-1-carboxylate (100 mg) in dioxane (10 mL) was added POCl3 (2.5 mL) at 20°C. The mixture was stirred at 90°C for 4 h. The reaction mixture was diluted and adjusted to pH = 7 with sat. NH4Cl solution. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica column chromatography (petroleum ether/EtOAc = 3/1) to give the target compound (95 mg) as a solid. MS: (M+H+): 391.2. C) Methyl (1s,3s)-3-((5-(4-fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)- 1H-benzo[d]imidazol-7-yl)oxy)cyclobutane-1-carboxylate [00395] To a stirred mixture of methyl (1s,3s)-3-((2-chloro-5-(4- fluorophenoxy)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutane-1-carboxylate (85 mg) in dioxane (1.0 mL) was added 4-isobutylpiperidin-4-ol hydrochloride (126 mg), CuI (8.28 mg) and DIPEA (189 uL). Then the mixture was stirred at 105°C for 36 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/EtOAc = 55/45) to give the target compound (70 mg) as a solid. D) (1s,3s)-3-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)-1H- benzo[d]imidazol-7-yl)oxy)cyclobutane-1-carboxylic acid [00396] To a stirred mixture of methyl (1s,3s)-3-((5-(4-fluorophenoxy)-2- (4-hydroxy-4-isobutylpiperidin-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutane- 1-carboxylate (70 mg) in dioxane (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (17.2 mg). The mixture was stirred at 20°C for 12 h. The reaction mixture was diluted with water and adjusted to pH = 4 with 5 M HCl. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the target compound (45 mg) as an oil. E) ((1s,3s)-3-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)-1H- benzo[d]imidazol-7-yl)oxy)cyclobutyl)(4-hydroxypiperidin-1-yl)methanone [00397] The target compound was obtained in a similar manner to example 39 using (1s,3s)-3-((5-(4-fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)- 1H-benzo[d]imidazol-7-yl)oxy)cyclobutane-1-carboxylic acid and piperidin-4-ol. [00398] 1H NMR (400 MHz, CD3OD) d: 7.07-7.00 (m, 2H), 6.98-6.91 (m, 2H), 6.51 (d, J = 1.7 Hz, 1H), 6.23 (d, J = 1.8 Hz, 1H), 4.74 (quin, J = 7.1 Hz, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.90-3.71 (m, 4H), 3.45-3.35 (m, 2H), 3.25-3.08 (m, 3H), 2.75-2.65 (m, 2H), 2.42 (q, J = 9.9 Hz, 2H), 1.95-1.78 (m, 3H), 1.70 (d, J = 4.0 Hz, 4H), 1.49-1.35 (m, 4H), 0.99 (d, J = 6.6 Hz, 6H). Example 73: 4-Hydroxy-4-isobutyl-N-(1-(4-(methylcarbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)piperidine-1-carboxamide [00399] To a mixture of 4-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-1H-indazol-1-yl)benzoic acid (100 mg) in DMF (1.0 mL) was added HOBt (40.2 mg), EDCI (57.0 mg), DIPEA (207 uL), and methanamine hydrochloride (20.1 mg). Then the mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the target compound (35.2 mg) as a solid. [00400] 1H NMR (400 MHz, DMSO-d6) d: 9.00 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 4.16 (s, 1H), 3.84 (d, J = 13.1 Hz, 2H), 3.20 (t, J = 11.1 Hz, 2H), 2.83 (d, J = 4.5 Hz, 3H), 1.83 (quind, J = 6.4, 12.8 Hz, 1H), 1.56-1.49 (m, 2H), 1.47- 1.37 (m, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 74: N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H-indazol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00401] The target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and ethanamine hydrochloride. [00402] 1H NMR (400 MHz, DMSO-d6) d: 9.01 (s, 1H), 8.63 (t, J = 5.4 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.92 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 4.17 (s, 1H), 3.84 (d, J = 13.1 Hz, 2H), 3.38-3.35 (m, 1H), 3.33-3.30 (m, 1H), 3.20 (t, J = 11.2 Hz, 2H), 1.83 (quind, J = 6.5, 12.9 Hz, 1H), 1.57-1.49 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (d, J = 5.8 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.7 Hz, 6H). Example 75: 4-Hydroxy-N-(1-(4-((2-hydroxyethyl)carbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-isobutylpiperidine-1-carboxamide [00403] The target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 2-aminoethanol. [00404] 1H NMR (400 MHz, CD3OD) d: 8.31 (s, 1H), 8.26 (s, 1H), 8.11- 8.04 (m, 2H), 7.89-7.83 (m, 2H), 7.71 (s, 1H), 3.92 (d, J = 13.5 Hz, 2H), 3.78-3.72 (m, 2H), 3.58-3.53 (m, 2H), 3.38-3.32 (m, 2H), 1.89 (quind, J = 6.4, 13.0 Hz, 1H), 1.70-1.55 (m, 4H), 1.42 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 76: 4-Hydroxy-4-isobutyl-N-(1-(4-((2-methoxyethyl)carbamoyl)phenyl)- 4-(trifluoromethyl)-1H-indazol-6-yl)piperidine-1-carboxamide [00405] The target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 2-methoxyethanamine. [00406] 1H NMR (400 MHz, DMSO-d6) d: 8.99 (s, 1H), 8.72-8.66 (m, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.92 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 4.16 (s, 1H), 3.83 (d, J = 13.3 Hz, 2H), 3.53-3.44 (m, 4H), 3.29 (s, 3H), 3.19 (t, J = 11.0 Hz, 2H), 1.88-1.78 (m, 1H), 1.56-1.49 (m, 2H), 1.47-1.37 (m, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 77: 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid A) Ethyl 4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1-yl)benzoate [00407] A mixture of 6-nitro-4-(trifluoromethyl)-1H-indazole (2.0 g) in dioxane (20 mL) was added ethyl 4-iodobenzoate (2.9 mL), CuI (824 mg), K3PO4 (3.7 g) and (1S,2S)-cyclohexane-1,2-diamine (988 mL). Then the mixture was stirred at 110°C for 16 h. The reaction mixture was filtered, adjusted to pH = 6 with 2 M HCl solution, and then extracted with EtOAc. Then the organic layer was washed with brine, dried over Na2SO4, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to give the target compound (1.6 g) as a solid. [00408] 1H NMR (400 MHz, CDCl3) d: 8.79 (s, 1H), 8.46-8.44 (m, 1H), 8.39- 8.36 (m, 1H), 8.28-8.23 (m, 2H), 7.78-7.73 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). B) Ethyl 4-(6-amino-4-(trifluoromethyl)-1H-indazol-1-yl)benzoate [00409] To a solution of ethyl 4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)benzoate (1.6 g) in EtOH (20 mL) was added 10% Pd/C. Then suspension was stirred under H2 atmosphere (15 psi) at 25°C for 3 h. The reaction mixture was filtered through Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give the target compound (1.3 g) as a solid. [00410] 1H NMR (400 MHz, CDCl3) d: 8.26-8.16 (m, 3H), 7.78 (d, J = 8.7 Hz, 2H), 7.10 (s, 1H), 6.95 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). C) Ethyl 4-(6-(((2,2,2-trichloroethoxy)carbonyl)amino)-4-(trifluoromethyl)-1H- indazol-1-yl)benzoate [00411] To a mixture of ethyl 4-(6-amino-4-(trifluoromethyl)-1H-indazol-1- yl)benzoate (500 mg) in EtOAc (5 mL) was added 2,2,2-trichloroethyl carbonochloridate (230 uL) and NaHCO3 (240 mg). Then the mixture was stirred at 25°C for 12 h. The reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 17/3 to 4/1) to give the target compound (800 mg) as a solid. [00412] 1H NMR (400 MHz, CDCl3) d: 8.34 (br s, 1H), 8.26-8.23 (m, 1H), 8.21-8.16 (m, 2H), 7.78-7.72 (m, 2H), 7.35 (s, 1H), 4.79 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). D) Ethyl 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoate [00413] To a mixture of ethyl 4-(6-(((2,2,2- trichloroethoxy)carbonyl)amino)-4-(trifluoromethyl)-1H-indazol-1-yl)benzoate (500 mg) in DMF (5 mL) was added 4-isobutylpiperidin-4-ol hydrochloride (221 mg) and DBU (718 uL). Then the mixture was stirred at 60°C for 1 h. Another batch of 300 mg of the starting material was combined and diluted with water. Then the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1 to 7/3 to 1/1) to give the target compound (660 mg) as an oil. [00414] 1H NMR (400 MHz, DMSO-d6) d: 8.99 (s, 1H), 8.47 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.15 (s, 1H), 3.87-3.77 (m, 2H), 3.18 (t, J = 11.1 Hz, 2H), 1.86-1.76 (m, 1H), 1.55-1.47 (m, 2H), 1.46-1.39 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 5.7 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). E) 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-1H- indazol-1-yl)benzoic acid [00415] To a mixture of ethyl 4-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-1H-indazol-1-yl)benzoate (560 mg) in dioxane (3.0 mL) and water (3.0 mL) was added LiOH.H2O (132 mg). Then the mixture was stirred at 25°C for 2 h. Another batch of 100 mg of the starting material was combined and diluted with water. The mixture was extracted with DCM, adjusted to pH = 4 with 1 M HCl solution, and filtered. The filter cake was dried under reduced pressure to give the target compound (430 mg) as a solid. [00416] 1H NMR (400 MHz, DMSO-d6) d: 9.00 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.96 (s, 1H), 7.87 (d, J = 8.6 Hz, 2H), 4.16 (s, 1H), 3.84 (d, J = 13.2 Hz, 2H), 3.20 (t, J = 11.2 Hz, 2H), 1.88-1.78 (m, 1H), 1.56- 1.49 (m, 2H), 1.47-1.37 (m, 2H), 1.31 (d, J = 5.8 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 78: 4-Cyano-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-isobutylpiperidine-1- carboxamide [00417] The target compound was obtained in a similar manner to Example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 4- isobutylpiperidine-4-carbonitrile. [00418] 1H NMR (400 MHz, CD3OD) d: 7.13-7.05 (m, 2H), 7.05-6.98 (m, 2H), 6.76 (t, J = 2.0 Hz, 1H), 6.61 (t, J = 1.9 Hz, 1H), 6.11 (t, J = 2.2 Hz, 1H), 4.58 (quin, J = 7.2 Hz, 1H), 4.15 (d, J = 14.1 Hz, 2H), 4.09-4.01 (m, 1H), 3.84 (tt, J = 3.9, 8.3 Hz, 1H), 3.78-3.69 (m, 1H), 3.22 (ddd, J = 3.2, 9.8, 13.5 Hz, 1H), 3.17- 3.02 (m, 4H), 2.68 (td, J = 6.1, 12.6 Hz, 2H), 2.33-2.23 (m, 2H), 2.03-1.80 (m, 5H), 1.58-1.48 (m, 4H), 1.48-1.35 (m, 2H), 1.04 (d, J = 6.7 Hz, 6H). Example 79: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(2-methyl-4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate [00419] The target compound was obtained in a similar manner to step D in Example 63 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-3-methylphenyl)boronic acid. [00420] 1H NMR (400 MHz, CDCl3) d: 8.99 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 7.79-7.74 (m, 2H), 7.58 (d, J = 9.7 Hz, 1H), 3.72 (s, 3H), 2.36 (s, 3H), 1.65 (s, 6H). B) 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid [00421] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(2-methyl-4-(6-nitro-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)propanoate. [00422] 1H NMR (400 MHz, CD3OD) d: 8.78 (s, 1H), 7.95 (s, 1H), 7.83- 7.76 (m, 2H), 7.67 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 3.92 (d, J = 13.3 Hz, 2H), 3.39-3.33 (m, 2H), 2.43 (s, 3H), 1.96-1.86 (m, 1H), 1.71-1.59 (m, 10H), 1.44 (d, J = 5.8 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H). Example 80: N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-(hydroxymethyl)-4-isobutylpiperidine-1- carboxamide A) Methyl (1s,3s)-3-(3-(4-(acetoxymethyl)-4-isobutylpiperidine-1- carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1-carboxylate [00423] To a mixture of methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate (300 mg) and (4-isobutyl-4-piperidyl)methyl acetate hydrochloride (190 mg) in DMF (5.0 mL) was added DBU (446 uL), and the reaction mixture was stirred at 60oC for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/0 to 7/3) to give the target compound (300 mg) as an oil. [00424] 1H NMR (400 MHz, CDCl3) d: 7.07-6.94 (m, 4H), 6.84 (s, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 6.10 (t, J = 2.0 Hz, 1H), 4.60-4.49 (m, 1H), 4.01 (s, 2H), 3.69 (s, 3H), 3.44 (t, J = 5.9 Hz, 4H), 2.82-2.66 (m, 3H), 2.48-2.36 (m, 2H), 2.08 (s, 3H), 1.70 (td, J = 6.2, 12.9 Hz, 1H), 1.61-1.45 (m, 4H), 1.36 (d, J = 5.3 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H). ) (1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-(hydroxymethyl)-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid [00425] To a solution of methyl (1s,3s)-3-(3-(4-(acetoxymethyl)-4- isobutylpiperidine-1-carboxamido)-5-(4-fluorophenoxy)phenoxy)cyclobutane-1- carboxylate (300 mg) in dioxane (6.0 mL) and water (3.0 mL) was added LiOH.H2O (110 mg), and the reaction mixture was stirred at 25oC for 12 h. The reaction mixture was diluted with water and acidified to pH = 2 with 2 M HCl. The resulting solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the target compound (260 mg) as an oil. MS: (M+H+): 515.5. C) N-(3-(4-Fluorophenoxy)-5-((1s,3s)-3-(4-hydroxypiperidine-1- carbonyl)cyclobutoxy)phenyl)-4-(hydroxymethyl)-4-isobutylpiperidine-1- carboxamide [00426] To a solution of (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4- (hydroxymethyl)-4-isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1- carboxylic acid (260 mg) and piperidin-4-ol (57 mg) in DMF (10 mL) was added HOBt (102 mg) and EDCI (145 mg) followed by DIPEA (264 uL) at 25°C. Then the mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated, and purified by HPLC to give the target compound (135 mg) as a solid. [00427] 1H NMR (400 MHz, CD3OD) d: 7.11-7.05 (m, 2H), 7.05-6.98 (m, 2H), 6.76 (t, J = 1.8 Hz, 1H), 6.62 (t, J = 1.8 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 4.58 (quin, J = 7.2 Hz, 1H), 4.09-3.99 (m, 1H), 3.84 (tt, J = 3.9, 8.3 Hz, 1H), 3.79-3.69 (m, 1H), 3.55-3.39 (m, 6H), 3.26-3.02 (m, 3H), 2.68 (td, J = 6.2, 12.5 Hz, 2H), 2.34-2.22 (m, 2H), 1.93-1.68 (m, 3H), 1.60-1.49 (m, 2H), 1.49-1.38 (m, 4H), 1.36 (d, J = 5.4 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). Example 81: N-(1-(4-(((1H-Tetrazol-5-yl)methyl)carbamoyl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00428] The target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 1H-tetrazol-5-ylmethanamine. [00429] 1H NMR (400 MHz, CD3OD) d: 8.32 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.73 (s, 1H), 4.91 (s, 2H), 3.92 (d, J = 13.4 Hz, 2H), 3.36 (d, J = 3.1 Hz, 2H), 1.89 (quind, J = 6.4, 12.8 Hz, 1H), 1.70- 1.56 (m, 4H), 1.42 (d, J = 5.6 Hz, 2H), 0.98 (d, J = 6.7 Hz, 6H). Example 82: 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzamido)propanoic acid A) Methyl 3-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzamido)propanoate [00430] The target compound was obtained in a similar manner to Example 73 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid and 3-aminopropanoate. [00431] 1H NMR (400 MHz, DMSO-d6) d: 8.99 (s, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 4.15 (s, 1H), 3.83 (d, J = 13.0 Hz, 2H), 3.62 (s, 3H), 3.57-3.49 (m, 2H), 3.15-3.24 (m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.87-1.77 (m, 1H), 1.56-1.48 (m, 2H), 1.46-1.37 (m, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). B) 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)benzamido)propanoic acid [00432] To a mixture of methyl 3-(4-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-1H-indazol-1-yl)benzamido)propanoate (250 mg) in dioxane (2.0 mL) and water (2.0 mL) was added LiOH.H2O (53.4 mg). Then the mixture was stirred at 25°C for 2 h. The reaction mixture was diluted with water and adjusted to pH = 4 with 1 M HCl solution. Then the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the target compound (161 mg) as a solid. [00433] 1H NMR (400 MHz, CD3OD) d: 8.30 (s, 1H), 8.25 (s, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H), 3.92 (d, J = 13.3 Hz, 2H), 3.67 (t, J = 6.9 Hz, 2H), 3.35 (d, J =2.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 1.89 (tt, J = 6.3, 12.8 Hz, 1H), 1.71-1.54 (m, 4H), 1.41 (d, J = 5.8 Hz, 2H), 0.98 (d, J =6.6 Hz, 6H). Example 83: 4-(Cyanomethyl)-N-(3-(4-fluorophenoxy)-5-((1s,3s)-3-(4- hydroxypiperidine-1-carbonyl)cyclobutoxy)phenyl)-4-isobutylpiperidine-1- carboxamide [00434] The target compound was obtained in a similar manner to example 48 using methyl (1s,3s)-3-(3-(4-fluorophenoxy)-5-(((2,2,2- trichloroethoxy)carbonyl)amino)phenoxy)cyclobutane-1-carboxylate and 2-(4- isobutyl-1^2-piperidin-4-yl)acetonitrile. [00435] 1H NMR (400 MHz, CD3OD) d: 7.13-7.05 (m, 2H), 7.05-6.99 (m, 2H), 6.76 (t, J = 2.0 Hz, 1H), 6.61 (t, J = 2.0 Hz, 1H), 6.11 (t, J = 2.2 Hz, 1H), 4.58 (quin, J = 7.2 Hz, 1H), 4.09-4.00 (m, 1H), 3.84 (tt, J = 4.0, 8.4 Hz, 1H), 3.79-3.69 (m, 1H), 3.62-3.51 (m, 2H), 3.49-3.39 (m, 2H), 3.26-3.18 (m, 1H), 3.17-3.02 (m, 2H), 2.74-2.64 (m, 2H), 2.63 (s, 2H), 2.33-2.23 (m, 2H), 1.92-1.71 (m, 3H), 1.66- 1.53 (m, 4H), 1.48 (d, J = 5.3 Hz, 2H), 1.46-1.36 (m, 2H), 1.01 (d, J = 6.6 Hz, 6H). Example 84: 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4- isobutylpiperidine-1-carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4- yl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate A) tert-Butyl 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-oyl)oxy)piperidine-1- carboxylate [00436] To a stirred mixture of 2,5,8,11,14,17,20-heptaoxadocosan-22-oic acid (850 mg) in DCM (10 mL) was added tert-butyl 4-hydroxypiperidine-1- carboxylate (772 mg), DCC (792 mg), and DMAP (293 mg) at 25°C. Then the mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with 40 mL solution of EtOAc/hexane (3/1). Then the mixture was filtered, concentrated, and purified by silica gel column chromatography (EtOAc/MeOH = 1/0 to 94/6) to give the target compound (900 mg) as an oil. [00437] 1H NMR (400 MHz, CDCl3) d: 4.14 (s, 2H), 3.65 (d, J = 3.3 Hz, 24H), 3.38 (s, 3H), 3.24-3.17 (m, 2H), 1.96-1.89 (m, 3H), 1.72-1.65 (m, 2H), 1.45 (s, 9H), 1.40-1.28 (m, 2H). B) Piperidin-4-yl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate To a stirred mixture of tert-butyl 4-((2,5,8,11,14,17,20-heptaoxadocosan-22- oyl)oxy)piperidine-1-carboxylate (760 mg) in EtOAc (5.0 mL) was added 4 M HCl in EtOAc (40 mL) at 25°C. The mixture was stirred at 25°C for 3 h. The mixture was concentrated to give the target compound (400 mg) as a HCl salt. C) 1-((1s,3s)-3-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carbonyl)piperidin-4-yl 2,5,8,11,14,17,20- heptaoxadocosan-22-oate [00438] The target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and piperidin-4-yl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate. [00439] 1H NMR (400 MHz, CD3OD) d: 7.11-7.06 (m, 2H), 7.05-6.99 (m, 2H), 6.78 (t, J = 2.0 Hz, 1H), 6.62 (t, J = 1.9 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 5.13-5.05 (m, 1H), 4.59 (quin, J = 7.2 Hz, 1H), 4.18 (s, 2H), 3.86-3.79 (m, 3H), 3.73-3.71 (m, 1H), 3.70 (d, J = 2.3 Hz, 1H), 3.68-3.64 (m, 3H), 3.64-3.61 (m, 16H), 3.61 (br s, 1H), 3.55-3.51 (m, 2H), 3.51-3.37 (m, 3H), 3.35 (s, 3H), 3.30-3.21 (m, 2H), 3.15-2.99 (m, 1H), 2.75-2.64 (m, 2H), 2.37-2.23 (m, 2H), 1.98-1.82 (m, 3H), 1.71-1.50 (m, 6H), 1.40 (d, J = 5.7 Hz, 2H), 0.97 (d, J = 6.6 Hz, 6H). Example 85: N-(3-((1s,3s)-3-(4-((2,5,8,11,14,17,20-Heptaoxadocosan-22- yl)oxy)piperidine-1-carbonyl)cyclobutoxy)-5-(4-fluorophenoxy)phenyl)-4- hydroxy-4-isobutylpiperidine-1-carboxamide A) tert-Butyl 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)piperidine-1- carboxylate [00440] To a stirred mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.1 g) in THF (10 mL) was added 60% NaH (178 mg) at 0°C. After stirred at 25°C for 10 min, 2,5,8,11,14,17,20-heptaoxadocosan-22-yl 4- methylbenzenesulfonate (1.1 g) was added to the mixture. The mixture was stirred at 25°C for 12 h, then at 60°C for 4 hr. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc/MeOH = 1/0 to 93/7) to give the target compound (1.6 g) as an oil. B) 4-((2,5,8,11,14,17,20-Heptaoxadocosan-22-yl)oxy)piperidine [00441] To a stirred mixture of tert-butyl 4-((2,5,8,11,14,17,20- heptaoxadocosan-22-yl)oxy)piperidine-1-carboxylate (1.6 g) in EtOAc (5.0 mL) was added 4 M HCl in EtOAc (4.0 mL) at 25°C. The mixture was stirred at 25 °C for 3 hr. The mixture was concentrated to give the target compound (1.3 g) as a HCl salt. C) N-(3-((1s,3s)-3-(4-((2,5,8,11,14,17,20-Heptaoxadocosan-22- yl)oxy)piperidine-1-carbonyl)cyclobutoxy)-5-(4-fluorophenoxy)phenyl)-4- hydroxy-4-isobutylpiperidine-1-carboxamide [00442] The target compound was obtained in a similar manner to example 39 using (1s,3s)-3-(3-(4-fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)cyclobutane-1-carboxylic acid and 4-((2,5,8,11,14,17,20- heptaoxadocosan-22-yl)oxy)piperidine. [00443] 1H NMR (400 MHz, CD3OD) d: 7.13-7.05 (m, 2H), 7.05-6.99 (m, 2H), 6.77 (s, 1H), 6.63 (t, J = 1.8 Hz, 1H), 6.10 (t, J = 2.1 Hz, 1H), 4.58 (quin, J = 7.2 Hz, 1H), 3.92-3.79 (m, 3H), 3.72-3.59 (m, 28H), 3.55-3.49 (m, 2H), 3.35 (s, 3H), 3.34-3.32 (m, 1H), 3.29 (d, J = 2.9 Hz, 1H), 3.27-3.21 (m, 2H), 3.07 (quin, J = 8.9 Hz, 1H), 2.74-2.64 (m, 2H), 2.35-2.22 (m, 2H), 1.87 (dt, J = 6.1, 12.6 Hz, 3H), 1.66-1.47 (m, 6H), 1.40 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 86: (1s,4s)-4-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine- 1-carboxamido)phenoxy)cyclohexane-1-carboxylic acid [00444] The target compound was obtained in a similar manner to example 34 using 3-(4-fluorophenoxy)-5-nitrophenol and methyl (1r,4r)-4- hydroxycyclohexane-1-carboxylate. [00445] 1H NMR (400 MHz, CD3OD) d: 7.12-7.05 (m, 2H), 7.04-6.99 (m, 2H), 6.81 (t, J = 2.0 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 6.19 (t, J = 2.1 Hz, 1H), 4.44 (br s, 1H), 3.82 (d, J = 13.4 Hz, 2H), 3.30-3.21 (m, 2H), 2.39 (t, J = 9.7 Hz, 1H), 2.00-1.81 (m, 5H), 1.77-1.50 (m, 8H), 1.40 (d, J = 5.7 Hz, 2H), 0.97 (d, J = 6.7 Hz, 6H). Example 87: 2-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid [00446] The target compound was obtained in a similar manner to step D to I in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (2- (methoxycarbonyl)phenyl)boronic acid. [00447] 1H NMR (400 MHz, CD3OD) d: 7.98 (dd, J = 7.6, 1.4 Hz, 1H), 7.91 (s, 1H), 7.74-7.69 (m, 1H), 7.61 (s, 1H), 7.60-7.56 (m, 2H), 7.23-7.14 (m, 4H), 6.71 (d, J = 1.3 Hz, 1H), 3.79 (d, J = 13.2 Hz, 2H), 3.28-3.19 (m, 2H), 1.86 (dt, J = 12.9, 6.4 Hz, 1H), 1.63-1.48 (m, 4H), 1.38 (d, J = 5.8 Hz, 2H), 0.96 (d, J = 6.7 Hz, 6H). Example 88: 3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)benzoic acid [00448] The target compound was obtained in a similar manner to step D to I in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid. [00449] 1H NMR (400 MHz, CD3OD) d: 8.32 (t, J = 1.8 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.69-7.64 (m, 2H), 7.23-7.15 (m, 4H), 6.77 (d, J = 1.5 Hz, 1H), 3.83 (d, J = 13.5 Hz, 2H), 3.28-3.13 (m, 2H), 1.86 (dt, J = 13.0, 6.3 Hz, 1H), 1.64-1.50 (m, 4H), 1.39 (d, J = 5.8 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). Example 89: 4-Hydroxy-N-(3-(4-(hydroxy(^1-oxidaneyl)methyl)phenoxy)-5- (trifluoromethoxy)phenyl)-4-isobutylpiperidine-1-carboxamide A) ((4-(3-Bromo-5-(trifluoromethoxy)phenoxy)phenyl)(methoxy)methyl)-^1- oxidane [00450] A mixture of methyl 4-hydroxybenzoate (300 mg), 2,2,6,6- tetramethylheptane-3,5-dione (101 uL), 1,3-dibromo-5- (trifluoromethoxy)benzene (946 mg), Cs2CO3 (771 mg), CuCl (23.6 uL), and NMP (6.0 mL) was stirred at 120°C for 20 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/EtOAc = 1/0 to 94/6) to afford the target compound (1.4 g) as an oil. [00451] 1H NMR (400 MHz, CDCl3) d: 8.10-8.04 (m, 2H), 7.18 (s, 1H), 7.12- 7.09 (m, 1H), 7.07-7.03 (m, 2H), 6.85 (s, 1H), 3.92 (s, 3H). B) 4-Hydroxy-N-(3-(4-(hydroxy(L1-oxidaneyl)methyl)phenoxy)-5- (trifluoromethoxy)phenyl)-4-isobutylpiperidine-1-carboxamide [00452] The target compound was obtained in a similar manner to step E to I in Example 63 using ((4-(3-bromo-5- (trifluoromethoxy)phenoxy)phenyl)(methoxy)methyl)-L1-oxidane. [00453] 1H NMR (400 MHz, CD3OD) d: 8.04 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 0.9 Hz, 1H), 7.14 (t, J = 2.0 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 1.0 Hz, 1H), 3.84 (d, J = 13.4 Hz, 2H), 3.30-3.23 (m, 2H), 1.87 (quind, J = 6.3, 12.8 Hz, 1H), 1.66-1.50 (m, 4H), 1.40 (d, J = 5.7 Hz, 2H), 0.97 (d, J = 6.6 Hz, 6H). Example 90: N-(1-(2,4-Dioxothiazolidin-5-yl)-4-(trifluoromethyl)-1H-indazol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) Methyl 2-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)acetate [00454] The target compound was obtained in a similar manner to step D in Example 63 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(2-methoxy-2- oxoethyl)phenyl)boronic acid. [00455] 1H NMR (400 MHz, DMSO-d6) d: 8.77 (d, J = 9.0 Hz, 2H), 8.37 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 3.86 (s, 2H), 3.67 (s, 3H). B) Methyl 2-bromo-2-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)acetate [00456] To a solution of methyl 2-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol- 1-yl)phenyl)acetate (650 mg) in CCl4 (8.0 mL) was added benzoyl peroxide (41.5 mg) and NBS (305 mg), and the reaction mixture was stirred at 80°C for 36 h. The reaction mixture was diluted with H2O, extracted with EtOAc, washed with brine, dried over Na2SO4, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 9/1) to give the target compound (620 mg) as a solid. C) 2-Imino-5-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)thiazolidin-4- one [00457] To a solution of methyl 2-bromo-2-(4-(6-nitro-4-(trifluoromethyl)- 1H-indazol-1-yl)phenyl)acetate (520 mg) in EtOH (5.0 mL) was added thiourea (95 mg). Then the reaction mixture was stirred at 70°C for 1.5 h. The reaction mixture was diluted with H2O, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the target compound (440 mg) as a solid. D) 5-(4-(6-Nitro-4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)thiazolidine-2,4-dione [00458] To a solution of 2-imino-5-(4-(6-nitro-4-(trifluoromethyl)-1H- indazol-1-yl)phenyl)thiazolidin-4-one (480 mg) in EtOH (2.5 mL) and THF (2.5 mL) was added conc. HCl (5.0 mL) and water (1.0 mL). Then the reaction mixture was stirred at 100°C for 12 h. The reaction mixture was diluted with H2O (20 mL) and adjusted to pH = 7 with 1 M NaOH. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 20/1) to give the target compound (2.0 g) as an oil. [00459] 1H NMR (400 MHz, DMSO-d6) d: 12.39 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.39 (d, J = 0.7 Hz, 1H), 7.95-7.89 (m, 2H), 7.76 (d, J = 8.6 Hz, 2H), 6.00 (s, 1H). E) N-(1-(2,4-Dioxothiazolidin-5-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)-4- hydroxy-4-isobutylpiperidine-1-carboxamide [00460] The target compound was obtained in a similar manner to step B to D in Example 46 using 5-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)thiazolidine-2,4-dione. [00461] 1H NMR (400 MHz, DMSO-d6) d: 12.38 (s, 1H), 8.97 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.78-7.66 (m, 4H), 5.96 (s, 1H), 3.83 (d, J = 13.3 Hz, 2H), 3.19 (t, J = 11.1 Hz, 2H), 1.83 (quind, J = 6.3, 12.8 Hz, 1H), 1.56- 1.47 (m, 2H), 1.47-1.36 (m, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 91: 4-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)-1H- benzo[d]imidazol-7-yl)oxy)benzoic acid A) Ethyl 4-(3-amino-5-fluoro-2-nitrophenoxy)benzoate [00462] To a solution of 3,5-difluoro-2-nitro-aniline (2.0 g) in THF (30 mL) was added 60% NaH (689 mg) at 0°C. After stirred for 30 min, ethyl 4- hydroxybenzoate (2.3 g) was added to the mixture. The mixture was stirred at 25°C for 15.5 h. The mixture was poured into Na2CO3 solution and extracted with EtOAc. The organic layer was washed with bine, dried with anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 9/1) to give the target compound (1.5 g) as a solid. [00463] 1H NMR (400 MHz, CDCl3) d: 8.03-8.13 (m, 2 H), 7.05-7.13 (m, 2 H), 6.29 (dd, J = 9.7, 2.6 Hz, 1 H), 6.03 (dd, J = 9.2, 2.6 Hz, 1 H), 5.52 (br s, 2 H), 4.31-4.44 (m, 2 H), 1.40 (t, J = 7.0 Hz, 3 H). B) Ethyl 4-(3-amino-5-(4-fluorophenoxy)-2-nitrophenoxy)benzoate [00464] A mixture of ethyl 4-(3-amino-5-fluoro-2-nitrophenoxy)benzoate (1.5 g), 4-fluorophenol (525 mg), K2CO3 (2.3 g) and DMF (15 mL) was stirred at 90°C for 12 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried with anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/Ethyl acetate = 97/3 to 85/15) to the target compound (1.0 g) as a solid. [00465] 1H NMR (400 MHz, CDCl3) d: 8.04 (d, J = 8.8 Hz, 2 H), 6.98-7.13 (m, 6 H), 5.94-5.98 (m, 2 H), 5.57 (br s, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H). C) Ethyl 4-(2,3-diamino-5-(4-fluorophenoxy)phenoxy)benzoate [00466] A solution of ethyl 4-(3-amino-5-(4-fluorophenoxy)-2- nitrophenoxy)benzoate (900 mg) in MeOH (10 mL) was added to a mixture of 20% Pd(OH)2 (1.5 g) in MeOH (5 mL) at 15°C. The mixture was stirred at 15°C for 2 h under H2 atmosphere (15 psi). The reaction mixture was diluted with MeOH, filtered through a pad of Celite, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 7/3) to give the target compound (730 mg) as an oil. [00467] 1H NMR (400 MHz, CDCl3) d: 7.91 (d, J = 8.8 Hz, 2H), 6.96-6.78 (m, 6H), 6.20 (d, J = 2.6 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.40 (br s, 4H), 1.30 (t, J = 7.1 Hz, 3H). D) 4-((5-(4-Fluorophenoxy)-2-(4-hydroxy-4-isobutylpiperidin-1-yl)-1H- benzo[d]imidazol-7-yl)oxy)benzoic acid [00468] The target compound was obtained in a similar manner to step A to D Example 72 using ethyl 4-(2,3-diamino-5-(4- fluorophenoxy)phenoxy)benzoate. [00469] 1H NMR (400 MHz, CD3OD) d: 7.99 (d, J = 8.8 Hz, 2H), 7.10-6.95 (m, 6H), 6.75 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 2.1 Hz, 1H), 3.79 (d, J = 12.8 Hz, 2H), 3.47-3.38 (m, 2H), 1.88 (quind, J = 6.3, 12.9 Hz, 1H), 1.73-1.60 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.7 Hz, 6H). Example 92: 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-(4-(6-bromo-4-(4-fluorophenoxy)-1H-indazol-1-yl)phenyl)-2- methylpropanoate [00470] The target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (4-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00471] 1H NMR (400 MHz, DMSO-d6) d: 8.28 (s, 1H), 7.69-7.76 (m, 3H), 7.54 (d, J = 8.8 Hz, 2H), 7.28-7.37 (m, 4H), 6.58 (d, J = 0.88 Hz, 1H), 3.63 (s, 3H), 1.57 (s, 6H). B) 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 1H-indazol-1-yl)phenyl)-2-methylpropanoic acid [00472] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 2-(4-(6-bromo-4-(4-fluorophenoxy)-1H-indazol-1- yl)phenyl)-2-methylpropanoate. [00473] 1H NMR (400 MHz, CD3OD) d: 7.97 (s, 1H), 7.73 (s, 1H), 7.64- 7.69 (m, 2H), 7.58-7.63 (m, 2H), 7.14-7.22 (m, 4H), 6.68 (d, J = 1.1 Hz, 1H), 3.80- 3.84 (m, 2H), 3.20-3.30 (m, 2H), 1.85-1.87 (m, 1H), 1.62 (s, 6H), 1.49-1.61 (m, 4H), 1.39 (d, J = 5.7 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). Example 93: 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)benzyl)azetidine-3-carboxylic acid A) Methyl 3-(4-fluorophenoxy)-5-nitrobenzoate [00474] To a mixture of methyl 3,5-dinitrobenzoate (5.0 g) in DMF (50 mL) was added K2CO3 (5.7 g) and 4-fluorophenol (2.5 g), and the mixture was stirred at 80°C for 20 h. The reaction mixture was diluted with EtOAc, washed with water, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 49/1 to 97/3 to 19/1) to give the target compound (2.0 g) as a solid. [00475] 1H NMR (400 MHz, DMSO-d6) d: 8.34 (s, 1H), 7.98 (br s, 1H), 7.79 (s, 1H), 7.44-7.22 (m, 4H), 3.90 (s, 3H). B) (3-(4-Fluorophenoxy)-5-nitrophenyl)methanol [00476] To a mixture of methyl 3-(4-fluorophenoxy)-5-nitrobenzoate (2.0 g) in dioxane (20 mL) and water (20 mL) was added NaBH4 (1.8 g) at 0°C, and the mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with sat. NH4Cl solution and adjusted to pH = 6 with 2 M HCl solution. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 17/3 to 4/1) to give the target compound (1.0 g) as a solid. [00477] 1H NMR (400 MHz, CDCl3) d: 7.94 (s, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.31 (s, 1H), 7.16-7.08 (m, 2H), 7.08-7.01 (m, 2H), 4.79 (s, 2H). C) 3-(4-Fluorophenoxy)-5-nitrobenzyl methanesulfonate [00478] To a mixture of (3-(4-fluorophenoxy)-5-nitrophenyl)methanol (1.1 g) in DCM (10 mL) was added TEA (1.2 mL) and MsCl (502 uL) at 0°C, and the mixture was stirred at 25°C for 1 h. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (1.5 g) as an oil. [00479] 1H NMR (400 MHz, CDCl3) d: 7.89 (s, 1H), 7.65 (t, J = 2.1 Hz, 1H), 7.27 (s, 1H), 7.09-7.03 (m, 2H), 7.01-6.96 (m, 2H), 5.19 (s, 2H), 3.01 (s, 3H). D) Methyl 1-(3-(4-fluorophenoxy)-5-nitrobenzyl)azetidine-3-carboxylate [00480] To a mixture of 3-(4-fluorophenoxy)-5-nitrobenzyl methanesulfonate (1.5 g), methyl azetidine-3-carboxylate hydrochloride (999 mg), DIPEA (2.7 mL), and MeCN (20 mL) was added NaI (329 mg), and the mixture was stirred at 50°C for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3 solution, water and brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 9:1 to 17/3 to 4/1) to give the target compound (900 mg) as an oil. [00481] 1H NMR (400 MHz, CDCl3) d: 7.86 (s, 1H), 7.60 (t, J = 2.1 Hz, 1H), 7.24 (s, 1H), 7.13-7.07 (m, 2H), 7.06-7.00 (m, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 3.58-3.52 (m, 2H), 3.39-3.32 (m, 3H). E) 1-(3-(4-Fluorophenoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)benzyl)azetidine-3-carboxylic acid [00482] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 1-(3-(4-fluorophenoxy)-5-nitrobenzyl)azetidine- 3-carboxylate. [00483] 1H NMR (400 MHz, CD3OD) d: 7.22 (t, J = 1.6 Hz, 1H), 7.16-7.03 (m, 5H), 6.71-6.68 (m, 1H), 4.23 (s, 2H), 4.19-4.10 (m, 4H), 3.85 (d, J = 13.3 Hz, 2H), 3.41-3.35 (m, 1H), 1.93-1.83 (m, 1H), 1.68-1.51 (m, 4H), 1.40 (d, J = 5.8 Hz, 2H), 0.98 (d, J = 6.7 Hz, 6H). Example 94: 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylcyclohexane-1- carboxamido)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-(3-(6-bromo-4-(4-fluorophenoxy)-1H-indazol-1-yl)phenyl)-2- methylpropanoate [00484] The target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00485] 1H NMR (400 MHz, CDCl3) d: 8.03 (d, J = 0.61 Hz, 1 H), 7.58 (t, J = 1.8 Hz, 1 H), 7.41-7.50 (m, 3 H), 7.31 (dt, J = 7.5, 1.6 Hz, 1 H), 7.03-7.09 (m, 4 H), 6.53 (d, J = 1.2 Hz, 1 H), 3.60-3.71 (m, 3 H), 1.58 (s, 6 H). B) 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylcyclohexane-1- carboxamido)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid [00486] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 2-(3-(6-bromo-4-(4-fluorophenoxy)-1H-indazol-1- yl)phenyl)-2-methylpropanoate. [00487] 1H NMR (400 MHz, DMSO-d6) d: 8.60 (s, 1 H) 8.07 (d, J = 0.88 Hz, 1 H), 7.91 (s, 1 H), 7.62 (s, 1 H), 7.50-7.55 (m, 2 H), 7.34-7.39 (m, 1 H), 7.19- 7.32 (m, 4 H), 6.77 (d, J = 1.3 Hz, 1 H), 4.09 (br s, 1 H), 3.72 (d, J = 13.2 Hz, 2 H), 3.09 (t, J = 10.9 Hz, 2 H), 1.78 (dt, J = 12.7, 6.2 Hz, 1 H), 1.51 (s, 6 H), 1.41- 1.48 (m, 2 H), 1.30-1.38 (m, 2 H), 1.26 (d, J = 5.7 Hz, 2 H), 0.88 (d, J = 6.8 Hz, 6 H). Example 95: 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-(3-(6-bromo-4-(4-fluorophenoxy)-2H-indazol-2-yl)phenyl)-2- methylpropanoate [00488] The target compound was obtained in a similar manner to step D in Example 63 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (3-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid. B) 2-(3-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 2H-indazol-2-yl)phenyl)-2-methylpropanoic acid [00489] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 2-(3-(6-bromo-4-(4-fluorophenoxy)-2H-indazol-2- yl)phenyl)-2-methylpropanoate. [00490] 1H NMR (400 MHz, DMSO-d6) d: 9.06 (s, 1 H), 8.39 (s, 1 H), 8.00- 8.03 (m, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 7.63 (s, 1 H), 7.45-7.51 (m, 1 H), 7.22- 7.37 (m, 5 H), 6.52 (d, J = 1.3 Hz, 1 H), 4.09 (s, 1 H), 3.73 (d, J = 13.0 Hz, 2 H), 3.11 (t, J = 10.9 Hz, 2 H), 1.79 (dt, J = 12.7, 6.5 Hz, 1 H), 1.53 (s, 6 H), 1.46 (d, J = 13.5 Hz, 3 H), 1.32-1.40 (m, 2 H), 1.27 (d, J = 5.7 Hz, 2 H), 0.89 (d, J = 6.8 Hz, 6 H). Example 96: 4-(3-(Difluoromethoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid A) Methyl 4-(3-methoxy-5-nitrophenoxy)benzoate [00491] To a solution of 3-methoxy-5-nitro-phenol (10 g) and methyl 4- fluorobenzoate (9.1 g) in DMF (40 mL) was added K2CO3 (16.3 g). The mixture was stirred at 120°C for 24 h. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1 to 10/1) to give the target compound (5.0 g) as a solid. [00492] 1H NMR (400 MHz, DMSO-d6) d: 8.00 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.40 (s, 1H), 7.23-7.14 (m, 3H), 3.90-3.83 (m, 6H). B) Methyl 4-(3-hydroxy-5-nitrophenoxy)benzoate [00493] To a solution of methyl 4-(3-methoxy-5-nitrophenoxy)benzoate (4.7 g) in DCM (100 mL) was added BBr3 (7.5 mL) at 0°C, and the mixture was stirred at 25°C for 4 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 5/1) to give the target compound (3.4 g) as a solid. [00494] 1H NMR (400 MHz, DMSO-d6) d: 10.76 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.40 (t, J = 1.9 Hz, 1H), 7.28 (t, J = 2.0 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.89 (t, J = 2.1 Hz, 1H), 3.85 (s, 3H). C) Methyl 4-(3-(difluoromethoxy)-5-nitrophenoxy)benzoate [00495] To a solution of methyl 4-(3-hydroxy-5-nitrophenoxy)benzoate (1.6 g) in DMF (20 mL) was added sodium 2-chloro-2,2-difluoroacetate (2.5 g) and NaOH (243 mg) at 25°C, and the mixture was stirred at 55°C for 12 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with bine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1 to 10/1) to give the target compound (800 mg) as an oil. [00496] 1H NMR (400 MHz, DMSO-d6) d: 8.12-8.06 (m, 2H), 7.91 (t, J = 2.1 Hz, 1H), 7.77 (t, J = 2.1 Hz, 1H), 7.55-7.50 (m, 2H), 7.33-7.28 (m, 2H), 3.91 (s, 3H). D) 4-(3-(Difluoromethoxy)-5-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)phenoxy)benzoic acid [00497] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 4-(3-(difluoromethoxy)-5- nitrophenoxy)benzoate. [00498] 1H NMR (400 MHz, DMSO-d6) d: 12.85 (br s, 1H), 8.69 (s, 1H), 8.00-7.94 (m, 2H), 7.38-7.01 (m, 5H), 6.51 (t, J = 2.1 Hz, 1H), 4.11 (s, 1H), 3.75 (d, J = 13.2 Hz, 2H), 3.18-3.07 (m, 2H), 1.81 (quind, J = 6.4, 12.8 Hz, 1H), 1.52- 1.44 (m, 2H), 1.42-1.32 (m, 2H), 1.29 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 97: 4-Hydroxy-4-isobutyl-N-(2-(4-(methylcarbamoyl)phenyl)-4- (trifluoromethyl)-2H-indazol-6-yl)piperidine-1-carboxamide A) 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-2H- indazol-2-yl)benzoic acid [00499] The target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4- (methoxycarbonyl)phenyl)boronic acid. B) 4-Hydroxy-4-isobutyl-N-(2-(4-(methylcarbamoyl)phenyl)-4-(trifluoromethyl)- 2H-indazol-6-yl)piperidine-1-carboxamide [00500] To a solution of 4-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-2H-indazol-2-yl)benzoic acid (30 mg), HOBt (12.1 mg), EDCI (17.1 mg), DIPEA (62.2 uL) in DMF (1.0 mL) was added methanamine hydrochloride (6.2 uL). The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated and purified by HPLC to give the target compound (9.1 mg) as a solid. [00501] 1H NMR (400 MHz, CD3OD) d: 8.91 (s, 1H), 8.16-8.12 (m, 2H), 8.04-8.00 (m, 2H), 7.97 (s, 1H), 7.68 (s, 1H), 3.93 (d, J = 13.4 Hz, 2H), 3.39-3.33 (m, 2H), 2.96 (s, 3H), 1.91 (quind, J = 6.4, 12.8 Hz, 1H), 1.72-1.58 (m, 4H), 1.44 (d, J = 5.7 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H). Example 98: 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(3-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)propanoate [00502] A mixture of 6-nitro-4-(trifluoromethyl)-1H-indazole (250 mg), (3- (1-methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid (275 mg), Cu(OAc)2 (393 mg), pyridine (174 uL), and DCM (8.0 mL) was stirred at 25°C for 12 h under O2 atmosphere (15 psi). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 19/1) to give the target compound (230 mg) as a solid. [00503] 1H NMR (400 MHz, DMSO-d6) d: 8.76 (d, J = 15.2 Hz, 2H), 8.38 (s, 1H), 7.73-7.79 (m, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 3.66 (s, 3H), 1.60 (s, 6H). B) 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)phenyl)-2-methylpropanoic acid [00504] The target compound was obtained in a similar manner to step B to step E in Example 46 using methyl 2-methyl-2-(3-(6-nitro-4-(trifluoromethyl)- 1H-indazol-1-yl)phenyl)propanoate. [00505] 1H NMR (400 MHz, CD3OD) d: 8.23 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 12.0 Hz, 2H), 7.61-7.54 (m, 2H), 7.52-7.47 (m, 1H), 3.90 (d, J = 13.3 Hz, 2H), 3.35 (d, J = 3.4 Hz, 2H), 1.89 (quind, J = 6.4, 13.0 Hz, 1H), 1.70-1.55 (m, 10H), 1.42 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 99 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-2H- indazol-2-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(3-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate [00506] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00507] 1H NMR (400 MHz, DMSO-d6) d: 9.59-9.63 (m, 1H), 9.09 (s, 1H), 8.20 (s, 1H), 8.10-8.15 (m, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.63 (s, 3H), 1.62 (s, 6H). B) 2-(3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 2H-indazol-2-yl)phenyl)-2-methylpropanoic acid [00508] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(3-(6-nitro-4-(trifluoromethyl)-2H- indazol-2-yl)phenyl)propanoate. [00509] 1H NMR (400 MHz, CD3OD) d: 8.81 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.58-7.49 (m, 1H), 3.93 (d, J = 14.4 Hz, 2H), 3.37-3.35 (m, 2H), 1.95-1.86 (m, 1H), 1.65 (s, 10H), 1.44 (d, J = 5.7 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H). Example 100: 2-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid [00510] The target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2- iodobenzoate. [00511] 1H NMR (400 MHz, CD3OD) d: 8.23 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 12.0 Hz, 2H), 7.61-7.54 (m, 2H), 7.52-7.47 (m, 1H), 3.90 (d, J = 13.3 Hz, 2H), 3.35 (d, J = 3.4 Hz, 2H), 1.89 (quind, J = 6.4, 13.0 Hz, 1H), 1.70-1.55 (m, 10H), 1.42 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 101: 2-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)benzoic acid A) Methyl 2-(6-nitro-4-(trifluoromethyl)-2H-indazol-2-yl)benzoate [00512] The target compound was obtained in a similar manner to step A in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2- iodobenzoate. [00513] 1H NMR (400 MHz, DMSO-d6) d: 9.35 (s, 1H), 9.07 (s, 1H), 8.23 (d, J = 0.6 Hz, 1H), 7.98 (dd, J = 1.3, 7.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.86 (dt, J = 1.5, 7.7 Hz, 1H), 7.80-7.74 (m, 1H), 3.57 (s, 3H). B) 2-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-2H- indazol-2-yl)benzoic acid [00514] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)benzoate. [00515] 1H NMR (400 MHz, CD3OD) d: 8.51 (s, 1H), 7.99-7.88 (m, 2H), 7.74-7.60 (m, 4H), 3.92 (d, J = 13.4 Hz, 2H), 3.38-3.32 (m, 2H), 1.90 (quind, J = 6.4, 12.9 Hz, 1H), 1.72-1.57 (m, 4H), 1.44 (d, J = 5.7 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H). Example 102: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)-2-methylpropanoic acid [00516] The target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00517] 1H NMR (400 MHz, CD3OD) d: 8.21 (s, 2H), 7.70-7.61 (m, 5H), 3.90 (d, J = 13.3 Hz, 2H), 3.35 (d, J = 3.3 Hz, 1H), 3.29 (d, J = 3.3 Hz, 1H), 1.88 (quind, J = 6.4, 12.8 Hz, 1H), 1.69-1.64 (m, 2H), 1.63 (s, 6H), 1.62-1.54 (m, 2H), 1.41 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 103: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate [00518] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00519] 1H NMR (400 MHz, DMSO-d6) d: 9.53 (s, 1H), 9.08 (s, 1H), 8.23- 8.17 (m, 3H), 7.62-7.56 (m, 2H), 3.63 (s, 3H), 1.59 (s, 6H). B) 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 2H-indazol-2-yl)phenyl)-2-methylpropanoic acid [00520] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)benzoate. [00521] 1H NMR (400 MHz, DMSO-d6) d: 8.79 (s, 1H), 7.99-7.93 (m, 3H), 7.67 (s, 1H), 7.64-7.59 (m, 2H), 3.92 (d, J = 13.3 Hz, 2H), 3.39-3.33 (m, 2H), 1.91 (td, J = 6.3, 12.9 Hz, 1H), 1.71-1.64 (m, 3H), 1.64-1.58 (m, 7H), 1.44 (d, J = 5.7 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H). Example 104: 3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzoic acid [00522] The target compound was obtained in a similar manner to Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid. [00523] 1H NMR (400 MHz, CD3OD) d: 8.33 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 0.98 Hz, 1H), 8.16 (s, 1H), 8.08 (td, J = 1.2, 7.8 Hz, 1H), 7.93 (ddd, J = 1.0, 2.2, 8.0 Hz, 1H), 7.78 (s, 1H), 7.72-7.67 (m, 1H), 3.90 (d, J = 13.3 Hz, 2H), 3.35 (d, J = 3.3 Hz, 2H), 1.89 (tt, J = 6.4, 12.8 Hz, 1H), 1.69-1.55 (m, 4H), 1.42 (d, J = 5.8 Hz, 2H), 0.98 (d, J = 6.7 Hz, 6H). Example 105: 3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)benzoic acid A) Methyl 2-methyl-2-(4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate [00524] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (3- (methoxycarbonyl)phenyl)boronic acid. MS: (M+H+): 365.9. B) 3-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-2H- indazol-2-yl)benzoic acid [00525] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(4-(6-nitro-4-(trifluoromethyl)-2H- indazol-2-yl)phenyl)propanoate. [00526] 1H NMR (400 MHz, CD3OD) d: 8.85 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.18 (td, J = 1.2, 8.1 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.94 (s, 1H), 7.70- 7.63 (m, 2H), 3.93 (d, J =13.3 Hz, 2H), 3.40-3.33 (m, 2H), 1.95-1.85 (m, 1H), 1.72-1.58 (m, 4H), 1.43 (d, J = 5.8 Hz, 2H), 0.99 (d, J = 6.7 Hz, 6H). Example 106: 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-2H-indazol-2-yl)phenyl)-2-methylpropanoic acid A) Methyl 2-(4-(6-bromo-4-(4-fluorophenoxy)-2H-indazol-2-yl)phenyl)-2- methylpropanoate [00527] The target compound was obtained in a similar manner to step A in Example 98 using 6-bromo-4-(4-fluorophenoxy)-1H-indazole and (4-(1- methoxy-2-methyl-1-oxopropan-2-yl)phenyl)boronic acid. [00528] 1H NMR (400 MHz, DMSO-d6) d: 9.27 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 6.6 Hz, 4H), 6.24 (d, J = 1.3 Hz, 1H), 3.62 (s, 3H), 1.56 (s, 6H). B) 2-(4-(4-(4-Fluorophenoxy)-6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 2H-indazol-2-yl)phenyl)-2-methylpropanoic acid [00529] The target compound was obtained in a similar manner to step E to I in Example 63 using methyl 2-(4-(6-bromo-4-(4-fluorophenoxy)-2H-indazol-2- yl)phenyl)-2-methylpropanoate. [00530] 1H NMR (400 MHz, CD3OD) d: 8.66 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 7.14-7.24 (m, 4H), 6.54 (s, 1H), 3.84 (d, J = 13.7 Hz, 2H), 3.25 (s, 2H), 1.82-1.96 (m, 1H), 1.52-1.67 (m, 10H), 1.41 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.8 Hz, 6H). Example 107: 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5-(2,2,2- trifluoroethoxy)phenoxy)benzoic acid A) Methyl 4-(3-nitro-5-(2,2,2-trifluoroethoxy)phenoxy)benzoate [00531] To a solution of methyl 4-(3-hydroxy-5-nitrophenoxy)benzoate (400 mg) in DMF (10 mL) was added 60% NaH (110 mg) at 0°C. After stirred at 0°C for 10 min, 2,2,2-trifluoroethyltrifluoromethanesulfonate (321 mg) was added, and the mixture was stirred at 25°C for 6 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 6/1) to give the target compound (800 mg) as an oil. [00532] 1H NMR (400 MHz, DMSO-d6) d: 8.05-8.00 (m, 2H), 7.75 (t, J = 2.2 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 7.37 (t, J = 2.3 Hz, 1H), 7.24-7.19 (m, 2H), 5.01-4.96 (m, 2H), 3.85 (s, 3H). B) 4-(3-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-5-(2,2,2- trifluoroethoxy)phenoxy)benzoic acid [00533] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 4-(3-nitro-5-(2,2,2- trifluoroethoxy)phenoxy)benzoate. [00534] 1H NMR (400 MHz, DMSO-d6) d: 12.8 (br s, 1H), 8.56 (s, 1H), 7.98- 7.92 (m, 2H), 7.14 (t, J = 2.1 Hz, 1H), 7.09-7.04 (m, 2H), 6.94 (t, J = 2.0 Hz, 1H), 6.46 (t, J = 2.2 Hz, 1H), 4.69 (q, J = 8.8 Hz, 2H), 3.74 (d, J = 13.0 Hz, 2H), 3.18- 3.07 (m, 2H), 1.81 (quind, J = 6.3, 12.8 Hz, 1H), 1.52-1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.29 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 108: 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)propanoic acid [00535] The target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 3-(4- iodophenyl)propanoate. [00536] 1H NMR (400 MHz, DMSO-d6) d: 8.96 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.92 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 3.82 (d, J = 13.2 Hz, 2H), 3.18 (t, J = 11.1 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.82 (quind, J = 6.4, 12.8 Hz, 1H), 1.56-1.47 (m, 2H), 1.46-1.36 (m, 2H), 1.30 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 109: 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)propanoic acid A) Methyl 3-(4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2-yl)phenyl)propanoate [00537] The target compound was obtained in a similar manner to step A in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 3-(4- iodophenyl)propanoate. [00538] 1H NMR (400 MHz, DMSO-d6) d: 9.53 (s, 1H), 9.08 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H). B) 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 2H-indazol-2-yl)phenyl)propanoic acid [00539] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 3-(4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate. [00540] 1H NMR (400 MHz, DMSO-d6) d: 9.08 (s, 1H), 8.79 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 4.17 (s, 1H), 3.85 (d, J = 12.7 Hz, 2H), 3.24 (br s, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.60 (br s, 2H), 1.85 (td, J = 6.4, 12.9 Hz, 1H), 1.57-1.50 (m, 2H), 1.49-1.40 (m, 2H), 1.33 (d, J = 5.6 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H). Example 110: 2-((4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)benzyl)oxy)acetic acid [00541] The target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2-((4- iodobenzyl)oxy)acetate. [00542] 1H NMR (400 MHz, DMSO-d6) d: 8.99 (s, 1H), 8.31 (d, J = 10.8 Hz, 2H), 7.94 (s, 1H), 7.72-7.64 (m, 2H), 7.62-7.54 (m, 2H), 4.63 (s, 2H), 3.96 (s, 2H), 3.83 (d, J = 13.2 Hz, 2H), 3.18 (t, J = 11.1 Hz, 2H), 1.82 (quind, J = 6.3, 12.8 Hz, 1H), 1.55-1.46 (m, 2H), 1.45-1.35 (m, 2H), 1.30 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 111: 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid A) Methyl 4-(6-bromo-4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoate [00543] The target compound was obtained in a similar manner to step A in Example 98 using 6-bromo-4-(trifluoromethyl)-1H-benzo[d]imidazole and (4- (methoxycarbonyl)phenyl)boronic acid. [00544] 1H NMR (400 MHz, CD3OD) d: 8.87 (s, 1H), 8.22-8.17 (m, 3H), 7.91 (d, J = 8.6 Hz, 2H), 7.83 (s, 1H), 3.92 (s, 3H). B) Methyl 4-(6-((tert-butoxycarbonyl)amino)-4-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)benzoate [00545] To a stirred mixture of methyl 4-(6-bromo-4-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)benzoate (560 mg) in dioxane (8.0 mL) was added NH2Boc (321 mg), Cs2CO3 (777 mg), Pd2(dba)3 (54.6 mg), and Xantphos (103 mg). The mixture stirred at 110°C for 12 hr. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 89/11 to 86/14) to give the target compound (450 mg) as an oil. C) Methyl 4-(6-amino-4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoate [00546] To a stirred mixture of methyl 4-(6-((tert-butoxycarbonyl)amino)-4- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoate (450 mg) in EtOAc (5 mL) was added 4 M HCl in EtOAc (30 mL). The mixture was stirred at 25°C for 3 hr. The reaction mixture was diluted with water and the mixture was adjusted to pH = 7 with sat. NaHCO3 solution. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 71/29 to 65/35) to the target compound (290 mg) as an oil. [00547] 1H NMR (400 MHz, CD3OD) d: 8.33 (s, 1H), 8.29-8.24 (m, 2H), 7.77-7.73 (m, 2H), 7.10 (d, J = 3.5 Hz, 2H), 3.96 (s, 3H). D) 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)benzoic acid [00548] The target compound was obtained in a similar manner to step G to I in Example 63 using methyl 4-(6-amino-4-(trifluoromethyl)-1H- benzo[d]imidazol-1-yl)benzoate. [00549] 1H NMR (400 MHz, CD3OD) d: 8.52 (s, 1H), 8.12-8.07 (m, 3H), 7.79-7.74 (m, 2H), 7.70 (d, J = 1.0 Hz, 1H), 3.89 (d, J = 13.4 Hz, 2H), 3.50-3.41 (m, 2H), 3.34 (d, J = 3.2 Hz, 1H), 3.28 (d, J = 3.2 Hz, 1H), 1.93-1.83 (m, 1H), 1.70-1.54 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 6.6 Hz, 6H). Example 112: N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H- benzo[d]imidazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00550] The target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid and ethanamine hydrochloride. [00551] 1H NMR (400 MHz, CD3OD) d: 8.52 (s, 1H), 8.12-8.07 (m, 3H), 7.79-7.74 (m, 2H), 7.70 (d, J = 1.0 Hz, 1H), 3.89 (d, J = 13.4 Hz, 2H), 3.50-3.41 (m, 2H), 3.34 (d, J = 3.2 Hz, 1H), 3.28 (d, J = 3.2 Hz, 1H), 1.93-1.83 (m, 1H), 1.70-1.54 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 6.6 Hz, 6H). Example 113: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenoxy)acetic acid [00552] The target compound was obtained in a similar manner to Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and methyl 2-(4- iodophenoxy)acetate. [00553] 1H NMR (400 MHz, DMSO-d6) d: 8.19 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 4.78 (s, 2H), 3.91 (d, J = 13.5 Hz, 2H), 3.35 (d, J = 2.9 Hz, 1H), 3.29 (br s, 1H), 1.96-1.83 (m, 1H), 1.70- 1.54 (m, 4H), 1.42 (d, J = 5.7 Hz, 2H), 0.99 (d, J = 6.6 Hz, 6H). Example 114: N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)-1H-indol-6- yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00554] The target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indol-1-yl)benzoic acid and ethanamine hydrochloride. [00555] 1H NMR (400 MHz, CD3OD) d: 8.22 (d, J = 8.8 Hz, 2H), 7.99 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 3.5 Hz, 1H), 7.57 (s, 1H), 6.77 (br s, 1H), 3.89 (d, J = 13.2 Hz, 2H), 3.33 (d, J = 3.1 Hz, 1H), 3.27 (d, J = 3.1 Hz, 1H), 1.94-1.83 (m, 1H), 1.69-1.54 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 0.98 (d, J = 6.6 Hz, 6H). Example 115: 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indol-1-yl)benzoic acid A) 5-Bromo-2-methyl-1-nitro-3-(trifluoromethyl)benzene [00556] 2-Methyl-1-nitro-3-(trifluoromethyl)benzene (8.9 g) was dissolved in H2SO4 (90 mL).1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (7.4 g) was added in portions and the resulting mixture was stirred at 25°C for 3 h. The reaction mixture was diluted with ice water, extracted with EtOAc, washed with sat. NaHCO3 solution and brine, dried over Na2SO4, concentrated, and purified by silia gel column chromatography (petroleum ether/ethyl acetate = 100/0) to give the target compound (12.8 g) as an oil. [00557] 1H NMR (400 MHz, CDCl3) d: 8.05 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 2.52 (d, J = 1.5 Hz, 3H). B) (E)-2-(4-bromo-2-nitro-6-(trifluoromethyl)phenyl)-N,N-dimethylethen-1-amine [00558] To a stirred mixture of 5-bromo-2-methyl-1-nitro-3- (trifluoromethyl)benzene (1.0 g) in DMF (6 mL) was added DMFDMA (2.5 mL). Then the mixture was stirred at 110°C for 12 h. The mixture poured into water and extracted with EtOAc. The organic layer was washed with sat. sodium bicarbonate solution, sat. ammoniumchloride solution, and brine. The mixture was dried over Na2SO4 and concentrated to give the target compound (1.1 g) as an oil. C) 6-Bromo-4-(trifluoromethyl)-1H-indole [00559] To a stirred mixture of (E)-2-(4-bromo-2-nitro-6- (trifluoromethyl)phenyl)-N,N-dimethylethen-1-amine (1.1 g) in AcOH (22 mL) was added Fe (598 mg) in portions. Then the mixture was stirred at 120°C for 5 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 100/1) to give the target compound (700 mg) as an oil. D) Ethyl 4-(6-bromo-4-(trifluoromethyl)-1H-indol-1-yl)benzoate [00560] The target compound was obtained in a similar manner to step A in Example 77 using 6-bromo-4-(trifluoromethyl)-1H-indole and ethyl 4- iodobenzoate. [00561] 1H NMR (400 MHz, CDCl3) d: 8.22-8.13 (m, 2H), 7.96 (s, 1H), 7.68 (s, 1H), 7.50-7.43 (m, 2H), 7.33 (d, J = 3.4 Hz, 1H), 6.80 (br s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.38-1.34 (m, 3H). E) 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-1H- indol-1-yl)benzoic acid [00562] The target compound was obtained in a similar manner to step E and I in Example 63 using ethyl 4-(6-bromo-4-(trifluoromethyl)-1H-indol-1- yl)benzoate. [00563] 1H NMR (400 MHz, CD3OD) d: 8.06-8.02 (m, 2H), 7.99 (s, 1H), 7.70-7.65 (m, 2H), 7.60 (d, J = 3.4 Hz, 1H), 7.52 (s, 1H), 6.77 (br s, 1H), 3.88 (d, J = 13.2 Hz, 2H), 3.45 (q, J = 7.3 Hz, 2H), 3.33 (d, J = 3.4 Hz, 1H), 3.27 (d, J = 3.4 Hz, 1H), 1.88 (quind, J = 6.3, 12.8 Hz, 1H), 1.69-1.54 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H). Example 116: 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)indolin-1-yl)benzoic acid A) Methyl 4-(6-bromo-4-(trifluoromethyl)indolin-1-yl)benzoate [00564] To a stirred mixture of ethyl 4-(6-bromo-4-(trifluoromethyl)-1H- indol-1-yl)benzoate (1.0 g) in TFA (10 mL) was added NaBH3CN (1.2 g) in portions at 0°C. Then the mixture was allowed to warm to 25°C and stirred for 12 h. The reaction mixture was diluted with water and adjusted to pH = 7 with sat. NaHCO3 solution. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated, and purified by sílica gel column chromatography (petroleum ether/ethyl acetate = 95/5) to give the target compound (900 mg) as a solid. [00565] 1H NMR (400 MHz, CDCl3) d: 8.07 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.35 (s, 1H), 7.25-7.19 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 8.5 Hz, 2H), 3.27 (t, J = 8.5 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). B) 4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)indolin-1-yl)benzoic acid [00566] The target compound was obtained in a similar manner to step E and I in Example 63 using methyl 4-(6-bromo-4-(trifluoromethyl)indolin-1- yl)benzoate. [00567] 1H NMR (400 MHz, CD3OD) d: 8.60 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.70 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.7 Hz, 2H), 4.07 (t, J = 8.3 Hz, 2H), 3.78 (d, J = 13.1 Hz, 2H), 3.23-3.09 (m, 4H), 1.82 (tt, J = 6.3, 12.8 Hz, 1H), 1.54- 1.45 (m, 2H), 1.44-1.35 (m, 2H), 1.30 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H). Example 117: N-(1-(4-(Ethylcarbamoyl)phenyl)-4-(trifluoromethyl)indolin-6-yl)- 4-hydroxy-4-isobutylpiperidine-1-carboxamide [00568] The target compound was obtained in a similar manner to Example 39 using 4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)indolin-1-yl)benzoic acid and ethanamine hydrochloride. [00569] 1H NMR (400 MHz, CD3OD) d: 7.87-7.81 (m, 2H), 7.58 (s, 1H), 7.34-7.28 (m, 2H), 7.11 (d, J = 1.3 Hz, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.86 (d, J = 13.3 Hz, 2H), 3.41 (q, J = 7.2 Hz, 2H), 3.30-3.18 (m, 4H), 1.88 (quind, J = 6.3, 12.8 Hz, 1H), 1.67-1.52 (m, 4H), 1.41 (d, J = 5.7 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H). Example 118: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)-3-methylphenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(3-methyl-4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)propanoate [00570] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-2-methylphenyl)boronic acid. [00571] 1H NMR (400 MHz, DMSO-d6) d: 8.75 (s, 1H), 8.34 (s, 2H), 7.55- 7.47 (m, 2H), 7.41 (dd, J = 1.8, 8.3 Hz, 1H), 3.66 (s, 3H), 2.08 (s, 3H), 1.60 (s, 6H). B) 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)-3-methylphenyl)-2-methylpropanoic acid [00572] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(3-methyl-4-(6-nitro-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)propanoate. [00573] 1H NMR (400 MHz, DMSO-d6) d: 12.5 (br s, 1H), 8.90 (s, 1H), 8.29 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 7.48 (s, 1H), 7.39 (s, 2H), 4.13 (br s, 1H), 3.79 (d, J = 13.1 Hz, 2H), 3.21-3.09 (m, 2H), 2.05 (s, 3H), 1.81 (quind, J = 6.3, 12.8 Hz, 1H), 1.56 (s, 6H), 1.52-1.46 (m, 2H), 1.44-1.34 (m, 2H), 1.30 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Example 119: 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)-3-methylphenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(3-methyl-4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)propanoate [00574] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-2-methylphenyl)boronic acid. [00575] 1H NMR (400 MHz, DMSO-d6) d: 9.22 (s, 1H), 9.09 (s, 1H), 8.23 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.38 (dd, J = 1.8, 8.3 Hz, 1H), 3.59 (s, 3H), 2.10 (s, 3H), 1.58 (s, 6H). B) 3-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 2H-indazol-2-yl)phenyl)propanoic acid [00576] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(3-methyl-4-(6-nitro-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)propanoate. [00577] 1H NMR (400 MHz, CD3OD) d: 8.44 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.43 (d, J = 1.1 Hz, 2H), 3.97-3.88 (m, 2H), 3.40-3.33 (m, 2H), 2.21 (s, 3H), 1.97-1.83 (m, 1H), 1.63 (br s, 3H), 1.62-1.57 (m, 7H), 1.43 (d, J = 5.7 Hz, 2H), 0.99 (d, J = 6.6 Hz, 6H). Example 120 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)-1H- indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid A) Methyl 2-methyl-2-(2-methyl-4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)propanoate [00578] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(1-methoxy-2- methyl-1-oxopropan-2-yl)-3-methylphenyl)boronic acid. 1H NMR (400 MHz, CDCl3) d: 8.83 (s, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.54-7.48 (m, 2H), 3.75 (s, 3H), 2.35 (s, 3H), 1.67 (s, 6H). B) 2-(4-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)-2-methylphenyl)-2-methylpropanoic acid [00579] The target compound was obtained in a similar manner to step B to E in Example 46 using methyl 2-methyl-2-(2-methyl-4-(6-nitro-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)propanoate. [00580] 1H NMR (400 MHz, CD3OD) d: 8.20 (s, 2H), 7.70 (s, 1H), 7.65- 7.59 (m, 1H), 7.55-7.49 (m, 2H), 3.96-3.85 (m, 2H), 3.37-3.32 (m, 1H), 3.30-3.27 (m, 1H), 2.43 (s, 3H), 1.93-1.85 (m, 1H), 1.69-1.54 (m, 10H), 1.44-1.39 (m, 2H), 0.98 (dd, J = 1.3, 6.6 Hz, 6H). Example 121: 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 4-(trifluoromethyl)-2H-indazol-2-yl)phenyl)butanoic acid A) Ethyl 2-ethyl-2-(4-(6-nitro-4-(trifluoromethyl)-2H-indazol-2- yl)phenyl)butanoate [00581] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(3- (ethoxycarbonyl)pentan-3-yl)phenyl)boronic acid. [00582] 1H NMR (400 MHz, CDCl3) d: 8.99 (s, 1H), 8.68-8.64 (m, 1H), 8.34- 8.30 (m, 1H), 7.95-7.90 (m, 2H), 7.55-7.48 (m, 2H), 4.22-4.14 (m, 2H), 2.19-2.05 (m, 4H), 1.21 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.5 Hz, 6H). B) 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-2H-indazol-2-yl)phenyl)butanoic acid [00583] The target compound was obtained in a similar manner to step B to step E in Example 46 using ethyl 2-ethyl-2-(4-(6-nitro-4-(trifluoromethyl)-2H- indazol-2-yl)phenyl)butanoate. [00584] 1H NMR (400 MHz, CD3OD) d: 8.80 (s, 1H), 7.99-7.92 (m, 3H), 7.67 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 3.92 (d, J = 13.5 Hz, 2H), 3.39-3.32 (m, 2H), 2.18-2.04 (m, 4H), 1.96-1.85 (m, 1H), 1.73-1.57 (m, 4H), 1.44 (d, J = 5.7 Hz, 2H), 1.00 (d, J = 6.6 Hz, 6H), 0.81 (t, J = 7.4 Hz, 6H). Example 122: 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)- 4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)butanoic acid A) Ethyl 2-ethyl-2-(4-(6-nitro-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)butanoate [00585] The target compound was obtained in a similar manner to step A in Example 98 using 6-nitro-4-(trifluoromethyl)-1H-indazole and (4-(3- (ethoxycarbonyl)pentan-3-yl)phenyl)boronic acid. [00586] 1H NMR (400 MHz, CDCl3) d: 8.83 (s, 1H), 8.50-8.45 (m, 1H), 8.41 (d, J = 0.7 Hz, 1H), 7.69-7.64 (m, 2H), 7.58-7.51 (m, 2H), 4.24-4.16 (m, 2H), 2.21- 2.08 (m, 4H), 1.27-1.22 (m, 3H), 0.82 (t, J = 7.4 Hz, 6H). B) 2-Ethyl-2-(4-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)phenyl)butanoic acid [00587] The target compound was obtained in a similar manner to step B to step E in Example 46 using ethyl 2-ethyl-2-(4-(6-nitro-4-(trifluoromethyl)-1H- indazol-1-yl)phenyl)butanoate. [00588] 1H NMR (400 MHz, DMSO-d6) d: 8.97 (s, 1H), 8.31 (s, 2H), 7.96 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 4.15 (s, 1H), 3.83 (d, J = 13.3 Hz, 2H), 3.19 (t, J = 11.1 Hz, 2H), 2.09-1.93 (m, 4H), 1.83 (quind, J = 6.4, 12.8 Hz, 1H), 1.55-1.48 (m, 2H), 1.46-1.37 (m, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H), 0.74 (t, J = 7.3 Hz, 6H). Example 123: 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanoic acid sodium salt A) Ethyl 2-(5-(6-(4-hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanoate [00589] The target compound was obtained in a similar manner to step A to step D in Example 77 using 6-nitro-4-(trifluoromethyl)-1H-indazole and ethyl 2- (5-iodopyridin-2-yl)-2-methylpropanoate. [00590] 1H NMR (400 MHz, CDCl3) d: 8.91 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 15.9 Hz, 2H), 7.98 (dd, J = 2.6, 8.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.07 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.86 (d, J = 13.3 Hz, 2H), 3.40-3.30 (m, 2H), 1.90-1.81 (m, 1H), 1.67 (s, 6H), 1.65-1.60 (m, 3H), 1.43 (d, J = 5.9 Hz, 2H), 1.25-1.19 (m, 5H), 0.98 (d, J = 6.7 Hz, 6H). B) 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanoic acid sodium salt [00591] To a solution of ethyl 2-(5-(6-(4-hydroxy-4-isobutylpiperidine-1- carboxamido)-4-(trifluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)-2- methylpropanoate (0.050 g) in dioxane (0.4 mL) and H2O (0.4 mL) was added NaOH (7.0 mg). The mixture was stirred at 20°C for 12 h. The reaction mixture was purified by prep-HPLC to give the target compound (15.4 mg) as a solid. [00592] 1H NMR (400 MHz, DMSO-d6) d: 9.18 (s, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.32 (d, J = 10.4 Hz, 2H), 8.01 (s, 1H), 7.94 (dd, J = 2.6, 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 4.15 (br s, 1H), 3.84 (d, J = 13.2 Hz, 2H), 3.18 (t, J = 11.1 Hz, 2H), 1.82 (td, J = 6.3, 12.9 Hz, 1H), 1.53-1.48 (m, 2H), 1.46 (s, 6H), 1.44-1.36 (m, 2H), 1.30 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H). Example 124: N-(1-(4-(2-(1H-Tetrazol-5-yl)propan-2-yl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide A) 2-(4-(6-Bromo-4-(trifluoromethyl)-1H-indazol-1-yl)phenyl)-2- methylpropanenitrile [00593] The target compound was obtained in a similar manner to step A in Example 77 using 6-bromo-4-(trifluoromethyl)-1H-indazole and 2-(4- iodophenyl)-2-methylpropanenitrile. [00594] 1H NMR (400 MHz, DMSO-d6) d: 8.53-8.47 (m, 2H), 7.93 (s, 1H), 7.84 (s, 2H), 7.80-7.74 (m, 2H), 1.77 (s, 6H). B) tert-Butyl (1-(4-(2-cyanopropan-2-yl)phenyl)-4-(trifluoromethyl)-1H-indazol-6- yl)carbamate [00595] A mixture of 2-(4-(6-bromo-4-(trifluoromethyl)-1H-indazol-1- yl)phenyl)-2-methylpropanenitrile (300 mg), NH2Boc (258 mg), Pd2(dba)3 (67.3 mg), Xantphos (85.1 mg), and Cs2CO3 (838 mg) in dioxane (10 mL) was stirred at 110°C for 12 h under N2 atmosphere. The reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 93/7) to give the target compound (320 mg) as a solid. [00596] 1H NMR (400 MHz, CDCl3) d: 8.30-8.23 (m, 2H), 7.77-7.72 (m, 2H), 7.70-7.65 (m, 2H), 7.31 (s, 1H), 6.89 (s, 1H), 1.81 (s, 6H), 1.55-1.54 (m, 1H), 1.55 (s, 8H). C) tert-Butyl (1-(4-(2-(1H-tetrazol-5-yl)propan-2-yl)phenyl)-4-(trifluoromethyl)- 1H-indazol-6-yl)carbamate [00597] To a mixture of tert-butyl (1-(4-(2-cyanopropan-2-yl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-yl)carbamate (25 mg) and NH4Cl (30.1 mg) in DMF (1.0 mL) was added NaN3 (36.6 mg). The mixture stirred at 120°C for 3 h under microwave irradiation. Another batch of 15 mg of the starting material was combined, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the target compound (300 mg) as an oil. D) 1-(4-(2-(1H-Tetrazol-5-yl)propan-2-yl)phenyl)-4-(trifluoromethyl)-1H-indazol- 6-amine [00598] To a stirred solution of tert-butyl (1-(4-(2-(1H-tetrazol-5-yl)propan- 2-yl)phenyl)-4-(trifluoromethyl)-1H-indazol-6-yl)carbamate (300 mg) in EtOAc (2.0 mL) was added 4 M HCl in EtOAc (30 mL) at 20°C. Then the mixture was stirred for 3 h at 20°C, and concentrated to give the target compound (200 mg) as an oil. E) N-(1-(4-(2-(1H-Tetrazol-5-yl)propan-2-yl)phenyl)-4-(trifluoromethyl)-1H- indazol-6-yl)-4-hydroxy-4-isobutylpiperidine-1-carboxamide [00599] The target compound was obtained in a similar manner to step C to step D in Example 46 using 1-(4-(2-(1H-Tetrazol-5-yl)propan-2-yl)phenyl)-4- (trifluoromethyl)-1H-indazol-6-amine. [00600] 1H NMR (400 MHz, DMSO-d6) d: 8.95 (s, 1H), 8.31 (d, J = 7.3 Hz, 2H), 7.92 (s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 4.15 (s, 1H), 3.82 (d, J = 12.6 Hz, 2H), 3.24-3.12 (m, 2H), 1.91-1.74 (m, 7H), 1.55-1.48 (m, 2H), 1.47-1.36 (m, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 125: 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4- (trifluoromethyl)-1H-indazol-1-yl)thiophen-2-yl)-2-methylpropanoic acid A) Methyl 2-(5-(6-bromo-4-(trifluoromethyl)-1H-indazol-1-yl)thiophen-2-yl)-2- methylpropanoate [00601] The target compound was obtained in a similar manner to step A in Example 77 using 6-bromo-4-(trifluoromethyl)-1H-indazole and methyl 2-(5- iodothiophen-2-yl)-2-methylpropanoate. MS: (M+H+): 448.7. B) 2-(5-(6-(4-Hydroxy-4-isobutylpiperidine-1-carboxamido)-4-(trifluoromethyl)- 1H-indazol-1-yl)thiophen-2-yl)-2-methylpropanoic acid [00602] The target compound was obtained in a similar manner to step E to step I in Example 63 using methyl 2-(5-(6-bromo-4-(trifluoromethyl)-1H- indazol-1-yl)thiophen-2-yl)-2-methylpropanoate. [00603] 1H NMR (400 MHz, DMSO-d6) d: 9.05 (s, 1H), 8.30 (d, J = 11.6 Hz, 2H), 7.95 (s, 1H), 7.14 (d, J = 3.9 Hz, 1H), 6.97 (d, J = 3.8 Hz, 1H), 4.15 (br s, 1H), 3.84 (d, J = 13.0 Hz, 2H), 3.19 (t, J = 11.2 Hz, 2H), 1.82 (quind, J = 6.4, 12.9 Hz, 1H), 1.58-1.48 (m, 8H), 1.46-1.37 (m, 2H), 1.31 (d, J = 5.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). Examples 126-127: Stroke and sepsis in vivo data Background and significance [00604] During inflammation, the vascular endothelium becomes activated, increasing permeability and coagulation. Increasing evidence indicates that sustained endothelial activation in numerous clinical settings including ischemia, sepsis and systemic inflammatory response syndrome, significantly contributes to tissue edema, perpetuates the inflammatory response, and exacerbates tissue injury ultimately resulting in organ failure and death. For instance, blood brain barrier (BBB) disruption exacerbates neuronal injury in stroke; severe endothelial dysfunction during sepsis; and systemic inflammatory response syndrome leads to increased vascular leakage and disseminated intravascular coagulation significantly contributing to multiorgan failure and death. However, no therapies specifically targeting the endothelium are yet available. Instead, non-specific therapies are used in clinical practice. Although these treatments have failed to significantly improve outcomes, they are still used due to the lack of alternative therapies. Several lines of evidence point to a role for S1PR2 in endothelial dysfunction and in the pathophysiology of these diseases. S1PR2 null mice subjected to ischemic stroke show a dramatic decrease in infarct ratio and total edema compared with WT mice. Treatment of the mice with the S1PR2 antagonist JTE013 after stroke also resulted in a dramatic decrease in infarct ratio and edema as well as improved neurological outcomes. S1PR2 is potently induced in cerebral microvessels during ischemia causing endothelial barrier dysfunction and exacerbation of brain injury. S1PR2 has also been demonstrated to play a critical role in vascular inflammation associated with sepsis. In the absence of S1PR2 or in the presence of JTE013-mediated inhibition of S1PR2 signaling, decreased vascular permeability is observed in response to endotoxin or polymicrobial sepsis challenge. [00605] Together these data suggest that antagonism of S1PR2 may be a useful approach for treating stroke, systemic inflammatory response syndrome, sepsis and other diseases characterized by vascular dysfunction. The pathophysiological relevance of these findings is strengthened by the expression of S1PR2 in the endothelium of several organs, including brain and its upregulation in human stroke. Mouse stroke model [00606] The middle cerebral artery (MCA) and branches are the most commonly affected vessels in human ischemic stroke. Techniques that occlude these vessels are thus most similar to human ischemic infarcts. Among these models, the intra-arterial suture occlusion of the MCA (tMCAO) is the most common. This model is less invasive and involves temporary occlusion for a specific duration. This model has several advantages. It closely mimics human ischemic stroke, the large infarct size is reproducible, it is highly controllable by reperfusion, and the procedure is relatively simple to perform. [00607] To evaluate the efficacy of the compounds described herein in treating injury associated with I/R, mice were subjected to several studies using the mouse tMCAO model. Animals were treated with either positive control S1PR2 antagonist JTE-013 or the compounds as described herein. All studies were conducted in a blinded fashion. As shown in FIG.1, treatment of animals with compound 39120 mg/kg b.i.d. IP resulted in significant reduction of several stroke parameters including 60.7% reduction in infarct size (without edema correction), 66.7% reduction in infarct size (corrected for edema), 53.7% reduction in edema ratio, and 28.6% improvement in neurological outcomes. PK- PD correlation studies indicated that maximum protection correlates with plasma Cmax=843 nM (free plasma protein concentration) and an exposure of 3.69µg*h/mL (AUC) (not shown). [00608] In order to test the efficacy of a delayed administration of compound 39 instead of dosing compound 39 one-hour post-ischemia as was done previously, compounds were administered 4.5 hours after the onset of stroke. The administration of compound 39 4.5 h after the onset of ischemia significantly decreased infarct size, edema ratio (~50% protection) and improved neurological outcomes at 24 hours (FIG.2). [00609] Together, these studies demonstrate that treatment of male C57BL/6J mice with compound 39 after ischemic stroke significantly ameliorates brain injury and improves neurological outcomes. The therapeutic time window of administration of the S1PR2 antagonist after the onset of stroke is at least 4.5 hours. Since endothelial dysfunction is also the cause of stroke and other ischemic diseases, S1PR2 antagonists can also be used for preventive treatment. [00610] Given that S1PR2 is expressed in the endothelium of several organs in humans, including brain and it is upregulated in human stroke, the therapeutic potential of S1PR2 antagonists is very high. Mouse Sepsis Model [00611] To address the utility of the compounds described herein in treating vascular leakage associated with septic challenge, mice were subjected to the cecal ligation and puncture (CLP) model of polymicrobial sepsis. The CLP model for polymicrobial sepsis is the model which most closely resemble human sepsis. Advantages of the CLP model include the polymicrobial flora used for development of sepsis, nonrequirement for growing microbes, and the similar cytokine profile to human sepsis. CLP involves exposure and ligation of a portion of the cecum, followed by needle puncture and extrusion of fecal content into the body cavity. The severity of disease can be controlled by the size of needle puncture and length of cecal ligation. A rise in pro-inflammatory cytokines (including IL-6 and TNF-a) is observed after CLP. [00612] To evaluate the efficacy of compound 39 in treating the vascular leakage associated with sepsis, the CLP mouse model was conducted with male C57BL/6 mice treated with a single dose of vehicle (20% HPBCD/saline), JTE- 01330 mg/kg IP, or TDI-662160 mg/kg IP. The CLP surgery was conducted followed by compound administration. After an additional 4.5 hours, Evans Blue dye was injected, and brain samples were then analyzed 7.5 hours after administration of compounds. Animals in each treatment arm were excluded from this study if perfusion was incomplete. [00613] All studies were conducted in a blinded fashion. Vascular leakage in the brain was assessed using Evans Blue dye fluorescence compared with the wet weight of the brain. Treatment with compound 39 demonstrated significant improvement in BBB leakage in the CLP mouse model of sepsis with a 33% decrease in RFU/g wet weight compared with the vehicle treatment (FIG.3). JTE- 013 showed a trend toward decreased leakage, although the effect was not statistically significant. A comparison of reduction in vascular leakage by compound 39 (33% decrease) with mice lacking S1PR2 (25% decrease) reveals that inhibition of leakage by compound 39 is demonstrating full or nearly full efficacy for inhibition of this pathway. Systemic plasma drug concentrations were measured at 4.5 hours. These measurements showed that 2.81 µM and 2.80 µM free drug concentrations (56.2 µM and 85.1 µM total drug concentrations) were attained for compound 39 and JTE-013, respectively. These PK results established that useful systemic plasma drug exposures were maintained during this study. In addition, when wild type (S1pr2+/+) and S1pr2-/- mice were subjected to polymicrobial sepsis (CLP; see Example 128), S1pr2-/- mice exhibited significantly decreased vascular leakage in the lungs (FIG.4, left panel) and improved survival (FIG.4 right panel). Therefore, genetic deletion of S1PR2 in mice results in dramatic reduction of vascular leakage (in lungs and brain) and mortality after sepsis. [00614] Together these data demonstrate that antagonism of S1PR2 is efficacious in the treatment of vascular leakage associated with sepsis. The S1PR2 antagonists were administered after the onset of sepsis, thus, they could be used to prevent or mitigate tissue injury and multiple organ dysfunction, ultimately decreasing mortality and chronic morbidity and disabilities in sepsis survivors. [00615] Since S1PR2 is expressed in the endothelium in human tissues and upregulated during inflammation, hypoxia and ischemia, the therapeutic potential of S1PR2 antagonists is very high. Example 128: In vivo studies [00616] C57BL6 mice (Jax laboratories) male, 24-28g, were used for the study. Wild type and S1pr2 -/- mice were used. All animal experiments used randomization to treatment groups and blinded assessment. tMCAO mouse model of stroke and treatments [00617] Transient focal cerebral ischemia was induced in mice by middle cerebral artery occlusion as we have previously described (tMCAO). Thirty-three mice (male, 24-28 g, C57BL6) were used in this study. Criteria for exclusion were development of subarachnoid hemorrhage, lack of reduction of cerebral blood flow or lack of recovery after reperfusion. Surgeries, as well as all behavioral and histological assessments were performed by an investigator blinded to the drug treatment. Mice were anesthetized with 3% isoflurane vaporized in O2 for induction and 1.5% isoflurane for maintenance. Temperature was maintained at 36.5 ± 0.5ºC, controlled by a thermostatic blanket (CMA 450 Temp Controller for mice, Harvard Apparatus, Holliston, MA) throughout the procedure. The left common carotid artery was exposed and the occipital artery branches of the external carotid artery (ECA) were isolated and coagulated. The ECA was dissected distally and coagulated along with the terminal lingual and maxillary artery branches. The internal carotid artery (ICA) was isolated and the extracranial branch of the ICA was then dissected. A rubber silicon-coated monofilament suture (Filament size 6-0, diameter 0.09-0.11 mm, length 20mm; diameter with coating 0.23 +/- 0.02 mm; coating length 5 mm, Doccol Corp., Sharon, MA) was introduced into the ECA lumen through an incision and then gently advanced approximately 9 to 9.5 mm in the ICA lumen to block MCA blood flow. For reperfusion, the suture was withdrawn 60 min after MCAO. 2-D laser speckle flowmetry (PeriCam PSI HR, Perimed, Jarfalla, Sweeden) was used to confirm MCA occlusion and reperfusion. After removal of the suture, animals randomly received an intraperitoneal injection of vehicle or compounds. Determination of physiological parameters [00618] Physiological parameters (arterial O2 saturation, heart rate, pulse distention and respiratory rate) were recorded before, during and after tMCAO using the Mouse Ox Plus (Starr Life Sciences Corp., Oakmon, PA). After the surgery, all animals were maintained in a small animal heated recovery chamber (IMS Vetcare Chamber Recovery Unit, Harvard Apparatus, Holliston, MA). After recovery, animals were returned to their cages with free access to food and water. Neurobehavioral Testing [00619] Neurological function was evaluated at 24 h after reperfusion. Neurological deficit was graded on a score of 0 to 4 as previously described: 0, no observable deficit; 1, weakness in right forelimb; 2, forelimb flexion and circling when held by tail; 3, forelimb flexion, decreased resistance to lateral push, and spontaneous circling; and 4, forelimb flexion and being unable or difficult to ambulate. TTC staining and determination of infarct and edema ratios and infarct volumes [00620] Twenty-four hours after reperfusion, mice were anesthetized and decapitated. The brain was quickly removed from cranium, placed in -20 oC freezer for 20 min, and then cut into 1.5mm coronal slices using a rodent brain matrix. Sections were stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC; Sigma Co., St. Louis, MO) at 37°C for 10 min and scanned. Infarct area on each slice was determined by using Image analysis software (Image J, the National Institutes of Health, Bethesda, MD) to obtain the infarct ratios, edema ratios and infarct volumes per brain (in millimeters3). Infarct areas were calculated by using the following equation to correct for edema formation in the ischemic hemisphere: I=X-Y, where X is the area of the contralateral (non-ischemic) hemisphere and Y is the area of the intact regions of the ipsilateral (ischemic) hemisphere. Infarct ratios were obtained after normalization by the contralateral hemisphere. Edema ratios were calculated with the following formula: E=(Z-X)/X, where Z is the area of the ipsilateral hemisphere. Polymicrobial sepsis: cecal ligation and puncture model [00621] Under isoflurane anesthesia, a small incision was made in the peritoneal cavity (1.5 cm) to exteriorize the cecum, which was ligated at half the distance between the distal pole and the base of the cecum. Cecal puncture was conducted with a 18G needle and a small droplet of cecal content will be extruded from both holes to ensure patency. The cecum was relocated in the abdominal cavity and the incision sutured. Then, mice received pre-warmed normal saline (5mL/100g body weight) to avoid hypothermia. Determination of vascular leakage [00622] Two percent Evans blue dye solution is injected into animals 3 hours (brain leakage) or 40 minute (lung leakage) prior to endpoint . At endpoint 7.5 hours after drug administration, the mice were transcardially perfused with cold PBS/5 mM EDTA, and organs were harvested, weighed, and frozen. Organs were homogenized in 50% tricholoroacetic acid/PBS and incubated O/N at 4°C. Fluorescence intensity was measured at Ex 620/ Em 680. Vascular permeability was calculated as RFU/g wet weight. Statistical analyses, randomization and blinding [00623] All values reported are mean±s.e.m. P values were calculated with GraphPad Prism software, using one-way non-parametric ANOVA (Kruskal Wallis) followed by Dunn’s test or t test. The criterion for statistical significance was set at P<0.05. [00624]

Claims

What is claimed is: 1. A compound of the Formula (I): Het1—L1—Ar1—L2—G1 Formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: Het1 is cycloalkyl or heterocyclyl; G1 is aryl, heterocyclyl, heterocyclyl alkyl, carboxyalkyl, carboxyalkyloxy, carboxyalkyloxyalkyl, amidoalkyl, carboxy or amido; Ar1 is a divalent aryl group or a divalent heteroaryl group; L1 is a bond, an acyl linker or an amido linker; L2 is a bond, heterocycloalkyl linker, cycloalkyloxy linker or an aryloxy linker; Het1 and G1 are different when Het1 and G1 are simultaneously heterocyclyl; provided that Ar1 is a divalent heteroaryl group when L2 is an aryloxy linker.
2. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L1 is an acyl linker of the formula -C(O)-R11-, wherein R11 is a bond, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L1 is an amido linker of the formula -C(O)-N(R12)-, wherein R12 is H or alkyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L2 is a cycloalkyloxy linker.
5. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L2 is a bond.
6. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L2 has the formula:
Figure imgf000195_0001
,
7. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1 is a four-, five- or six-membered heterocyclyl group.
8. The compound of claim 7 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1 has the formula:
Figure imgf000195_0002
X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, aryl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; and Y is N or CH.
9. The compound of claim 7 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1 has the formula:
Figure imgf000195_0003
10. The compound of claim 7 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L1 is an amido linker.
11. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1 has the formula:
Figure imgf000196_0001
wherein: each m is independently 0 or 1, R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl; Y is N or CH; and Z is O, NR6, wherein R6 is H or alkyl, or CR2R3.
12. The compound of claim 11 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1 has the formula:
Figure imgf000196_0002
.
13. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein G1 is carboxyalkyl having the formula -alkyl-C(O)O-R6, wherein R6 is H, alkyl or a counterion.
14. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein G1 is C(O)OH.
15. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein G1 is amidoalkyl having the formula -alkyl-C(O)NR7R8, wherein R7 and R8 are each, independently, hydrogen, alkyl, aryl or R7 and R8, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
16. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein G1 is amido having the formula C(O)NR7R8, wherein R7 and R8 are each, independently, hydrogen, alkyl, aryl or R7 and R8, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
17. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Ar1 is a divalent aryl group of formula
Figure imgf000197_0001
wherein p is 0, 1, 2 or 3; and each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido or two R9 groups on adjacent carbon atoms to which they are attached, can form an aryl group.
18. The compound of claim 17 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein R9 is aryl, aryloxy, alkoxy, trihaloalkyl or SF5.
19. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Ar1 is a divalent heteroaryl group of the formula:
Figure imgf000198_0001
wherein: each p is independently 0, 1, 2 or 3; each of A1 and A2 is independently, CR10 or N; A3 is NR10, O or S; A4 is CR10 or N; A5 is CR10 or N; A6 is NR10, O or S; A7 is CR10 or N; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl.
20. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Ar1 is:
Figure imgf000199_0001
each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl.
21. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Ar1 is:
Figure imgf000200_0001
wherein each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl.
22. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: Het1 is a four-, five- or six-membered heterocyclyl group, wherein a heteroatom in Het1 is directly attached to L1.
23. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Het1—L1 has the formula:
Figure imgf000201_0001
wherein X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; and R12 is H or alkyl.
24. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein L2—G1 has the formula:
Figure imgf000201_0002
, , , wherein d is 0, 1, 2, 3, 4, or 5; R13 and R14 are each independently H, alkyl or aryl, wherein each repeating CR13R14 unit can be the same or different; and G2 is OR15 or NR16R17, wherein R15 is H or alkyl and R16 and R17 are each independently H or alkyl or R16 and R17 together with the nitrogen atom to which they are attached, form a heterocyclyl group.
25. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000202_0001
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: X is -(CH2)nC(R2)(R3)(CH2)n-, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; Q and Q1 are each independently N or CH; and T is N or CR18, wherein R18 is alkyl, alkoxy, aryloxy, arylamino, SF5, trihaloalkyl, dihaloalkyl, trihaloalkoxy, or dihaloalkoxy; provided that Q, Q1, and T are not N at the same time.
26. The compound of claim 25 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000203_0001
27. The compound of claim 25 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000203_0002
28. The compound of claim 25 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000203_0003
29. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000203_0004
wherein X3 is O or NR20, wherein R20 is H or alkyl; and R19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy.
30. The compound of claim 29 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000204_0001
31. The compound of claim 29 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000204_0002
.
32. The compound of any one of claims 29-31 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein X3 is O.
33. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000205_0001
wherein: each m is independently 0, 1 or 2, R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl; Y is N or CH; and Z is O, NR6, wherein R6 is H or alkyl, or CR2R3; Q and Q1 are each independently N or CH; T is N or CR18, wherein R18 is alkyl, alkoxy, aryloxy, arylamino, SF5, trihaloalkyl, dihaloalkyl, trihaloalkoxy, or dihaloalkoxy; provided that Q, Q1, and T are not N at the same time.
34. The compound of claim 33 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000206_0001
35. The compound of claim 33 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000206_0002
36. The compound of claim 33 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000206_0003
.
37. The compound of claim 33 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000207_0001
wherein X3 is O or NR20, wherein R20 is H or alkyl; and R19 is halo, cyano, alkyl, alkoxy, acetamido, alkylamido, alkenyl, alkynyl, alkoxycarbonyl or carboxy.
38. The compound of claim 33 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000207_0002
.
39. The compound of claim 37 or 38 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein X3 is O. 40. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000208_0001
, wherein: X is -(CH2)nC(R2)(R3)(CH2)n -, each n is independently 0, 1 or 2, R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl group or R2 and R3 are each independently fluoro, chloro, bromo, iodo, amino, amido, alkyl, cycloalkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, dialkylamido, OP(O)(OR1)2, wherein each R1 is hydrogen or alkyl, provided R2 and R3 are not the same; Y is N or CH; p is 0, 1, 2 or 3; A6 is NR10, O or S; A7 is CR10 or N; each R9 independently is fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, SF5, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino or dialkylamido; and R10 is independently H, alkyl or aryl. 41. The compound of claim 1 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein the compound is a compound of the formula:
Figure imgf000209_0001
, , ,
Figure imgf000210_0001
, , ,
Figure imgf000211_0001
Figure imgf000212_0001
42. The compound of any one of claims 23-41 or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein Y is N.
43. A compound of the formula:
, ,
Figure imgf000213_0001
, , ,
Figure imgf000214_0001
Figure imgf000215_0001
, ,
Figure imgf000216_0001
,
Figure imgf000217_0001
,
Figure imgf000218_0001
, or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
44. A compound of the formula:
Figure imgf000219_0001
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
45. A compound of the formula:
Figure imgf000220_0001
,
Figure imgf000221_0001
,
Figure imgf000222_0001
,
Figure imgf000223_0001
Figure imgf000224_0001
, or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
46. A compound of the formula:
Figure imgf000225_0001
,
Figure imgf000226_0001
,
Figure imgf000227_0001
,
Figure imgf000228_0001
Figure imgf000229_0001
,
Figure imgf000230_0001
Figure imgf000231_0001
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
47. A compound of the formula:
Figure imgf000231_0002
, or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
48. A compound of the formula:
Figure imgf000232_0001
^ or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
49. A pharmaceutical composition comprising one or more compounds of any preceding claim and a pharmaceutically acceptable carrier.
50. A method for treating a fibrotic disease, abnormal vascular leak and pathological angiogenesis, and tumor-associated angiogenesis comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
51. The method of claim 50, wherein the abnormal vascular leak and pathological angiogenesis is associated with the wet form of age-related macular degeneration and diabetic retinopathy.
52. The method of claim 50, wherein the fibrotic disease is fibrosis of the lung, liver, kidney, retina, skin or heart.
53. A method for treating highly vascular tumors comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
54. The method of claim 53, wherein the highly vascular tumors are renal carcinoma, glioblastoma, sarcomas, and neuroblastoma.
55. The method of claim 53, wherein the tumors are highly fibrotic such as pancreatic cancer.
56. A method for treating a fibrotic disease, abnormal vascular leak and pathological angiogenesis, and tumor-associated angiogenesis comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
57. A method for chimeric antigen receptor T-cell therapy comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
58. A method for treating cytokine release syndrome, comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
59. A method for treating pathological angiogenesis in a subject, comprising administering a therapeutically effective amount a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
60. A method for treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
61. A method for treating diabetes comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
62. A method for treating or preventing stroke comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
63. A method for treating or preventing sepsis-induced changes in blood- brain barrier permeability comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
64. A method for treating nonalcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
65. A method for treating nonalcoholic fatty liver disease (NAFLD) comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
66. A method for treating hepatobiliary conditions comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
67. A method for at least one of regulating proliferation of cholangiocytes and promoting ductular reaction comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
68. A method for ameliorating blood brain barrier dysfunction and brain damage associated with chronic traumatic encephalopathy; and at least one of traumatic brain injury, hypertensive encephalopathy, neurodegenerative diseases, vascular dementias, and multiple sclerosis, comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
69. A method for at least one of treating and preventing at least one of inflammatory response syndrome and sepsis; restoring endothelial function, preventing vascular leak, disseminated intravascular coagulation, systemic vascular failure, ischemia and acute multiple organ dysfunction, kidney, heart, liver and brain injury and death; treating or preventing vascular complications of diabetes comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
70. A method of treating and preventing chronic complications of systemic inflammatory response syndrome and sepsis comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
71. A method of treating and preventing conditions caused by one or more coronaviruses comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
72. A method of treating and preventing chronic complications of COVID-19 comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
73. A method of treating a condition characterized by at least one of acute lung injury, vascular leakage, endothelial inflammation, disseminated intravascular coagulation and systemic vascular dysfunction leading to at least one of hypoxia, ischemia, multiple organ failure, coma, and death, the method comprising administering a therapeutically effective amount of a compound of claims 1-48 or a pharmaceutical composition comprising a compound of claims 1-48 to a subject in need thereof.
74. The method of claim 73, wherein the condition is caused by a coronavirus infection or a filoviridae infection.
75. The method of claim 73, wherein the condition is caused by COVID-19.
76. The method of claim 73, wherein the condition is caused by ebolavirus infection or Marburg virus infection.
77. The method of claim 73, wherein the condition is caused by a flaviviridae infection.
PCT/US2020/045455 2019-08-07 2020-08-07 Small molecule inhibitors of s1p2 receptor and uses thereof Ceased WO2021026479A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962884046P 2019-08-07 2019-08-07
US62/884,046 2019-08-07

Publications (2)

Publication Number Publication Date
WO2021026479A1 true WO2021026479A1 (en) 2021-02-11
WO2021026479A9 WO2021026479A9 (en) 2021-04-08

Family

ID=74504178

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/045455 Ceased WO2021026479A1 (en) 2019-08-07 2020-08-07 Small molecule inhibitors of s1p2 receptor and uses thereof

Country Status (1)

Country Link
WO (1) WO2021026479A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113979891A (en) * 2021-11-08 2022-01-28 上海高准医药有限公司 Preparation method of Cliborol and intermediate product thereof
CN115433107A (en) * 2022-09-19 2022-12-06 南京欧际医药科技服务有限公司 S1PR2 antagonist and application thereof in preparation of drugs for treating lung diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150051176A1 (en) * 2013-08-15 2015-02-19 Allergan, Inc. Aryl derivatives as sphingosine-1 phosphate receptors modulators
US20160039757A1 (en) * 2013-03-26 2016-02-11 Ono Pharmaceutical Co., Ltd. Phenyl derivative
US20190084947A1 (en) * 2008-05-14 2019-03-21 The Scripps Research Institute Novel modulators of sphingosine phosphate receptors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190084947A1 (en) * 2008-05-14 2019-03-21 The Scripps Research Institute Novel modulators of sphingosine phosphate receptors
US20160039757A1 (en) * 2013-03-26 2016-02-11 Ono Pharmaceutical Co., Ltd. Phenyl derivative
US20150051176A1 (en) * 2013-08-15 2015-02-19 Allergan, Inc. Aryl derivatives as sphingosine-1 phosphate receptors modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Pubchem Compound [online] 8 August 2005 (2005-08-08), "1,1'-Biphenyl, 4-cyclohexyl", XP055790731, retrieved from ncbi Database accession no. 119782 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113979891A (en) * 2021-11-08 2022-01-28 上海高准医药有限公司 Preparation method of Cliborol and intermediate product thereof
CN113979891B (en) * 2021-11-08 2024-09-13 上海高准医药有限公司 Preparation method of clenbuterol and intermediate product thereof
CN115433107A (en) * 2022-09-19 2022-12-06 南京欧际医药科技服务有限公司 S1PR2 antagonist and application thereof in preparation of drugs for treating lung diseases
CN115433107B (en) * 2022-09-19 2024-06-18 南京欧际医药科技服务有限公司 S1PR2 antagonist and application thereof in preparation of medicines for treating lung diseases

Also Published As

Publication number Publication date
WO2021026479A9 (en) 2021-04-08

Similar Documents

Publication Publication Date Title
JP4775259B2 (en) Aniline derivative
CA2684037C (en) Compounds with anti-cancer activity
DK2380881T3 (en) NEW BICYCLIC HETEROCYCLIC COMPOUND
CN101511821B (en) Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
CA3169975A1 (en) Heterocyclic glp-1 agonists
CN113710276B (en) Benzodiazepine derivatives as RSV inhibitors
AU2019233207B2 (en) Heteroaryl compounds as kinase inhibitor
WO2023164050A1 (en) Compounds as glp-1r agonists
TW201024275A (en) Small molecule bradykinin B2 receptor modulators
ES2871052T3 (en) Tricyclic poly (ADP-ribose) polymerase inhibitors
CA2688326C (en) Tetrahydroisoquinolin-1-one derivative or salt thereof
US11964960B2 (en) Pyridinone- and pyridazinone-based compounds and uses thereof
WO2021026479A1 (en) Small molecule inhibitors of s1p2 receptor and uses thereof
US12454537B2 (en) HIV-1 protease inhibitors and uses thereof
EA037264B1 (en) Heterocyclic sulfonamide derivative and medicament containing same
CN107531598A (en) Compositions for treating fibrosis and fibrosis-related disorders
AU2006227101A1 (en) Methods for treating or preventing acute myelogenous leukemia
CA2914541A1 (en) Novel aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection
HK40083024A (en) Quinoline compounds with anti-cancer activity
TW202430154A (en) Cathepsin l inhibitors
TW202339707A (en) Heterocycle-containing lonp1 inhibitor compounds, uses and methods
HK1139143B (en) Compounds with anti-cancer activity

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: 20849951

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20849951

Country of ref document: EP

Kind code of ref document: A1