WO2021026479A1 - Inhibiteurs à petites molécules de récepteur s1p2 et leurs utilisations - Google Patents

Inhibiteurs à petites molécules de récepteur s1p2 et leurs utilisations Download PDF

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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
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compound
alkyl
clathrate
polymorph
prodrug
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WO2021026479A9 (fr
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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
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Stamford, Andrew
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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]

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Abstract

La présente divulgation concerne un composé de formule Het1-L1-Ar1-L2-G1, ou un sel, un polymorphe, un promédicament, un solvate ou un clathrate pharmaceutiquement acceptable de celui-ci, qui sont utiles pour traiter divers états pathologiques. Dans de tels composés, Het1, G1, Ar1, L1 et L2 sont tels que définis dans la description. Des compositions pharmaceutiques de ces composés sont également divulguées.
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CN113979891A (zh) * 2021-11-08 2022-01-28 上海高准医药有限公司 一种克立硼罗及其中间产物的制备方法
CN115433107A (zh) * 2022-09-19 2022-12-06 南京欧际医药科技服务有限公司 S1pr2拮抗剂及其在制备治疗肺部疾病药物中的用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113979891A (zh) * 2021-11-08 2022-01-28 上海高准医药有限公司 一种克立硼罗及其中间产物的制备方法
CN115433107A (zh) * 2022-09-19 2022-12-06 南京欧际医药科技服务有限公司 S1pr2拮抗剂及其在制备治疗肺部疾病药物中的用途
CN115433107B (zh) * 2022-09-19 2024-06-18 南京欧际医药科技服务有限公司 S1pr2拮抗剂及其在制备治疗肺部疾病药物中的用途

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