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US20230234946A1 - Compounds for modulating s1p1 activity and methods of using the same - Google Patents

Compounds for modulating s1p1 activity and methods of using the same Download PDF

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Publication number
US20230234946A1
US20230234946A1 US18/296,018 US202318296018A US2023234946A1 US 20230234946 A1 US20230234946 A1 US 20230234946A1 US 202318296018 A US202318296018 A US 202318296018A US 2023234946 A1 US2023234946 A1 US 2023234946A1
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oxadiazol
optionally substituted
pain
compound
pharmaceutically acceptable
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US18/296,018
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Philip Michael Pitis
Robert Eugene Boyd
Tamara Ann Miskowski Daubert
Michael John Hawkins
Guodong Liu
Aimee Crombie Speerschneider
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Trevena Inc
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Trevena Inc
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Priority to US18/296,018 priority Critical patent/US20230234946A1/en
Publication of US20230234946A1 publication Critical patent/US20230234946A1/en
Assigned to TREVENA, INC. reassignment TREVENA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIU, GUODONG, SPEERSCHNEIDER, Aimee Crombie, BOYD, Robert Eugene, DAUBERT, Tamara Ann Miskowski, HAWKINS, MICHAEL JOHN, PITIS, PHILIP MICHAEL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Embodiments disclosed herein are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, for modulating S1P1 receptor activity and/or methods for treating and/or preventing pain, such as neuropathic pain, chemotherapy induced neuropathic pain (CINP), chemotherapy induced peripheral neuropathy (CIPN), or treating cancer or inhibiting tumor growth, and the like as described herein.
  • pain such as neuropathic pain, chemotherapy induced neuropathic pain (CINP), chemotherapy induced peripheral neuropathy (CIPN), or treating cancer or inhibiting tumor growth, and the like as described herein.
  • CINP chemotherapy induced neuropathic pain
  • CIPN chemotherapy induced peripheral neuropathy
  • compounds, or pharmaceutically acceptable salts thereof are provided that, in part, modulate the activity of the S1P1 receptor.
  • the compounds can have, for example, a formula as described herein.
  • the compound is selected from a compound described herein.
  • methods of treating the conditions described herein are provided.
  • the condition is CIPN, CINP, pain, neuropathy, and the like.
  • the condition is cancer and the like.
  • the compound is a compound having a formula of Formula I or Formula II:
  • AA, B 1 , B 2 , B 3 , B 4 , D 1 , V, R 30 , and R 31 are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.
  • compositions comprising one or more compounds as described herein, which can also comprise a pharmaceutically acceptable carrier.
  • the compounds described herein can be provided in any form, such as a solid or solution (e.g., aqueous solution), such as is described herein.
  • a solid or solution e.g., aqueous solution
  • the compounds described herein for example, can be obtained and employed in lyophilized form alone or with suitable additives.
  • kits for treating and/or preventing pain such as neuropathic pain, chemotherapy induced neuropathic pain (CINP), chemotherapy induced peripheral neuropathy (CIPN), or treating cancer or inhibiting tumor growth, and the like as described herein.
  • the methods comprise administering a one or more compounds described herein to a subject or subjects.
  • the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by +10% and remain within the scope of the disclosed embodiments.
  • acylamino means an amino group substituted by an acyl group (e.g., —O—C( ⁇ O)—H or —O—C( ⁇ O)-alkyl).
  • An example of an acylamino is —NHC( ⁇ O)H or —NHC( ⁇ O)CH 3 .
  • lower acylamino refers to an amino group substituted by a lower acyl group (e.g., —O—C( ⁇ O)—H or —O—C( ⁇ O)—C 1-6 alkyl).
  • An example of a lower acylamino is —NHC( ⁇ O)H or —NHC( ⁇ O)CH 3 .
  • alkenyl means a straight or branched alkyl group having one or more double carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • the alkenyl chain is from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.
  • the alkoxy chain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.
  • alkyl means a saturated hydrocarbon group which is straight-chained or branched.
  • An alkyl group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms.
  • allylamino means an amino group substituted by an alkyl group having from 1 to 6 carbon atoms.
  • An example of an alkylamino is —NHCH 2 CH 3 .
  • alkylene or “alkylenyl” means a divalent alkyl linking group.
  • An example of an alkylene (or alkylenyl) is methylene or methylenyl (—CH 2 —).
  • amino means —C( ⁇ NH)NH 2 .
  • amino means —NH 2 .
  • aminoalkoxy means an alkoxy group substituted by an amino group.
  • An example of an aminoalkoxy is —OCH 2 CH 2 NH 2 .
  • aminoalkyl means an alkyl group substituted by an amino group.
  • aminosulfonyl means —S( ⁇ O) 2 NH 2 .
  • aminoalkylthio means an alkylthio group substituted by an amino group.
  • An example of an aminoalkylthio is —SCH 2 CH 2 NH 2 .
  • amphiphilic means a three-dimensional structure having discrete hydrophobic and hydrophilic regions.
  • An amphiphilic compound suitably has the presence of both hydrophobic and hydrophilic elements.
  • animal includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.
  • the term “antagonize” or “antagonizing” means reducing or completely eliminating an effect, such as an activity of the S 1 P 1 receptor.
  • an anti-receptor effective amount of a compound can be measured by the anti-receptor effectiveness of the compound.
  • an anti-receptor effective amount inhibits an activity of the receptor by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90%, or by at least 95%.
  • an “anti-receptor effective amount” is also a “therapeutically effective amount” whereby the compound reduces or eliminates at least one effect of a S 1 P 1 receptor.
  • the effect is the beta-arrestin effect. In some embodiments, the effect is the G-protein mediated effect.
  • aryl means a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons.
  • aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like.
  • aryl groups include, but are not limited to:
  • arylalkyl means a C 1-6 alkyl substituted by aryl.
  • arylamino means an amino group substituted by an aryl group.
  • An example of an arylamino is —NH(phenyl).
  • cancer means a spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.
  • carbamoyl means —C( ⁇ O)—NH 2 .
  • carbocycle means a 5- or 6-membered, saturated or unsaturated cyclic ring, optionally containing O, S, or N atoms as part of the ring.
  • Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocycles recited above.
  • carrier means a diluent, adjuvant, or excipient with which a compound is administered.
  • Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
  • the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • contacting means bringing together of two elements in an in vitro system or an in vivo system.
  • “contacting” a S 1 P 1 receptor compound with a S 1 P 1 receptor with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the S 1 P 1 receptor.
  • cyano means —CN
  • cycloalkyl means non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic ring systems such as fused ring systems, bridged ring systems, and spiro ring systems.
  • polycyclic ring systems include 2, 3, or 4 fused rings.
  • a cycloalkyl group can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6, from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).
  • cycloalkylalkyl means a C 1-6 alkyl substituted by cycloalkyl.
  • dialkylamino means an amino group substituted by two alkyl groups, each having from 1 to 6 carbon atoms.
  • diazamino means —N(NH 2 ) 2 .
  • the term “facially amphiphilic” or “facial amphiphilicity” means compounds with polar (hydrophilic) and nonpolar (hydrophobic) side chains that adopt conformation(s) leading to segregation of polar and nonpolar side chains to opposite faces or separate regions of the structure or molecule.
  • guanidino means —NH( ⁇ NH)NH 2 .
  • halo means halogen groups including, but not limited to fluoro, chloro, bromo, and iodo.
  • haloalkoxy means an —O-haloalkyl group.
  • An example of an haloalkoxy group is OCF 3 .
  • haloalkyl means a C 1-6 alkyl group having one or more halogen substituents.
  • haloalkyl groups include, but are not limited to, CF 3 , C 2 F 5 , CH 2 F, CHF 2 , CCl 3 , CHCl 2 , CH 2 CF 3 , and the like.
  • heteroaryl means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen.
  • the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which are, independently, sulfur, oxygen, or nitrogen.
  • the heteroaryl group has from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms, from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms.
  • the heteroaryl group contains 2 to 14 carbon atoms, from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl,
  • Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.
  • heteroarylalkyl means a C 1-6 alkyl group substituted by a heteroaryl group.
  • heteroarylamino means an amino group substituted by a heteroaryl group.
  • An example of a heteroarylamino is —NH-(2-pyridyl).
  • heteroarylene means a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group in a molecule.
  • heterocycle or “heterocyclic ring” means a 5- to 7-membered mono- or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms chosen from N, O and S, and wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,
  • heterocycloalkyl means non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups, where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Hetercycloalkyl groups can be mono or polycyclic (e.g., fused, bridged, or spiro systems). In some embodiments, the heterocycloalkyl group has from 1 to 20 carbon atoms, or from 3 to 20 carbon atoms.
  • the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like.
  • ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • a ring-forming S atom can be substituted by 1 or 2 oxo (form a S(O) or S(O) 2 ).
  • a ring-forming C atom can be substituted by oxo (form carbonyl).
  • heterocycloalkyl moieties that have one or more aromatic rings fused (having a bond in common with) to the nonaromatic heterocyclic ring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups.
  • Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • heterocycloalkylalkyl refers to a C 1-6 alkyl substituted by heterocycloalkyl.
  • hydroxyalkyl or “hydroxylalkyl” means an alkyl group substituted by a hydroxyl group.
  • examples of a hydroxylalkyl include, but are not limited to, —CH 2 OH and —CH 2 CH 2 OH.
  • the term “individual” or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.
  • inhibiting activity means reducing by any measurable amount the activity of an enzyme or receptor, such as the S 1 P 1 receptor.
  • the phrase “in need thereof” means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal can be in need thereof. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.
  • in situ gellable means embracing not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid in the exterior of the eye, but also more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye.
  • integer from X to Y means any integer that includes the endpoints.
  • integer from X to Y means 1, 2, 3, 4, or 5.
  • isolated means that the compounds described herein are separated from other components of either (a) a natural source, such as a plant or cell, or (b) a synthetic organic chemical reaction mixture, such as by conventional techniques.
  • the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.
  • N-alkyl refers to a alkyl chain that is substituted with an amine group.
  • Non-limiting examples include, but are not limited to
  • the alkyl chain can be linear, branched, cyclic, or any combination thereof.
  • the alkyl comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 carbons.
  • nitro means —NO 2 .
  • n-membered typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n.
  • pyridine is an example of a 6-membered heteroaryl ring
  • thiophene is an example of a 5-membered heteroaryl ring.
  • the phrase “ophthalmically acceptable” means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated.
  • transient effects such as minor irritation or a “stinging” sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being “ophthalmically acceptable” as herein defined.
  • substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties.
  • a “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent groups, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
  • pharmaceutically acceptable means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • the salt of a compound described herein is a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt(s) includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts.
  • the present embodiments also include quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moiety.
  • phenyl means —C 6 H 5 .
  • a phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.
  • prodrug means a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process.
  • the term “purified” means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of a compound described herein by weight of the isolate.
  • quaternary ammonium salts means derivatives of the disclosed compounds with one or more tertiary amine moieties wherein at least one of the tertiary amine moieties in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (and the cations are balanced by anions such as Cl ⁇ , CH 3 COO ⁇ , and CF 3 COO ⁇ ), for example methylation or ethylation.
  • semiconductor means ⁇ NNHC( ⁇ O)NH 2 .
  • the phrase “solubilizing agent” means agents that result in formation of a micellar solution or a true solution of the drug.
  • solution/suspension means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form, in suspension in a liquid matrix.
  • substantially isolated means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.
  • suitable substituent or “substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds described herein or the intermediates useful for preparing them.
  • suitable substituents include, but are not limited to: C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 5 -C 6 aryl, C 1 -C 6 alkoxy, C 3 -C 5 heteroaryl, C 3 -C 6 cycloalkyl, C 5 -C 6 aryloxy, —CN, —OH, oxo, halo, haloalkyl, —NO 2 , —CO 2 H, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NH(C 6 aryl), —N(C 5 -C 6 aryl) 2 , ——
  • the phrase “therapeutically effective amount” means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutic effect is dependent upon the disorder being treated or the biological effect desired.
  • the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.
  • the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic measures wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • treatment of pain or “treating pain” means an activity that alleviates or ameliorates any of the primary phenomena or secondary symptoms associated with the pain or other condition described herein.
  • ureido means —NHC( ⁇ O)—NH 2 .
  • substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, propyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the Markush groups defined for R.
  • an optionally multiple substituent is designated in the form, for example,
  • substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence.
  • T 1 is defined to include hydrogens, such as when T 1 is CH 2 , NH, etc., any H can be replaced with a substituent.
  • the present embodiments encompass the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof, are within the scope of the embodiments.
  • the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the compounds can be provided as a substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated.
  • Compounds that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparation of optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ⁇ N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are provided herein.
  • Cis and trans geometric isomers of the compounds are also included within the present embodiments and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.
  • the composition comprises a compound, or a pharmaceutically acceptable salt thereof, that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomeric pure, which means that the ratio of one enantiomer to the other in the composition is at least 90:1 at least 95:1, at least 98:1, or at least 99:1, or is completely in the form of one enantiomer over the other.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and the various optically active camphorsulfonic acids such as 0-camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include, but are not limited to, stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms.
  • Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds, or salts thereof are substantially isolated.
  • Partial separation can include, for example, a composition enriched in the compound.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • thioamides and thioesters are anticipated to have very similar properties.
  • the distance between aromatic rings can impact the geometrical pattern of the compound and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine.
  • the distance between and the relative orientation of monomers within the compounds can also be altered by replacing the amide bond with a surrogate having additional atoms.
  • the compounds also include derivatives referred to as prodrugs.
  • N-oxides can also form N-oxides.
  • a reference herein to a compound that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom can be oxidized to form an N-oxide.
  • N-oxides include N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (see, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).
  • variable can be any option described herein, except as otherwise noted or dictated by context.
  • the compound is as described in the appended exemplary, non-limiting claims, or a pharmaceutically acceptable salt thereof.
  • W is O, S, or NR1;
  • X is O, S, or NR 4 ;
  • V is O, S, or NR 32 ;
  • Z is CHR 42 or NR 43 ;
  • n 0, 1, 2, 3, or 4;
  • Y 1 and Y 2 are independently O, S, NR 5 , C ⁇ O, C ⁇ S or C ⁇ NR 6 ;
  • Y 3 is O, S, CH 2 , or NR 34 ;
  • n 0, 1, 2, or 3;
  • a 1 is O, S, NR 7 , C ⁇ O, or C ⁇ S;
  • a 2 and A 3 are independently CR 29 or N;
  • B 1 is an optionally substituted aryl or heteroaryl group, a carbocycle, or
  • B 2 , B 3 , and B 4 are independently CR 38 or N;
  • D 1 is H, OH, NH 2 , NO 2 , cycle, optionally substituted aryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl;
  • R 2 and R 3 are independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or R 2 and R 3 are together optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 29 , R 31 , R 32 , R 33 , R 34 , R 38 , and R 43 are independently H, OH, NH 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • R 30 is independently H, CN, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or optionally substituted haloalkyl;
  • R 42 is independently Br, C 1 , F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • D 1 and B 1 are:
  • Z 1 and Z 2 are independently N or CR 39 ;
  • Z 3 is O, S, or NR 27 ;
  • R 27 and R 39 are independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • one of Z 1 and Z 2 is N. In some embodiments, both Z 1 and Z 2 are N. In some embodiments, Z 3 is O.
  • D 1 and B 1 have a formula of:
  • Z 4 is O, S, or NR 28 ;
  • Z 5 is N or CH
  • R 19 , and R 20 are each independently H, OH, NH 2 , NO 2 , cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, alkylthio, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R 19 , and R 20 together form an aryl or cycle that is attached to one or more of the atoms of B 1 .
  • R 28 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • Z 5 is N. In some embodiments, Z 4 is 0. In some embodiments, Z 5 is N and Z 4 is O.
  • D 1 is
  • R 21 , R 22 , and R 23 are each independently H, OH, NH 2 , NO 2 , cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R 21 , R 22 , and R 23 together form an aryl or cycle that is attached to one or more of the atoms of D 1 .
  • one of R 21 , R 22 , and R 23 is H. In some embodiments, two of R 21 , R 22 , and R 23 are H. In some embodiments, R 23 is Me, OH, NH 2 , C 1 , NHSO 2 Me, SO 2 NH 2 , NH(CO)Me, or (CO)NH 2 . In some embodiments, R 21 and R 22 are H and R 23 is Me, OH, NH 2 , C 1 , NHSO 2 Me, SO 2 NH 2 , NH(CO)Me, or (CO)NH 2 .
  • D 1 is optionally substituted aryl or optionally substituted hetero aryl.
  • D 1 is
  • R 24 , R 25 , and R 26 are each independently H, OH, NH 2 , NO 2 , cycle (e.g. carbocycle or heterocyle), aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R 24 , R 25 , and R 26 together form an aryl or cycle that is attached to one or more of the atoms of D 1 .
  • cycle e.g. carbocycle or heterocyle
  • aryl branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl
  • one of R 24 , R 25 , and R 26 is H. In some embodiments, two of R 24 , R 25 , and R 26 are H. In some embodiments, R 26 is H, Me, OH, CF 3 , or OMe. In some embodiments, R 24 and R 25 are H and R 26 is H, Me, OH, CF 3 , or OMe.
  • AA is
  • W is O.
  • X is O.
  • R 2 and R 3 are independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • R 2 and R 3 are the same.
  • R 2 and R 3 are ethyl.
  • D 1 is
  • one of R 24 , R 25 , and R 26 is H. In some embodiments, two of R 24 , R 25 , and R 26 are H and the other member is as defined herein. In some embodiments, D 1 is
  • D 1 is
  • R 24 is H. In some embodiments, R 24 is OH. In some embodiments, D 1 is
  • R 24 is OMe.
  • D 1 is
  • one of R 24 , R 25 , and R 26 is H. In some embodiments, two of R 24 , R 25 , and R 26 are H and the other member is as defined herein.
  • D 1 is
  • D 1 is
  • D 1 is
  • R 24 is halide. In some embodiments, R 24 is F.
  • R 24 is Me. In some embodiments, R 24 is OMe. In some embodiments, R 24 is OH.
  • R 2 and R 3 are together
  • n 1
  • AA is
  • Y 1 is NR 5 . In some embodiments, R 5 is H.
  • Y 2 is C ⁇ NR 6 . In some embodiments, R 6 is H.
  • Y 2 is C ⁇ O. In some embodiments, Y 3 is O. In some embodiments, Y 3 is CH 2 . In some embodiments, m is 0. In some embodiments, m is 1.
  • AA is
  • a 1 is O. In some embodiments, A 1 is S. In some embodiments, A 2 is N. In some embodiments, A 3 is N. In some embodiments, A 3 is CR 29 . In some embodiments, R 29 is H.
  • a 2 is CR 29 . In some embodiments, R 29 is H.
  • a 1 is NR 7 . In some embodiments, R 7 is Me,
  • D 1 is
  • R 21 , R 22 , and R 23 is H.
  • D 1 is
  • R 21 , R 22 , and R 23 are H.
  • D 1 is
  • R 21 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 21 is ethyl or methyl. In some embodiments, D 1 is
  • D 1 is
  • Z 6 is O, S, NR 40 , or CHR 37 ;
  • Z 7 , Z 8 , Z 9 and Z 10 are independently N or CR 41 ;
  • R 35 , R 36 , R 37 , R 40 , and R 41 are each independently H, OH, NH 2 , cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R 35 and R 36 together form an aryl or cycle that is attached to one or more of the atoms of D 1 .
  • one of R 35 and R 36 is H. In some embodiments, both R 35 and R 36 are H. In some embodiments, Z 6 is NH. In some embodiments, one of Z 7 , Z 8 and Z 9 is N.
  • Z 7 is N.
  • Z 8 is CH.
  • Z 9 is CH. In some embodiments, both Z 8 and Z 9 are CH.
  • AA is
  • W is O.
  • X is O.
  • R 2 and R 3 are independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • both R 2 and R 3 are the same.
  • both R 2 and R 3 are methyl or ethyl.
  • n is 1.
  • D 1 is pyrazoly.
  • D 1 is
  • the compound, or a pharmaceutically acceptable salt thereof is a compound of Formula I having a formula of
  • Z 1 , Z 2 , and Z 3 are as defined herein and above.
  • Z 2 is N. In some embodiments, Z 1 is N. In some embodiments, Z 3 is O. In some embodiments, Z 2 and Z 1 are N and Z 3 is as defined herein. In some embodiments, Z 2 and Z 1 are N and Z 3 is O. In some embodiments, the compound is a compound of Formula I having a formula of
  • Z 3 is O and Z 1 and Z 2 are independently N or CR 39 .
  • Z 1 is N
  • Z 2 is N or CR 39 and Z 3 is O, S, or NR 27 .
  • Z 1 and Z 2 are N and Z 3 is O.
  • the compound is a compounds of Formula II having a formula of
  • R 30 is CN.
  • V is NH.
  • R 31 is C—C 5 alkyl. In some embodiments, R 31 is
  • R 31 is C—C 5 haloalkyl.
  • R 31 is
  • R 30 is CF 3 .
  • V is O or NH.
  • R 30 is CF 3 .
  • B 1 -D 1 is
  • D1 is as defined herein and above. In some embodiments, D 1 is
  • R 31 is
  • variable substituted by substituents, or as shown below, or as illustrated in the appending claims, if a variable (substituent) is not explicitly defined then the variable is as defined above, which would be readily apparent based upon the present embodiments.
  • the compound has a formula of:
  • the present embodiments provide a pharmaceutical composition comprising one or more compounds as provided or described herein, such as any compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • the present embodiments provide methods of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, multiple sclerosis, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and
  • the present embodiments provide methods of treating or preventing neuropathy, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy in a subject, the method comprising administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein.
  • the present embodiments provide methods of treating cancer in a subject, the method comprising administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein.
  • the present embodiments provide methods of treating cancer in a subject, wherein the cancer is ovarian, breast, lung, brain, colon, prostate, esophageal, pancreatic, brain, glioblastoma, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer.
  • the cancer is ovarian, breast, lung, brain, colon, prostate, esophageal, pancreatic, brain, glioblastoma, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leuk
  • the subject is a subject in need thereof.
  • the cancer therapeutic is selected from those described herein.
  • the condition is prevented.
  • a compound, or a pharmaceutically acceptable salt thereof is chosen from a compound of as shown in the following table and/or as described herein, including in the Examples section of the present disclosure. Any of the compounds provided for herein can be prepared as pharmaceutically acceptable salts and/or as part of a pharmaceutical composition as provided for herein. Examples of such salts are provided for herein. As described herein, the compounds can be prepared according to the schemes and methods described herein.
  • the compounds described herein may be shown with specific stereochemistries around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture. Such isomers or racemic mixtures are encompassed by the present disclosure. Additionally, although the compounds are shown collectively in a table, any compounds, or a pharmaceutically acceptable salt thereof, can be chosen from the table and used in the embodiments provided for herein.
  • compositions comprising a compound or pharmaceutically acceptable salt thereof of any compound described herein are provided.
  • the compounds described herein can be made according to the methods described herein and in the examples.
  • the methods described herein can be adapted based upon the compounds desired and described herein.
  • the method is made according to the following schemes, wherein Q and L are the substituents as shown and described herein and would be apparent to one of skill in the art based upon the present disclosure.
  • this method can be used to make one or more compounds as described herein and will be apparent to one of skill in the art which compounds can be made according to the methods described herein.
  • the conditions and temperatures can be varied, such as shown in the examples described herein. These schemes are non-limiting synthetic schemes and the synthetic routes can be modified as would be apparent to one of skill in the art reading the present specification.
  • the compounds can also be prepared according to the schemes described in the Examples.
  • the compounds can be used to modulate the S 1 P 1 receptor.
  • the compounds can be referred to as S 1 P 1 receptor modulating compounds.
  • the present embodiments provide pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof any compound described herein.
  • the compounds described herein can be made according to the methods described herein and in the examples.
  • the methods described herein can be adapted based upon the compounds desired and described herein.
  • the method is made according to the following schemes, wherein Q and L are the substituents as shown and described herein and would be apparent to one of skill in the art based upon the present disclosure.
  • this method can be used to make one or more compounds as described herein and will be apparent to one of skill in the art which compounds can be made according to the methods described herein.
  • the compounds are made according to schemes described in the examples.
  • the schemes can be used to prepare the compounds and compositions described herein.
  • the conditions and temperatures can be varied, or the synthesis can be performed according to the examples described herein with modifications that are readily apparent based upon the compound being synthesized.
  • the compounds described herein can be administered in any conventional manner by any route where they are active.
  • Administration can be systemic, topical, or oral.
  • administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular routes, or intravaginal, by inhalation, by depot injections, or by implants.
  • the mode of administration can depend on the conditions or disease to be targeted or treated.
  • the selection of the specific route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.
  • This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, wherein the implant is of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the compounds described herein can be administered either alone or in combination (concurrently or serially) with other pharmaceuticals.
  • the compounds can be administered in combination with other analgesics, antidepressants, anti-anxiety compounds, anti-overactive bladder compounds, compounds for the treatment of cancer, and the like.
  • Examples of other pharmaceuticals or medicaments are known to one of skill in the art and include, but are not limited to those described herein.
  • the amount of compound to be administered is that amount which is therapeutically effective.
  • the dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).
  • the standard dosing for protamine can be used and adjusted (i.e., increased or decreased) depending upon the factors described above.
  • the selection of the specific dose regimen can be selected or adjusted or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response.
  • the amount of a compound described herein that will be effective in the treatment and/or prevention of a particular disease, condition, or disorder will depend on the nature and extent of the disease, condition, or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • a suitable dosage range for oral administration is, generally, from about 0.001 milligram to about 200 milligrams per kilogram body weight, from about 0.01 milligram to about 100 milligrams per kilogram body weight, from about 0.01 milligram to about 70 milligrams per kilogram body weight, from about 0.1 milligram to about 50 milligrams per kilogram body weight, from 0.5 milligram to about 20 milligrams per kilogram body weight, or from about 1 milligram to about 10 milligrams per kilogram body weight.
  • the oral dose is about 5 milligrams per kilogram body weight.
  • suitable dosage ranges for intravenous (i.v.) administration are from about 0.01 mg to about 500 mg per kg body weight, from about 0.1 mg to about 100 mg per kg body weight, from about 1 mg to about 50 mg per kg body weight, or from about 10 mg to about 35 mg per kg body weight.
  • suitable dosage ranges for other modes of administration can be calculated based on the forgoing dosages as known by those skilled in the art.
  • recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration or administration by inhalation are in the range of from about 0.001 mg to about 200 mg per kg of body weight, from about 0.01 mg to about 100 mg per kg of body weight, from about 0.1 mg to about 50 mg per kg of body weight, or from about 1 mg to about 20 mg per kg of body weight.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.
  • the compounds described herein can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion.
  • the compounds can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours.
  • Formulations for injection can be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an optionally added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the injectable is in the form of short-acting, depot, or implant and pellet forms injected subcutaneously or intramuscularly.
  • the parenteral dosage form is the form of a solution, suspension, emulsion, or dry powder.
  • the compounds described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, caches, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by, for example, adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, or cherry
  • coloring agents such as peppermint, oil of wintergreen, or cherry
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such
  • Dragee cores can be provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added.
  • compositions can take the form of tablets or lozenges formulated in a conventional manner.
  • the compounds described herein can be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, such as gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds described herein can also be formulated in rectal compositions such as suppositories or retention enemas, such as containing conventional suppository bases such as cocoa butter or other glycerides.
  • rectal compositions such as suppositories or retention enemas, such as containing conventional suppository bases such as cocoa butter or other glycerides.
  • vaginal compositions such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.
  • the compounds can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
  • the compounds are present in creams, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, gels, jellies, and foams, or in patches containing any of the same.
  • the compounds described herein can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med., 1989, 321, 574).
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J.
  • a controlled-release system can be placed in proximity of the target of the compounds described herein, such as the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled-release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 may be used.
  • the compounds can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the pharmaceutical compositions can also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the compounds described herein can be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or rinses (e.g., Caphosol).
  • topical analgesics e.g., lidocaine
  • barrier devices e.g., GelClair
  • rinses e.g., Caphosol
  • the compounds described herein can be delivered in a vesicle, in particular a liposome (see, Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
  • a liposome see, Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
  • Suitable compositions include, but are not limited to, oral non-absorbed compositions. Suitable compositions also include, but are not limited to saline, water, cyclodextrin solutions, and buffered solutions of pH 3-9.
  • excipients can be formulated with numerous excipients including, but not limited to, purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid/sodium citrate (pH3), citric acid/sodium citrate (pH5), tris(hydroxymethyl)amino methane HCl (pH7.0), 0.9% saline, and 1.2% saline, and any combination thereof.
  • excipient is chosen from propylene glycol, purified water, and glycerin.
  • the formulation can be lyophilized to a solid and reconstituted with, for example, water prior to use.
  • the compounds When administered to a mammal (e.g., to an animal for veterinary use or to a human for clinical use) the compounds can be administered in isolated form.
  • the compounds When administered to a human, the compounds can be sterile.
  • Water is a suitable carrier when the compound of Formula I is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions described herein can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing a liquid, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use.
  • suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. R. Gennaro (Editor) Mack Publishing Co.
  • the compounds are formulated in accordance with routine procedures as a pharmaceutical composition adapted for administration to humans.
  • compounds are solutions in sterile isotonic aqueous buffer.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the pharmaceutical compositions can be in unit dosage form.
  • the composition can be divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • a composition is in the form of a liquid wherein the active agent (i.e., one of the facially amphiphilic polymers or oligomers disclosed herein) is present in solution, in suspension, as an emulsion, or as a solution/suspension.
  • the liquid composition is in the form of a gel.
  • the liquid composition is aqueous.
  • the composition is in the form of an ointment.
  • the composition is in the form of a solid article.
  • the ophthalmic composition is a solid article that can be inserted in a suitable location in the eye, such as between the eye and eyelid or in the conjunctival sac, where it releases the active agent as described, for example, U.S. Pat. Nos. 3,863,633; 3,867,519; 3,868,445; 3,960,150; 3,963,025; 4,186,184; 4,303,637; 5,443,505; and 5,869,079. Release from such an article is usually to the cornea, either via the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact.
  • Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be bioerodible or non-bioerodible.
  • Bioerodible polymers that can be used in the preparation of ocular implants carrying one or more compounds include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates and polyether lactones.
  • Suitable non-bioerodible polymers include silicone elastomers.
  • compositions described herein can contain preservatives.
  • Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercuric salts (e.g., phenylmercuric acetate, borate and nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, and salts thereof; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.
  • mercury-containing substances such as phenylmercuric salts (e.g., pheny
  • one or more stabilizers can be included in the compositions to enhance chemical stability where required.
  • Suitable stabilizers include, but are not limited to, chelating agents or complexing agents, such as, for example, the calcium complexing agent ethylene diamine tetraacetic acid (EDTA).
  • EDTA calcium complexing agent
  • an appropriate amount of EDTA or a salt thereof, e.g., the disodium salt can be included in the composition to complex excess calcium ions and prevent gel formation during storage.
  • EDTA or a salt thereof can suitably be included in an amount of about 0.010% to about 0.5%.
  • the EDTA or a salt thereof, more particularly disodium EDTA can be present in an amount of about 0.025% to about 0.1% by weight.
  • antioxidants can also be included in the compositions. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents know to those of skill in the art. Such preservatives are typically employed at a level of from about 0.001% to about 1.0% by weight.
  • the compounds are solubilized at least in part by an acceptable solubilizing agent.
  • an acceptable solubilizing agent for example polysorbate 80
  • polyglycols e.g., polyethylene glycol 400 (PEG-400)
  • glycol ethers e.g., glycol ethers
  • Suitable solubilizing agents for solution and solution/suspension compositions are cyclodextrins.
  • Suitable cyclodextrins can be chosen from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, alkylcyclodextrins (e.g., methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, diethyl- ⁇ -cyclodextrin), hydroxyalkylcyclodextrins (e.g., hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin), carboxy-alkylcyclodextrins (e.g., carboxymethyl- ⁇ -cyclodextrin), sulfoalkylether cyclodextrins (e.g., sulfobutylether- ⁇ -cyclodextrin), and the like
  • the composition optionally contains a suspending agent.
  • a suspending agent for example, in those embodiments in which the composition is an aqueous suspension or solution/suspension, the composition can contain one or more polymers as suspending agents.
  • Useful polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers, for example, hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • One or more acceptable pH adjusting agents and/or buffering agents can be included in the compositions, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • One or more acceptable salts can be included in the compositions in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions.
  • salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • the salt is sodium chloride.
  • one or more acceptable surfactants preferably nonionic surfactants, or co-solvents can be included in the compositions to enhance solubility of the components of the compositions or to impart physical stability, or for other purposes.
  • Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40; polysorbate 20, 60 and 80; polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F-68, F84 and P-103); cyclodextrin; or other agents known to those of skill in the art.
  • co-solvents or surfactants are employed in the compositions at a level of from about 0.010% to about 2% by weight.
  • kits comprising one or more containers filled with one or more compounds described herein are provided.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration for treating a condition, disease, or disorder described herein.
  • the kit contains more than one compound described herein.
  • the kit comprises a compound described herein in a single injectable dosage form, such as a single dose within an injectable device such as a syringe with a needle.
  • Embodiments disclosed herein also provide for the compounds for the use of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, ms, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not
  • methods of treating and/or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, ms, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, or
  • the methods comprise administering one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, to the subject to treat or prevent such conditions.
  • the condition is CINP and CIPN, or other types of neuropathic pain or neuropathy.
  • the methods are performed without causing significant lymphopenia or immunosuppression. In some embodiments, the methods are performed without causing lymphopenia or immunosuppression.
  • the compounds, or pharmaceutically acceptable salts thereof are administered to the subject for any condition or indication provided for herein without causing significant lymphopenia or immunosuppression. In some embodiments, the methods are performed without causing lymphopenia or immunosuppression.
  • the methods comprise administering to the subject one or more compounds described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same.
  • the subject is a subject in need of such treatment.
  • the subject is a mammal, such as, but not limited to, a human.
  • the present embodiments also provide the use of one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, in the modulation of a S 1 P 1 receptor activity, such as the presence on the surface of the cell.
  • the compounds, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same modulate the internalization, trafficking, and/or degradation of the S 1 P 1 receptor.
  • the compounds, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same modulate the G-protein modulated pathway of the S 1 P 1 receptor.
  • modulation can refer to either inhibition or enhancement of a specific activity.
  • the modulation of the S 1 P 1 receptor can refer to the inhibition and/or activation of the G-protein mediated pathway of the S 1 P 1 receptor.
  • the modulation refers to the inhibition or activation of the ⁇ -arrestin mediated pathway of the S 1 P 1 receptor.
  • the modulation refers to the inhibition or activation of the internalization of the S 1 P 1 receptor.
  • the activity of a S 1 P 1 receptor can be measured by any method including but not limited to the methods described herein.
  • the compounds described herein are agonists or antagonists of the S 1 P 1 receptor.
  • the ability of the compounds to stimulate or inhibit S 1 P 1 receptor signaling may be measured using any assay known in the art used to detect S 1 P 1 receptor mediated signaling or S 1 P 1 receptor activity, or the absence of such signaling/activity.
  • S 1 P 1 receptor activity refers to the ability of a S 1 P 1 receptor to transduce a signal. Such activity can be measured, e.g., in a heterologous cell, by coupling an S 1 P 1 receptor (or a chimeric S 1 P 1 receptor) to a downstream effector such as adenylate cyclase.
  • a “natural ligand-induced activity” as used herein, refers to activation of the S 1 P 1 receptor by a natural ligand of the S 1 P 1 receptor. Activity can be assessed using any number of endpoints to measure S 1 P 1 receptor activity.
  • assays for testing compounds that modulate S 1 P 1 receptor-mediated signal transduction include the determination of any parameter that is indirectly or directly under the influence of a S 1 P 1 receptor, e.g., a functional, physical, or chemical effect.
  • Samples or assays comprising S 1 P 1 receptors that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition.
  • Control samples (untreated with inhibitors) are assigned a relative S 1 P 1 receptor activity value of 100%.
  • Inhibition of a S 1 P 1 receptor is achieved when the S 1 P 1 receptor activity value relative to the control is about 80%, 50%, or 25%.
  • Activation of a S 1 P 1 receptor is achieved when the S 1 P 1 receptor activity value relative to the control (untreated with activators) is 110%, 150%, or 200-500% (i.e., two to five fold higher relative to the control), or 1000-3000% or higher.
  • the effects of the compounds upon the function of an S 1 P 1 receptor can be measured by examining any of the parameters described above. Any suitable physiological change that affects S 1 P 1 receptor activity can be used to assess the influence of a compound on the S 1 P 1 receptors and natural ligand-mediated S 1 P 1 receptor activity. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as changes in intracellular second messengers such as cAMP.
  • Modulators of S 1 P 1 receptor activity can be tested using S 1 P 1 receptor polypeptides as described herein, either recombinant or naturally occurring.
  • the protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal.
  • neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the S 1 P 1 receptor polypeptides described herein. Modulation is tested using one of the in vitro or in vivo assays described herein.
  • Signal transduction and cellular trafficking can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor.
  • a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor.
  • ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
  • Ligand binding to an S 1 P 1 receptor, a domain, or chimeric protein can be tested in a number of formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. For example, in an assay, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator, such as the compound described herein. Alternatively, the binding of the candidate modulator may be measured in the presence of the natural ligand. Often, competitive assays that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used.
  • Binding can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
  • spectroscopic characteristics e.g., fluorescence, absorbance, refractive index
  • hydrodynamic e.g., shape
  • the cells can be grown in appropriate media in the appropriate cell plate.
  • the cells can be plated, for example, at 5000-10000 cells per well in a 384 well plate. In some embodiments, the cells are plated at about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 cells/per well.
  • the plates can have any number of wells and the number of cells can be modified accordingly.
  • Any medicament having utility in an application described herein can be used in co-therapy, co-administration or co-formulation with a composition as described above.
  • additional medicaments include, medicines for cancer.
  • Many medicines that are used to treat cancer cause CIPN or CINP. Therefore, the compounds described herein can be administered either before, concurrently with, or after such therapeutics are administered to a subject.
  • PD-1 antibodies such as Nivolumab or Pembrolizumab.
  • the compounds, or pharmaceutically acceptable salts thereof, provided herein can be administered with, either concurrently or sequentially, or as part of a cancer treatment protocol, the additional therapeutics provided for herein.
  • the compounds provided herein can also be used to treat cancer.
  • the compounds, or pharmaceutically acceptable salts thereof can be used to inhibit tumor growth.
  • the compounds, or pharmaceutically acceptable salts thereof are used to treat cancers, such as, but not limited to, ovarian cancer, breast cancer, lung cancer, brain cancer, colon cancer, prostate cancer, esophageal cancer, pancreatic cancer, brain cancer, glioblastoma cancer, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer.
  • the cancer is breast or ovarian cancer, breast cancer, lung cancer, brain cancer, colon cancer, prostate
  • the additional medicament can be administered in co-therapy (including co-formulation) with the one or more of the compounds described herein.
  • the response of the disease or disorder to the treatment is monitored and the treatment regimen is adjusted, if necessary, in light of such monitoring.
  • the residue was purified by prep-HPLC (column: Phenomenex Gemini 150 ⁇ 25 mm ⁇ 10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 12 min) to give the product 9-1 as a white solid (20 mg, 6% yield).
  • N′-(2,2-diethyl-4-oxo-chromane-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (420 mg, 934.37 umol, 93.12% yield) was obtained as yellow solid without further purification.
  • the cooled reaction mixture was directly purified by prep-HPLC (column: Boston Green ODS 150 ⁇ 30 5 u; mobile phase: [water(0.225% FA)-ACN]; B %: 47%-77%, 10 min) to give the product 33-1 (20 mg, 12% yield).
  • Stable clonal Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA- ⁇ -arrestin2 and the human sphingosine-1-phosphate receptor 1 (NM_001400, S1P 1 ) with a C-terminal ProlinkTM tag were purchased from DiscoverX corporation (Cat #: 93-0207C2).
  • Cell lines were cultured in AssayCompleteTM Media 6 (DiscoverX Corporation, Cat #: 920018GF2) at 37° C. and 5% CO 2 in a humidified CO 2 and temperature-controlled incubator.
  • AssayCompleteTM Media 6 DiscoverX Corporation, Cat #: 920018GF2
  • cells were washed with dulbecco's phosphate buffered saline (CellGro, Cat #: 21-031-CV) and lifted from the culturing flask by incubation (37° C., 5 min) with CellStripper (Cellgro, Cat #: 25-056-CI).
  • Lifted cells were resuspended to 250,000 cells per milliliter in AssayCompleteTM Cell Plating 11 Reagent (DiscoverX Corporation, Cat #: 93-0563R11B) and plated at 5,000 cells per well in white-opaque 384 well plates (Greiner Bio-One Item #: 20-784080). Plated cells were incubated overnight at 37° C. and 5% CO 2 in a humidified CO 2 and temperature-controlled incubator.
  • Agonist-promoted G-protein responses were determined by measuring changes in intracellular cAMP using the HTRF® cAMP HiRange kit (CisBio, Cat #: 62AM6PEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology.
  • AssayCompleteTM Cell Plating 11 Reagent was removed and replaced with Ham's F-12 (CellGro, Cat #: 10-080-CM) containing isobutyl-methyl-xanthine (IBMX; 500 ⁇ M; Tocris Bioscience, Cat #: 2845), and NKH-477 (1.5 ⁇ M; Tocris Bioscience, Cat #: 1603) along with test or control compounds at the desired concentrations.
  • 0-arrestin2 recruitment to the sphingosine-1-phosphate 1 receptor was determined using the ⁇ -arrestin PathHunter®) Detection kit (DiscoverX Corporation, Cat #: 93-0001).
  • 0-arrestin2 is fused to an N-terminal deletion mutant of ⁇ -galactosidase (termed the enzyme acceptor or EA) and the C-terminus of the GPCR of interest is fused to a smaller (42 amino acids), weakly-complementing fragment 15 termed ProLinkTM.
  • EA enzyme acceptor
  • ProLinkTM weakly-complementing fragment
  • AssayCompleteTM Cell Plating 11 Reagent was removed and replaced with Ham's F-12 containing IBMX (500 ⁇ M), and NKH-477 (1.5 ⁇ M) along with test or control compounds at the desired concentrations.
  • Ham's F-12 containing IBMX (500 ⁇ M), and NKH-477 (1.5 ⁇ M) along with test or control compounds at the desired concentrations.
  • the components of the ⁇ -arrestin PathHunter® Detection kit were added as per the manufacturer's instructions. After an hour incubation at room temperature, plates were analyzed by a BMG PheraStar microplate reader.
  • the compounds as indicated herein were able to modulate the activities (inhibition of cAMP production and ⁇ -arrestin2 recruitment) of the sphingosine-1-phosphate 1 receptor as indicated herein.
  • the tables below include the efficacy of the compound as compared to a positive control, referred to as “SPAN”. These values are normalized to fingolimod, a known agonist of the sphingosine-1-phosphate 1 receptor.
  • the tables also include potency values (pEC50) for modulating discrete receptor-mediated activities (inhibition of cAMP production and ⁇ -arrestin2 recruitment). This value represents the estimated concentration to promote half of the maximal efficacy (or SPAN) observed for each compound.
  • a response was defined as a lifting or shaking of the paw upon stimulation. This was repeated ten times for each mouse. The final measurement for each mouse is the % non-response to stimulation for the ten trials. The % non-response to stimulation is converted to a % MPE.
  • a series of injections of PAC (6 mg/kg, i.p.) on days 1, 3, 5 and 7 is used to induce peripheral neuropathy. After approximately 14 days from the initiation of PAC injections, animals are re-assessed for mechanical sensitivity. Animals that exhibit a 50% response rate and lower can be included in studies with test compounds.
  • a compound was tested for the ability to prevent the development of OXA induced peripheral neuropathy.
  • animals were tested for mechanical allodynia. Animals treated with a test compound did not exhibit peripheral neuropathy.
  • the data for exemplary compounds is provided below.
  • Example 4 The S 1 P 1 Receptor Compounds can be Used to Treat Inflammation and Pain
  • FCA Freund's Complete Adjuvant
  • Rats are tested for mechanical allodynia in a Randall-Selitto apparatus.
  • the inflamed paw is put on a pedestal and a pointed force of increasing intensity (0 to 250 grams) is applied to the paw.
  • a pointed force of increasing intensity (0 to 250 grams) is applied to the paw.
  • the test is stopped and the force to induce that struggle is recorded.
  • Data is presented as mean grams of force to withdrawal or a percentage of the maximum possible effect.
  • Stable clonal Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA- ⁇ -arrestin2 and the human sphingosine-1-phosphate receptor 2 (NM 004230.3, S1P 2 ), human sphingosine-1-phosphate receptor 3 (NM_005226, S1P 3 ) and sphingosine-1-phosphate receptor 5 (NM_001166215.1, S1P 5 ) with a C-terminal ProlinkTM tag were purchased from DiscoverX corporation (S1P 2 : Cat #93-0256C2, S1P 3 : Cat #93-0217C2, S1P 5 : Cat #93-0583C2).
  • Cell lines were cultured in AssayCompleteTM Media 6 (DiscoverX Corporation, Cat #: 920018GF2) at 37° C. and 5% CO 2 in a humidified CO 2 and temperature-controlled incubator.
  • AssayCompleteTM Media 6 DiscoverX Corporation, Cat #: 920018GF2
  • cells were washed with dulbecco's phosphate buffered saline (CellGro, Cat #: 21-031-CV) and lifted from the culturing flask by incubation (37° C., 5 min) with CellStripper (Cellgro, Cat #: 25-056-CI).
  • S1P2 Agonist-promoted G-protein responses were determined by measuring changes in intracellular inositol monophosphate using the IP-one TB kit (CisBio, Cat #: 62IPAPEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology.
  • AssayCompleteTM Cell Plating 2 Reagent was removed and replaced with 1 ⁇ IP-one stimulation buffer (as per manufacturer's instructions) along with test or control compounds at the desired concentrations.
  • 1 ⁇ IP-one stimulation buffer as per manufacturer's instructions
  • the components of the IP-one TB kit were added as per the manufacturer's instructions.
  • plates were analyzed by a BMG PheraStar microplate reader. Responses were measured as the ratio of signal over background, fluorescence emission at 665 nm to fluorescence emission at 620 nm.
  • the tables also include potency values (pEC50) for modulating discrete receptor-mediated activities (inhibition of cAMP production or inositol monophosphate accumulation). This value represents the estimated concentration to promote half of the maximal efficacy (or SPAN) observed for each compound. Exemplary compounds that were found to be selective are shown below.
  • Example 6 The S 1 P 1 Receptor Compounds can be Used to Treat Diabetic Neuropathy
  • Opioid analgesia at Peripheral Sites a Target for Opioids Released during Stress and Inflammation? Anesthesia and Analgesia 66(12), 1277-81, 1987; and Morrow, T. J. Animal Models of Painful Diabetic Neuropathy: The STZ rat model. Current Protocols in Neuroscience, November; Chapter 9, Unit 9.18, 2004.
  • IP intraperitoneal
  • streptozotocin STZ 50 mg/kg
  • 10 mM citric acid buffer 10 mM citric acid buffer
  • rats were preselected for experimentation only if the pain threshold 7-14 days after STZ injection (pre-treatment) was reduced by 10 grams of force relative to the response of the individual paw before STZ challenge (pre-induction), namely, with clear presence of allodynia.
  • the rats were randomized based on pre-dose mechanical allodynia scores to balanced treatment groups.
  • the animals were tested prior to study inclusion for mechanical allodynia by the manual von Frey test on Day 20 (Chaplan up/down method using von Frey filaments on the plantar surface of the paw).
  • the manual von Frey test was repeated at 0.5 or 1 hr following administrations of test articles, vehicle, and reference compound via the specified route(s) and on Day 21 post-surgery.
  • a light beam under the floor was aimed at the plantar surface of the left hind paw.
  • the time was measured automatically when the paw was withdrawn away from the thermal stimulus.
  • a cut-off latency of 23 sec was imposed. The latency to withdrawal was obtained for each rat and defined as the heat pain threshold.
  • compounds 103 and 293 were tested and found to have active doses between 50 and 100 mg/kg in both mechanical allodynia and thermal hyperalgesia.
  • Example 7 The S 1 P 1 Receptor Compounds can be Used to Treat Peripheral Neuropathy
  • Opioid analgesia at Peripheral Sites a Target for Opioids Released during Stress and Inflammation? Anesthesia and Analgesia 66(12), 1277-81, 1987; and Kim, S. H. and Chung, J. M. An experimental model of peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50: 335-63, 1992.
  • rats were preselected for experimentation only if the pain threshold 7-14 days after SNL surgery (pre-treatment) was reduced by 10 grams of force relative to the response of the individual paw before surgery (pre-induction), namely, with clear presence of allodynia.
  • the rats were randomized based on pre-dose mechanical allodynia scores to balanced treatment groups.
  • the animals were tested prior to study inclusion for mechanical allodynia by the manual von Frey test on Day 20 (Chaplan up/down method using von Frey filaments on the plantar surface of the paw).
  • the manual von Frey test was repeated at 0.5 or 1 hr following administrations of test articles, vehicle, and reference compound via the specified route(s) and on Day 21 post-surgery.
  • compound 103 was tested and found to have active doses between 50 and 100 mg/kg.
  • Example 8 Compounds do not Inhibit hERG Channel Activity
  • mice Female athymic nude mice (Crl:NU(NCr)-Foxn1nu, Charles River Laboratories) were implanted with A2780 human ovarian carcinoma cells to initiate tumor growth.
  • Paclitaxel dosing solutions were prepared in 5% ethanol, 5% Cremophor EL in D5W (Vehicle 1).
  • Ozanimod and Compound 103 dosing solutions were prepared in 10% dimethylacetamide, 10% Cremophor EL, 80% sterile water with 10% ⁇ -cyclodextrin (Vehicle 2).
  • Group 5 the Compound 103 monotherapy group, received Compound 103 p.o., qd to end plus Vehicle 1, i.v., qod ⁇ 5.
  • Combination Group 6 received Compound 103 p.o., qd to end plus paclitaxel i.v., qod ⁇ 5.
  • TTE time to endpoint
  • the combination of paclitaxel and ozanimod was associated with 185% TGD, providing statistically significant survival benefit over either of the corresponding monotherapies, and one study survivor with a CR/TFS tumor regression response.
  • the combination of paclitaxel and Compound 103 provided 193% TGD, a significant result compared with paclitaxel monotherapy, but not statistically different (P>0.05) from the result for ozanimod monotherapy.
  • the present example evaluated test agents ozanimod and Compound 103 each in combination with paclitaxel for efficacy in the A2780 human ovarian carcinoma model in female athymic mice. All regimens were acceptably-tolerated. Control tumors exhibited progressive growth, attaining the 2000 mm3 endpoint in a median 9.8 days, establishing a maximum possible TGD of 50.2 days (512%) for the 60-day study. Paclitaxel as monotherapy provided significant (P ⁇ 0.05) survival benefit (128% TGD) compared to controls, whereas the ozanimod and Compound 103 monotherapy regimens were associated with non-significant (P>0.05) TGD of 31% and 15%, respectively, compared with the control.

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Abstract

The present embodiments are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for modulating the activity of S1P1 receptor and methods of using the same.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. Non-Provisional application Ser. No. 16/613,152, filed Nov. 13, 2019, which is a National Phase Entry of International Patent Application No. PCT/US2018/03689, filed Jun. 12, 2018, which claims priority to U.S. Provisional Application No. 62/519,575, filed Jun. 14, 2017, each of which is hereby incorporated by reference in its entirety.
    • FIELD
  • Embodiments disclosed herein are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, for modulating S1P1 receptor activity and/or methods for treating and/or preventing pain, such as neuropathic pain, chemotherapy induced neuropathic pain (CINP), chemotherapy induced peripheral neuropathy (CIPN), or treating cancer or inhibiting tumor growth, and the like as described herein.
    • BACKGROUND
  • Pain is still a prevalent and pervasive problem, especially neuropathic pain, which has few good treatments or preventive therapeutics. This is especially true in conditions such chemotherapy induced neuropathic pain (CINP) and chemotherapy induced peripheral neuropathy (CIPN). Thus, there is a need for new compounds and compositions for treating and/or preventing such conditions. The compounds and compositions described herein fulfill these needs as well as others.
    • SUMMARY OF EMBODIMENTS
  • In some embodiments, compounds, or pharmaceutically acceptable salts thereof, are provided that, in part, modulate the activity of the S1P1 receptor. The compounds can have, for example, a formula as described herein. In some embodiments, the compound is selected from a compound described herein. In some embodiments, methods of treating the conditions described herein are provided. In some embodiments, the condition is CIPN, CINP, pain, neuropathy, and the like. In some embodiments, the condition is cancer and the like.
  • In some embodiments, the compound is a compound having a formula of Formula I or Formula II:
  • Figure US20230234946A1-20230727-C00001
  • or a pharmaceutically acceptable salt thereof, wherein AA, B1, B2, B3, B4, D1, V, R30, and R31 are as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.
  • In some embodiments, also provided are pharmaceutical compositions comprising one or more compounds as described herein, which can also comprise a pharmaceutically acceptable carrier.
  • In some embodiments, the compounds described herein can be provided in any form, such as a solid or solution (e.g., aqueous solution), such as is described herein. The compounds described herein, for example, can be obtained and employed in lyophilized form alone or with suitable additives.
  • Also provided are methods for treating and/or preventing pain such as neuropathic pain, chemotherapy induced neuropathic pain (CINP), chemotherapy induced peripheral neuropathy (CIPN), or treating cancer or inhibiting tumor growth, and the like as described herein. In some embodiments, the methods comprise administering a one or more compounds described herein to a subject or subjects.
    • DESCRIPTION OF EMBODIMENTS
  • Unless defined otherwise, all technical and scientific terms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belong.
  • As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise.
  • As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by +10% and remain within the scope of the disclosed embodiments.
  • As used herein, the term “acylamino” means an amino group substituted by an acyl group (e.g., —O—C(═O)—H or —O—C(═O)-alkyl). An example of an acylamino is —NHC(═O)H or —NHC(═O)CH3. The term “lower acylamino” refers to an amino group substituted by a lower acyl group (e.g., —O—C(═O)—H or —O—C(═O)—C1-6alkyl). An example of a lower acylamino is —NHC(═O)H or —NHC(═O)CH3.
  • As used herein, the term “alkenyl” means a straight or branched alkyl group having one or more double carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In some embodiments, the alkenyl chain is from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.
  • The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each optionally substituted, that is bonded through an oxygen atom. For example, the term “alkoxy” means a straight or branched —O-alkyl group of 1 to 20 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.
  • As used herein, the term “alkyl” means a saturated hydrocarbon group which is straight-chained or branched. An alkyl group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and the like.
  • As used herein, the term “allylamino” means an amino group substituted by an alkyl group having from 1 to 6 carbon atoms. An example of an alkylamino is —NHCH2CH3.
  • As used herein, the term “alkylene” or “alkylenyl” means a divalent alkyl linking group. An example of an alkylene (or alkylenyl) is methylene or methylenyl (—CH2—).
  • As used herein, the term “alkylthio” means an —S-alkyl group having from 1 to 6 carbon atoms. An example of an alkylthio group is —SCH2CH3.
  • As used herein, the term “alkynyl” means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.
  • As used herein, the term “amidino” means —C(═NH)NH2.
  • As used herein, the term “amino” means —NH2.
  • As used herein, the term “aminoalkoxy” means an alkoxy group substituted by an amino group. An example of an aminoalkoxy is —OCH2CH2NH2.
  • As used herein, the term “aminoalkyl” means an alkyl group substituted by an amino group.
  • An example of an aminoalkyl is —CH2CH2NH2.
  • As used herein, the term “aminosulfonyl” means —S(═O)2NH2.
  • As used herein, the term “aminoalkylthio” means an alkylthio group substituted by an amino group. An example of an aminoalkylthio is —SCH2CH2NH2.
  • As used herein, the term “amphiphilic” means a three-dimensional structure having discrete hydrophobic and hydrophilic regions. An amphiphilic compound suitably has the presence of both hydrophobic and hydrophilic elements.
  • As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.
  • As used herein, the term “antagonize” or “antagonizing” means reducing or completely eliminating an effect, such as an activity of the S1P1 receptor.
  • As used herein, the phrase “anti-receptor effective amount” of a compound can be measured by the anti-receptor effectiveness of the compound. In some embodiments, an anti-receptor effective amount inhibits an activity of the receptor by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90%, or by at least 95%. In some embodiments, an “anti-receptor effective amount” is also a “therapeutically effective amount” whereby the compound reduces or eliminates at least one effect of a S1P1 receptor.
  • In some embodiments, the effect is the beta-arrestin effect. In some embodiments, the effect is the G-protein mediated effect.
  • As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to:
  • Figure US20230234946A1-20230727-C00002
    Figure US20230234946A1-20230727-C00003
    Figure US20230234946A1-20230727-C00004
    Figure US20230234946A1-20230727-C00005
    Figure US20230234946A1-20230727-C00006
  • As used herein, the term “arylalkyl” means a C1-6alkyl substituted by aryl.
  • As used herein, the term “arylamino” means an amino group substituted by an aryl group. An example of an arylamino is —NH(phenyl).
  • As used herein, the term “arylene” means an aryl linking group, i.e., an aryl group that links one group to another group in a molecule.
  • As used herein, the term “cancer” means a spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.
  • As used herein, the term “carbamoyl” means —C(═O)—NH2.
  • As used herein, the term “carbocycle” means a 5- or 6-membered, saturated or unsaturated cyclic ring, optionally containing O, S, or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocycles recited above.
  • As used herein, the term “carrier” means a diluent, adjuvant, or excipient with which a compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
  • As used herein, the term, “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.
  • As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. For example, “contacting” a S1P1 receptor compound with a S1P1 receptor with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the S1P1 receptor.
  • As used herein, the term “cyano” means —CN.
  • As used herein, the term “cycloalkyl” means non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic ring systems such as fused ring systems, bridged ring systems, and spiro ring systems. In some embodiments, polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkyl group can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6, from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).
  • As used herein, the term “cycloalkylalkyl” means a C1-6alkyl substituted by cycloalkyl.
  • As used herein, the term “dialkylamino” means an amino group substituted by two alkyl groups, each having from 1 to 6 carbon atoms.
  • As used herein, the term “diazamino” means —N(NH2)2.
  • As used herein, the term “facially amphiphilic” or “facial amphiphilicity” means compounds with polar (hydrophilic) and nonpolar (hydrophobic) side chains that adopt conformation(s) leading to segregation of polar and nonpolar side chains to opposite faces or separate regions of the structure or molecule.
  • As used herein, the term “guanidino” means —NH(═NH)NH2.
  • As used herein, the term “halo” means halogen groups including, but not limited to fluoro, chloro, bromo, and iodo.
  • As used herein, the term “haloalkoxy” means an —O-haloalkyl group. An example of an haloalkoxy group is OCF3.
  • As used herein, the term “haloalkyl” means a C1-6alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.
  • As used herein, the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which are, independently, sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms, from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl groups, and the like. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.
  • As used herein, the term “heteroarylalkyl” means a C1-6alkyl group substituted by a heteroaryl group.
  • As used herein, the term “heteroarylamino” means an amino group substituted by a heteroaryl group. An example of a heteroarylamino is —NH-(2-pyridyl).
  • As used herein, the term “heteroarylene” means a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group in a molecule.
  • As used herein, the term “heterocycle” or “heterocyclic ring” means a 5- to 7-membered mono- or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms chosen from N, O and S, and wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
  • As used herein, the term “heterocycloalkyl” means non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups, where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Hetercycloalkyl groups can be mono or polycyclic (e.g., fused, bridged, or spiro systems). In some embodiments, the heterocycloalkyl group has from 1 to 20 carbon atoms, or from 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. In addition, ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. For example, a ring-forming S atom can be substituted by 1 or 2 oxo (form a S(O) or S(O)2). For another example, a ring-forming C atom can be substituted by oxo (form carbonyl). Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (having a bond in common with) to the nonaromatic heterocyclic ring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • As used herein, the term “heterocycloalkylalkyl” refers to a C1-6alkyl substituted by heterocycloalkyl.
  • As used herein, the term “hydoxy” or “hydroxyl” means an —OH group.
  • As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” means an alkyl group substituted by a hydroxyl group. Examples of a hydroxylalkyl include, but are not limited to, —CH2OH and —CH2CH2OH.
  • As used herein, the term “individual” or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.
  • As used herein, the phrase “inhibiting activity,” such as enzymatic or receptor activity means reducing by any measurable amount the activity of an enzyme or receptor, such as the S1P1 receptor.
  • As used herein, the phrase “in need thereof” means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal can be in need thereof. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.
  • As used herein, the phrase “in situ gellable” means embracing not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid in the exterior of the eye, but also more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye.
  • As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from X to Y” means 1, 2, 3, 4, or 5.
  • As used herein, the term “isolated” means that the compounds described herein are separated from other components of either (a) a natural source, such as a plant or cell, or (b) a synthetic organic chemical reaction mixture, such as by conventional techniques.
  • As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.
  • As used herein, the term “N-alkyl” refers to a alkyl chain that is substituted with an amine group. Non-limiting examples, include, but are not limited to
  • Figure US20230234946A1-20230727-C00007
  • and the like. The alkyl chain can be linear, branched, cyclic, or any combination thereof. In some embodiments, the alkyl comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 carbons.
  • As used herein, the term “nitro” means —NO2.
  • As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.
  • As used herein, the phrase “ophthalmically acceptable” means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. However, it will be recognized that transient effects such as minor irritation or a “stinging” sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being “ophthalmically acceptable” as herein defined.
  • As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent groups, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
  • As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • In some embodiments, the salt of a compound described herein is a pharmaceutically acceptable salt thereof. As used herein, the phrase “pharmaceutically acceptable salt(s),” includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. The present embodiments also include quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moiety.
  • As used herein, the term “phenyl” means —C6H5. A phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.
  • As used herein, the term “prodrug” means a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process.
  • As used herein, the term “purified” means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of a compound described herein by weight of the isolate.
  • As used herein, the phrase “quaternary ammonium salts” means derivatives of the disclosed compounds with one or more tertiary amine moieties wherein at least one of the tertiary amine moieties in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (and the cations are balanced by anions such as Cl−, CH3COO−, and CF3COO−), for example methylation or ethylation.
  • As used herein, the term “semicarbazone” means ═NNHC(═O)NH2.
  • As used herein, the phrase “solubilizing agent” means agents that result in formation of a micellar solution or a true solution of the drug.
  • As used herein, the term “solution/suspension” means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form, in suspension in a liquid matrix.
  • As used herein, the phrase “substantially isolated” means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.
  • As used herein, the phrase “suitable substituent” or “substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds described herein or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C5-C6aryl, C1-C6alkoxy, C3-C5heteroaryl, C3-C6cycloalkyl, C5-C6aryloxy, —CN, —OH, oxo, halo, haloalkyl, —NO2, —CO2H, —NH2, —NH(C1-C8alkyl), —N(C1-C8alkyl)2, —NH(C6aryl), —N(C5-C6aryl)2, —CHO, —CO(C1-C6alkyl), —CO((C5-C6)aryl), —CO2((C1-C6)alkyl), and —C02((C5-C6)aryl). One of skill in art can readily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compounds described herein.
  • As used herein, the phrase “therapeutically effective amount” means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. The therapeutic effect is dependent upon the disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects. The amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.
  • As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic measures wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Thus, “treatment of pain” or “treating pain” means an activity that alleviates or ameliorates any of the primary phenomena or secondary symptoms associated with the pain or other condition described herein.
  • As used herein, the term “ureido” means —NHC(═O)—NH2.
  • At various places in the present specification, substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, C4alkyl, C5alkyl, and C6alkyl.
  • For compounds in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties selected from the Markush groups defined for R. In another example, when an optionally multiple substituent is designated in the form, for example,
  • Figure US20230234946A1-20230727-C00008
  • then it is understood that substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence. In the above example, where the variable T1 is defined to include hydrogens, such as when T1 is CH2, NH, etc., any H can be replaced with a substituent.
  • It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
  • It is understood that the present embodiments encompass the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof, are within the scope of the embodiments. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the compounds can be provided as a substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).
  • The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated. Compounds that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparation of optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included within the present embodiments and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.
  • In some embodiments, the composition comprises a compound, or a pharmaceutically acceptable salt thereof, that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomeric pure, which means that the ratio of one enantiomer to the other in the composition is at least 90:1 at least 95:1, at least 98:1, or at least 99:1, or is completely in the form of one enantiomer over the other.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and the various optically active camphorsulfonic acids such as 0-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.
  • Compounds may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms.
  • Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation can include, for example, a composition enriched in the compound. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • Although the disclosed compounds are suitable, other functional groups can be incorporated into the compound with an expectation of similar results. In particular, thioamides and thioesters are anticipated to have very similar properties. The distance between aromatic rings can impact the geometrical pattern of the compound and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine. The distance between and the relative orientation of monomers within the compounds can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacing a carbonyl group with a dicarbonyl alters the distance between the monomers and the propensity of dicarbonyl unit to adopt an anti-arrangement of the two carbonyl moiety and alter the periodicity of the compound. Pyromellitic anhydride represents still another alternative to simple amide linkages which can alter the conformation and physical properties of the compound. Modern methods of solid phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 Daltons. Other substitution patterns are equally effective.
  • The compounds also include derivatives referred to as prodrugs.
  • Compounds containing an amine function can also form N-oxides. A reference herein to a compound that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom can be oxidized to form an N-oxide. Examples of N-oxides include N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (see, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).
  • Embodiments of various compounds and salts thereof are provided. Where a variable is not specifically recited, the variable can be any option described herein, except as otherwise noted or dictated by context.
  • In some embodiments, the compound is as described in the appended exemplary, non-limiting claims, or a pharmaceutically acceptable salt thereof.
  • In some embodiments, compounds having Formula I or Formula II, or a pharmaceutically acceptable salt thereof, are provided:
  • Figure US20230234946A1-20230727-C00009
  • wherein:
  • AA is
  • Figure US20230234946A1-20230727-C00010
  • W is O, S, or NR1;
  • X is O, S, or NR4;
  • V is O, S, or NR32;
  • Z is CHR42 or NR43;
  • n is 0, 1, 2, 3, or 4;
  • Y1 and Y2 are independently O, S, NR5, C═O, C═S or C═NR6;
  • Y3 is O, S, CH2, or NR34;
  • m is 0, 1, 2, or 3;
  • A1 is O, S, NR7, C═O, or C═S;
  • A2 and A3 are independently CR29 or N;
  • B1 is an optionally substituted aryl or heteroaryl group, a carbocycle, or
  • Figure US20230234946A1-20230727-C00011
  • B2, B3, and B4 are independently CR38 or N;
  • D1 is H, OH, NH2, NO2, cycle, optionally substituted aryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl;
  • R2 and R3, are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or R2 and R3 are together optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • R1, R4, R5, R6, R7, R29, R31, R32, R33, R34, R38, and R43 are independently H, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • R30 is independently H, CN, CF3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or optionally substituted haloalkyl;
  • R42 is independently Br, C1, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • In some embodiments of compounds of Formula I or Formula II, D1 and B1 are:
  • Figure US20230234946A1-20230727-C00012
  • wherein:
  • Z1 and Z2 are independently N or CR39;
  • Z3 is O, S, or NR27;
  • R27 and R39 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • In some embodiments, one of Z1 and Z2 is N. In some embodiments, both Z1 and Z2 are N. In some embodiments, Z3 is O.
  • In some embodiments of compounds, or a pharmaceutically acceptable salt thereof, of Formula I or Formula II, D1 and B1 have a formula of:
  • Figure US20230234946A1-20230727-C00013
  • wherein:
  • Z4 is O, S, or NR28;
  • Z5 is N or CH;
  • R19, and R20 are each independently H, OH, NH2, NO2, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, alkylthio, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R19, and R20 together form an aryl or cycle that is attached to one or more of the atoms of B1.
  • R28 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • In some embodiments, Z5 is N. In some embodiments, Z4 is 0. In some embodiments, Z5 is N and Z4 is O.
  • In some embodiments of compounds of Formula I or Formula II, D1 is
  • Figure US20230234946A1-20230727-C00014
  • wherein R21, R22, and R23 are each independently H, OH, NH2, NO2, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R21, R22, and R23 together form an aryl or cycle that is attached to one or more of the atoms of D1.
  • In some embodiments, one of R21, R22, and R23 is H. In some embodiments, two of R21, R22, and R23 are H. In some embodiments, R23 is Me, OH, NH2, C1, NHSO2Me, SO2NH2, NH(CO)Me, or (CO)NH2. In some embodiments, R21 and R22 are H and R23 is Me, OH, NH2, C1, NHSO2Me, SO2NH2, NH(CO)Me, or (CO)NH2.
  • In some embodiments of compounds of Formula I or Formula II, D1 is optionally substituted aryl or optionally substituted hetero aryl.
  • In some embodiments of compounds of Formula I or Formula II, D1 is
  • Figure US20230234946A1-20230727-C00015
  • wherein R24, R25, and R26 are each independently H, OH, NH2, NO2, cycle (e.g. carbocycle or heterocyle), aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R24, R25, and R26 together form an aryl or cycle that is attached to one or more of the atoms of D1.
  • In some embodiments, one of R24, R25, and R26 is H. In some embodiments, two of R24, R25, and R26 are H. In some embodiments, R26 is H, Me, OH, CF3, or OMe. In some embodiments, R24 and R25 are H and R26 is H, Me, OH, CF3, or OMe.
  • In some embodiments of compounds of Formula I or Formula II, AA is
  • Figure US20230234946A1-20230727-C00016
  • In some embodiments, W is O. In some embodiments, X is O. In some embodiments, R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R2 and R3 are the same. In some embodiments, R2 and R3 are ethyl.
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00017
  • In some embodiments, one of R24, R25, and R26 is H. In some embodiments, two of R24, R25, and R26 are H and the other member is as defined herein. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00018
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00019
  • In some embodiments, R24 is H. In some embodiments, R24 is OH. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00020
  • In some embodiments, R24 is OMe.
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00021
  • In some embodiments, one of R24, R25, and R26 is H. In some embodiments, two of R24, R25, and R26 are H and the other member is as defined herein.
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00022
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00023
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00024
  • In some embodiments, R24 is halide. In some embodiments, R24 is F.
  • In some embodiments, R24 is Me. In some embodiments, R24 is OMe. In some embodiments, R24 is OH.
  • In some embodiments of compounds of Formula I or Formula II, R2 and R3 are together
  • Figure US20230234946A1-20230727-C00025
  • In some embodiments, n is 1.
  • In some embodiments of compounds of Formula I or Formula II, AA is
  • Figure US20230234946A1-20230727-C00026
  • In some embodiments, Y1 is NR5. In some embodiments, R5 is H.
  • In some embodiments, Y2 is C═NR6. In some embodiments, R6 is H.
  • In some embodiments, Y2 is C═O. In some embodiments, Y3 is O. In some embodiments, Y3 is CH2. In some embodiments, m is 0. In some embodiments, m is 1.
  • In some embodiments of compounds of Formula I or Formula II, AA is
  • Figure US20230234946A1-20230727-C00027
  • In some embodiments, A1 is O. In some embodiments, A1 is S. In some embodiments, A2 is N. In some embodiments, A3 is N. In some embodiments, A3 is CR29. In some embodiments, R29 is H.
  • In some embodiments, A2 is CR29. In some embodiments, R29 is H.
  • In some embodiments, A1 is NR7. In some embodiments, R7 is Me,
  • Figure US20230234946A1-20230727-C00028
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00029
  • and one of R21, R22, and R23 is H.
  • In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00030
  • and two of R21, R22, and R23 are H. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00031
  • In some embodiments, R21 is optionally substituted C1-C6 alkyl. In some embodiments, R21 is ethyl or methyl. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00032
  • In some embodiments of compounds of Formula I or Formula II, D1 is
  • Figure US20230234946A1-20230727-C00033
  • wherein:
  • Z6 is O, S, NR40, or CHR37;
  • Z7, Z8, Z9 and Z10 are independently N or CR41;
  • R35, R36, R37, R40, and R41 are each independently H, OH, NH2, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R35 and R36 together form an aryl or cycle that is attached to one or more of the atoms of D1.
  • In some embodiments, one of R35 and R36 is H. In some embodiments, both R35 and R36 are H. In some embodiments, Z6 is NH. In some embodiments, one of Z7, Z8 and Z9 is N.
  • In some embodiments, Z7 is N. In some embodiments, Z8 is CH. In some embodiments, Z9 is CH. In some embodiments, both Z8 and Z9 are CH.
  • In some embodiments, AA is
  • Figure US20230234946A1-20230727-C00034
  • In some embodiments, W is O. In some embodiments, X is O. In some embodiments, R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, both R2 and R3 are the same. In some embodiments, both R2 and R3 are methyl or ethyl. In some embodiments, n is 1. In some embodiments, D1 is pyrazoly. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00035
  • In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula I having a formula of
  • Figure US20230234946A1-20230727-C00036
  • or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, and Z3 are as defined herein and above.
  • In some embodiments, Z2 is N. In some embodiments, Z1 is N. In some embodiments, Z3 is O. In some embodiments, Z2 and Z1 are N and Z3 is as defined herein. In some embodiments, Z2 and Z1 are N and Z3 is O. In some embodiments, the compound is a compound of Formula I having a formula of
  • Figure US20230234946A1-20230727-C00037
  • or a pharmaceutically acceptable salt thereof.
  • In some embodiments of compounds of Formula II, D1 and B1 is
  • Figure US20230234946A1-20230727-C00038
  • In some embodiments, Z3 is O and Z1 and Z2 are independently N or CR39.
  • In some embodiments, Z1 is N, Z2 is N or CR39 and Z3 is O, S, or NR27. In some embodiments, Z1 and Z2 are N and Z3 is O.
  • In some embodiments, the compound is a compounds of Formula II having a formula of
  • Figure US20230234946A1-20230727-C00039
  • or a pharmaceutically acceptable salt thereof. In some embodiments, R30 is CN. In some embodiments, V is NH. In some embodiments, R31 is C—C5 alkyl. In some embodiments, R31 is
  • Figure US20230234946A1-20230727-C00040
  • In some embodiments, R31 is C—C5 haloalkyl.
  • In some embodiments, R31 is
  • Figure US20230234946A1-20230727-C00041
  • In some embodiments of compounds of Formula II, D1, B1, and AA together is
  • Figure US20230234946A1-20230727-C00042
  • In some embodiments, R30 is CF3. In some embodiments, V is O or NH.
  • In some embodiments, R30 is CF3.
  • In some embodiments, B1-D1 is
  • Figure US20230234946A1-20230727-C00043
  • wherein D1 is as defined herein and above. In some embodiments, D1 is
  • Figure US20230234946A1-20230727-C00044
  • In some embodiments, R31 is
  • Figure US20230234946A1-20230727-C00045
  • In the preceding embodiments, or as shown below, or as illustrated in the appending claims, if a variable (substituent) is not explicitly defined then the variable is as defined above, which would be readily apparent based upon the present embodiments.
  • In some embodiments, the compound has a formula of:
  • Figure US20230234946A1-20230727-C00046
  • or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the present embodiments provide a pharmaceutical composition comprising one or more compounds as provided or described herein, such as any compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the present embodiments provide methods of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, multiple sclerosis, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof in a subject comprising administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein.
  • In some embodiments, the present embodiments provide methods of treating or preventing neuropathy, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy in a subject, the method comprising administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein.
  • In some embodiments, the present embodiments provide methods of treating cancer in a subject, the method comprising administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein.
  • In some embodiments, the present embodiments provide methods of treating cancer in a subject, wherein the cancer is ovarian, breast, lung, brain, colon, prostate, esophageal, pancreatic, brain, glioblastoma, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer.
  • In some embodiments, wherein the subject is a subject in need thereof. In some embodiments, wherein the cancer therapeutic is selected from those described herein.
  • In some embodiments, the condition is prevented.
  • In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, is chosen from a compound of as shown in the following table and/or as described herein, including in the Examples section of the present disclosure. Any of the compounds provided for herein can be prepared as pharmaceutically acceptable salts and/or as part of a pharmaceutical composition as provided for herein. Examples of such salts are provided for herein. As described herein, the compounds can be prepared according to the schemes and methods described herein.
  • Compound Chemical
    Structure Number Name
    Figure US20230234946A1-20230727-C00047
         		1 1-cyclopentyl-5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00048
         		2 5-(2-bromophenyl)-3-(1-ethyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00049
         		3 1-(2-methylpropyl)-6-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00050
         		4 l-cyclopentyl-5-{3-[4-(pyridin-3- ylmethoxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00051
         		5 5-[3-(4-fluorophenyl)-1,2,4- oxadiazol-5-yl]-1-propyl-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00052
         		6 5-[3-(5-methylpyrazin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00053
         		7 1-cyclopentyl-5-(3-phenyl-1,2,4- oxadiazol-5-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00054
         		8 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methylpyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00055
         		9 5-[3-(5-phenylpyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00056
         		10 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00057
         		11 l-cyclohexyl-5-[3-(3- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00058
         		12 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (trifluoromethyl)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00059
         		13 4-[5-(1-cyclopentyl-1H-1,2,3- benzotriazol-5-yl)-1,2,4-oxadiazol- 3-yl]phenol
    Figure US20230234946A1-20230727-C00060
         		14 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- isopropoxy-3- (trifluoromethyl)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00061
         		15 5-[3-(4-phenoxyphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00062
         		16 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (methylthio)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00063
         		17 5-[3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00064
         		18 5-(5-cyclobutyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00065
         		19 5-[3-(6-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00066
         		20 3-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00067
         		21 5-[4-(2-fluorophenyl)-1,3-oxazol-2- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00068
         		22 2-isopropoxy-5-(3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00069
         		23 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (phenoxymethyl)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00070
         		24 3-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol
    Figure US20230234946A1-20230727-C00071
         		25 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- isopropylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00072
         		26 l-[5-{3-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00073
         		27 2,2-diethyl-6-{3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00074
         		28 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,3,4-oxadiazol-2-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00075
         		29 2,2-diethyl-6-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- thiadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00076
         		30 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N,N- dimethylbenzenesulfonamide
    Figure US20230234946A1-20230727-C00077
         		31 2,2-diethyl-6-(3-(3-methylpyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00078
         		32 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00079
         		33 3-(1-isopropylbenzotriazol-5-yl)-5- [2-(trifluoromethyl)phenyl]-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00080
         		34 2,2-diethyl-6-(3-(5-methylthiophen- 2-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00081
         		35 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00082
         		36 4′,4′-difluoro-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[l-benzopyran-2,1′- cyclohexane]-4-one
    Figure US20230234946A1-20230727-C00083
         		37 5-(4-fluorophenyl)-2-(1- isopropylbenzotriazol-5-yl)thiazole
    Figure US20230234946A1-20230727-C00084
         		38 2,2-diethyl-6-(3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00085
         		39 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 2-(prop-2-en-1-yl)-2H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00086
         		40 5-(2-bromophenyl)-3-(1- cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00087
         		41 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[l- benzopyran-2,l′-cyclohexane]-4- one
    Figure US20230234946A1-20230727-C00088
         		42 3-(1-allyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- bromophenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00089
         		43 5-(2-bromophenyl)-3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00090
         		44 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methylpyrazin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00091
         		45 5-(2-bromophenyl)-3-(1-(pyridin-2- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00092
         		46 l-cyclopentyl-5-{3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00093
         		47 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (methylthio)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00094
         		48 5-(2-bromophenyl)-3-(1-(pyridin-4- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00095
         		49 5-{3-[4-(phenoxymethyl)phenyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00096
         		50 5-[4-(4-chlorophenyl)-5-methyl- 1,3-oxazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00097
         		51 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methoxypyrazin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00098
         		52 3-(1-benzyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- bromophenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00099
         		53 5-{3-[4-(benzyloxy)phenyl]-1,2,4- oxadiazol-5-yl}-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00100
         		54 5-[3-(3-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-propyl-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00101
         		55 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4- methoxy-2-methylphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00102
         		56 5-[3-(2-methyl-1-phenylpropyl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00103
         		57 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00104
         		58 4′,4′-dimethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[1-benzopyran-2,1′- cyclohexane]-4-one
    Figure US20230234946A1-20230727-C00105
         		59 l-tert-butyl-5-[3-(2-methylphenyl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00106
         		60 6-(3-(4-(dimethylamino)phenyl)- 1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00107
         		61 2-(allylamino)-5-(3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00108
         		62 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00109
         		63 5-(2-fluorophenyl)-2-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)thiazole
    Figure US20230234946A1-20230727-C00110
         		64 5-(3-fluorophenyl)-3-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00111
         		65 2,2-diethyl-6-(3-(4- methoxyphenyl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00112
         		66 2,2-diethyl-6-(3-(o-tolyl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00113
         		67 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,3,4- thiadiazol-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00114
         		68 6-[3-(4-chlorophenyl)-1,2,4- oxadiazol-5-yl]-2,2-diethyl- chroman-4-one
    Figure US20230234946A1-20230727-C00115
         		69 3-(1-isopropylbenzotriazol-5-yl)-5- (4-methoxyphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00116
         		70 2-{5-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3,4-thiadiazol- 2-yl}phenol
    Figure US20230234946A1-20230727-C00117
         		71 2,2-diethyl-6-(3-(3- methoxyphenyl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00118
         		72 2,2-diethyl-6-[3-(4- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00119
         		73 5-(2-bromophenyl)-3-(1-methyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00120
         		74 5-[5-(5-methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00121
         		75 l-(2-methylpropyl)-5-{3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00122
         		76 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-propyl-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00123
         		77 5-[3-(2-methoxypyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1-methyl-2,3- dihydro-1H-1,2,3-benzotriazole; cyclopentane
    Figure US20230234946A1-20230727-C00124
         		78 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- (pyrazin-2-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00125
         		79 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- l-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00126
         		80 l-cyclopentyl-5-{3-[4- (difluoromethoxy)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00127
         		81 methyl2-(5-(5-(2-bromophenyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)acetate
    Figure US20230234946A1-20230727-C00128
         		82 5-[3-(5-chlorothiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00129
         		83 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-cyclopropyl-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00130
         		84 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00131
         		85 5-{3-[4-(benzyloxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-cyclopropyl-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00132
         		86 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methyipyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00133
         		87 l-cyclopropyl-5-[3-(6- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00134
         		88 5-(3-benzyl-1,2,4-oxadiazol-5-yl)- l-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00135
         		89 5-[5-(oxan-4-yl)-1,2,4-oxadiazol-3- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00136
         		90 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxy-2-methylphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00137
         		91 1-cyclopentyl-5-[3-(4- methoxynaphthalen-1-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00138
         		92 5-(3-benzyl-1,2,4-oxadiazol-5-yl)- l-cyclopentyl-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00139
         		93 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00140
         		94 l-cyclopropyl-5-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00141
         		95 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00142
         		96 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(2- methylpropyl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00143
         		97 3-(1H-benzo[d][1,2,3]triazol-5-yl)- 5-(2-bromophenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00144
         		98 5-(2-bromophenyl)-3-(1- (cyclopropylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00145
         		99 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00146
         		100 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00147
         		101 5-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00148
         		102 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00149
         		103 2,2-diethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00150
         		104 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00151
         		105 2,2-diethyl-6-[3-(6-hydroxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00152
         		106 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)benzenesulfonamide
    Figure US20230234946A1-20230727-C00153
         		107 2-(isopropylamino)-5-(3-(2- oxoindolin-5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile
    Figure US20230234946A1-20230727-C00154
         		108 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00155
         		109 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00156
         		110 5-(3-fluorophenyl)-2-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)thiazole
    Figure US20230234946A1-20230727-C00157
         		111 2,2-diethyl-6-[3-(2-pyridyl)-1,2,4- oxadiazol-5-yl]chroman-4-one
    Figure US20230234946A1-20230727-C00158
         		112 2-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-thiadiazol- 5-yl}phenol
    Figure US20230234946A1-20230727-C00159
         		113 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00160
         		114 5-{3-[4-bromo-2- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-cyclopentyl-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00161
         		115 5-(2-bromophenyl)-3-(1- cyclohexyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00162
         		116 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxypyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00163
         		117 1-cyclohexyl-5-[3-(4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00164
         		118 l-cyclopentyl-5-{3-[3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00165
         		119 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- methylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00166
         		120 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00167
         		121 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- isopropoxyphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00168
         		122 5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-(3-methylbutyl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00169
         		123 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00170
         		124 l-cyclopentyl-5-[3-(6- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00171
         		125 5-[5-(4,4-difluorocyclohexyl)- 1,2,4-oxadiazol-3-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00172
         		126 5-{3-[(3,5-dimethyiphenyl)methyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00173
         		127 5-(5-cyclohexyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00174
         		128 l-(propan-2-yl)-5-(3- {[1,2,4]triazolo[4,3-a]pyridin-6- yl}-1,2,4-oxadiazol-5-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00175
         		129 5-{3-(4-methoxynaphthalen-1-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00176
         		130 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00177
         		131 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- (phenoxymethyl)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00178
         		132 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00179
         		133 5-(5,6-dimethylpyrazin-2-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00180
         		134 3-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1- yl)propanoicacid
    Figure US20230234946A1-20230727-C00181
         		135 5-[3-(2-ethylpyrimidin-5-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00182
         		136 5-[3-(2,4-dimethoxy-6- methyiphenyl)-1,2,4-oxadiazol-5- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00183
         		137 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,2,4-thiadiazol-3-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00184
         		138 5-[5-(2-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00185
         		139 2-methyl-1-{5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1- yl}propan-2-ol
    Figure US20230234946A1-20230727-C00186
         		140 2-methyl-1-{5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol
    Figure US20230234946A1-20230727-C00187
         		141 5-(3-(1H-indazol-5-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile
    Figure US20230234946A1-20230727-C00188
         		142 3-(1-isopropyl-1H-indol-5-yl)-5-(3- methyipyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00189
         		143 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- thiadiazol-3-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00190
         		144 5-[5-(2-methoxyphenyl)-1,3,4- thiadiazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00191
         		145 5-(3-(1H-benzo[d][1,2,3]triazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- (allylamino)benzonitrile
    Figure US20230234946A1-20230727-C00192
         		146 2,2-diethyl-6-(3-(2-fluoropyridin-4- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00193
         		147 2,2-diethyl-6-(3-(2- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00194
         		148 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[l- benzopyran-2,4′-oxane]-4-one
    Figure US20230234946A1-20230727-C00195
         		149 N-(4-(5-(4-(allylamino)-3- cyanophenyl)-1,2,4-oxadiazol-3- yl)phenyl)methanesulfonamide
    Figure US20230234946A1-20230727-C00196
         		150 2-(allylamino)-5-(3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00197
         		151 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N,N- dimethylbenzamide
    Figure US20230234946A1-20230727-C00198
         		152 6-(3-(1H-indazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00199
         		153 2,2-diethyl-6-(3-(4- (methylamino)phenyl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00200
         		154 5-{3-[l-(2-methyiphenyl)ethyl]- 1,2,4-oxadiazol-5-yl}-1-(2- methylpropyl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00201
         		155 l-cyclopropyl-5-[3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00202
         		156 5-(2,6-dimethylpyridin-4-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00203
         		157 5-[3-(5-methylpyrazin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00204
         		158 l-cyclohexyl-5-[3-(3,5- dimethylphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00205
         		159 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00206
         		160 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1-propyl-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00207
         		161 methyl 3-(5-(5-(2-bromophenyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1- yl)propanoate
    Figure US20230234946A1-20230727-C00208
         		162 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00209
         		163 5-[4-(2-chlorophenyl)-2,3-dihydro- 1,3-oxazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00210
         		164 l-cyclopentyl-5-[3-(4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00211
         		165 l-(propan-2-yl)-5-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00212
         		166 5-(2,4-dimethylphenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00213
         		167 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- isopropylpyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00214
         		168 2-{5-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}quinoline
    Figure US20230234946A1-20230727-C00215
         		169 5-[3-(3-methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00216
         		170 5-[3-(5-chlorothiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00217
         		171 l-cyclopropyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00218
         		172 5-{3-[l-(2-methylphenyl)ethyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00219
         		173 l-cyclopropyl-5-[3-(2- methoxyphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00220
         		174 l-cyclopentyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00221
         		175 1-cyclopentyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00222
         		176 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[l- benzopyran-2,1′-cyclopentane]-4- one
    Figure US20230234946A1-20230727-C00223
         		177 5-(3-(1H-benzo[d]imidazol-5-yl)- 1,2,4-oxadiazol-5-yl)-2- (allylamino)benzonitrile
    Figure US20230234946A1-20230727-C00224
         		178 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,3,4-thiadiazol-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00225
         		179 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)benzamide
    Figure US20230234946A1-20230727-C00226
         		180 2-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-3-yl)phenol
    Figure US20230234946A1-20230727-C00227
         		181 N-(benzo[d]isoxazol-3-yl)-1- isopropyl-1H- benzo[d][1,2,3]triazole-5- carboxamide
    Figure US20230234946A1-20230727-C00228
         		182 l-(2,2-difluoroethyl)-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00229
         		183 5-[4-(2-bromophenyl)-1,3-oxazol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00230
         		184 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00231
         		185 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylbenzamide
    Figure US20230234946A1-20230727-C00232
         		186 2,2-bis(methoxymethyl)-6-[3- (pyridin-3-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one
    Figure US20230234946A1-20230727-C00233
         		187 2,2-diethyl-6-[3-(2- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00234
         		188 2,2-dibutyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00235
         		189 2-(allylamino)-5-(3-(2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00236
         		190 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00237
         		192 l-cyclopentyl-5-[3-(5- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00238
         		193 5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-propyl-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00239
         		194 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00240
         		195 2-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)acetic acid
    Figure US20230234946A1-20230727-C00241
         		196 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00242
         		197 1-cyclopentyl-5-{3-[4-methoxy-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00243
         		198 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-cyclopentyl-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00244
         		199 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1- (cyclopropylmethyl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00245
         		200 5-[5-(adamantan-1-yl)-1,2,4- oxadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00246
         		201 5-(5,6-dimethylpyridin-3-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00247
         		202 5-{3-[(2-methyiphenyl)methyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00248
         		203 1-cyclopentyl-5-[3-(3- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00249
         		204 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00250
         		205 l-propyl-5-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00251
         		206 2-methyl-1-{5-[3-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}propan-2- ol
    Figure US20230234946A1-20230727-C00252
         		207 l-tert-butyl-5-[3-(2- methoxyphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00253
         		208 5-(3-(1H-indol-5-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile
    Figure US20230234946A1-20230727-C00254
         		209 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)phenyl)acetamide
    Figure US20230234946A1-20230727-C00255
         		210 2-((cyclopropylmethyl)amino)-5- (3-(2-oxoindolin-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00256
         		211 6-(3-(1H-benzo[d]imidazol-5-yl)- 1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00257
         		212 2,2-diethyl-6-(3-(3- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00258
         		213 5-[3-(2-methoxyphenyl)-1,2,4- thiadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00259
         		214 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[l- benzopyran-2,4′-oxane]-4-one
    Figure US20230234946A1-20230727-C00260
         		215 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethyl)phenyl)thiazole
    Figure US20230234946A1-20230727-C00261
         		216 2-(1-isopropylbenzotriazol-5-yl)-5- (o-tolyl)thiazole
    Figure US20230234946A1-20230727-C00262
         		217 4′,4′-difluoro-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[l-benzopyran-2,1′- cyclohexane]-4-one
    Figure US20230234946A1-20230727-C00263
         		218 2,2-dipropyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00264
         		219 5-{8H-indeno[1,2-d][1,3]oxazol-2- yl}-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00265
         		220 5-(2-bromophenyl)-2-(1- isopropylbenzotriazol-5-yl)thiazole
    Figure US20230234946A1-20230727-C00266
         		221 6-(3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00267
         		222 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,2,4-thiadiazol-3- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00268
         		223 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,3,4- oxadiazol-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00269
         		224 2-(allylamino)-5-(3-(2-oxoindolin- 5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile
    Figure US20230234946A1-20230727-C00270
         		225 2,2-diethyl-6-(3-(m-tolyl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00271
         		226 2,2-diethyl-6-(3-(3-fluoropyridin-4- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00272
         		227 2,2-diethyl-6-[3-(3- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00273
         		228 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00274
         		229 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- methyipyrazin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00275
         		230 3-(3,4-dimethoxyphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00276
         		231 5-[3-(2-methoxyphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00277
         		232 1-cyclopentyl-5-[3-(4- fluorophenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00278
         		233 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00279
         		234 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methyipyrazin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00280
         		235 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(p- tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00281
         		236 5-[3-(6-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00282
         		237 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- (methylthio)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00283
         		238 2-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)ethanol
    Figure US20230234946A1-20230727-C00284
         		239 l-(cyclopropylmethyl)-5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00285
         		240 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00286
         		241 l-(propan-2-yl)-5-[3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00287
         		242 l-propyl-5-{3-[3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00288
         		243 3-(2,6-dimethylphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00289
         		244 l-(propan-2-yl)-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00290
         		245 1-cyclohexyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00291
         		246 5-(4-isopropoxy-3- (trifluoromethyl)phenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00292
         		247 5-(5-methyl-4-phenyl-1,3-oxazol-2- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00293
         		248 5-([l,l′-biphenyl]-4-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00294
         		249 l-(propan-2-yl)-5-[3-(pyrimidin-5- yl)-1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00295
         		250 5-[4-(4-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00296
         		251 3-(2,6-dimethoxyphenyl)-5-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00297
         		252 5-(3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile
    Figure US20230234946A1-20230727-C00298
         		253 1-tert-butyl-5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00299
         		254 4′,4′-dimethyl-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[l-benzopyran-2,1′- cyclohexane]-4-one
    Figure US20230234946A1-20230727-C00300
         		255 5-(4-fluorophenyl)-3-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00301
         		256 6-(3-(4-aminophenyl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00302
         		257 2,2-diethyl-6-(3-(2- methoxyphenyl)-1,2,4-thiadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00303
         		258 2,2-diethyl-6-(3-(2-hydroxypyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00304
         		259 2-(isopropylamino)-5-(3-(2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00305
         		260 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylbenzotriazol-5-yl)- 1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00306
         		261 6-[3-(3-chlorophenyl)-1,2,4- oxadiazol-5-yl]-2,2-diethyl- chroman-4-one
    Figure US20230234946A1-20230727-C00307
         		262 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)phenyl)methanesulfonamide
    Figure US20230234946A1-20230727-C00308
         		263 2,2-diethyl-6-[3-(2-hydroxy-4- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00309
         		264 6-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00310
         		265 2,2-diethyl-6-(3-(3-methylthiophen- 2-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00311
         		266 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylbenzenesulfonamide
    Figure US20230234946A1-20230727-C00312
         		267 2-(allylamino)-5-(3-(2- aminobenzo[d]thiazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00313
         		268 2,2-diethyl-6-[3-(2- methoxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00314
         		269 2,2-diethyl-6-[3-(p-tolyl)-1,2,4- oxadiazol-5-yl]chroman-4-one
    Figure US20230234946A1-20230727-C00315
         		270 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- l-(prop-2-en-1-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00316
         		271 l-(3-methylbutyl)-5-(3-phenyl- 1,2,4-oxadiazol-5-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00317
         		272 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methoxypyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00318
         		273 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(m- tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00319
         		274 2,2-dimethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00320
         		275 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3,4- dimethoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00321
         		276 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (methylthio)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00322
         		277 5-[4-(2-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00323
         		278 5-(5-cyclopentyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole5-(5-cyclopentyl- 1,2,4-oxadiazol-3-yl)-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00324
         		279 2-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00325
         		280 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclohexane]-4- one
    Figure US20230234946A1-20230727-C00326
         		281 1-cyclopentyl-5-[3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00327
         		282 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00328
         		283 5-(2-bromophenyl)-3-(1-(pyridin-3- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00329
         		284 1-cyclohexyl-5-{3-[4-methoxy-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00330
         		285 1-cyclopropyl-5-[3-(4- phenoxyphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00331
         		286 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00332
         		287 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00333
         		288 1-(cyclopropylmethyl)-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00334
         		289 5-[3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl]-1-(2- methylpropyl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00335
         		290 5-(4-cyclohexylphenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00336
         		291 2,2-dimethyl-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00337
         		292 1-cyclohexyl-5-(3-phenyl-1,2,4- oxadiazol-5-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00338
         		293 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00339
         		294 5-(4-phenyl-1,3-oxazol-2-yl)-1- (propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00340
         		295 1-cyclopropyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00341
         		296 5-{3-[4-(benzyloxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00342
         		297 5-{4H,5H-naphtho[2,1- d][1,3]oxazol-2-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00343
         		298 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclopentane]-4- one
    Figure US20230234946A1-20230727-C00344
         		299 3-(1-isopropylbenzotriazol-5-yl)-5- (3-methoxyphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00345
         		300 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,3,4-oxadiazol-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00346
         		301 2,2-diethyl-6-[3-(6-methoxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00347
         		302 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00348
         		303 2,2-diethyl-6-(3-(4- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00349
         		304 3-chroman-8-yl-5-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00350
         		305 2,2-diethyl-6-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00351
         		306 1-cyclobutyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00352
         		307 5-(2-fluorophenyl)-3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00353
         		308 6-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00354
         		309 2,2-diethyl-6-(3-(pyridin-3-yl)- 1,2,4-thiadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00355
         		310 2,2-diethyl-6-[3-(5-hydroxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one
    Figure US20230234946A1-20230727-C00356
         		311 2,2-diethyl-6-(3-(5- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00357
         		312 2,2-diethyl-6-(3-(3-hydroxypyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00358
         		313 2,2-diethyl-6-(3-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00359
         		314 2,2-diethyl-6-(3-(2- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00360
         		315 2,2-diethyl-6-(3-(2-methylpyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00361
         		316 N-(4-(5-(3-cyano-4- (isopropylamino)phenyl)-1,2,4- oxadiazol-3-yl)phenyl)acetamide
    Figure US20230234946A1-20230727-C00362
         		320 3-(2-chlorophenyl)-5-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00363
         		321 5-(1-isopropyl-1H-indol-5-yl)-3-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00364
         		322 3-(2-bromophenyl)-5-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00365
         		323 2-(5-(1-isopropyl-1H-indol-5-yl)- 1,2,4-oxadiazol-3-yl)phenol
    Figure US20230234946A1-20230727-C00366
         		324 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00367
         		325 3-(2,6-dimethoxyphenyl)-5-(1- isopropylindol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00368
         		326 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00369
         		327 3-chroman-8-yl-5-(1- isopropylindol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00370
         		328 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylindol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00371
         		329 5-(1-isopropyl-1H-indazol-5-yl)-3- (o-tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00372
         		330 3-(2-chlorophenyl)-5-(1-isopropyl- 1H-indazol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00373
         		331 5-(1-isopropyl-1H-indazol-5-yl)-3- (2-(trifluoromethoxy)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00374
         		332 3-(2-bromophenyl)-5-(1-isopropyl- 1H-indazol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00375
         		333 2-(5-(1-isopropyl-1H-indazol-5-yl)- 1,2,4-oxadiazol-3-yl)phenol
    Figure US20230234946A1-20230727-C00376
         		334 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H-indazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00377
         		335 3-(2,6-dimethoxyphenyl)-5-(1- isopropylindazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00378
         		336 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H-indazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00379
         		337 3-chroman-8-yl-5-(1- isopropylindazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00380
         		338 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylindazol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00381
         		339 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1,3-dihydro-2,1- benzoxazol-3-one
    Figure US20230234946A1-20230727-C00382
         		340 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1-methyl-1,3- dihydro-2,1-benzoxazol-3-one
    Figure US20230234946A1-20230727-C00383
         		341 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1,2,3,4- tetrahydroquinolin-2-one
    Figure US20230234946A1-20230727-C00384
         		342 methyl N-({6-[5-(2- methoxyphenyl)-1,3,4-oxadiazol-2- yl]-2-oxo-2,3-dihydro-1,3- benzoxazol-3- yl}sulfonyl)carbamate
    Figure US20230234946A1-20230727-C00385
         		343 2-[(2-fluoroethyl)amino]-5-[3-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,2,4-oxadiazol-5- yl]benzonitrile
    Figure US20230234946A1-20230727-C00386
         		344 2-[(2,2-difluoroethyl)amino]-5-[3- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,2,4-oxadiazol-5- yl]benzonitrile
    Figure US20230234946A1-20230727-C00387
         		345 2-amino-5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]benzonitrile
    Figure US20230234946A1-20230727-C00388
         		346 2-[(2-fluoroprop-2-en-1-yl)amino]- 5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]benzonitrile
    Figure US20230234946A1-20230727-C00389
         		347 2-[(2,2-difluoropropyl)amino]-5-[3- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,2,4-oxadiazol-5- yl]benzonitrile
    Figure US20230234946A1-20230727-C00390
         		348 2-[(2-fluoropropyl)amino]-5-[3-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,2,4-oxadiazol-5- yl]benzonitrile
    Figure US20230234946A1-20230727-C00391
         		349 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-2,3-dihydro-1,3- benzoxazol-2-one
    Figure US20230234946A1-20230727-C00392
         		350 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-3-methyl-2,3- dihydro-1,3-benzoxazol-2-one
    Figure US20230234946A1-20230727-C00393
         		351 5-[5-(1H-indazol-5-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00394
         		352 2-[(cyclopropylmethyl)amino]-5- [5-(1H-indazol-5-yl)-1,3,4- oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00395
         		353 2-[(2-fluoroethyl)amino]-5-[5-(1H- indazol-5-yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00396
         		354 2-[(2,2-difluoroethyl)amino]-5-[5- (1H-indazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00397
         		355 2-[(2,2-difluoropropyl)amino]-5-{5- (1H-indazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00398
         		356 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(propan- 2-yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00399
         		357 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2- [(cyclopropylmethyl)amino]benzo- nitrile
    Figure US20230234946A1-20230727-C00400
         		358 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2- fluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00401
         		359 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00402
         		360 5-(4-methyl-2-phenyl-1,3-oxazol-5- yl)-1H,2H,3H-pyrrolo[2,3- b]pyridin-2-one
    Figure US20230234946A1-20230727-C00403
         		361 4-[5-(4-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1H-indole
    Figure US20230234946A1-20230727-C00404
         		362 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1,3-benzothiazole
    Figure US20230234946A1-20230727-C00405
         		363 5-[3-(4-methoxyphenyl)-1,2,4- thiadiazol-5-yl]-1H-indole
    Figure US20230234946A1-20230727-C00406
         		364 5-[5-(3-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1H-indole
    Figure US20230234946A1-20230727-C00407
         		365 6-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one
    Figure US20230234946A1-20230727-C00408
         		366 5-[5-(3-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole
    Figure US20230234946A1-20230727-C00409
         		367 1-methyl-6-[3-(2-methylphenyl)- 1,2,4-oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one
    Figure US20230234946A1-20230727-C00410
         		368 5-(1H-indol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00411
         		369 5-(1H-benzo[d]imidazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00412
         		370 5-(1-isopropyl-1H-indazol-5-yl)-3- (2-methoxyphenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00413
         		371 5-(1H-indazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00414
         		372 5-(1-isopropyl-1H-indol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00415
         		373 5-(1-isopropyl-1H- benzo[d]imidazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00416
         		374 5-[3-(2-fluorophenyl)-1,2,4- thiadiazol-5-yl]-1-(propan-2-yl)- 1H-indole
    Figure US20230234946A1-20230727-C00417
         		375 5-[5-(2-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole
    Figure US20230234946A1-20230727-C00418
         		376 4-methyl-3-(5-{thieno[2,3- b]pyridin-6-yl}-1,2,4-oxadiazol-3- yl)pyridine
    Figure US20230234946A1-20230727-C00419
         		377 1-methyl-5-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-2,3-dihydro-1H- indol-2-one
    Figure US20230234946A1-20230727-C00420
         		378 8-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}cubane-1-carboxylate
    Figure US20230234946A1-20230727-C00421
         		379 8-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}cubane-1-carboxylicacid
    Figure US20230234946A1-20230727-C00422
         		380 5-[5-(2-fluorophenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole
    Figure US20230234946A1-20230727-C00423
         		381 5-[3-(2-methylphenyl)-1,2,4- thiadiazol-5-yl]-1-(propan-2-yl)- 1H-indole
    Figure US20230234946A1-20230727-C00424
         		382 3-(2-methylphenyl)-5-[3-(propan-2- yl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00425
         		383 3-(2-methoxyphenyl)-5-[3-(propan- 2-yl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00426
         		384 1-methyl-6-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one
    Figure US20230234946A1-20230727-C00427
         		385 5-[4-(3-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00428
         		386 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-1,2,3,4-tetrahydroquinolin-2- one
    Figure US20230234946A1-20230727-C00429
         		387 5-(2-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00430
         		388 5-(2-bromophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00431
         		389 3-(1-isopropyl-1H-indol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00432
         		390 3-(1-isopropyl-1H-indol-5-yl)-5-(2- (trifluoromethyl)phenyl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00433
         		391 3-(1-isopropyl-1H-indol-5-yl)-5-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00434
         		392 3-(1-isopropyl-1H-indol-5-yl)-5-(3- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00435
         		393 3-(1-isopropyl-1H-indol-5-yl)-5-(4- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00436
         		394 5-(3-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00437
         		395 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-4-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00438
         		396 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-3-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00439
         		397 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-2-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00440
         		398 3-(1-isopropyl-1H-indol-5-yl)-5-(2- methoxyphenyl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00441
         		399 5-(3-fluoropyridin-4-yl)-3-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00442
         		400 5-(4-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00443
         		401 2-(1-isopropyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4-(2- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00444
         		402 4-(2-fluorophenyl)-2-(1-isopropyl- 1H-pyrrolo[2,3-b]pyridin-5- yl)thiazole
    Figure US20230234946A1-20230727-C00445
         		403 4-(2-fluorophenyl)-2-(1- isopropylindol-5-yl)thiazole
    Figure US20230234946A1-20230727-C00446
         		404 2-(1-isopropylindol-5-yl)-4-[2- (trifluoromethyl)phenyl]thiazole
    Figure US20230234946A1-20230727-C00447
         		405 2-(1-isopropylindol-5-yl)-4-(3- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00448
         		406 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-3-methyl-2,3- dihydro-1,3-benzoxazol-2-one
    Figure US20230234946A1-20230727-C00449
         		407 2-(1-isopropylpyrrolo[2,3- b]pyridin-5-yl)-4-(o-tolyl)thiazole
    Figure US20230234946A1-20230727-C00450
         		408 2-(1-isopropylpyrrolo[2,3- b]pyridin-5-yl)-4-[2- (trifluoromethyl)phenyl]thiazole
    Figure US20230234946A1-20230727-C00451
         		409 2-(1-isopropylpyrrolo[3,2- b]pyridin-5-yl)-4-(o-tolyl)thiazole
    Figure US20230234946A1-20230727-C00452
         		410 2-(1-isopropylpyrrolo[3,2- b]pyridin-5-yl)-4-(3- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00453
         		411 2-(1-isopropyl-1H-pyrrolo[3,2- b]pyridin-5-yl)-4-(2- methoxyphenyl)thiazole
    Figure US20230234946A1-20230727-C00454
         		412 4-(2-bromophenyl)-2-(1-isopropyl- 1H-pyrrolo[3,2-b]pyridin-5- yl)thiazole
    Figure US20230234946A1-20230727-C00455
         		413 3-(2-bromophenyl)-5-[3-(propan-2- yl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole
    Figure US20230234946A1-20230727-C00456
         		414 4-methyl-3-{5-[3-(propan-2-yl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-6- yl]-1,2,4-oxadiazol-3-yl}pyridine
    Figure US20230234946A1-20230727-C00457
         		415 6-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-3,4- dihydroquinolin-2(1H)-one
    Figure US20230234946A1-20230727-C00458
         		416 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)indolin-2- one
    Figure US20230234946A1-20230727-C00459
         		417 1-cyclobutyl-5-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00460
         		418 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methyibenzo[d]oxazole
    Figure US20230234946A1-20230727-C00461
         		419 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methylbenzo[d]oxazole
    Figure US20230234946A1-20230727-C00462
         		420 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methylbenzo[d]oxazole
    Figure US20230234946A1-20230727-C00463
         		421 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methyIbenzo[d]oxazole
    Figure US20230234946A1-20230727-C00464
         		422 2-(isopropylamino)-5-(3-(2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00465
         		423 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00466
         		424 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00467
         		425 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00468
         		426 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00469
         		427 4-chloro-2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole
    Figure US20230234946A1-20230727-C00470
         		428 4-bromo-2-(1- isopropylbenzotriazol-5-yl)-1,3- benzoxazole
    Figure US20230234946A1-20230727-C00471
         		429 7-bromo-2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole
    Figure US20230234946A1-20230727-C00472
         		430 N-[(4Z)-2,2-diethyl-6-[3-(pyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4- ylidene]hydroxylamine
    Figure US20230234946A1-20230727-C00473
         		431 N-[(4E)-2,2-diethyl-6-[3-(pyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4- ylidene]hydroxylamine
    Figure US20230234946A1-20230727-C00474
         		432 l-(propan-2-yl)-5-{4-[2- (trifluoromethyl)phenyl]-1,3- oxazol-2-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00475
         		433 5-[4-(2-methylphenyl)-1,3-oxazol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00476
         		434 4-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-3- azatricyclo[8.4.0.02,6]tetradeca- 1(14),2(6),3,10,12-pentaene
    Figure US20230234946A1-20230727-C00477
         		435 2-(isopropylamino)-5-(3-(2-oxo- 1,2,3,4-tetrahydroquinolin-7-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00478
         		436 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methoxy-4-methyibenzo[d]oxazole
    Figure US20230234946A1-20230727-C00479
         		437 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methyibenzo[d]oxazole
    Figure US20230234946A1-20230727-C00480
         		438 2-{2-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3-oxazol-4- yl}aniline
    Figure US20230234946A1-20230727-C00481
         		439 5-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00482
         		440 5-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- ((cyclopropylmethyl)amino)benzo nitrile
    Figure US20230234946A1-20230727-C00483
         		441 5-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00484
         		442 2-(isopropylamino)-5-(3-(1-oxo- 1,2,3,4-tetrahydroisoquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00485
         		443 5-(3-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-5-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00486
         		444 2-((cyclopropylmethyl)amino)-5- (3-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-5- yl)benzonitrile
    Figure US20230234946A1-20230727-C00487
         		445 6-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)benzo[d]oxazol-2(3H)-one
    Figure US20230234946A1-20230727-C00488
         		446 6-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00489
         		447 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methyibenzo[d]oxazole
    Figure US20230234946A1-20230727-C00490
         		448 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methylbenzo[d]oxazole
    Figure US20230234946A1-20230727-C00491
         		449 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methylbenzo[d]oxazole
    Figure US20230234946A1-20230727-C00492
         		450 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00493
         		451 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00494
         		452 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00495
         		453 4-chloro-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole
    Figure US20230234946A1-20230727-C00496
         		454 7-bromo-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole
    Figure US20230234946A1-20230727-C00497
         		455 l-(propan-2-yl)-5-{3-[3- (trifluoromethyl)pyridin-4-yl]- 1,2,4-oxadiazol-5-yl}-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00498
         		456 4-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-10-thia-3- azatricyclo[7.3.0.02,6]dodeca- 1(9),2(6),3,11-tetraene
    Figure US20230234946A1-20230727-C00499
         		457 4-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-10-thia-3- azatricyclo[7.3.0.02,6]dodeca- 1(9),2(6),3,7,1l-pentaene
    Figure US20230234946A1-20230727-C00500
         		458 N-(2-{2-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3-oxazol-4- yl}phenyl)acetamide
    Figure US20230234946A1-20230727-C00501
         		459 l-(propan-2-yl)-5-[4-(thiophen-2- yl)-1,3-oxazol-2-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00502
         		460 2-methyl-1-(5-{3-[3- (trifluoromethyl)pyridin-4-yl]- 1,2,4-oxadiazol-5-yl}-1H-1,2,3- benzotriazol-1-yl)propan-2-ol
    Figure US20230234946A1-20230727-C00503
         		461 4-bromo-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole
    Figure US20230234946A1-20230727-C00504
         		462 5-{4H-chromeno[4,3- d][1,3]oxazol-2-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00505
         		463 5-[4-(3-chlorothiophen-2-yl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00506
         		464 6-(3-(1H-pyrrol-2-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00507
         		465 2,2-diethyl-6-(3-(furan-2-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00508
         		466 6-(3-(1H-imidazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00509
         		467 2,2-diethyl-6-(3-(thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00510
         		468 2,2-diethyl-6-(3-(thiophen-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00511
         		469 6-(3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00512
         		470 6-(3-(1H-pyrazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00513
         		471 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-1,2,3,4- tetrahydroquinolin-7-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00514
         		472 5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00515
         		473 5-[5-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00516
         		474 l-(propan-2-yl)-5-[4-(pyridin-2-yl)- 1,3-oxazol-2-yl]-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00517
         		475 2-[(cyclopropylmethyl)amino]-5- [5-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,3,4- oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00518
         		476 2-[(2-fluoroethyl)amino]-5-[-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00519
         		477 2-[(2,2-difluoroethyl)amino]-5-[5- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00520
         		478 2,2-bis(hydroxymethyl)-6-[3- (pyridin-3-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one
    Figure US20230234946A1-20230727-C00521
         		479 3-bromo-2,2-bis(hydroxymethyl)-6- [3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00522
         		480 2,2-dimethyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-2,3-dihydro- 1-benzofuran-3-one
    Figure US20230234946A1-20230727-C00523
         		481 2,2-dimethyl-5-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-2,3-dihydro- 1-benzofuran-3-one
    Figure US20230234946A1-20230727-C00524
         		482 2,2-bis(hydroxymethyl)-6-[3- (pyridin-4-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one
    Figure US20230234946A1-20230727-C00525
         		483 3-bromo-2,2-bis(hydroxymethyl)-6- [3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00526
         		484 5-[5-(2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00527
         		485 6-(3-(1H-pyrrol-3-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00528
         		486 2-[(cyclopropylmethyl)amino]-5- [5-(2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00529
         		487 2-[(2-fluoroethyl)amino]-5-[5-(2- oxo-2,3-dihydro-1,3-benzoxazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00530
         		488 2-[(2,2-difluoroethyl)amino]-5-[5- (2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00531
         		489 5-[3-(1H-1,3-benzodiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00532
         		490 5-[3-(2,5-dimethylfuran-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00533
         		491 5-[3-(2-methylfuran-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00534
         		492 2-methyl-1-{5-[3-(2-methylfuran-3- yl)-1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol
    Figure US20230234946A1-20230727-C00535
         		493 l-{5-[3-(2,5-dimethylfuran-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methyipropan- 2-ol
    Figure US20230234946A1-20230727-C00536
         		494 2,2-bis(methoxymethyl)-6-{3- (pyridin-4-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one
    Figure US20230234946A1-20230727-C00537
         		495 2,2-diethyl-6-(3-(furan-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00538
         		496 2-(isopropylamino)-5-(3-(2- oxoindolin-6-yl)-1,2,4-oxadiazol-5- yl)benzonitrile
    Figure US20230234946A1-20230727-C00539
         		497 2-((cyclopropylmethyl)amino)-5- (3-(2-oxoindolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00540
         		498 5-{5-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}-2,1,3-benzoxadiazole
    Figure US20230234946A1-20230727-C00541
         		499 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00542
         		500 6-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2,2-diethyl- 3,4-dihydro-2H-1-benzopyran-4- one
    Figure US20230234946A1-20230727-C00543
         		501 l-{5-[3-(1H-1,3-benzodiazol-6-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methyipropan- 2-ol
    Figure US20230234946A1-20230727-C00544
         		502 6-(3-(5-aminopyridin-3-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00545
         		503 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)oxazolo[5,4-c]pyridine
    Figure US20230234946A1-20230727-C00546
         		504 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)oxazolo[5,4-c]pyridine
    Figure US20230234946A1-20230727-C00547
         		505 2,2-dimethyl-3-(5-(5-(o-tolyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol
    Figure US20230234946A1-20230727-C00548
         		506 4-isopropoxy-4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-[l,1′- biphenyl]-3-carbonitrile
    Figure US20230234946A1-20230727-C00549
         		507 4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- (isopropylamino)-[1,1′-biphenyl]-3- carbonitrile
    Figure US20230234946A1-20230727-C00550
         		508 4-(allylamino)-4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-[l,1′- biphenyl]-3-carbonitrile
    Figure US20230234946A1-20230727-C00551
         		509 2,2-diethyl-6-(5-(pyridin-3- yl)pyrimidin-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00552
         		510 2,2-diethyl-6-(5-(pyridin-4- yl)pyrimidin-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00553
         		511 5-[3-(1H-1,3-benzodiazol-6-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00554
         		512 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-2-yl)acetamide
    Figure US20230234946A1-20230727-C00555
         		513 6-(3-(2-aminopyridin-4-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00556
         		514 2-(isopropylamino)-5-(3-(1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00557
         		515 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methoxybenzo[d]oxazole
    Figure US20230234946A1-20230727-C00558
         		516 5-[4-(2-methylphenyl)-1H-pyrrol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00559
         		517 5-[l-methyl-4-(2-methyiphenyl)- 1H-pyrrol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00560
         		518 l-{5-[3-(l,4-dimethyl-1H-pyrazol- 3-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00561
         		519 5-[3-(l,4-dimethyl-1H-pyrazol-3- yl)-1,2,4-oxadiazol-5-yl]-1- (propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00562
         		520 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoropropyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00563
         		521 2,2-diethyl-6-(3-(quinolin-6-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00564
         		522 2,2-diethyl-6-(3-(isoquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00565
         		523 3-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2,2-dimethyipropan-1-ol
    Figure US20230234946A1-20230727-C00566
         		524 2,2-dimethyl-3-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00567
         		525 3-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol
    Figure US20230234946A1-20230727-C00568
         		526 3-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol
    Figure US20230234946A1-20230727-C00569
         		527 3-(5-(5-(2-ethylphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol
    Figure US20230234946A1-20230727-C00570
         		528 2,2-dimethyl-3-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00571
         		529 2,2-dimethyl-3-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00572
         		530 2,2-diethyl-6-(5-(pyridin-2- yl)pyrimidin-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00573
         		531 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- methoxyphenyl}acetamide
    Figure US20230234946A1-20230727-C00574
         		532 N-(3-methoxy-4-{5-[l-(propan-2- yl)-1H-1,2,3-benzotriazol-5-yl]- 1,2,4-oxadiazol-3- yl}phenyl)acetamide
    Figure US20230234946A1-20230727-C00575
         		533 N-{4-[5-(2,1,3-benzoxadiazol-5- yl)-1,2,4-oxadiazol-3-yl]-3- methoxyphenyl}acetamide
    Figure US20230234946A1-20230727-C00576
         		534 5-[l-(2-methoxyethyl)-4-(2- methylphenyl)-1H-pyrrol-2-yl]-1- (propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00577
         		535 2-methyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00578
         		536 2-methyl-7-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00579
         		537 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)nicotinamide
    Figure US20230234946A1-20230727-C00580
         		538 N-(5-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-3-yl)acetamide
    Figure US20230234946A1-20230727-C00581
         		539 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d]imidazol-2(3H)-one
    Figure US20230234946A1-20230727-C00582
         		540 2,2-dimethyl-3-(5-(5-(3- methyipyrazin-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00583
         		541 2,2-dimethyl-3-(5-(5-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00584
         		542 5-[4-(2-fluorophenyl)-1H-pyrrol-2- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00585
         		543 5-(5-phenyl-1H-pyrrol-3-yl)-1- (propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00586
         		544 5-(1-methyl-5-phenyl-1H-pyrrol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00587
         		545 N-(5-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-3- yl)methanesulfonamide
    Figure US20230234946A1-20230727-C00588
         		546 2,2-diethyl-6-(3-(6-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00589
         		547 2,2-diethyl-6-(3-(2-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00590
         		548 2,2-diethyl-6-(3-(6- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00591
         		549 2,2-diethyl-6-(3-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00592
         		550 2,2-diethyl-6-(3-(6-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00593
         		551 2,2-diethyl-6-(3-(5-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00594
         		552 2,2-diethyl-6-(5-(2-hydroxypyridin- 4-yl)pyrimidin-2-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00595
         		553 2,2-diethyl-6-[3-(6- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00596
         		554 2,2-diethyl-6-(3-(thiophen-3-yl)- 1,2,4-oxadiazol-5-yl)-2,3- dihydroquinolin-4(1H)-one
    Figure US20230234946A1-20230727-C00597
         		555 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)picolinamide
    Figure US20230234946A1-20230727-C00598
         		556 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-2- yl)methanesulfonamide
    Figure US20230234946A1-20230727-C00599
         		557 2,2-diethyl-6-(3-(5- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00600
         		558 2,2-diethyl-6-(3-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00601
         		559 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00602
         		560 5-[5-(2-methyl-1H-1,3- benzodiazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00603
         		561 2-[(2,2-difluoroethyl)amino]-5-{5- (2-methyl-1H-1,3-benzodiazol-5- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00604
         		562 2,2-diethyl-6-(3-(2- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00605
         		563 2,2-diethyl-6-(3-(5-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00606
         		564 2,2-diethyl-6-(3-(2-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00607
         		565 1-isopropyl-5-(5-(2- methoxyphenyl)pyrimidin-2-yl)- 1H-benzo[d][1,2,3]triazole
    Figure US20230234946A1-20230727-C00608
         		566 5-[4-(2-methoxyphenyl)-1H-pyrrol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00609
         		567 2-methyl-1-{5-[3-(1-methyl-1H- imidazol-2-yl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1- yl}propan-2-ol
    Figure US20230234946A1-20230727-C00610
         		568 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- methoxyphenyl}methanesulfon amide
    Figure US20230234946A1-20230727-C00611
         		569 5-[3-(1-methyl-1H-imidazol-2-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00612
         		570 2-methyl-1-{5-[3-(1,3-oxazol-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol
    Figure US20230234946A1-20230727-C00613
         		571 5-[5-(2-methyl-1H-1,3- benzodiazol-5-yl)-1,2,4-oxadiazol- 3-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00614
         		572 5-[5-(1-methyl-1H-1,3- benzodiazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00615
         		573 2-[(2,2-difluoroethyl)amino]-5-[5- (1-methyl-1H-1,3-benzodiazol-5- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00616
         		574 5-{5-[l-(2-hydroxyethyl)-1H-1,3- benzodiazol-5-yl]-1,3,4-oxadiazol- 2-yl}-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00617
         		575 5-[2-(2-methoxyphenyl)-1,3- oxazol-4-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00618
         		576 2-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}aniline
    Figure US20230234946A1-20230727-C00619
         		577 l-{5-[3-(1H-indol-7-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol
    Figure US20230234946A1-20230727-C00620
         		578 2-[(2,2-difluoroethyl)amino]-5-{5- [l-(2-hydroxyethyl)-1H-1,3- benzodiazol-5-yl]-1,3,4-oxadiazol- 2-yl}benzonitrile
    Figure US20230234946A1-20230727-C00621
         		579 5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00622
         		580 2-[(2,2-difluoroethyl)amino]-5-[5- (1-methyl-1H-1,3-benzodiazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00623
         		581 [(4-[5-[l-(2-hydroxy-2- methylpropyl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl]phenyl)methyl]phosphonate
    Figure US20230234946A1-20230727-C00624
         		582 N-{3-methoxy-4-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5- yl]phenyl}acetamide
    Figure US20230234946A1-20230727-C00625
         		583 diethyl[(4-{5-[l-(propan-2-yl)-1H- 1,2,3-benzotriazol-5-yl]-1,2,4- oxadiazol-3- yl}phenyl)methyl]phosphonate
    Figure US20230234946A1-20230727-C00626
         		584 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- (trifluoromethoxy)phenyl} acetamide
    Figure US20230234946A1-20230727-C00627
         		585 5-[5-(1H-1,3-benzodiazol-4-yl)- 1,3,4-oxadiazol-2-yl]-2-[(propan- 2-yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00628
         		586 5-[5-(1H-1,3-benzodiazol-4-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00629
         		587 N-methyl-2-{2-[1-(propan-2-yl)- 1H-1,2,3-benzotriazol-5-yl]-1,3- oxazol-4-yl}aniline
    Figure US20230234946A1-20230727-C00630
         		588 2-ethyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00631
         		589 2-ethyl-7-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00632
         		590 l-{5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methyipropan- 2-ol
    Figure US20230234946A1-20230727-C00633
         		591 2,2-diethyl-6-(3-(thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)-2,3- dihydroquinolin-4(1H)-one
    Figure US20230234946A1-20230727-C00634
         		592 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylpicolinamide
    Figure US20230234946A1-20230727-C00635
         		593 2-methyl-1-(5-(5-(o-tolyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00636
         		594 2,2-diethyl-6-(5-(2- methoxyphenyl)pyrimidin-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00637
         		595 2-isopropoxy-5-(5-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00638
         		596 5-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00639
         		597 2-methyl-1-{5-[3-(3-methylpyridin- 4-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}propan-2- ol
    Figure US20230234946A1-20230727-C00640
         		598 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2- (cyclopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00641
         		599 N-methyl-2-{3-1-(propan-2-yl)- 1H-1,2,3-benzotriazol-5-yl]-1,2,4- oxadiazol-5-yl}aniline
    Figure US20230234946A1-20230727-C00642
         		600 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(1,3- difluoropropan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00643
         		601 5-[5-(2-methylphenyl)-1H-pyrrol- 3-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole
    Figure US20230234946A1-20230727-C00644
         		602 2-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}pyridin-3-ol
    Figure US20230234946A1-20230727-C00645
         		603 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)pyridine-3- sulfonamide
    Figure US20230234946A1-20230727-C00646
         		604 2,2-diethyl-6-(3-(3- methoxythiophen-2-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one
    Figure US20230234946A1-20230727-C00647
         		605 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxypyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00648
         		606 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00649
         		607 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxypyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00650
         		608 4-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}-2,3-dihydro-1H-inden-1-one
    Figure US20230234946A1-20230727-C00651
         		609 2-methyl-2-(5-(5-(o-tolyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00652
         		610 2-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2-methylpropan-1-ol
    Figure US20230234946A1-20230727-C00653
         		611 2-methyl-2-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol
    Figure US20230234946A1-20230727-C00654
         		612 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxypyridin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00655
         		613 7-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one
    Figure US20230234946A1-20230727-C00656
         		614 7-[3-(2-methoxyphenyl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one
    Figure US20230234946A1-20230727-C00657
         		615 N,N-dimethyl-2-{3-[l-(propan-2- yl)-1H-1,2,3-benzotriazol-5-yl]- 1,2,4-oxadiazol-5-yl}aniline
    Figure US20230234946A1-20230727-C00658
         		616 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)pyridine-2- sulfonamide
    Figure US20230234946A1-20230727-C00659
         		617 2,2-diethyl-6-(3-(pyrazin-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00660
         		618 2-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol
    Figure US20230234946A1-20230727-C00661
         		619 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methoxypyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00662
         		620 2,2-diethyl-6-(3-(pyrimidin-5-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00663
         		621 2,2-diethyl-6-(3-(pyridazin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00664
         		622 6-(3-(benzo[d]oxazol-6-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one
    Figure US20230234946A1-20230727-C00665
         		623 2-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol
    Figure US20230234946A1-20230727-C00666
         		624 2-(5-(5-(2-ethyiphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol
    Figure US20230234946A1-20230727-C00667
         		625 2-methyl-2-(5-(5-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00668
         		626 2-methyl-2-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00669
         		627 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxypyridin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00670
         		628 2-(isopropylamino)-5-(5-(2-oxo- 2,3-dihydro-1H-benzo[d]imidazol- 5-yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00671
         		629 7-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-1,2,3,4-tetrahydroquinoxalin- 2-one
    Figure US20230234946A1-20230727-C00672
         		630 2-propyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00673
         		631 2,2-diethyl-6-[5-(5-fluoropyridin-3- yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00674
         		632 2,2-diethyl-6-[5-(5-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00675
         		633 2-butyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00676
         		634 2-[(1-hydroxy-2-methylpropan-2- yl)amino]-5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00677
         		635 2-[(2,2-difluoro-3- hydroxypropyl)amino]-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00678
         		636 4-{3-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}-2,3-dihydro-1H-inden-1-ol
    Figure US20230234946A1-20230727-C00679
         		637 5-[5-(2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00680
         		638 5-[5-(1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00681
         		639 2,2-diethyl-6-(3-(pyrimidin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00682
         		640 2,2-diethyl-6-(3-(pyrimidin-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00683
         		641 2-methyl-2-(5-(5-(3-methylpyrazin- 2-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol
    Figure US20230234946A1-20230727-C00684
         		642 2-(5-(5-(1H-benzo[d]imidazol-6- yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol
    Figure US20230234946A1-20230727-C00685
         		643 2-(5-(5-(2-fluoropyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol
    Figure US20230234946A1-20230727-C00686
         		644 2-methyl-2-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- l-ol
    Figure US20230234946A1-20230727-C00687
         		645 7-[3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one
    Figure US20230234946A1-20230727-C00688
         		646 l-(propan-2-yl)-5-[3-(1H-pyrazol- 4-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00689
         		647 l-{5-[3-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00690
         		648 2,2-diethyl-6-(3-(pyridazin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00691
         		649 2-(isopropylamino)-5-(5-(pyridin- 3-yl)-1,3,4-oxadiazol-2- yl)benzonitrile
    Figure US20230234946A1-20230727-C00692
         		650 5-(3-(1-(1-hydroxy-2- methylpropan-2-yl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)indolin-2-one
    Figure US20230234946A1-20230727-C00693
         		651 2-[(2,2-difluoroethyl)amino]-5-{5- (2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00694
         		652 2-[(2,2-difluoroethyl)amino]-5-{5- (1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)-1,3,4- oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00695
         		653 2-methyl-1-{6-[3-(1H-pyrazol-4- yl)-1,2,4-oxadiazol-5-yl]-3H- indazol-3-yl}propan-2-ol
    Figure US20230234946A1-20230727-C00696
         		654 1-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2-methylpropan-2-ol
    Figure US20230234946A1-20230727-C00697
         		655 2-methyl-1-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00698
         		656 l-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00699
         		657 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00700
         		662 l-{5-[3-(2-methoxy-4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00701
         		663 2,2-diethyl-6-[5-(2-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00702
         		664 2,2-diethyl-6-[5-(5-hydroxypyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00703
         		665 5-[5-(1-tert-butyl-1H-1,3- benzodiazol-6-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00704
         		666 2,2-diethyl-N-[(1E)- (hydroxyimino)[2- (trifluoromethyl)pyridin-3- yl]methyl]-4-oxo-3,4-dihydro-2H- 1-benzopyran-7-carboxamide
    Figure US20230234946A1-20230727-C00705
         		667 2-(isopropylamino)-5-(5-(pyridin- 4-yl)-1,3,4-oxadiazol-2- yl)benzonitrile
    Figure US20230234946A1-20230727-C00706
         		668 2-methyl-1-(5-(5-(3-methylpyrazin- 2-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00707
         		669 l-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00708
         		670 1-(5-(5-(2-ethylphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-2-ol
    Figure US20230234946A1-20230727-C00709
         		671 2-methyl-1-(5-(5-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00710
         		672 2-methyl-1-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00711
         		673 2-methyl-1-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol
    Figure US20230234946A1-20230727-C00712
         		675 l-{5-[3-(2,6-dimethylpyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methyipropan- 2-ol
    Figure US20230234946A1-20230727-C00713
         		676 5-[5-(1-tert-butyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00714
         		677 2,2-diethyl-6-[3-(1-methyl-1H- indol-3-yl)-1,2,4-oxadiazol-5-yl]- 3,4-dihydro-2H-1-benzopyran-4- one
    Figure US20230234946A1-20230727-C00715
         		678 5-[3-(1-methyl-1H-indol-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00716
         		679 5-[3-(2,6-dimethylpyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00717
         		680 2-methyl-1-{5-[3-(4-methyl-1,3- oxazol-5-yl)-1,2,4-oxadiazol-5-yl]- 1H-1,2,3-benzotriazol-1-yl}propan- 2-ol
    Figure US20230234946A1-20230727-C00718
         		681 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4- methoxypyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00719
         		682 5-[3-(1-methyl-1H-indol-3-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00720
         		683 5-[3-(4-methyl-1,3-oxazol-5-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00721
         		684 2,2-diethyl-6-[3-(1-ethyl-1H-indol- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00722
         		685 5-[5-(1-methyl-1H-1,3- benzodiazol-4-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00723
         		686 2-[(2,2-difluoroethyl)amino]-5-{5- (1-methyl-1H-1,3-benzodiazol-4- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00724
         		687 4-{5-[l-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}-2,3-dihydro-1H-inden-1-one
    Figure US20230234946A1-20230727-C00725
         		688 2-((2,2-difluoroethyl)amino)-5-(5- (pyridin-4-yl)-1,3,4-oxadiazol-2- yl)benzonitrile
    Figure US20230234946A1-20230727-C00726
         		689 5-(5-(1H-pyrazol-4-yl)-1,3,4- oxadiazol-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00727
         		690 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methyipyridin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00728
         		691 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methylpyridin-3-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00729
         		692 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methyipyridin-4-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00730
         		693 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methyipyridin-2-yl)-1,2,4- oxadiazole
    Figure US20230234946A1-20230727-C00731
         		694 5-{5-[l-(propan-2-yl)-1H-1,3- benzodiazol-6-yl]-1,3,4-oxadiazol- 2-yl}-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00732
         		695 5-{5-(1-ethyl-1H-1,3-benzodiazol- 6-yl)-1,3,4-oxadiazol-2-yl]-2- [(propan-2-yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00733
         		696 2,2-diethyl-6-[5-(2- methoxypyridin-3-yl)-1,2,4- oxadiazol-3-yl]-3,4-dihydro-2H-1- benzopyran-4-one
    Figure US20230234946A1-20230727-C00734
         		697 2,2-diethyl-6-{5-[4- (trifluoromethyl)pyridin-3-yl]- 1,2,4-oxadiazol-3-yl}-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00735
         		698 2,2-diethyl-6-[5-(2-fluoropyridin-3- yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00736
         		699 2,2-diethyl-6-{5-[2- (trifluoromethyl)pyridin-3-yl]- 1,2,4-oxadiazol-3-yl}-3,4-dihydro- 2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00737
         		700 6-[5-(5-aminopyridin-3-yl)-1,2,4- oxadiazol-3-yl]-2,2-diethyl-3,4- dihydro-2H-1-benzopyran-4-one
    Figure US20230234946A1-20230727-C00738
         		701 2-[(2,2-difluoroethyl)amino]-5-{5- [l-(propan-2-yl)-1H-1,3- benzodiazol-6-yl]-1,3,4-oxadiazol- 2-yl}benzonitrile
    Figure US20230234946A1-20230727-C00739
         		702 2-[(2,2-difluoroethyl)amino]-5-[5- (1-ethyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00740
         		703 5-[3-(1-ethyl-1H-indol-3-yl)-1,2,4- oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00741
         		704 2-[(2-fluoroethyl)amino]-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00742
         		705 5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-1H-indazol-3-amine
    Figure US20230234946A1-20230727-C00743
         		706 2-[(2,2-difluoropropyl)amino]-5-[5- (1-methyl-1H-1,3-benzodiazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00744
         		707 2-(cyclopropylamino)-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00745
         		708 2-[(1,3-difluoropropan-2- yl)amino]-5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00746
         		709 5-[3-(3-methoxypyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1-(oxan-4- yl)-1H-1,2,3-benzotriazole
    Figure US20230234946A1-20230727-C00747
         		710 5-[5-(1,2-dimethyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00748
         		711 2-[(2,2-difluoroethyl)amino]-5-[5- (1,2-dimethyl-1H-1,3-benzodiazol- 6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00749
         		712 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00750
         		713 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2- fluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00751
         		718 2,2-diethyl-6-(5-(2-methylpyridin- 3-yl)-1,3,4-oxadiazol-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00752
         		719 2,2-diethyl-6-(5-(2-methylpyridin- 3-yl)-1,3,4-thiadiazol-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00753
         		720 2,2-diethyl-6-(5-(2-fluoropyridin-3- yl)-1,3,4-thiadiazol-2-yl)chroman- 4-one
    Figure US20230234946A1-20230727-C00754
         		721 5-(5-(1H-indol-5-yl)-1,3,4- oxadiazol-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00755
         		724 2,2-diethyl-6-(5-(5-methylpyridin- 3-yl)-1,3,4-thiadiazol-2- yl)chroman-4-one
    Figure US20230234946A1-20230727-C00756
         		725 2,2-diethyl-6-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)chroman-4- one
    Figure US20230234946A1-20230727-C00757
         		726 2-(cyclopropylmethylamino)-5-[3- (2-oxo-3H-1,3-benzoxazol-6-yl)- 1,2,4-oxadiazol-5-yl]benzonitrile
    Figure US20230234946A1-20230727-C00758
         		727 2-((cyclopropylmethyl)amino)-5- (3-(1-oxoisoindolin-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00759
         		728 2-(isopropylamino)-5-(3-(2-oxo- 2,3-dihydro-1H-benzo[d]imidazol- 5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile
    Figure US20230234946A1-20230727-C00760
         		729 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile
    Figure US20230234946A1-20230727-C00761
         		730 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00762
         		730 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00763
         		731 N-[4-(5-{3-cyano-4-[(propan-2- yl)amino]phenyl}-1,2,4-oxadiazol- 3-yl)-3-methoxyphenyl]acetamide
    Figure US20230234946A1-20230727-C00764
         		732 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00765
         		733 2-[(2,2-difluoroethyl)amino]-5-{5- (isoquinolin-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile
    Figure US20230234946A1-20230727-C00766
         		734 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2- [(cyclopropylmethyl)amino]benzo nitrile
    Figure US20230234946A1-20230727-C00767
         		735 5-[5-(isoquinolin-6-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile
    Figure US20230234946A1-20230727-C00768
         		736 2-[(propan-2-yl)amino]-5-[5- (quinolin-6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00769
         		736 2-[(propan-2-yl)amino]-5-[5- (quinolin-6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile
    Figure US20230234946A1-20230727-C00770
         		737 2-(isopropylamino)-5-(5-(pyridin- 3-yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00771
         		738 2-isopropoxy-5-(5-(pyridin-3- yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00772
         		739 2-(isopropylamino)-5-(5-(pyridin- 4-yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00773
         		740 2-isopropoxy-5-(5-(pyridin-4- yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00774
         		741 2-(isopropylamino)-5-(5-(pyridin- 2-yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00775
         		742 2-isopropoxy-5-(5-(pyridin-2- yl)pyrimidin-2-yl)benzonitrile
    Figure US20230234946A1-20230727-C00776
         		743 5-(5-(2-hydroxypyridin-4- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00777
         		744 5-(5-(2-hydroxypyridin-4- yl)pyrimidin-2-yl)-2- isopropoxybenzonitrile
    Figure US20230234946A1-20230727-C00778
         		745 2-isopropoxy-5-(5-(2- methoxyphenyl)pyrimidin-2- yl)benzonitrile
    Figure US20230234946A1-20230727-C00779
         		746 5-(5-(2,2-diethyl-4-oxochroman-6- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00780
         		747 2-(isopropylamino)-5-(5-(2- methoxyphenyl)pyrimidin-2- yl)benzonitrile
    Figure US20230234946A1-20230727-C00781
         		748 5-(5-(benzo[c][1,2,5]oxadiazol-5- yl)pyrimidin-2-yl)-2- isopropoxybenzonitrile
    Figure US20230234946A1-20230727-C00782
         		749 5-(5-(benzo[c][1,2,5]oxadiazol-5- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile
    Figure US20230234946A1-20230727-C00783
         		750 N-isopropyl-4-(5-(2- methoxyphenyl)pyrimidin-2-yl)-2- (trifluoromethyl)aniline
    Figure US20230234946A1-20230727-C00784
         		751 2-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5-(2- methoxyphenyl)pyrimidine
    Figure US20230234946A1-20230727-C00785
         		752 2-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5- (pyridin-4-yl)pyrimidine
  • Although the compounds described herein may be shown with specific stereochemistries around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture. Such isomers or racemic mixtures are encompassed by the present disclosure. Additionally, although the compounds are shown collectively in a table, any compounds, or a pharmaceutically acceptable salt thereof, can be chosen from the table and used in the embodiments provided for herein.
  • In some embodiments, pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof of any compound described herein are provided.
  • The compounds described herein can be made according to the methods described herein and in the examples. The methods described herein can be adapted based upon the compounds desired and described herein. In some embodiments, the method is made according to the following schemes, wherein Q and L are the substituents as shown and described herein and would be apparent to one of skill in the art based upon the present disclosure. In some embodiments, this method can be used to make one or more compounds as described herein and will be apparent to one of skill in the art which compounds can be made according to the methods described herein.
  • The conditions and temperatures can be varied, such as shown in the examples described herein. These schemes are non-limiting synthetic schemes and the synthetic routes can be modified as would be apparent to one of skill in the art reading the present specification. The compounds can also be prepared according to the schemes described in the Examples.
  • The compounds can be used to modulate the S1P1 receptor. Thus, in some embodiments, the compounds can be referred to as S1P1 receptor modulating compounds.
  • Although the compounds in the tables above or in the examples section are shown with specific stereochemistries around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture.
  • In some embodiments, the present embodiments provide pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof any compound described herein.
  • The compounds described herein can be made according to the methods described herein and in the examples. The methods described herein can be adapted based upon the compounds desired and described herein. In some embodiments, the method is made according to the following schemes, wherein Q and L are the substituents as shown and described herein and would be apparent to one of skill in the art based upon the present disclosure. In some embodiments, this method can be used to make one or more compounds as described herein and will be apparent to one of skill in the art which compounds can be made according to the methods described herein.
  • In some embodiments, the compounds are made according to schemes described in the examples. The schemes can be used to prepare the compounds and compositions described herein. The conditions and temperatures can be varied, or the synthesis can be performed according to the examples described herein with modifications that are readily apparent based upon the compound being synthesized.
  • The conditions and temperatures can be varied, such as shown in the examples described herein. These schemes are non-limiting synthetic schemes and the synthetic routes can be modified as would be apparent to one of skill in the art reading the present specification.
  • The compounds described herein can be administered in any conventional manner by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular routes, or intravaginal, by inhalation, by depot injections, or by implants. The mode of administration can depend on the conditions or disease to be targeted or treated. The selection of the specific route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.
  • In some embodiments, it may be desirable to administer one or more compounds, or a pharmaceutically acceptable salt thereof, locally to an area in need of treatment. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, wherein the implant is of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • The compounds described herein can be administered either alone or in combination (concurrently or serially) with other pharmaceuticals. For example, the compounds can be administered in combination with other analgesics, antidepressants, anti-anxiety compounds, anti-overactive bladder compounds, compounds for the treatment of cancer, and the like. Examples of other pharmaceuticals or medicaments are known to one of skill in the art and include, but are not limited to those described herein.
  • The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance (see, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980)).
  • The amount of compound to be administered is that amount which is therapeutically effective. The dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician). The standard dosing for protamine can be used and adjusted (i.e., increased or decreased) depending upon the factors described above. The selection of the specific dose regimen can be selected or adjusted or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response.
  • The amount of a compound described herein that will be effective in the treatment and/or prevention of a particular disease, condition, or disorder will depend on the nature and extent of the disease, condition, or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, a suitable dosage range for oral administration is, generally, from about 0.001 milligram to about 200 milligrams per kilogram body weight, from about 0.01 milligram to about 100 milligrams per kilogram body weight, from about 0.01 milligram to about 70 milligrams per kilogram body weight, from about 0.1 milligram to about 50 milligrams per kilogram body weight, from 0.5 milligram to about 20 milligrams per kilogram body weight, or from about 1 milligram to about 10 milligrams per kilogram body weight. In some embodiments, the oral dose is about 5 milligrams per kilogram body weight.
  • In some embodiments, suitable dosage ranges for intravenous (i.v.) administration are from about 0.01 mg to about 500 mg per kg body weight, from about 0.1 mg to about 100 mg per kg body weight, from about 1 mg to about 50 mg per kg body weight, or from about 10 mg to about 35 mg per kg body weight. Suitable dosage ranges for other modes of administration can be calculated based on the forgoing dosages as known by those skilled in the art. For example, recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration or administration by inhalation are in the range of from about 0.001 mg to about 200 mg per kg of body weight, from about 0.01 mg to about 100 mg per kg of body weight, from about 0.1 mg to about 50 mg per kg of body weight, or from about 1 mg to about 20 mg per kg of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.
  • The compounds described herein can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The compounds can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Formulations for injection can be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an optionally added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In some embodiments, the injectable is in the form of short-acting, depot, or implant and pellet forms injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is the form of a solution, suspension, emulsion, or dry powder.
  • For oral administration, the compounds described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, caches, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by, for example, adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are suitably of pharmaceutical grade.
  • Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added.
  • For buccal administration, the compositions can take the form of tablets or lozenges formulated in a conventional manner.
  • For administration by inhalation, the compounds described herein can be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as gelatin for use in an inhaler or insufflator, can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • The compounds described herein can also be formulated in rectal compositions such as suppositories or retention enemas, such as containing conventional suppository bases such as cocoa butter or other glycerides. The compounds described herein can also be formulated in vaginal compositions such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.
  • In transdermal administration, the compounds can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism. In some embodiments, the compounds are present in creams, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, gels, jellies, and foams, or in patches containing any of the same.
  • The compounds described herein can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • In some embodiments, the compounds can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see, also Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, a controlled-release system can be placed in proximity of the target of the compounds described herein, such as the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533) may be used.
  • It is also known in the art that the compounds can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The pharmaceutical compositions can also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. In some embodiments, the compounds described herein can be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or rinses (e.g., Caphosol).
  • In some embodiments, the compounds described herein can be delivered in a vesicle, in particular a liposome (see, Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
  • Suitable compositions include, but are not limited to, oral non-absorbed compositions. Suitable compositions also include, but are not limited to saline, water, cyclodextrin solutions, and buffered solutions of pH 3-9.
  • The compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated with numerous excipients including, but not limited to, purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid/sodium citrate (pH3), citric acid/sodium citrate (pH5), tris(hydroxymethyl)amino methane HCl (pH7.0), 0.9% saline, and 1.2% saline, and any combination thereof. In some embodiments, excipient is chosen from propylene glycol, purified water, and glycerin.
  • In some embodiments, the formulation can be lyophilized to a solid and reconstituted with, for example, water prior to use.
  • When administered to a mammal (e.g., to an animal for veterinary use or to a human for clinical use) the compounds can be administered in isolated form.
  • When administered to a human, the compounds can be sterile. Water is a suitable carrier when the compound of Formula I is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • The compositions described herein can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing a liquid, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. R. Gennaro (Editor) Mack Publishing Co.
  • In some embodiments, the compounds are formulated in accordance with routine procedures as a pharmaceutical composition adapted for administration to humans. Typically, compounds are solutions in sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • The pharmaceutical compositions can be in unit dosage form. In such form, the composition can be divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • In some embodiments, a composition is in the form of a liquid wherein the active agent (i.e., one of the facially amphiphilic polymers or oligomers disclosed herein) is present in solution, in suspension, as an emulsion, or as a solution/suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.
  • In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted in a suitable location in the eye, such as between the eye and eyelid or in the conjunctival sac, where it releases the active agent as described, for example, U.S. Pat. Nos. 3,863,633; 3,867,519; 3,868,445; 3,960,150; 3,963,025; 4,186,184; 4,303,637; 5,443,505; and 5,869,079. Release from such an article is usually to the cornea, either via the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be bioerodible or non-bioerodible. Bioerodible polymers that can be used in the preparation of ocular implants carrying one or more compounds include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates and polyether lactones. Suitable non-bioerodible polymers include silicone elastomers.
  • The compositions described herein can contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercuric salts (e.g., phenylmercuric acetate, borate and nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, and salts thereof; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.
  • Optionally, one or more stabilizers can be included in the compositions to enhance chemical stability where required. Suitable stabilizers include, but are not limited to, chelating agents or complexing agents, such as, for example, the calcium complexing agent ethylene diamine tetraacetic acid (EDTA). For example, an appropriate amount of EDTA or a salt thereof, e.g., the disodium salt, can be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or a salt thereof can suitably be included in an amount of about 0.010% to about 0.5%. In those embodiments containing a preservative other than EDTA, the EDTA or a salt thereof, more particularly disodium EDTA, can be present in an amount of about 0.025% to about 0.1% by weight.
  • One or more antioxidants can also be included in the compositions. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents know to those of skill in the art. Such preservatives are typically employed at a level of from about 0.001% to about 1.0% by weight.
  • In some embodiments, the compounds are solubilized at least in part by an acceptable solubilizing agent. Certain acceptable nonionic surfactants, for example polysorbate 80, can be useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400 (PEG-400), and glycol ethers.
  • Suitable solubilizing agents for solution and solution/suspension compositions are cyclodextrins. Suitable cyclodextrins can be chosen from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkylcyclodextrins (e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkylcyclodextrins (e.g., hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxy-alkylcyclodextrins (e.g., carboxymethyl-β-cyclodextrin), sulfoalkylether cyclodextrins (e.g., sulfobutylether-β-cyclodextrin), and the like. Ophthalmic applications of cyclodextrins have been reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.
  • In some embodiments, the composition optionally contains a suspending agent. For example, in those embodiments in which the composition is an aqueous suspension or solution/suspension, the composition can contain one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers, for example, hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • One or more acceptable pH adjusting agents and/or buffering agents can be included in the compositions, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • One or more acceptable salts can be included in the compositions in an amount required to bring osmolality of the composition into an acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions. In some embodiments, salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, the salt is sodium chloride.
  • Optionally, one or more acceptable surfactants, preferably nonionic surfactants, or co-solvents can be included in the compositions to enhance solubility of the components of the compositions or to impart physical stability, or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40; polysorbate 20, 60 and 80; polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F-68, F84 and P-103); cyclodextrin; or other agents known to those of skill in the art. Typically, such co-solvents or surfactants are employed in the compositions at a level of from about 0.010% to about 2% by weight.
  • In some embodiments, pharmaceutical packs or kits comprising one or more containers filled with one or more compounds described herein are provided. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration for treating a condition, disease, or disorder described herein. In some embodiments, the kit contains more than one compound described herein. In some embodiments, the kit comprises a compound described herein in a single injectable dosage form, such as a single dose within an injectable device such as a syringe with a needle.
  • Modulation of the S1P1 receptor has been found to be a target for the treatment of certain disorders. The compounds described herein can be used in the preparation of a medicament or pharmaceutical composition to treat and/or prevent neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, ms, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof.
  • Embodiments disclosed herein also provide for the compounds for the use of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, ms, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof.
  • In some embodiments, methods of treating and/or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, hiv-related neuropathy or pain associated with hiv-related neuropathy, pain or neuropathy resulting from spinal cord injury, nerve lesions, tissue injury, ms, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex regional pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof. In some embodiments, the methods comprise administering one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, to the subject to treat or prevent such conditions. In some embodiments, the condition is CINP and CIPN, or other types of neuropathic pain or neuropathy. In some embodiments, the methods are performed without causing significant lymphopenia or immunosuppression. In some embodiments, the methods are performed without causing lymphopenia or immunosuppression.
  • In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, are administered to the subject for any condition or indication provided for herein without causing significant lymphopenia or immunosuppression. In some embodiments, the methods are performed without causing lymphopenia or immunosuppression.
  • In some embodiments, the methods comprise administering to the subject one or more compounds described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same. In some embodiments, the subject is a subject in need of such treatment. As described herein, in some embodiments, the subject is a mammal, such as, but not limited to, a human.
  • In some embodiments, also provided are one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for use in the manufacture of a medicament for the treatment of methods of treating and/or preventing pain, including, but not limited to the conditions described herein, in a subject, such as those described herein. In some embodiments, the subject is a subject in need thereof.
  • The present embodiments also provide the use of one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, in the modulation of a S1P1 receptor activity, such as the presence on the surface of the cell. In some embodiments, the compounds, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same modulate the internalization, trafficking, and/or degradation of the S1P1 receptor. In some embodiments, the compounds, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the same modulate the G-protein modulated pathway of the S1P1 receptor.
  • As used herein, “modulation” can refer to either inhibition or enhancement of a specific activity. For example, the modulation of the S1P1 receptor can refer to the inhibition and/or activation of the G-protein mediated pathway of the S1P1 receptor. In some embodiments, the modulation refers to the inhibition or activation of the β-arrestin mediated pathway of the S1P1 receptor. In some embodiments, the modulation refers to the inhibition or activation of the internalization of the S1P1 receptor. The activity of a S1P1 receptor can be measured by any method including but not limited to the methods described herein.
  • The compounds described herein are agonists or antagonists of the S1P1 receptor. The ability of the compounds to stimulate or inhibit S1P1 receptor signaling may be measured using any assay known in the art used to detect S1P1 receptor mediated signaling or S1P1 receptor activity, or the absence of such signaling/activity. “S1P1 receptor activity” refers to the ability of a S1P1 receptor to transduce a signal. Such activity can be measured, e.g., in a heterologous cell, by coupling an S1P1 receptor (or a chimeric S1P1 receptor) to a downstream effector such as adenylate cyclase.
  • A “natural ligand-induced activity” as used herein, refers to activation of the S1P1 receptor by a natural ligand of the S1P1 receptor. Activity can be assessed using any number of endpoints to measure S1P1 receptor activity.
  • Generally, assays for testing compounds that modulate S1P1 receptor-mediated signal transduction include the determination of any parameter that is indirectly or directly under the influence of a S1P1 receptor, e.g., a functional, physical, or chemical effect.
  • Samples or assays comprising S1P1 receptors that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples (untreated with inhibitors) are assigned a relative S1P1 receptor activity value of 100%. Inhibition of a S1P1 receptor is achieved when the S1P1 receptor activity value relative to the control is about 80%, 50%, or 25%. Activation of a S1P1 receptor is achieved when the S1P1 receptor activity value relative to the control (untreated with activators) is 110%, 150%, or 200-500% (i.e., two to five fold higher relative to the control), or 1000-3000% or higher.
  • The effects of the compounds upon the function of an S1P1 receptor can be measured by examining any of the parameters described above. Any suitable physiological change that affects S1P1 receptor activity can be used to assess the influence of a compound on the S1P1 receptors and natural ligand-mediated S1P1 receptor activity. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as changes in intracellular second messengers such as cAMP.
  • Modulators of S1P1 receptor activity can be tested using S1P1 receptor polypeptides as described herein, either recombinant or naturally occurring. The protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal. For example, neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the S1P1 receptor polypeptides described herein. Modulation is tested using one of the in vitro or in vivo assays described herein. Signal transduction and cellular trafficking can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor. Furthermore, ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
  • Ligand binding to an S1P1 receptor, a domain, or chimeric protein can be tested in a number of formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. For example, in an assay, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator, such as the compound described herein. Alternatively, the binding of the candidate modulator may be measured in the presence of the natural ligand. Often, competitive assays that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used. Binding can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
  • Another technology that can be used to evaluate S1P1 receptor-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion regarding BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):12736 43 (2001).
  • After the receptor is expressed in a cell, the cells can be grown in appropriate media in the appropriate cell plate. The cells can be plated, for example, at 5000-10000 cells per well in a 384 well plate. In some embodiments, the cells are plated at about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 cells/per well. The plates can have any number of wells and the number of cells can be modified accordingly.
  • Any medicament having utility in an application described herein can be used in co-therapy, co-administration or co-formulation with a composition as described above. Such additional medicaments include, medicines for cancer. Many medicines that are used to treat cancer cause CIPN or CINP. Therefore, the compounds described herein can be administered either before, concurrently with, or after such therapeutics are administered to a subject. Non-limiting examples of such therapeutics include, but are not limited to: Platinum-based drugs, such as but not limited to, carboplatin (Paraplatin), cisplatin, oxaliplatin; taxanes: paclitaxel (Taxol), paclitaxel nanoparticle albumin-bound (Abraxane), docetaxel (Taxotere), and cabazitaxel (Jevtana); Epothilones, such as ixabepilone (Ixempra); Plant alkaloids: vinblastine (Velban, Alkaban-AQ), vincristine (Oncovin, Vincasar PES, Vincrex), vinorelbine (Navelbine), and etoposide (Toposar, VePesid, Etopophos); halidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst), Bortezomib (Velcade); carfilzomib (Kyprolis), and Eribulin (Halaven). Other examples of therapeutics that the presently described compounds can be combined with include, but are not limited to, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus), Afinitor Disperz (Everolimus), Alimta (PEMETREXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Beleodaq (Belinostat Injection), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Blincyto (Blinatumomab Injection), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Cyramza (Ramucirumab Injection), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone), Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Farydak (Panobinostat), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gazyva (Obinutuzumab Injection), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Used to treat, Brain Tumors Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Ibrance (Palbociclib), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Imbruvica (Ibrutinib), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado-trastuzumab Emtansine), Keytruda (Pembrolizumab Injection), Kyprolis (Carfilzomib), Lanvima (Lenvatinib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lonsurf (Trifluridine and Tipiracil), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lynparza (Olaparib), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Odomzo (Sonidegib), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Opdivo (Nivolumab Injection), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Sylvant (Siltuximab Injection), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Unituxin (Dinutuximab Injection), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Yondelis (Trabectedin Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar (Streptozocin), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zydelig (Idelalisib), Zykadia (Ceritinib), Zytiga (Abiraterone), or any combination thereof. Other examples include, but are not limited to, PD-1 antibodies, such as Nivolumab or Pembrolizumab. In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, provided herein can be administered with, either concurrently or sequentially, or as part of a cancer treatment protocol, the additional therapeutics provided for herein.
  • In some embodiments, the compounds provided herein can also be used to treat cancer. In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, can be used to inhibit tumor growth. In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, are used to treat cancers, such as, but not limited to, ovarian cancer, breast cancer, lung cancer, brain cancer, colon cancer, prostate cancer, esophageal cancer, pancreatic cancer, brain cancer, glioblastoma cancer, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer. In some embodiments, the cancer is breast or ovarian cancer. In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, provided herein are combined with a taxane, such as paclitaxel.
  • The additional medicament can be administered in co-therapy (including co-formulation) with the one or more of the compounds described herein.
  • In some embodiments, the response of the disease or disorder to the treatment is monitored and the treatment regimen is adjusted, if necessary, in light of such monitoring.
  • Frequency of administration is typically such that the dosing interval, for example, the period of time between one dose and the next, during waking hours is from about 2 to about 12 hours, from about 3 to about 8 hours, or from about 4 to about 6 hours. It will be understood by those of skill in the art that an appropriate dosing interval is dependent to some degree on the length of time for which the selected composition is capable of maintaining a concentration of the compound(s) in the subject and/or in the target tissue (e.g., above the EC50 (the minimum concentration of the compound which modulates the receptor's activity by 90%). Ideally the concentration remains above the EC50 for at least 100% of the dosing interval. Where this is not achievable it is desired that the concentration should remain above the EC50 for at least about 60% of the dosing interval, or should remain above the EC50 for at least about 40% of the dosing interval.
  • The present disclosure also provides the following non-limiting embodiments: In order that the embodiments disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the embodiments in any manner. Throughout these examples, there may be molecular cloning reactions, and other standard recombinant DNA techniques described and these were carried out according to methods described in Maniatis et al., Molecular Cloning—A Laboratory Manual, 2nd ed., Cold Spring Harbor Press (1989), using commercially available reagents, except where otherwise noted.
  • The following examples are illustrative, but not limiting, of the methods and compositions described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy, synthesis, and other embodiments disclosed herein are within the spirit and scope of the embodiments.
    • EXAMPLES Example 1: Synthesis of Compounds
  • Certain synthetic schemes, both general and specific, are provided herein. The compounds disclosed herein can be made according to the methods described herein or intermediates that lead to the compounds disclosed herein can be made according to the methods described herein. The substitutions can be varied according to the compound or intermediate being made based upon the following examples and other modifications known to one of skill in the art.
  • The following compounds were prepared according to the following examples or the examples were varied according to one of skill in the art to prepare the compounds.
  • Com-
    pound
    Num- Chemical Exact Actual
    Structure ber Name Mass Peak
    Figure US20230234946A1-20230727-C00786
         		 1 1-cyclopentyl-5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 417.37 418.1
    Figure US20230234946A1-20230727-C00787
         		 2 5-(2-bromophenyl)-3-(1-ethyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 370.21 371
    Figure US20230234946A1-20230727-C00788
         		 3 1-(2-methylpropyl)-6-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 334.38 355.2
    Figure US20230234946A1-20230727-C00789
         		 4 1-cyclopentyl-5-{3-[4-(pyridin-3- ylmethoxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 506.49 507.2
    Figure US20230234946A1-20230727-C00790
         		 5 5-[3-(4-fluorophenyl)-1,2,4- oxadiazol-5-yl]-1-propyl-1H-1,2,3- benzotriazole 323.33 324.2
    Figure US20230234946A1-20230727-C00791
         		 6 5-[3-(5-methylpyrazin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 363.38 364.1
    Figure US20230234946A1-20230727-C00792
         		 7 1-cyclopentyl-5-(3-phenyl-1,2,4- oxadiazol-5-yl)-1H-1,2,3- benzotriazole 331.38 332.1
    Figure US20230234946A1-20230727-C00793
         		 8 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methylpyridin-4-yl)-1,2,4- oxadiazole 320.36 321
    Figure US20230234946A1-20230727-C00794
         		 9 5-[3-(5-phenylpyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 382.43 383.1
    Figure US20230234946A1-20230727-C00795
         		 10 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole 415.38 416.1
    Figure US20230234946A1-20230727-C00796
         		 11 1-cyclohexyl-5-[3-(3- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 359.43 360.2
    Figure US20230234946A1-20230727-C00797
         		 12 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (trifluoromethyl)phenyl)-1,2,4- oxadiazole 399.38 400.1
    Figure US20230234946A1-20230727-C00798
         		 13 4-[5-(1-cyclopentyl-1H-1,2,3- benzotriazol-5-yl)-1,2,4-oxadiazol- 3-yl]phenol 347.38 348.1
    Figure US20230234946A1-20230727-C00799
         		 14 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- isopropoxy-3- (trifluoromethyl)phenyl)-1,2,4- oxadiazole 457.46 458.1
    Figure US20230234946A1-20230727-C00800
         		 15 5-[3-(4-phenoxyphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 397.44 398.2
    Figure US20230234946A1-20230727-C00801
         		 16 3-(1-cyclopentyl-1H- benzo[d]1,2,3[triazol-5-yl)-5-(2- (methylthio)phenyl)-1,2,4-oxadiazole 377.47 378.1
    Figure US20230234946A1-20230727-C00802
         		 17 5-[3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 339.78 340.1
    Figure US20230234946A1-20230727-C00803
         		 18 5-(5-cyclobutyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole 283.34 284
    Figure US20230234946A1-20230727-C00804
         		 19 5-[3-(6-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 336.36 337.1
    Figure US20230234946A1-20230727-C00805
         		 20 3-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 431.42 432
    Figure US20230234946A1-20230727-C00806
         		 21 5-[4-(2-fluorophenyl)-l,3-oxazol-2- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 322.34 323
    Figure US20230234946A1-20230727-C00807
         		 22 2-isopropoxy-5-(3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 388.43 389
    Figure US20230234946A1-20230727-C00808
         		 23 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (phenoxymethyl)phenyl)-1,2,4- oxadiazole 411.47 412
    Figure US20230234946A1-20230727-C00809
         		 24 3-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 400.24 400
    Figure US20230234946A1-20230727-C00810
         		 25 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- isopropylpyridin-3-yl)-1,2,4- oxadiazole 348.41 349.3
    Figure US20230234946A1-20230727-C00811
         		 26 1-{5-[3-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol 379.42 380.1
    Figure US20230234946A1-20230727-C00812
         		 27 2,2-diethyl-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one 349.39 350.1
    Figure US20230234946A1-20230727-C00813
         		 28 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,3,4-oxadiazol-2-yl)chroman-4- one 349.39 350.1
    Figure US20230234946A1-20230727-C00814
         		 29 2,2-diethyl-6-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- thiadiazol-5-yl)chroman-4-one 447.56 448.2
    Figure US20230234946A1-20230727-C00815
         		 30 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N,N- dimethylbenzenesulfonamide 455.53 456.1
    Figure US20230234946A1-20230727-C00816
         		 31 2,2-diethyl-6-(3-(3-methylpyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.42 364.2
    Figure US20230234946A1-20230727-C00817
         		 32 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 349.35 350.1
    Figure US20230234946A1-20230727-C00818
         		 33 3-(1-isopropylbenzotriazol-5-yl)-5- [2-(trifluoromethyl)phenyl]-1,2,4- oxadiazole 373.34 374.1
    Figure US20230234946A1-20230727-C00819
         		 34 2,2-diethyl-6-(3-(5-methylthiophen- 2-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 368.45 369.3
    Figure US20230234946A1-20230727-C00820
         		 35 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 335.37 336
    Figure US20230234946A1-20230727-C00821
         		 36 4′,4′-difluoro-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospirol[1]-benzopyran-2,1′- cyclohexane]-4-one 397.38 298.1
    Figure US20230234946A1-20230727-C00822
         		 37 5-(4-fluorophenyl)-2-(1- isopropylbenzotriazol-5-yl)thiazole 338.40 339.2
    Figure US20230234946A1-20230727-C00823
         		 38 2,2-diethyl-6-(3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 379.42 380.1
    Figure US20230234946A1-20230727-C00824
         		 39 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 2-(prop-2-en-1-yl)-2H-1,2,3- benzotriazole 303.33 304.3
    Figure US20230234946A1-20230727-C00825
         		 40 5-(2-bromophenyl)-3-(1- cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 410.28 409.9
    Figure US20230234946A1-20230727-C00826
         		 41 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclohexane]-4- one 361.40 262.1
    Figure US20230234946A1-20230727-C00827
         		 42 3-(1-allyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- bromophenyl)-1,2,4-oxadiazole 382.22 382
    Figure US20230234946A1-20230727-C00828
         		 43 5-(2-bromophenvl)-3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole 384.24 384
    Figure US20230234946A1-20230727-C00829
         		 44 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methylpyrazin-2-yl)-1,2,4- oxadiazole 321.34 322.1
    Figure US20230234946A1-20230727-C00830
         		 45 5-(2-bromophenyl)-3-(1-(pyridin-2- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 433.27 435.1
    Figure US20230234946A1-20230727-C00831
         		 46 1-cyclopentyl-5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 351.43 352.1
    Figure US20230234946A1-20230727-C00832
         		 47 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- (methylthio)phenyl)-1,2,4- oxadiazole 377.47 378.1
    Figure US20230234946A1-20230727-C00833
         		 48 5-(2-bromophenyl)-3-(1-(pyridin-4- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 433.27 435
    Figure US20230234946A1-20230727-C00834
         		 49 5-{3-[4-(phenoxymethyl)phenyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 411.47 412.3
    Figure US20230234946A1-20230727-C00835
         		 50 5-[4-(4-chlorophenyl)-5-methyl- 1,3-oxazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 352.82 353
    Figure US20230234946A1-20230727-C00836
         		 51 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methoxypyrazin-2-yl)-1,2,4- oxadiazole 337.34 338
    Figure US20230234946A1-20230727-C00837
         		 52 3-(1-benzyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- bromophenyl)-1,2,4-oxadiazole 432.28 432
    Figure US20230234946A1-20230727-C00838
         		 53 5-{3-[4-(benzyloxy)phenyl]-1,2,4- oxadiazol-5-yl}-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 411.47 412.3
    Figure US20230234946A1-20230727-C00839
         		 54 5-[3-(3-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-propyl-1H-1,2,3- benzotriazole 319.37 320.2
    Figure US20230234946A1-20230727-C00840
         		 55 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4- methoxy-2-methylphenyl)-1,2,4- oxadiazole 349.39 350
    Figure US20230234946A1-20230727-C00841
         		 56 5-[3-(2-methyl-1-phenylpropyl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 361.45 362.1
    Figure US20230234946A1-20230727-C00842
         		 57 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 293.28 294.1
    Figure US20230234946A1-20230727-C00843
         		 58 4′,4′-dimethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[1-benzopyran-2,1′- cyclohexane]-4-one 389.46 390.2
    Figure US20230234946A1-20230727-C00844
         		 59 l-tert-butyl-5-[3-(2-methylphenyl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 333.40 334.1
    Figure US20230234946A1-20230727-C00845
         		 60 6-(3-(4-(dimethylamino)phenyl)- 1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one 391.47 392.3
    Figure US20230234946A1-20230727-C00846
         		 61 2-(allylamino)-5-(3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 371.40 372.1
    Figure US20230234946A1-20230727-C00847
         		 62 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 363.42 364.1
    Figure US20230234946A1-20230727-C00848
         		 63 5-(2-fluorophenyl)-2-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)thiazole 338.40 339.1
    Figure US20230234946A1-20230727-C00849
         		 64 5-(3-fluorophenyl)-3-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole 323.33 324.1
    Figure US20230234946A1-20230727-C00850
         		 65 2,2-diethyl-6-(3-(4- methoxyphenyl)-1,2,4-oxadiazol-5- yl)chroman-4-one 378.43 379.1
    Figure US20230234946A1-20230727-C00851
         		 66 2,2-diethyl-6-(3-(o-tolyl)-1,2,4- oxadiazol-5-yl)chroman-4-one 362.43 363.1
    Figure US20230234946A1-20230727-C00852
         		 67 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,3,4- thiadiazol-2-yl)chroman-4-one 447.56 448.1
    Figure US20230234946A1-20230727-C00853
         		 68 6-[3-(4-chlorophenyl)-1,2,4- oxadiazol-5-yl]-2,2-diethyl- chroman-4-one 382.84 383.1
    Figure US20230234946A1-20230727-C00854
         		 69 3-(1-isopropylbenzotriazol-5-yl)-5- (4-methoxyphenyl)-1,2,4- oxadiazole 335.37 336.1
    Figure US20230234946A1-20230727-C00855
         		 70 2-{5-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3,4-thiadiazol- 2-yl}phenol 337.40 338
    Figure US20230234946A1-20230727-C00856
         		 71 2,2-diethyl-6-(3-(3- methoxyphenyl)-1,2,4-oxadiazol-5- yl)chroman-4-one 378.43 379.1
    Figure US20230234946A1-20230727-C00857
         		 72 2,2-diethyl-6-[3-(4- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 364.40 365.1
    Figure US20230234946A1-20230727-C00858
         		 73 5-(2-bromophenyl)-3-(1-methyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole 356.18 356
    Figure US20230234946A1-20230727-C00859
         		 74 5-[5-(5-methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 325.39 326.1
    Figure US20230234946A1-20230727-C00860
         		 75 1-(2-methylpropyl)-5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 339.42 340.1
    Figure US20230234946A1-20230727-C00861
         		 76 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl-1-propyl-1H-1,2,3- benzotriazole 333.40 334.3
    Figure US20230234946A1-20230727-C00862
         		 77 5-[3-(2-methoxypyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1-methyl-2,3- dihydro-1H-1,2,3-benzotriazole; cyclopentane 346.39 347.1
    Figure US20230234946A1-20230727-C00863
         		 78 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- (pyrazin-2-yl)-1,2,4-oxadiazole 307.32 308
    Figure US20230234946A1-20230727-C00864
         		 79 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1-(propan-2-yl)-1H-1,2,3- benzotriazole 305.34 306.3
    Figure US20230234946A1-20230727-C00865
         		 80 1-cyclopentyl-5-{3-[4- (difluoromethoxy)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 397.39 398.1
    Figure US20230234946A1-20230727-C00866
         		 81 methyl 2-(5-(5-(2-bromophenyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)acetate 414.22 414.1
    Figure US20230234946A1-20230727-C00867
         		 82 5-[3-(5-chlorothiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 387.84 388
    Figure US20230234946A1-20230727-C00868
         		 83 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-cyclopropyl-1H- 1,2,3-benzotriazole 382.22 382.2
    Figure US20230234946A1-20230727-C00869
         		 84 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole 415.38 416
    Figure US20230234946A1-20230727-C00870
         		 85 5-{3-[4-(benzyloxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-cyclopropyl-1H- 1,2,3-benzotriazole 477.45 478.2
    Figure US20230234946A1-20230727-C00871
         		 86 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methylpyridin-4-yl)-1,2,4- oxadiazole 322.37 321.1
    Figure US20230234946A1-20230727-C00872
         		 87 1-cyclopropyl-5-[3-(6- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 318.34 319.1
    Figure US20230234946A1-20230727-C00873
         		 88 5-(3-benzyl-1,2,4-oxadiazol-5-yl)- 1-(propan-2-yl)-1H-1,2,3- benzotriazole 319.37 320.1
    Figure US20230234946A1-20230727-C00874
         		 89 5-[5-(oxan-4-yl)-1,2,4-oxadiazol-3- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 313.36 314
    Figure US20230234946A1-20230727-C00875
         		 90 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxy-2-methylphenyl)-1,2,4- oxadiazole 349.39 350.1
    Figure US20230234946A1-20230727-C00876
         		 91 l-cyclopentyl-5-[3-(4- methoxynaphthalen-1-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 411.47 412.2
    Figure US20230234946A1-20230727-C00877
         		 92 5-(3-benzyl-1,2,4-oxadiazol-5-yl)- 1-cyclopentyl-1H-1,2,3- benzotriazole 345.41 346.1
    Figure US20230234946A1-20230727-C00878
         		 93 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 375.43 376.2
    Figure US20230234946A1-20230727-C00879
         		 94 1-cyclopropyl-5-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 318.34 319.3
    Figure US20230234946A1-20230727-C00880
         		 95 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 361.41 362.1
    Figure US20230234946A1-20230727-C00881
         		 96 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(2- methylpropyl)-1H-1,2,3- benzotriazole 333.40 334.2
    Figure US20230234946A1-20230727-C00882
         		 97 3-(1H-benzo[d][1,2,3]triazol-5-yl)- 5-(2-bromophenyl)-1,2,4- oxadiazole 342.16 343.9
    Figure US20230234946A1-20230727-C00883
         		 98 5-(2-bromophenyl)-3-(1- (cyclopropylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 396.25 396
    Figure US20230234946A1-20230727-C00884
         		 99 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole 319.37 320
    Figure US20230234946A1-20230727-C00885
         		100 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methylpyridin-3-yl)-1,2,4- oxadiazole 320.36 321.1
    Figure US20230234946A1-20230727-C00886
         		101 5-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 320.36 321.1
    Figure US20230234946A1-20230727-C00887
         		102 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 293.28 294.1
    Figure US20230234946A1-20230727-C00888
         		103 2,2-diethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]3,4-dihydro- 2H-1-benzopyran-4-one 349.39 350.2
    Figure US20230234946A1-20230727-C00889
         		104 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)chroman-4- one 365.45 366.1
    Figure US20230234946A1-20230727-C00890
         		105 2,2-diethyl-6-[3-(6-hydroxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 365.39 366.1
    Figure US20230234946A1-20230727-C00891
         		106 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)benzene sulfonamide 427.48 428.1
    Figure US20230234946A1-20230727-C00892
         		107 2-(isopropylamino)-5-(3-(2- oxoindolin-5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile 359.39 360.1
    Figure US20230234946A1-20230727-C00893
         		108 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxyphenyl)thiazole 350.44 351.2
    Figure US20230234946A1-20230727-C00894
         		109 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxyphenyl)thiazole 350.44 351.1
    Figure US20230234946A1-20230727-C00895
         		110 5-(3-fluorophenyl)-2-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)thiazole 338.40 339.1
    Figure US20230234946A1-20230727-C00896
         		111 2,2-diethyl-6-[3-(2-pyridyl)-1,2,4- oxadiazol-5-yl]chroman-4-one 349.39 350.1
    Figure US20230234946A1-20230727-C00897
         		112 2-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl-1,2,4-thiadiazol- 5-yl}phenol 337.40 338
    Figure US20230234946A1-20230727-C00898
         		113 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1H-1,2,3-benzotriazole 263.26 264.1
    Figure US20230234946A1-20230727-C00899
         		114 5-{3-[4-bromo-2- (trifluorornethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-cyclopentyl-1H- 1,2,3-benzotriazole 478.27 478.1
    Figure US20230234946A1-20230727-C00900
         		115 5-(2-bromophenyl)-3-(1- cyclohexyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 424.30 426
    Figure US20230234946A1-20230727-C00901
         		116 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxypyridin-4-yl)-1,2,4- oxadiazole 336.36 337
    Figure US20230234946A1-20230727-C00902
         		117 1-cyclohexyl-5-[3-(4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 359.43 360.1
    Figure US20230234946A1-20230727-C00903
         		118 1-cyclopentyl-5-{3-[3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 399.38 400.1
    Figure US20230234946A1-20230727-C00904
         		119 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- methylpyridin-3-yl)-1,2,4- oxadiazole 320.36 321.1
    Figure US20230234946A1-20230727-C00905
         		120 3-(1-cyclopentyl-1H- benzo[d]|[1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)-1,2,4- oxadiazole 361.41 362
    Figure US20230234946A1-20230727-C00906
         		121 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- isopropoxyphenyl)-1,2,4- oxadiazole 389.46 390.3
    Figure US20230234946A1-20230727-C00907
         		122 5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-(3-methylbutyl)- 1H-1,2,3-benzotriazole 419.38 420.2
    Figure US20230234946A1-20230727-C00908
         		123 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 345.41 346.2
    Figure US20230234946A1-20230727-C00909
         		124 1-cyclopentyl-5-[3-(6- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 362.39 363.1
    Figure US20230234946A1-20230727-C00910
         		125 5-[5-(4,4-difluorocyclohexyl)- 1,2,4-oxadiazol-3-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 347.37 348
    Figure US20230234946A1-20230727-C00911
         		126 5-{3-[(3,5-dimethylphenyl)methyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 347.42 348.3
    Figure US20230234946A1-20230727-C00912
         		127 5-(5-cyclohexyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole 311.39 312
    Figure US20230234946A1-20230727-C00913
         		128 1-(propan-2-yl)-5-(3- {[1,2,4]triazolo[4,3-a]pyridin-6- yl}-1,2,4-oxadiazol-5-yl)-1H-1,2,3- benzotriazole 346.35 347.1
    Figure US20230234946A1-20230727-C00914
         		129 5-[3-(4-methoxynaphthalen-1-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 385.43 386.2
    Figure US20230234946A1-20230727-C00915
         		130 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxyphenyl)-1,2,4-oxadiazole 361.41 362
    Figure US20230234946A1-20230727-C00916
         		131 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- (phenoxymethyl)phenyl)-1,2,4- oxadiazole 411.47 412
    Figure US20230234946A1-20230727-C00917
         		132 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole 389.34 390
    Figure US20230234946A1-20230727-C00918
         		133 5-(5,6-dimethylpyrazin-2-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 335.37 356.1
    Figure US20230234946A1-20230727-C00919
         		134 3-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1- yl)propanoic acid 414.22 413.9
    Figure US20230234946A1-20230727-C00920
         		135 5-[3-(2-ethylpyrimidin-5-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 335.37 336.1
    Figure US20230234946A1-20230727-C00921
         		136 5-[3-(2,4-dimethoxy-6- methylphenyl)-1,2,4-oxadiazol-5- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 379.42 380.3
    Figure US20230234946A1-20230727-C00922
         		137 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,2,4-thiadiazol-3-yl)chroman-4- one 365.45 366
    Figure US20230234946A1-20230727-C00923
         		138 5-[5-(2-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 351.43 302
    Figure US20230234946A1-20230727-C00924
         		139 2-methyl-1-{5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1- yl}propan-2-ol 349.39 350.1
    Figure US20230234946A1-20230727-C00925
         		140 2-methyl-1-{5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol 355.42 356.1
    Figure US20230234946A1-20230727-C00926
         		141 5-(3-(1H-indazol-5-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile 342.36 343.1
    Figure US20230234946A1-20230727-C00927
         		142 5-(1-isopropyl-1H-indol-5-yl)-5-(3- methylpyridin-4-yl)-1,2,4- oxadiazole 318.38 318.15
    Figure US20230234946A1-20230727-C00928
         		143 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- thiadiazol-3-yl)chroman-4-one 447.56 448.1
    Figure US20230234946A1-20230727-C00929
         		144 5-[5-(2-methoxyphenyl)-1,3,4- thiadiazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 351.43 352
    Figure US20230234946A1-20230727-C00930
         		145 5-(3-(1H-benzo[d][1,2,3]triazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- (allylamino)benzonitrile 343.35 344.1
    Figure US20230234946A1-20230727-C00931
         		146 2,2-diethyl-6-(3-(2-fluoropyridin-4- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one 367.38 368.1
    Figure US20230234946A1-20230727-C00932
         		147 2,2-diethyl-6-(3-(2- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 379.42 380.2
    Figure US20230234946A1-20230727-C00933
         		148 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,4′-oxane]-4-one 363.37 364.1
    Figure US20230234946A1-20230727-C00934
         		149 N-(4-(5-(4-(allylamino)-3- cyanophenyl)-1,2,4-oxadiazol-3- yl)phenyl)methanesulfonamide 395.44 396.1
    Figure US20230234946A1-20230727-C00935
         		150 2-(allylamino)-5-(3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 385.43 368.3
    Figure US20230234946A1-20230727-C00936
         		151 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N,N- dimethylbenzamide 419.48 420.2
    Figure US20230234946A1-20230727-C00937
         		152 6-(3-(1H-indazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 388.43 389.2
    Figure US20230234946A1-20230727-C00938
         		153 2,2-diethyl-6-(3-(4- (methylamino)phenyl)-1,2,4- oxadiazol-5-yl)chroman-4-one 377.44 378.2
    Figure US20230234946A1-20230727-C00939
         		154 5-{3-[1-(2-methylphenyl)ethyl]- 1,2,4-oxadiazol-5-yl}-1-(2- methylpropyl)-1H-1,2,3- benzotriazole 361.45 362.2
    Figure US20230234946A1-20230727-C00940
         		155 1-cyclopropyl-5-[3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 334.34 335.1
    Figure US20230234946A1-20230727-C00941
         		156 5-(2,6-dimethylpyridin-4-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 334.38 335.2
    Figure US20230234946A1-20230727-C00942
         		157 5-[3-(5-methylpyrazin-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 321.34 322.1
    Figure US20230234946A1-20230727-C00943
         		158 1-cyclohexyl-5-[3-(3,5- dimethylphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole 373.46 374.2
    Figure US20230234946A1-20230727-C00944
         		159 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methylpyridin-3-yl)-1,2,4- oxadiazole 320.36 321.1
    Figure US20230234946A1-20230727-C00945
         		160 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1-propyl-1H-1,2,3-benzotriazole 305.34 306.1
    Figure US20230234946A1-20230727-C00946
         		161 methyl 3-(5-(5-(2-bromophenyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1- yl)propanoate 428.25 429.9
    Figure US20230234946A1-20230727-C00947
         		162 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole 2445.41 346.1
    Figure US20230234946A1-20230727-C00948
         		163 5-[4-(2-chlorophenyl)-2,3-dihydro- 1,3-oxazol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 338.80 339
    Figure US20230234946A1-20230727-C00949
         		164 1-cyclopentyl-5-[3-(4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 345.41 346.3
    Figure US20230234946A1-20230727-C00950
         		165 1-(propan-2-yl)-5-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 306.33 307.3
    Figure US20230234946A1-20230727-C00951
         		166 5-(2,4-dimethylphenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 333.40 334.2
    Figure US20230234946A1-20230727-C00952
         		167 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- isopropylpyridin-4-yl)-1,2,4- oxadiazole 348.41 349.1
    Figure US20230234946A1-20230727-C00953
         		168 2-{5-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}quinoline 356.39 357.1
    Figure US20230234946A1-20230727-C00954
         		169 5-[3-(3-methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 325.39 326.1
    Figure US20230234946A1-20230727-C00955
         		170 5-[3-(5-chlorothiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 345.81 346.1
    Figure US20230234946A1-20230727-C00956
         		171 1-cyclopropyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 317.35 318.3
    Figure US20230234946A1-20230727-C00957
         		172 5-{3-[1-(2-methylphenyl)ethyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 347.42 348.1
    Figure US20230234946A1-20230727-C00958
         		173 1-cyclopropyl-5-[3-(2- methoxyphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole 333.35 334.2
    Figure US20230234946A1-20230727-C00959
         		174 1-cyclopentyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 332.37 333.1
    Figure US20230234946A1-20230727-C00960
         		175 1-cyclopentyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 345.41 346.2
    Figure US20230234946A1-20230727-C00961
         		176 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclopentane]-4- one 347.37 348.1
    Figure US20230234946A1-20230727-C00962
         		177 5-(3-(1H-benzo[d]imidazol-5-yl)- 1,2,4-oxadiazol-5-yl)-2- (allylamino)benzonitrile 346.36 343.1
    Figure US20230234946A1-20230727-C00963
         		178 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,3,4-thiadiazol-2- yl)chroman-4-one 394.49 395.2
    Figure US20230234946A1-20230727-C00964
         		179 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)benzamide 391.43 392.1
    Figure US20230234946A1-20230727-C00965
         		180 2-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-3-yl)phenol 321.34 322.1
    Figure US20230234946A1-20230727-C00966
         		181 N-(benzo[d]isoxazol-3-yl)-1- isopropyl-1H- benzo[d][1,2,3]triazole-5- carboxamide 321.34 322.1
    Figure US20230234946A1-20230727-C00967
         		182 1-(2,2-difIuoroethyl)-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 341.32 342.1
    Figure US20230234946A1-20230727-C00968
         		183 5-[4-(2-bromophenyl)-1,3-oxazol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 383.25 383
    Figure US20230234946A1-20230727-C00969
         		184 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)thiazole 350.44 351
    Figure US20230234946A1-20230727-C00970
         		185 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylbenzamide 405.45 406.1
    Figure US20230234946A1-20230727-C00971
         		186 2,2-bis(methoxymethyl)-6-[3- (pyridin-3-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one 381.39 282.2
    Figure US20230234946A1-20230727-C00972
         		187 2,2-diethyl-6-[3-(2- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 364.40 365.1
    Figure US20230234946A1-20230727-C00973
         		188 2,2-dibutyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one 405.50 406.2
    Figure US20230234946A1-20230727-C00974
         		189 2-(allylamino)-5-(3-(2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 359.35 360.1
    Figure US20230234946A1-20230727-C00975
         		190 5-[3-(2-bromophenvl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 342.16 342
    Figure US20230234946A1-20230727-C00976
         		192 1-cyclopentyl-5-[3-(5- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 351.43 352.1
    Figure US20230234946A1-20230727-C00977
         		193 5-{3-[3-fluoro-4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-propyl-1H-1,2,3- benzotriazole 391.33 392.1
    Figure US20230234946A1-20230727-C00978
         		194 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methylpyridin-3-yl)-1,2,4- oxadiazole 320.36 321
    Figure US20230234946A1-20230727-C00979
         		195 2-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)acetic acid 400.19 400
    Figure US20230234946A1-20230727-C00980
         		196 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxyphenyl)-1,2,4-oxadiazole 361.41 362
    Figure US20230234946A1-20230727-C00981
         		197 1-cyclopentyl-5-{3-[4-methoxy-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 429.40 430.1
    Figure US20230234946A1-20230727-C00982
         		198 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-cyclopentyl-1H- 1,2,3-benzotriazole 366.81 367.1
    Figure US20230234946A1-20230727-C00983
         		199 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1- (cyclopropylmethyl)-1H-1,2,3- benzotriazole 352.78 353.1
    Figure US20230234946A1-20230727-C00984
         		200 5-[5-(adamantan-1-yl)-1,2,4- oxadiazol-3-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 363.47 364
    Figure US20230234946A1-20230727-C00985
         		201 5-(5,6-dimethylpyridin-3-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 334.38 335.1
    Figure US20230234946A1-20230727-C00986
         		202 5-{3-[(2-methylphenyl)methyl]- 1,2,4-oxadiazol-5-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 333.40 334.1
    Figure US20230234946A1-20230727-C00987
         		203 1-cyclopentyl-5-[3-(3- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 362.39 363.1
    Figure US20230234946A1-20230727-C00988
         		204 5-[3-(3,5-dimethylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 333.40 334.1
    Figure US20230234946A1-20230727-C00989
         		205 1-propyl-5-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 306.33 307.1
    Figure US20230234946A1-20230727-C00990
         		206 2-methyl-1-{5-[3-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}propan-2- ol 350.38 351.1
    Figure US20230234946A1-20230727-C00991
         		207 1-tert-butyl-5-[3-(2- methoxyphenyl)-1,2,4-oxadiazol- 5-yl]-1H-1,2,3-benzotriazole 349.39 350.2
    Figure US20230234946A1-20230727-C00992
         		208 5-(3-(1H-indol-5-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile 341.37 342.2
    Figure US20230234946A1-20230727-C00993
         		209 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)phenyl)acetamide 405.45 406.2
    Figure US20230234946A1-20230727-C00994
         		210 2-((cyclopropylmethyl)amino)-5- (3-(2-oxoindolin-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 371.40 372.1
    Figure US20230234946A1-20230727-C00995
         		211 6-(3-(1H-benzo[d]imidazol-5-yl)- 1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one 388.43 389.1
    Figure US20230234946A1-20230727-C00996
         		212 2,2-diethyl-6-(3-(3- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 379.42 380.2
    Figure US20230234946A1-20230727-C00997
         		213 5-[3-(2-methoxyphenyl)-1,2,4- thiadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 351.43 352
    Figure US20230234946A1-20230727-C00998
         		214 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,4′-oxane]-4-one 363.37 364.1
    Figure US20230234946A1-20230727-C00999
         		215 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethyl)phenyl)thiazole 388.41 389.2
    Figure US20230234946A1-20230727-C01000
         		216 2-(1-isopropylbenzotriazol-5-yl)-5- (o-tolyl)thiazole 334.44 335.1
    Figure US20230234946A1-20230727-C01001
         		217 4′,4′-difluoro-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[1-benzopyran-2,1′- cyclohexane]-4-one 397.38 398.2
    Figure US20230234946A1-20230727-C01002
         		218 2,2-dipropyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one 377.44 378.2
    Figure US20230234946A1-20230727-C01003
         		219 5-{8H-indeno[1,2-d][1,3]oxazol-2- yl}-1-(propan-2-yl)-1H-1,2,3- benzotriazole 316.36 317
    Figure US20230234946A1-20230727-C01004
         		220 5-(2-bromophenyl)-2-(1- isopropylbenzotriazol-5-yl)thiazole 399.31 401
    Figure US20230234946A1-20230727-C01005
         		221 6-(3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 382.84 383.1
    Figure US20230234946A1-20230727-C01006
         		222 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,2,4-thiadiazol-3- yl)chroman-4-one 394.49 395.1
    Figure US20230234946A1-20230727-C01007
         		223 2,2-diethyl-6-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,3,4- oxadiazol-2-yl)chroman-4-one 431.50 432.2
    Figure US20230234946A1-20230727-C01008
         		224 2-(allylamino)-5-(3-(2-oxoindolin- 5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile 357.37 358.1
    Figure US20230234946A1-20230727-C01009
         		225 2,2-diethyl-6-(3-(m-tolyl)-1,2,4- oxadiazol-5-yl)chroman-4-one 362.43 363.1
    Figure US20230234946A1-20230727-C01010
         		226 2,2-diethyl-6-(3-(3-fluoropyridin-4- yl)-1,2,4-oxadiazol-5-yl) chroman-4-one 367.38 368.1
    Figure US20230234946A1-20230727-C01011
         		227 2,2-diethyl-6-[3-(3- hydroxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 364.40 365.1
    Figure US20230234946A1-20230727-C01012
         		228 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxyphenyl)-1,2,4-oxadiazole 335.37 336
    Figure US20230234946A1-20230727-C01013
         		229 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(6- methylpyrazin-2-yl)-1,2,4- oxadiazole 321.34 322.1
    Figure US20230234946A1-20230727-C01014
         		230 3-(3,4-dimethoxyphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 365.39 366
    Figure US20230234946A1-20230727-C01015
         		231 5-[3-(2-methoxyphenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 377.40 378.2
    Figure US20230234946A1-20230727-C01016
         		232 1-cyclopentyl-5-[3-(4- fluorophenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 349.37 350.2
    Figure US20230234946A1-20230727-C01017
         		233 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 426.27 426.1
    Figure US20230234946A1-20230727-C01018
         		234 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methylpyrazin-2-yl)-1,2,4- oxadiazole 321.34 322.1
    Figure US20230234946A1-20230727-C01019
         		235 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(p- tolyl)-1,2,4-oxadiazole 345.41 346
    Figure US20230234946A1-20230727-C01020
         		236 5-[3-(6-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 320.36 321.1
    Figure US20230234946A1-20230727-C01021
         		237 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- (methylthio)phenyl)-1,2,4- oxadiazole 377.47 378.1
    Figure US20230234946A1-20230727-C01022
         		238 2-(5-(5-(2-bromophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)ethanol 386.21 386
    Figure US20230234946A1-20230727-C01023
         		239 1-(cyclopropylmethyl)-5[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 337.40 338.2
    Figure US20230234946A1-20230727-C01024
         		240 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole 389.34 390
    Figure US20230234946A1-20230727-C01025
         		241 1-(propan-2-yl)-5-[3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 306.33 307.2
    Figure US20230234946A1-20230727-C01026
         		242 1-propyl-5-{3-[3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 373.34 374.3
    Figure US20230234946A1-20230727-C01027
         		243 3-(2,6-dimethylphenyl)-5-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 333.40 334
    Figure US20230234946A1-20230727-C01028
         		244 1-(propan-2-yl)-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 306.33 307.1
    Figure US20230234946A1-20230727-C01029
         		245 1-cyclohexyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 359.43 360.2
    Figure US20230234946A1-20230727-C01030
         		246 5-(4-isopropoxy-3- (trifluoromethyl)phenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 431.42 432
    Figure US20230234946A1-20230727-C01031
         		247 5-(5-methyl-4-phenyl-1,3-oxazol-2- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole 318.38 319
    Figure US20230234946A1-20230727-C01032
         		248 5-([1,1′-biphenyl]-4-yl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 381.44 382.1
    Figure US20230234946A1-20230727-C01033
         		249 1-(propan-2-yl)-5-[3-(pyrimidin-5- yl)-1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 307.32 308.1
    Figure US20230234946A1-20230727-C01034
         		250 5-[4-(4-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole 334.38 335
    Figure US20230234946A1-20230727-C01035
         		251 3-(2,6-dimethoxyphenyl)-5-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole 365.39 366.1
    Figure US20230234946A1-20230727-C01036
         		252 5-(3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl)-2- (allylamino)benzonitrile 292.30 293.1
    Figure US20230234946A1-20230727-C01037
         		253 1-tert-butyl-5-[3-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 339.42 340.1
    Figure US20230234946A1-20230727-C01038
         		254 4′,4′-dimethyl-6[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4- dihydrospiro[1-benzopyran-2,1′- cyclohexane]-4-one 389.46 390.2
    Figure US20230234946A1-20230727-C01039
         		255 5-(4-fluorophenyl)-3-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole 323.33 324.1
    Figure US20230234946A1-20230727-C01040
         		256 6-(3-(4-aminophenyl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 363.42 364.2
    Figure US20230234946A1-20230727-C01041
         		257 2,2-diethyl-6-(3-(2- methoxyphenyl)-1,2,4-thiadiazol-5- yl)chroman-4-one 394.49 395.1
    Figure US20230234946A1-20230727-C01042
         		258 2,2-diethyl-6-(3-(2-hydroxypyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 365.39 366.3
    Figure US20230234946A1-20230727-C01043
         		259 2-(isopropylamino)-5-(3-(2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 373.42 374.1
    Figure US20230234946A1-20230727-C01044
         		260 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylbenzotriazol-5-yl)- 1,2,4-oxadiazole 353.36 354.1
    Figure US20230234946A1-20230727-C01045
         		261 6-[3-(3-chlorophenyl)-1,2,4- oxadiazol-5-yl]-2,2-diethyl- chroman-4-one 382.84 383.1
    Figure US20230234946A1-20230727-C01046
         		262 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)phenyl)methanesulfonamide 441.50 442
    Figure US20230234946A1-20230727-C01047
         		263 2,2-diethyl-6-[3-(2-hydroxy-4- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 365.39 366.1
    Figure US20230234946A1-20230727-C01048
         		264 6-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 320.36 321.1
    Figure US20230234946A1-20230727-C01049
         		265 2,2-diethyl-6-(3-(3-methylthiophen- 2-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 368.45 369.1
    Figure US20230234946A1-20230727-C01050
         		266 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylbenzenesulfonamide 441.50 442.1
    Figure US20230234946A1-20230727-C01051
         		267 2-(allylamino)-5-(3-(2- aminobenzo[d]thiazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 374.42 375.3
    Figure US20230234946A1-20230727-C01052
         		268 2,2-diethyl-6-[3-(2- methoxyphenyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 378.43 379.1
    Figure US20230234946A1-20230727-C01053
         		269 2,2-diethyl-6-[3-(p-tolyl)-1,2,4- oxadiazol-5-yl]chroman-4-one 362.43 363.1
    Figure US20230234946A1-20230727-C01054
         		270 5-(3-phenyl-1,2,4-oxadiazol-5-yl)- 1-(prop-2-en-1-yl)-1H-1,2,3- benzotriazole 303.33
    Figure US20230234946A1-20230727-C01055
         		271 1-(3-methylbutyl)-5-(3-phenyl- 1,2,4-oxadiazol-5-yl)-1H-1,2,3- benzotriazole 333.40 334.2
    Figure US20230234946A1-20230727-C01056
         		272 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(5- methoxypyridin-3-yl)-1,2,4- oxadiazole 336.36 337.1
    Figure US20230234946A1-20230727-C01057
         		273 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(m- tolyl)-1,2,4-oxadiazole 345.41 346
    Figure US20230234946A1-20230727-C01058
         		274 2,2-dimethyl-6-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one 321.34 322.1
    Figure US20230234946A1-20230727-C01059
         		275 3-(1-cyclopentyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3,4- dimethoxyphenyl)-1,2,4-oxadiazole 391.43 392.1
    Figure US20230234946A1-20230727-C01060
         		276 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- (methylthio)phenyl)-1,2,4- oxadiazole 351.43 352.1
    Figure US20230234946A1-20230727-C01061
         		277 5-[4-(2-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole 334.38 335
    Figure US20230234946A1-20230727-C01062
         		278 5-(5-cyclopentyl-1,2,4-oxadiazol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole5-(5-cyclopentyl- 1,2,4-oxadiazol-3-yl)-1-(propan-2- yl)-1H-1,2,3-benzotriazole 297.36 298
    Figure US20230234946A1-20230727-C01063
         		279 2-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 330.35 331
    Figure US20230234946A1-20230727-C01064
         		280 6-[3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclohexane]-4- one 361.40 362.1
    Figure US20230234946A1-20230727-C01065
         		281 1-cyclopentyl-5-[3-(2- methoxypyridin-4-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 362.39 363.1
    Figure US20230234946A1-20230727-C01066
         		282 5-[3-(2-bromophenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 384.24 384.2
    Figure US20230234946A1-20230727-C01067
         		283 5-(2-bromophenyl)-3-(1-(pyridin-3- ylmethyl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 433.27 434.9
    Figure US20230234946A1-20230727-C01068
         		284 1-cyclohexyl-5-{3-[4-methoxy-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1H-1,2,3- benzotriazole 443.43 444.2
    Figure US20230234946A1-20230727-C01069
         		285 1-cyclopropyl-5-[3-(4- phenoxyphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 395.42 396.2
    Figure US20230234946A1-20230727-C01070
         		286 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 335.37 356
    Figure US20230234946A1-20230727-C01071
         		287 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxyphenyl)-1,2,4-oxadiazole 335.37 356
    Figure US20230234946A1-20230727-C01072
         		288 1-(cyclopropylmethyl)-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 331.38 332.2
    Figure US20230234946A1-20230727-C01073
         		289 5-[3-(2-chlorophenyl)-1,2,4- oxadiazol-5-yl]-1-(2- methylpropyl)-1H-1,2,3- benzotriazole 353.81 354.2
    Figure US20230234946A1-20230727-C01074
         		290 5-(4-cyclohexylphenyl)-3-(1- isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazole 387.49 388.1
    Figure US20230234946A1-20230727-C01075
         		291 2,2-dimethyl-6-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-3,4-dihydro- 2H-1-benzopyran-4-one 321.34 322.1
    Figure US20230234946A1-20230727-C01076
         		292 1-cyclohexyl-5-(3-phenyl-1,2,4- oxadiazol-5-yl)-1H-1,2,3- benzotriazole 345.41 346.3
    Figure US20230234946A1-20230727-C01077
         		293 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 319.37 320.3
    Figure US20230234946A1-20230727-C01078
         		294 5-(4-phenyl-1,3-oxazol-2-yl)-1- (propan-2-yl)-1H-1,2,3- benzotriazole 304.35 305
    Figure US20230234946A1-20230727-C01079
         		295 1-cyclopropyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazole 304.31 305.2
    Figure US20230234946A1-20230727-C01080
         		296 5-{3-[4-(benzyloxy)-3- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl}-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 479.46 480.2
    Figure US20230234946A1-20230727-C01081
         		297 5-{4H,5H-naphtho[2,1- d][1,3]oxazol-2-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 330.39 331
    Figure US20230234946A1-20230727-C01082
         		298 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydrospiro[1- benzopyran-2,1′-cyclopentane]-4- one 347.37 348.1
    Figure US20230234946A1-20230727-C01083
         		299 3-(1-isopropylbenzotriazol-5-yl)-5- (3-methoxyphenyl)-1,2,4- oxadiazole 335.37 336.1
    Figure US20230234946A1-20230727-C01084
         		300 2,2-diethyl-6-(5-(2- methoxyphenyl)-1,3,4-oxadiazol-2- yl)chroman-4-one 378.43 379.3
    Figure US20230234946A1-20230727-C01085
         		301 2,2-diethyl-6-[3-(6-methoxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 379.42 380.3
    Figure US20230234946A1-20230727-C01086
         		302 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 385.43 386.2
    Figure US20230234946A1-20230727-C01087
         		303 2,2-diethyl-6-(3-(4- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 379.42 380.3
    Figure US20230234946A1-20230727-C01088
         		304 3-chroman-8-yl-5-(1- isopropylbenzotriazol-5-yl)-1,2,4- oxadiazole 361.41 362.1
    Figure US20230234946A1-20230727-C01089
         		305 2,2-diethyl-6-(3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 431.50 432.2
    Figure US20230234946A1-20230727-C01090
         		306 1-cyclobutyl-5-[3-(2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazole 331.38 332.1
    Figure US20230234946A1-20230727-C01091
         		307 5-(2-fluorophenyl)-3-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5-yl)- 1,2,4-oxadiazole 323.33 324
    Figure US20230234946A1-20230727-C01092
         		308 6-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 319.37 320.1
    Figure US20230234946A1-20230727-C01093
         		309 2,2-diethyl-6-(3-(pyridin-3-yl)- 1,2,4-thiadiazol-5-yl)chroman-4- one 365.45 366
    Figure US20230234946A1-20230727-C01094
         		310 2,2-diethyl-6-[3-(5-hydroxy-3- pyridyl)-1,2,4-oxadiazol-5- yl]chroman-4-one 365.39 366.1
    Figure US20230234946A1-20230727-C01095
         		311 2,2-diethyl-6-(3-(5- methoxypyridin-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 379.42 380.1
    Figure US20230234946A1-20230727-C01096
         		312 2,2-diethyl-6-(3-(3-hydroxypyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 365.39 366
    Figure US20230234946A1-20230727-C01097
         		313 2,2-diethyl-6-(3-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.39 418
    Figure US20230234946A1-20230727-C01098
         		314 2,2-diethyl-6-(3-(2- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.39 418
    Figure US20230234946A1-20230727-C01099
         		315 2,2-diethyl-6-(3-(2-methylpyridin- 4-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.42 364.1
    Figure US20230234946A1-20230727-C01100
         		316 N-(4-(5-(3-cyano-4- (isopropylamino)phenyl)-1,2,4- oxadiazol-3-yl)phenyl)acetamide 361.41 362.1
    Figure US20230234946A1-20230727-C01101
         		320 3-(2-chlorophenyl)-5-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 337.81 338
    Figure US20230234946A1-20230727-C01102
         		321 5-(1-isopropyl-1H-indol-5-yl)-3-(2- (trifluoromethoxy)phenyl)-1,2,4- oxadiazole 387.36 388.1
    Figure US20230234946A1-20230727-C01103
         		322 3-(2-bromophenyl)-5-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 382.26 384
    Figure US20230234946A1-20230727-C01104
         		323 2-(5-(1-isopropyl-1H-indol-5-yl)- 1,2,4-oxadiazol-3-yl)phenol 319.36 320.1
    Figure US20230234946A1-20230727-C01105
         		324 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole 361.45 362.1
    Figure US20230234946A1-20230727-C01106
         		325 3-(2,6-dimethoxyphenyl)-5-(1- isopropylindol-5-yl)-1,2,4- oxadiazole 363.42 364.1
    Figure US20230234946A1-20230727-C01107
         		326 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole 347.37 348.1
    Figure US20230234946A1-20230727-C01108
         		327 3-chroman-8-yl-5-(1- isopropylindol-5-yl)-1,2,4- oxadiazole 359.43 360.1
    Figure US20230234946A1-20230727-C01109
         		328 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylindol-5-yl)-1,2,4- oxadiazole 351.38 352.1
    Figure US20230234946A1-20230727-C01110
         		329 5-(1-isopropyl-1H-indazol-5-yl)-3- (o-tolyl)-1,2,4-oxadiazole 318.38 319.1
    Figure US20230234946A1-20230727-C01111
         		330 3-(2-chlorophenyl)-5-(1-isopropyl- 1H-indazol-5-yl)-1,2,4-oxadiazole 338.80 339
    Figure US20230234946A1-20230727-C01112
         		331 5-(1-isopropyl-1H-indazol-5-yl)-3- (2-(trifluoromethoxy)phenyl)-1,2,4- oxadiazole 388.35 389.1
    Figure US20230234946A1-20230727-C01113
         		332 3-(2-bromophenyl)-5-(1-isopropyl- 1H-indazol-5-yl)-1,2,4-oxadiazole 383.25 385.1
    Figure US20230234946A1-20230727-C01114
         		333 2-(5-(1-isopropyl-1H-indazol-5-yl)- 1,2,4-oxadiazol-3-yl)phenol 320.35 321.1
    Figure US20230234946A1-20230727-C01115
         		334 3-(2-isopropoxyphenyl)-5-(1- isopropyl-1H-indazol-5-yl)-1,2,4- oxadiazole 362.43 363.1
    Figure US20230234946A1-20230727-C01116
         		335 3-(2,6-dimethoxyphenyl)-5-(1- isopropylindazol-5-yl)-1,2,4- oxadiazole 364.41 365.1
    Figure US20230234946A1-20230727-C01117
         		336 3-(benzo[d][1,3]dioxol-4-yl)-5-(1- isopropyl-1H-indazol-5-yl)-1,2,4- oxadiazole 348.36 349.1
    Figure US20230234946A1-20230727-C01118
         		337 3-chroman-8-yl-5-(1- isopropylindazol-5-yl)-1,2,4- oxadiazole 360.42 361.1
    Figure US20230234946A1-20230727-C01119
         		338 3-(2-fluoro-6-methoxy-phenyl)-5- (1-isopropylindazol-5-yl)-1,2,4- oxadiazole 352.37 353.1
    Figure US20230234946A1-20230727-C01120
         		339 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1,3-dihydro-2,1- benzoxazol-3-one 309.28 310.2
    Figure US20230234946A1-20230727-C01121
         		340 5-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1-methyl-1,3- dihydro-2,1-benzoxazol-3-one 323.31 324.1
    Figure US20230234946A1-20230727-C01122
         		341 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-1,2,3,4- tetrahydroquinolin-2-one 321.34 322.1
    Figure US20230234946A1-20230727-C01123
         		342 methyl N-({6-[5-(2- methoxyphenyl)-1,3,4-oxadiazol-2- yl]-2-oxo-2,3-dihydro-1,3- benzoxazol-3- yl}sulfonyl)carbamate 446.39 447
    Figure US20230234946A1-20230727-C01124
         		343 2-[(2-fluoroethyl)amino]-5-[3-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,2,4-oxadiazol-5- yl]benzonitrile 377.38 378.1
    Figure US20230234946A1-20230727-C01125
         		344 2-[(2,2-difluoroethyl)amino]-5-[3- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,2,4-oxadiazol-5- yl]benzonitrile 395.37 396.1
    Figure US20230234946A1-20230727-C01126
         		345 2-amino-5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]benzonitrile 331.34 332.1
    Figure US20230234946A1-20230727-C01127
         		346 2-[(2-fluoroprop-2-en-1-yl)amino]- 5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]benzonitrile 389.39 390.1
    Figure US20230234946A1-20230727-C01128
         		347 2-[(2,2-difluoropropyl)amino]-5-[3- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,2,4-oxadiazol-5- yl]benzonitrile 409.40 410.1
    Figure US20230234946A1-20230727-C01129
         		348 2-[(2-fluoropropyl)amino]-5-[3-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,2,4-oxadiazol-5- yl]benzonitrile 391.41 392.1
    Figure US20230234946A1-20230727-C01130
         		349 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-2,3-dihydro-1,3- benzoxazol-2-one 309.28 310
    Figure US20230234946A1-20230727-C01131
         		350 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-3-methyl-2,3- dihydro-1,3-benzoxazol-2-one 323.31 324.1
    Figure US20230234946A1-20230727-C01132
         		351 5-[5-(1H-indazol-5-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile 344.38 345.2
    Figure US20230234946A1-20230727-C01133
         		352 2-[(cyclopropylmethyl)amino]-5- [5-(1H-indazol-5-yl)-1,3,4- oxadiazol-2-yl]benzonitrile 356.39 357.1
    Figure US20230234946A1-20230727-C01134
         		353 2-[(2-fluoroethyl)amino]-5-[5-(1H- indazol-5-yl)-1,3,4-oxadiazol-2- yl]benzonitrile 348.34 349.1
    Figure US20230234946A1-20230727-C01135
         		354 2-[(2,2-difluoroethyl)amino]-5-[5- (1H-indazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 366.33 367.1
    Figure US20230234946A1-20230727-C01136
         		355 2-[(2,2-difluoropropyl)amino]-5-[5- (1H-indazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 380.36 381.1
    Figure US20230234946A1-20230727-C01137
         		356 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(propan- 2-yl)amino]benzonitrile 344.38 345.1
    Figure US20230234946A1-20230727-C01138
         		357 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2- [(cyclopropylmethyl)amino] benzonitrile 356.39 357.1
    Figure US20230234946A1-20230727-C01139
         		358 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2- fluoroethyl)amino]benzonitrile 348.34 349.1
    Figure US20230234946A1-20230727-C01140
         		359 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile 366.33 367.1
    Figure US20230234946A1-20230727-C01141
         		360 5-(4-methyl-2-phenyl-1,3-oxazol-5- yl)-1H,2H,3H-pyrrolo[2,3- b]pyridin-2-one 291.1  292.1
    Figure US20230234946A1-20230727-C01142
         		361 4-[5-(4-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1H-indole 307.08 308
    Figure US20230234946A1-20230727-C01143
         		362 5-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1,3-benzothiazole 293.06 294.2
    Figure US20230234946A1-20230727-C01144
         		363 5-[3-(4-methoxyphenyl)-1,2,4- thiadiazol-5-yl]-1H-indole 307.08 308
    Figure US20230234946A1-20230727-C01145
         		364 5-[5-(3-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1H-indole 307.08 308
    Figure US20230234946A1-20230727-C01146
         		365 6-[3-(2-methylphenyl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one 305.12 306.1
    Figure US20230234946A1-20230727-C01147
         		366 5-[5-(3-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole 349.12 350
    Figure US20230234946A1-20230727-C01148
         		367 1-methyl-6-[3-(2-methylphenyl)- 1,2,4-oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one 319.13 320.2
    Figure US20230234946A1-20230727-C01149
         		368 5-(1H-indol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 291.1  292
    Figure US20230234946A1-20230727-C01150
         		369 5-(1H-benzo[d]imidazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 292.1  293.2
    Figure US20230234946A1-20230727-C01151
         		370 5-(1-isopropyl-1H-indazol-5-yl)-3- (2-methoxyphenyl)-1,2,4- oxadiazole 334.14 335.3
    Figure US20230234946A1-20230727-C01152
         		371 5-(1H-indazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 292.1  293.2
    Figure US20230234946A1-20230727-C01153
         		372 5-(1-isopropyl-1H-indol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 333.15 334.1
    Figure US20230234946A1-20230727-C01154
         		373 5-(1-isopropyl-1H- benzo[d]imidazol-5-yl)-3-(2- methoxyphenyl)-1,2,4-oxadiazole 334.14 335.2
    Figure US20230234946A1-20230727-C01155
         		374 5-[3-(2-fluorophenyl)-1,2,4- thiadiazol-5-yl]-1(propan-2-yl)- 1H-indole 337.1  338
    Figure US20230234946A1-20230727-C01156
         		375 5-[5-(2-methoxyphenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole 349.12 350
    Figure US20230234946A1-20230727-C01157
         		376 4-methyl-3-(5-{thieno[2,3- b]pyridin-6-yl}-1,2,4-oxadiazol-3- yl)pyridine 294.06 295
    Figure US20230234946A1-20230727-C01158
         		377 1-methyl-5-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-2,3-dihydro-1H- indol-2-one 292.1  293.1
    Figure US20230234946A1-20230727-C01159
         		378 8-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}cubane-1-carboxylate 389.15 390
    Figure US20230234946A1-20230727-C01160
         		379 8-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}cubane-1-carboxylic acid 375.13 376
    Figure US20230234946A1-20230727-C01161
         		380 5-[5-(2-fluorophenyl)-1,2,4- thiadiazol-3-yl]-1-(propan-2-yl)- 1H-indole 337.1  338
    Figure US20230234946A1-20230727-C01162
         		381 5-[3-(2-methylphenyl)-1,2,4- thiadiazol-5-yl]-1-(propan-2-yl)- 1H-indole 333.13 334
    Figure US20230234946A1-20230727-C01163
         		382 3-(2-methylphenyl)-5-[3-(propan-2- yl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole 320.14 321.2
    Figure US20230234946A1-20230727-C01164
         		383 3-(2-methoxyphenyl)-5-[3-(propan- 2-yl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole 336.13 337.1
    Figure US20230234946A1-20230727-C01165
         		384 1-methyl-6-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinolin-2-one 306.11 307.1
    Figure US20230234946A1-20230727-C01166
         		385 5-[4-(3-methoxyphenyl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole 334.14 335
    Figure US20230234946A1-20230727-C01167
         		386 6-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-1,2,3,4-tetrahydroquinolin-2- one 292.1  293.1
    Figure US20230234946A1-20230727-C01168
         		387 5-(2-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 321.13 322.3
    Figure US20230234946A1-20230727-C01169
         		388 5-(2-bromophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 381.05 382.2
    Figure US20230234946A1-20230727-C01170
         		389 3-(1-isopropyl-1H-indol-5-yl)-5-(o- tolyl)-1,2,4-oxadiazole 317.15 318.3
    Figure US20230234946A1-20230727-C01171
         		390 3-(1-isopropyl-1H-indol-5-yl)-5-(2- (trifluoromethyl)phenyl)-1,2,4- oxadiazole 371.12 372.3
    Figure US20230234946A1-20230727-C01172
         		391 3-(1-isopropyl-1H-indol-5-yl)-5-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole 334.14 335.3
    Figure US20230234946A1-20230727-C01173
         		392 3-(1-isopropyl-1H-indol-5-yl)-5-(3- methoxyphenyl)-1,2,4-oxadiazole 333.15 334.3
    Figure US20230234946A1-20230727-C01174
         		393 3-(1-isopropyl-1H-indol-5-yl)-5-(4- methoxyphenyl)-1,2,4-oxadiazole 333.15 334.2
    Figure US20230234946A1-20230727-C01175
         		394 5-(3-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 321.13 322.1
    Figure US20230234946A1-20230727-C01176
         		395 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-4-yl)-1,2,4-oxadiazole 304.13 305.1
    Figure US20230234946A1-20230727-C01177
         		396 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-3-yl)-1,2,4-oxadiazole 304.13 305.1
    Figure US20230234946A1-20230727-C01178
         		397 3-(1-isopropyl-1H-indol-5-yl)-5- (pyridin-2-yl)-1,2,4-oxadiazole 304.13 305.1
    Figure US20230234946A1-20230727-C01179
         		398 3-(1-isopropyl-1H-indol-5-yl)-5-(2- methoxyphenyl)-1,2,4-oxadiazole 333.15 334.2
    Figure US20230234946A1-20230727-C01180
         		399 5-(3-fluoropyridin-4-yl)-3-(1- isopropyl-1H-indol-5-yl)-1,2,4- oxadiazole 322.12 323
    Figure US20230234946A1-20230727-C01181
         		400 5-(4-fluorophenyl)-3-(1-isopropyl- 1H-indol-5-yl)-1,2,4-oxadiazole 321.13 322.1
    Figure US20230234946A1-20230727-C01182
         		401 2-(1-isopropyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4-(2- methoxyphenyl)thiazole 349.12 350
    Figure US20230234946A1-20230727-C01183
         		402 4-(2-fluorophenyl)-2-(1-isopropyl- 1H-pyrrolo[2,3-b]pyridin-5- yl)thiazole 337.1  338.1
    Figure US20230234946A1-20230727-C01184
         		403 4-(2-fluorophenyl)-2-(1- isopropylindol-5-yl)thiazole 336.11 337.1
    Figure US20230234946A1-20230727-C01185
         		404 2-(1-isopropylindol-5-yl)-4-[2- (trifluoromethyl)phenyl]thiazole 386.11 387.1
    Figure US20230234946A1-20230727-C01186
         		405 2-(1-isopropylindol-5-yl)-4-(3- methoxyphenyl)thiazole 348.13 349.1
    Figure US20230234946A1-20230727-C01187
         		406 6-[5-(2-methoxyphenyl)-1,3,4- oxadiazol-2-yl]-3-methyl-2,3- dihydro-1,3-benzoxazol-2-one 323.09 324.1
    Figure US20230234946A1-20230727-C01188
         		407 2-(1-isopropylpyrrolo[2,3- b]pyridin-5-yl)-4-(o-tolyl)thiazole 333.13 334.1
    Figure US20230234946A1-20230727-C01189
         		408 2-(1-isopropylpyrrolo[2,3- (trifluoromethyl)phenyl]thiazole 387.1  388.1
    Figure US20230234946A1-20230727-C01190
         		409 2-(1-isopropylpyrrolo[3,2- b]pyridin-5-yl)-4-(o-tolyl)thiazole 333.13 334.1
    Figure US20230234946A1-20230727-C01191
         		410 2-(1-isopropylpyrrolo[3,2- b]pyridin-5-yl)-4-(3- methoxyphenyl)thiazole 349.12 350.1
    Figure US20230234946A1-20230727-C01192
         		411 2-(1-isopropyl-1H-pyrrolo[3,2- b]pyridin-5-yl)-4-(2- methoxyphenyl)thiazole 349.12 350.1
    Figure US20230234946A1-20230727-C01193
         		412 4-(2-bromophenyl)-2-(1-isopropyl- 1H-pyrrolo[3,2-b]pyridin-5- yl)thiazole 397.02 400
    Figure US20230234946A1-20230727-C01194
         		413 3-(2-bromophenyl)-5- [3-(propan-2-yl)- 3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl]-1,2,4-oxadiazole 384.03 385.1
    Figure US20230234946A1-20230727-C01195
         		414 4-methyl-3-{5-[3-(propan-2-yl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-6- yl]-1,2,4-oxadiazol-3-yl}pyridine 321.13 322.1
    Figure US20230234946A1-20230727-C01196
         		415 6-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-3,4- dihydroquinolin-2(1H)-one 417.17 418.2
    Figure US20230234946A1-20230727-C01197
         		416 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)indolin-2- one 403.15 404.1
    Figure US20230234946A1-20230727-C01198
         		417 1-cyclobutyl-5-[3-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazole 332.14 333.1
    Figure US20230234946A1-20230727-C01199
         		418 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methylbenzo[d]oxazole 292.13 293.1
    Figure US20230234946A1-20230727-C01200
         		419 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methylbenzo[d]oxazole 292.13 293.1
    Figure US20230234946A1-20230727-C01201
         		420 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methylbenzo[d]oxazole 292.13 293.1
    Figure US20230234946A1-20230727-C01202
         		421 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methylbenzo[d]oxazole 292.13 293.1
    Figure US20230234946A1-20230727-C01203
         		422 2-(isopropylamino)-5-(3-(2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 361.12 362.1
    Figure US20230234946A1-20230727-C01204
         		423 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 373.12 374.2
    Figure US20230234946A1-20230727-C01205
         		424 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methoxybenzo[d]oxazole 308.13 309
    Figure US20230234946A1-20230727-C01206
         		425 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methoxybenzo[d]oxazole 308.13 309.1
    Figure US20230234946A1-20230727-C01207
         		426 2-(1-isopropyl-1H- benzo[d[[1,2,3]triazol-5-yl)-6- methoxybenzo[d]oxazole 308.13 309
    Figure US20230234946A1-20230727-C01208
         		427 4-chloro-2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole 312.08 313
    Figure US20230234946A1-20230727-C01209
         		428 4-bromo-2-(1- isopropylbenzotriazol-5-yl)-1,3- benzoxazole 356.03 357
    Figure US20230234946A1-20230727-C01210
         		429 7-bromo-2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole 356.03 359
    Figure US20230234946A1-20230727-C01211
         		430 N-[(4Z)-2,2-diethyl-6-[3-(pyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4- ylidene]hydroxylamine 364.15 365.1
    Figure US20230234946A1-20230727-C01212
         		431 N-[(4E)-2,2-diethyl-6-[3-(pyridin- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4- ylidene]hydroxylamine 364.15 365.1
    Figure US20230234946A1-20230727-C01213
         		432 1-(propan-2-yl)-5-{4-[2- (trifluoromethyl)phenyl]-1,3- oxazol-2-yl}-1H-1,2,3- benzotriazole 372.12 373
    Figure US20230234946A1-20230727-C01214
         		433 5-[4-(2-methylphenyl)-1,3-oxazol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 318.15 319
    Figure US20230234946A1-20230727-C01215
         		434 4-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-3- azatricyclo[8,4,0,02,6]tetradeca- 1(14),2(6),3,10,12-pentaene 344.16 345
    Figure US20230234946A1-20230727-C01216
         		435 2-(isopropylamino)-5-(3-(2-oxo- 1,2,3,4-tetrahydroquinolin-7-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 373.15 374
    Figure US20230234946A1-20230727-C01217
         		436 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methoxy-4-methylbenzo[d]oxazole 322.14 323
    Figure US20230234946A1-20230727-C01218
         		437 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methylbenzo[d]oxazole 306.15 307.2
    Figure US20230234946A1-20230727-C01219
         		438 2-{2-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3-oxazol-4- yl}aniline 319.14 320
    Figure US20230234946A1-20230727-C01220
         		439 5-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(oxan-4-yl)-1H- 1,2,3-benzotriazole 362.15 363.1
    Figure US20230234946A1-20230727-C01221
         		440 5-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- ((cyclopropylmethyl)amino) benzonitrile 388.11 389
    Figure US20230234946A1-20230727-C01222
         		441 5-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2- (isopropylamino)benzonitrile 376.11 377
    Figure US20230234946A1-20230727-C01223
         		442 2-(isopropylamino)-5-(3-(1-oxo- 1,2,3,4-tetrahydroisoquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 373.15 374
    Figure US20230234946A1-20230727-C01224
         		443 5-(3-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-5-yl)-2- (isopropylamino)benzonitrile 430.2  431
    Figure US20230234946A1-20230727-C01225
         		444 2-((cyclopropylmethyl)amino)-5- (3-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-5- yl)benzonitrile 442.2  443.3
    Figure US20230234946A1-20230727-C01226
         		445 6-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)benzo[d]oxazol-2(3H)-one 405.13 406
    Figure US20230234946A1-20230727-C01227
         		446 6-(3-(2-aminobenzo[d]thiazol-5- yl)-1,2,4-oxadiazol-5-yl)-2,2- diethylchroman-4-one 420.13 421
    Figure US20230234946A1-20230727-C01228
         		447 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methylbenzo[d]oxazole 306.15 307
    Figure US20230234946A1-20230727-C01229
         		448 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methylbenzo[d]oxazole 306.15 307
    Figure US20230234946A1-20230727-C01230
         		449 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methylbenzo[d]oxazole 306.15 307
    Figure US20230234946A1-20230727-C01231
         		450 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- methoxybenzo[d]oxazole 322.14 323
    Figure US20230234946A1-20230727-C01232
         		451 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-5- methoxybenzo[d]oxazole 322.14 323
    Figure US20230234946A1-20230727-C01233
         		452 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5-yl)-6- methoxybenzo[d]oxazole 322.14 323
    Figure US20230234946A1-20230727-C01234
         		453 4-chloro-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole 326.09 326.9
    Figure US20230234946A1-20230727-C01235
         		454 7-bromo-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole 370.04 371.1
    Figure US20230234946A1-20230727-C01236
         		455 1-(propan-2-yl)-5-{3-[3- (trifluoromethyl)pyridin-4-yl]- 1,2,4-oxadiazol-5-yl}-1H-1,2,3- benzotriazole 374.11 375.1
    Figure US20230234946A1-20230727-C01237
         		456 4-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-10-thia-3- azatricyclo[7,3,0,02,6]dodeca- 1(9),2(6),3,11-tetraene 336.1  337
    Figure US20230234946A1-20230727-C01238
         		457 4-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-5-oxa-10-thia-3- azatricyclo[7,3,0,02,6]dodeca- 1(9),2(6),3,7,11-pentaene 334.09 335
    Figure US20230234946A1-20230727-C01239
         		458 N-(2-{2-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,3-oxazol-4- yl}phenyl)acetamide 361.15 362
    Figure US20230234946A1-20230727-C01240
         		459 1-(propan-2-yl)-5-[4-(thiophen-2- yl)-1,3-oxazol-2-yl]-1H-1,2,3- benzotriazole 310.09 311
    Figure US20230234946A1-20230727-C01241
         		460 2-methyl-1-(5-{3-[3- (trifluoromethyl)pyridin-4-yl]- 1,2,4-oxadiazol-5-yl}-1H-1,2,3- benzotriazol-1-yl)propan-2-ol 404.12 405.1
    Figure US20230234946A1-20230727-C01242
         		461 4-bromo-2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)benzo[d]oxazole 370.04 372.9
    Figure US20230234946A1-20230727-C01243
         		462 5-{4H-chromeno[4,3- d][1,3]oxazol-2-yl}-1-(propan-2- yl)-1H-1,2,3-benzotriazole 332.13 333
    Figure US20230234946A1-20230727-C01244
         		463 5-[4-(3-chlorothiophen-2-yl)-1,3- oxazol-2-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole 344.05 345
    Figure US20230234946A1-20230727-C01245
         		464 6-(3-(1H-pyrrol-2-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 337.14 338.2
    Figure US20230234946A1-20230727-C01246
         		465 2,2-diethyl-6-(3-(furan-2-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 338.13 339.2
    Figure US20230234946A1-20230727-C01247
         		466 6-(3-(1H-imidazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 338.14 339.2
    Figure US20230234946A1-20230727-C01248
         		467 2,2-diethyl-6-(3-(thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 354.1  355.2
    Figure US20230234946A1-20230727-C01249
         		468 2,2-diethyl-6-(3-(thiophen-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 354.1  354.9
    Figure US20230234946A1-20230727-C01250
         		469 6-(3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 338.14 339.1
    Figure US20230234946A1-20230727-C01251
         		470 6-(3-(1H-pyrazol-5-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 338.14 339.1
    Figure US20230234946A1-20230727-C01252
         		471 2-((cyclopropylmethyl)amino)-5- (3-(2-oxo-1,2,3,4- tetrahydroquinolin-7-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 385.43
    Figure US20230234946A1-20230727-C01253
         		472 5-[3-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,2,4- oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile 413.11 414.1
    Figure US20230234946A1-20230727-C01254
         		473 5-[5-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile 373.15 374.1
    Figure US20230234946A1-20230727-C01255
         		474 1-(propan-2-yl)-5-[4-(pyridin-2-yl)- 1,3-oxazol-2-yl]-1H-1,2,3- benzotriazole 305.13 306
    Figure US20230234946A1-20230727-C01256
         		475 2-[(cyclopropylmethyl)amino]-5- [5-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)-1,3,4- oxadiazol-2-yl]benzonitrile 385.15 386.1
    Figure US20230234946A1-20230727-C01257
         		476 2-[(2-fluoroethyl)amino]-5-[5-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 377.13 378.1
    Figure US20230234946A1-20230727-C01258
         		477 2-[(2,2-difluoroethyl)amino]-5-[5- (2-oxo-1,2,3,4-tetrahydroquinolin- 6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile 395.12 396.1
    Figure US20230234946A1-20230727-C01259
         		478 2,2-bis(hydroxymethyl)-6-[3- (pyridin-3-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one 353.1  354.1
    Figure US20230234946A1-20230727-C01260
         		479 3-bromo-2,2-bis(hydroxymethyl)-6- [3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 431.01 432
    Figure US20230234946A1-20230727-C01261
         		480 2,2-dimethyl-5-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-2,3-dihydro- 1-benzofuran-3-one 307.1  308.1
    Figure US20230234946A1-20230727-C01262
         		481 2,2-dimethyl-5-[3-(pyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-2,3-dihydro- 1-benzofuran-3-one 307.1  308.1
    Figure US20230234946A1-20230727-C01263
         		482 2,2-bis(hydroxymethyl)-6-[3- (pyridin-4-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1- benzopyran-4-one 353.1  354.1
    Figure US20230234946A1-20230727-C01264
         		483 3-bromo-2,2-bis(hydroxymethyl)-6- [3-(pyridin-4-yl)-1,2,4-oxadiazol- 5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 431.01 432
    Figure US20230234946A1-20230727-C01265
         		484 5-[5-(2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 361.12 362.1
    Figure US20230234946A1-20230727-C01266
         		485 6-(3-(1H-pyrrol-3-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 337.14 338
    Figure US20230234946A1-20230727-C01267
         		486 2-[(cyclopropylmethyl)amino]-5- [5-(2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 373.12 374.1
    Figure US20230234946A1-20230727-C01268
         		487 2-[(2-fluoroethyl)amino]-5-[5-(2- oxo-2,3-dihydro-1,3-benzoxazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 365.09 366.1
    Figure US20230234946A1-20230727-C01269
         		488 2-[(2,2-difluoroethyl)amino]-5[5- (2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 383.08 384
    Figure US20230234946A1-20230727-C01270
         		489 5-[3-(1H-1,3-benzodiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile 384.09 385.2
    Figure US20230234946A1-20230727-C01271
         		490 5-[3-(2,5-dimethylfuran-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 323.14 324.1
    Figure US20230234946A1-20230727-C01272
         		491 5-[3-(2-methylfuran-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 309.12 310.1
    Figure US20230234946A1-20230727-C01273
         		492 2-methyl-1-{5-[3-(2-methylfuran-3- yl)-1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol 339.13 340.1
    Figure US20230234946A1-20230727-C01274
         		493 1-{5-[3-(2,5-dimethylfuran-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol 353.15 354.1
    Figure US20230234946A1-20230727-C01275
         		494 2,2-bis(methoxymethyl)-6-[3- (pyridin-4-yl)-1,2,4-oxadiazol-5- yl]-3,4-dihydro-2H-1-benzopyran- 4-one 381.13 382.1
    Figure US20230234946A1-20230727-C01276
         		495 2,2-diethyl-6-(3-(furan-3-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 338.13 339
    Figure US20230234946A1-20230727-C01277
         		496 2-(isopropylamino)-5-(3-(2- oxoindolin-6-yl)-1,2,4-oxadiazol-5- yl)benzonitrile 359.14 360.2
    Figure US20230234946A1-20230727-C01278
         		497 2-((cyclopropylmethyl)amino)-5- (3-(2-oxoindolin-6-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 371.14 372.3
    Figure US20230234946A1-20230727-C01279
         		498 5-{5-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}-2,1,3-benzoxadiazole 347.11 348.1
    Figure US20230234946A1-20230727-C01280
         		499 5-[3-(2-chloropyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 340.08 341
    Figure US20230234946A1-20230727-C01281
         		500 6-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2,2-diethyl- 3,4-dihydro-2H-1-benzopyran-4- one 390.13 391.1
    Figure US20230234946A1-20230727-C01282
         		501 1-{5-[3-(1H-1,3-benzodiazol-6-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol 375.14 376.1
    Figure US20230234946A1-20230727-C01283
         		502 6-(3-(5-aminopyridin-3-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 364.15 365.2
    Figure US20230234946A1-20230727-C01284
         		503 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)oxazolo[5,4-c]pyridine 279.11 280.2
    Figure US20230234946A1-20230727-C01285
         		504 2-(1-isobutyl-1H- benzo[d][1,2,3]triazol-5- yl)oxazolo[5,4-c]pyridine 293.13 294.3
    Figure US20230234946A1-20230727-C01286
         		505 2,2-dimethyl-3-(5-(5-(o-tolyl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 363.17 364.1
    Figure US20230234946A1-20230727-C01287
         		506 4-isopropoxy-4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)[1,1′- biphenyl]-3-carbonitrile 396.2  397.1
    Figure US20230234946A1-20230727-C01288
         		507 4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-4- (isopropylamino)-[1,1′-biphenyl]-3- carbonitrile 395.21 396.1
    Figure US20230234946A1-20230727-C01289
         		508 4-(allylamino)-4′-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)[1,1′- biphenyl]-3-carbonitrile 393.2  394.1
    Figure US20230234946A1-20230727-C01290
         		509 2,2-diethyl-6-(5-(pyridin-3- yl)pyrimidin-2-yl)chroman-4-one 359.16 360.3
    Figure US20230234946A1-20230727-C01291
         		510 2,2-diethyl-6-(5-(pyridin-4- yl)pyrimidin-2-yl)chroman-4-one 359.16 360.3
    Figure US20230234946A1-20230727-C01292
         		511 5-[3-(1H-1,3-benzodiazol-6-yl)- 1,2,4-oxadiazol-5- yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 345.13 346.1
    Figure US20230234946A1-20230727-C01293
         		512 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-2-yl)acetamide 406.16 407.3
    Figure US20230234946A1-20230727-C01294
         		513 6-(3-(2-aminopyridin-4-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 364.15 365.4
    Figure US20230234946A1-20230727-C01295
         		514 2-(isopropylamino)-5-(3-(1-oxo- 1,2,3,4-tetrahydroisoquinolin-7-yl)- 1,2,4-oxadiazol-5-yl)benzonitrile 373.15 374.3
    Figure US20230234946A1-20230727-C01296
         		515 2-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-7- methoxybenzo[d]oxazole 308.13 309.2
    Figure US20230234946A1-20230727-C01297
         		516 5-[4-(2-methylphenyl)-1H-pyrrol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 316.17 317
    Figure US20230234946A1-20230727-C01298
         		517 5-[1-methyl-4-(2-methylphenyl)- 1H-pyrrol-2-yl]-1-(propan-2-yl)- 1H-1,2,3-benzotriazole 330.18 331
    Figure US20230234946A1-20230727-C01299
         		518 1-{5-[3-(1,4-dimethyl-1H-pyrazol- 3-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol 353.16 354.1
    Figure US20230234946A1-20230727-C01300
         		519 5-[3-(1,4-dimethyl-1H-pyrazol-3- yl)-1,2,4-oxadiazol-5-yl]-1- (propan-2-yl)-1H-1,2,3- benzotriazole 323.15 324.1
    Figure US20230234946A1-20230727-C01301
         		520 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoropropyl)amino]benzonitrile 380.12 381.2
    Figure US20230234946A1-20230727-C01302
         		521 2,2-diethyl-6-(3-(quinolin-6-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 399.16 400.4
    Figure US20230234946A1-20230727-C01303
         		522 2,2-diethyl-6-(3-(isoquinolin-6-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 399.16 400.3
    Figure US20230234946A1-20230727-C01304
         		523 3-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2,2-dimethylpropan-1-ol 393.18 394.3
    Figure US20230234946A1-20230727-C01305
         		524 2,2-dimethyl-3-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 369.13 370.2
    Figure US20230234946A1-20230727-C01306
         		525 3-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol 379.16 380
    Figure US20230234946A1-20230727-C01307
         		526 3-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol 383.11 384
    Figure US20230234946A1-20230727-C01308
         		527 3-(5-(5-(2-ethylphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2,2- dimethylpropan-1-ol 377.19 378.1
    Figure US20230234946A1-20230727-C01309
         		528 2,2-dimethyl-3-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 418.14 419
    Figure US20230234946A1-20230727-C01310
         		529 2,2-dimethyl-3-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 418.14 419
    Figure US20230234946A1-20230727-C01311
         		530 2,2-diethyl-6-(5-(pyridin-2- yl)pyrimidin-2-yl)chroman-4-one 359.16 360.3
    Figure US20230234946A1-20230727-C01312
         		531 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- methoxyphenyl}acetamide 435.18 436.2
    Figure US20230234946A1-20230727-C01313
         		532 N-(3-methoxy-4-{5-[1-(propan-2- yl)-1H-1,2,3-benzotriazol-5-yl]- 1,2,4-oxadiazol-3-yl}phenyl) acetamide 392.16 393.1
    Figure US20230234946A1-20230727-C01314
         		533 N-{4-[5-(2,1,3-benzoxadiazol-5- yl)-1,2,4-oxadiazol-3-yl]-3- methoxyphenyl}acetamide 351.1 352
    Figure US20230234946A1-20230727-C01315
         		534 5-[1-(2-methoxyethyl)-4-(2- methylphenyl)-1H-pyrrol-2-yl]-1- (propan-2-yl)-1H-1,2,3- benzotriazole 374.21 375
    Figure US20230234946A1-20230727-C01316
         		535 2-methyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 307.1  308
    Figure US20230234946A1-20230727-C01317
         		536 2-methyl-7-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 307.1  308.1
    Figure US20230234946A1-20230727-C01318
         		537 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)nicotinamide 392.15 393.2
    Figure US20230234946A1-20230727-C01319
         		538 N-(5-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-3-yl)acetamide 406.16 407.3
    Figure US20230234946A1-20230727-C01320
         		539 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d]imidazol-2(3H)-one 404.15 405
    Figure US20230234946A1-20230727-C01321
         		540 2,2-dimethyl-3-(5-(5-(3- methylpyrazin-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 365.16 366.3
    Figure US20230234946A1-20230727-C01322
         		541 2,2-dimethyl-3-(5-(5-(4- methylpyridin-3-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 364.16 365
    Figure US20230234946A1-20230727-C01323
         		542 5-[4-(2-fluorophenyl)-1H-pyrrol-2- yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 320.14 321.2
    Figure US20230234946A1-20230727-C01324
         		543 5-(5-phenyl-1H-pyrrol-3-yl)-1- (propan-2-yl)-1H-1,2,3- benzotriazole 302.15 303
    Figure US20230234946A1-20230727-C01325
         		544 5-(1-methyl-5-phenyl-1H-pyrrol-3- yl)-1-(propan-2-yl)-1H-1,2,3- benzotriazole 316.17 317
    Figure US20230234946A1-20230727-C01326
         		545 N-(5-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-3- yl)methanesulfonamide 442.13 443.3
    Figure US20230234946A1-20230727-C01327
         		546 2,2-diethyl-6-(3-(6-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one 367.13 368.3
    Figure US20230234946A1-20230727-C01328
         		547 2,2-diethyl-6-(3-(2-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one 367.13 368.2
    Figure US20230234946A1-20230727-C01329
         		548 2,2-diethyl-6-(3-(6- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.13 418.2
    Figure US20230234946A1-20230727-C01330
         		549 2,2-diethyl-6-(3-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.16 364.3
    Figure US20230234946A1-20230727-C01331
         		550 2,2-diethyl-6-(3-(6-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.16 364.3
    Figure US20230234946A1-20230727-C01332
         		551 2,2-diethyl-6-(3-(5-fluoropyridin-3- yl)-1,2,4-oxadiazol-5-yl)chroman- 4-one 367.13 368.2
    Figure US20230234946A1-20230727-C01333
         		552 2,2-diethyl-6-(5-(2-hydroxypyridin- 4-yl)pyrimidin-2-yl)chroman-4-one 375.16 376.3
    Figure US20230234946A1-20230727-C01334
         		553 2,2-diethyl-6-[3-(6- methoxypyridin-2-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 379.15 380.1
    Figure US20230234946A1-20230727-C01335
         		554 2,2-diethyl-6-(3-(thiophen-3-yl)- 1,2,4-oxadiazol-5-yl)-2,3- dihydroquinolin-4(1H)-one 353.12 354.2
    Figure US20230234946A1-20230727-C01336
         		555 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3- yl)picolinamide 392.15 393
    Figure US20230234946A1-20230727-C01337
         		556 N-(4-(5-(2,2-diethyl-4- oxochroman-6-yl)-1,2,4-oxadiazol- 3-yl)pyridin-2- yl)methanesulfonamide 442.13 443.3
    Figure US20230234946A1-20230727-C01338
         		557 2,2-diethyl-6-(3-(5- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.13 418
    Figure US20230234946A1-20230727-C01339
         		558 2,2-diethyl-6-(3-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.13 418
    Figure US20230234946A1-20230727-C01340
         		559 2,2-diethyl-6-(5-(pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)chroman-4- one 349.14 350
    Figure US20230234946A1-20230727-C01341
         		560 5-[5-(2-methyl-1H-1,3- benzodiazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 358.15 359.2
    Figure US20230234946A1-20230727-C01342
         		561 2-[(2,2-difluoroethyl)aminol-5[5- (2-methyl-1H-1,3-benzodiazol-5- yl)-1,3,4-oxadiazol-2-yl] benzonitrile 380.12 381.2
    Figure US20230234946A1-20230727-C01343
         		562 2,2-diethyl-6-(3-(2- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 417.13 418
    Figure US20230234946A1-20230727-C01344
         		563 2,2-diethyl-6-(3-(5-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.16 364
    Figure US20230234946A1-20230727-C01345
         		564 2,2-diethyl-6-(3-(2-methylpyridin- 3-yl)-1,2,4-oxadiazol-5- yl)chroman-4-one 363.16 364
    Figure US20230234946A1-20230727-C01346
         		565 1-isopropyl-5-(5-(2- methoxyphenyl)pyrimidin-2-yl)- 1H-benzo[d][1,2,3]triazole 345.16 346.1
    Figure US20230234946A1-20230727-C01347
         		566 5-[4-(2-methoxyphenyl)-1H-pyrrol- 2-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 332.16 333.2
    Figure US20230234946A1-20230727-C01348
         		567 2-methyl-1-{5-[3-(1-methyl-1H- imidazol-2-yl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1- yl}propan-2-ol 339.14 340.1
    Figure US20230234946A1-20230727-C01349
         		568 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- methoxyphenyl} methanesulfonamide 471.15 472.1
    Figure US20230234946A1-20230727-C01350
         		569 5-[3-(1-methyl-1H-imidazol-2-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 309.13 310.1
    Figure US20230234946A1-20230727-C01351
         		570 2-methyl-1-{5-[3-(1,3-oxazol-4-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}propan-2-ol 326.11 327
    Figure US20230234946A1-20230727-C01352
         		571 5-[5-(2-methyl-1H-1,3- benzodiazol-5-yl)-1,2,4-oxadiazol- 3-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 359.15 360
    Figure US20230234946A1-20230727-C01353
         		572 5-[5-(1-methyl-1H-1,3- benzodiazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 358.15 359.1
    Figure US20230234946A1-20230727-C01354
         		573 2-[(2,2-difluoroethyl)amino]-5[5- (1-methyl-1H-1,3-benzodiazol-5- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 380.12 381.1
    Figure US20230234946A1-20230727-C01355
         		574 5-{5-[1-(2-hydroxyethyl)-1H-1,3- benzodiazol-5-yl]-1,3,4-oxadiazol- 2-yl}-2-[(propan-2- yl)amino]benzonitrile 388.16 389.1
    Figure US20230234946A1-20230727-C01356
         		575 5-[2-(2-methoxyphenyl)-1,3- oxazol-4-yl]-1-(propan-2-yl)-1H- 1,2,3-benzotriazole 334.14 335
    Figure US20230234946A1-20230727-C01357
         		576 2-{3[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}aniline 320.14 321.2
    Figure US20230234946A1-20230727-C01358
         		577 1-{5-[3-(1H-indol-7-yl)-1,2,4- oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol 374.15 375.2
    Figure US20230234946A1-20230727-C01359
         		578 2-[(2,2-difluoroethyl)amino]-5-{5- [1-(2-hydroxyethyl)-1H-1,3- benzodiazol-5-yl]-1,3,4-oxadiazol- 2-yl}benzonitrile 410.13 411.1
    Figure US20230234946A1-20230727-C01360
         		579 5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 358.15 359.2
    Figure US20230234946A1-20230727-C01361
         		580 2-[(2,2-difluoroethyl)amino]-5-[5- (1-methyl-1H-1,3-benzodiazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 380.12 381.1
    Figure US20230234946A1-20230727-C01362
         		581 [(4-{5-[1-(2-hydroxy-2- methylpropyl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}phenyl)methyl]phosphonate 485.18 486.2
    Figure US20230234946A1-20230727-C01363
         		582 N-{3-methoxy-4-[3-(pyridin-4-yl)- 1,2,4-oxadiazol-5- yl]phenyl}acetamide 310.11 311.2
    Figure US20230234946A1-20230727-C01364
         		583 diethyl [(4-{5-[1-(propan-2-yl)-1H- 1,2,3-benzotriazol-5-yl]-1,2,4- oxadiazol-3- yl}phenyl)methyl]phosphonate 455.17 456.1
    Figure US20230234946A1-20230727-C01365
         		584 N-{4-[5-(2,2-diethyl-4-oxo-3,4- dihydro-2H-1-benzopyran-6-yl)- 1,2,4-oxadiazol-3-yl]-3- (trifluoromethoxy)phenyl} acetamide 489.15 490.1
    Figure US20230234946A1-20230727-C01366
         		585 5-[5-(1H-1,3-benzodiazol-4-yl)- 1,3,4-oxadiazol-2-yl]-2-[(propan- 2-yl)amino]benzonitrile 344.14 345.1
    Figure US20230234946A1-20230727-C01367
         		586 5-[5-(1H-1,3-benzodiazol-4-yl)- 1,3,4-oxadiazol-2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile 366.1  367.1
    Figure US20230234946A1-20230727-C01368
         		587 N-methyl-2-{2-[1-(propan-2-yl)- 1H-1,2,3-benzotriazol-5-yl]-1,3- oxazol-4-yl}aniline 333.16 334
    Figure US20230234946A1-20230727-C01369
         		588 2-ethyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 321.11 322.1
    Figure US20230234946A1-20230727-C01370
         		589 2-ethyl-7-[3-(pyridin-4-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 321.11 322.1
    Figure US20230234946A1-20230727-C01371
         		590 1-{5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol 377.12 378.1
    Figure US20230234946A1-20230727-C01372
         		591 2,2-diethyl-6-(3-(thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)-2,3- dihydroquinolin-4(1H)-one 353.12 353.9
    Figure US20230234946A1-20230727-C01373
         		592 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)-N- methylpicolinamide 406.16 407
    Figure US20230234946A1-20230727-C01374
         		593 2-methyl-1-(5-(5-(o-tolyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 349.15 350
    Figure US20230234946A1-20230727-C01375
         		594 2,2-diethyl-6-(5-(2- methoxyphenyl)pyrimidin-2- yl)chroman-4-one 388.18 389
    Figure US20230234946A1-20230727-C01376
         		595 2-isopropoxy-5-(5-(1-isopropyl- 1H-benzo[d][1,2,3]triazol-5- yl)pyrimidin-2-yl)benzonitrile 398.19 399.2
    Figure US20230234946A1-20230727-C01377
         		596 5-(5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile 397.2  398.1
    Figure US20230234946A1-20230727-C01378
         		597 2-methyl-1-{5-[3-(3-methylpyridin- 4-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazol-1-yl}propan-2- ol 350.15 351.1
    Figure US20230234946A1-20230727-C01379
         		598 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2- (cyclopropylamino)benzonitrile 342.12 343.1
    Figure US20230234946A1-20230727-C01380
         		599 N-methyl-2-{3-[1-(propan-2-yl)- 1H-1,2,3-benzotriazol-5-yl]-1,2,4- oxadiazol-5-yl}aniline 334.15 335.2
    Figure US20230234946A1-20230727-C01381
         		600 5-[5-(1H-1,3-benzodiazol-5-yl)- 1,3,4-oxadiazol-2-yl]-2-[(1,3- difluoropropan-2- yl)amino]benzonitrile 380.12 381.1
    Figure US20230234946A1-20230727-C01382
         		601 5-[5-(2-methylphenyl)-1H-pyrrol- 3-yl]-1-(propan-2-yl)-1H-1,2,3- benzotriazole 316.17 317
    Figure US20230234946A1-20230727-C01383
         		602 2-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}pyridin-3-ol 322.12 323
    Figure US20230234946A1-20230727-C01384
         		603 5-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)pyridine-3- sulfonamide 428.12 428.9
    Figure US20230234946A1-20230727-C01385
         		604 2,2-diethyl-6-(3-(3- methoxythiophen-2-yl)-1,2,4- oxadiazol-5-yl)chroman-4-one 384.11 385.2
    Figure US20230234946A1-20230727-C01386
         		605 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(4- methoxypyridin-3-yl)-1,2,4- oxadiazole 336.13 337.2
    Figure US20230234946A1-20230727-C01387
         		606 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole 336.13 337.2
    Figure US20230234946A1-20230727-C01388
         		607 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(2- methoxypyridin-3-yl)-1,2,4- oxadiazole 336.13 337.2
    Figure US20230234946A1-20230727-C01389
         		608 4-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}-2,3-dihydro-1H-inden-1-one 359.14 360
    Figure US20230234946A1-20230727-C01390
         		609 2-methyl-2-(5-(5-(o-tolyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 349.15 350.1
    Figure US20230234946A1-20230727-C01391
         		610 2-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2-methylpropan-1-ol 379.16 380
    Figure US20230234946A1-20230727-C01392
         		611 2-methyl-2-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 355.11 355.9
    Figure US20230234946A1-20230727-C01393
         		612 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methoxypyridin-2-yl)-1,2,4- oxadiazole 336.13 337.2
    Figure US20230234946A1-20230727-C01394
         		613 7-[3-(4-methylpyridin-3-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one 307.11 307.1
    Figure US20230234946A1-20230727-C01395
         		614 7-[3-(2-methoxyphenyl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one 322.11 322.1
    Figure US20230234946A1-20230727-C01396
         		615 N,N-dimethyl-2-{3-[1-(propan-2- yl)-1H-1,2,3-benzotriazol-5-yl]- 1,2,4-oxadiazol-5-yl}aniline 348.17 349.1
    Figure US20230234946A1-20230727-C01397
         		616 4-(5-(2,2-diethyl-4-oxochroman-6- yl)-1,2,4-oxadiazol-3-yl)pyridine-2- sulfonamide 428.12 428.9
    Figure US20230234946A1-20230727-C01398
         		617 2,2-diethyl-6-(3-(pyrazin-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351.1
    Figure US20230234946A1-20230727-C01399
         		618 2-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol 369.1  369.9
    Figure US20230234946A1-20230727-C01400
         		619 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methoxypyridin-3-yl)-1,2,4- oxadiazole 336.13 337.2
    Figure US20230234946A1-20230727-C01401
         		620 2,2-diethyl-6-(3-(pyrimidin-5-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351.1
    Figure US20230234946A1-20230727-C01402
         		621 2,2-diethyl-6-(3-(pyridazin-3-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351.1
    Figure US20230234946A1-20230727-C01403
         		622 6-(3-(benzo[d]oxazol-6-yl)-1,2,4- oxadiazol-5-yl)-2,2- diethylchroman-4-one 389.14 390
    Figure US20230234946A1-20230727-C01404
         		623 2-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol 365.15 365.9
    Figure US20230234946A1-20230727-C01405
         		624 2-(5-(5-(2-ethylphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol 363.17 364.1
    Figure US20230234946A1-20230727-C01406
         		625 2-methyl-2-(5-(5-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 350.15 351.1
    Figure US20230234946A1-20230727-C01407
         		626 2-methyl-2-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 404.12 405.1
    Figure US20230234946A1-20230727-C01408
         		627 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxypyridin-2-yl)-1,2,4- oxadiazole 336.13 337.1
    Figure US20230234946A1-20230727-C01409
         		628 2-(isopropylamino)-5-(5-(2-oxo- 2,3-dihydro-1H-benzo[d]imidazol- 5-yl)pyrimidin-2-yl)benzonitrile 370.15 371.1
    Figure US20230234946A1-20230727-C01410
         		629 7-[3-(pyridin-3-yl)-1,2,4-oxadiazol- 5-yl]-1,2,3,4-tetrahydroquinoxalin- 2-one 293.09 292.1
    Figure US20230234946A1-20230727-C01411
         		630 2-propyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 335.13 336.1
    Figure US20230234946A1-20230727-C01412
         		631 2,2-diethyl-6-[5-(5-fluoropyridin-3- yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one 367.13 368.1
    Figure US20230234946A1-20230727-C01413
         		632 2,2-diethyl-6-[5-(5-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one 363.16 364.1
    Figure US20230234946A1-20230727-C01414
         		633 2-butyl-7-[3-(pyridin-3-yl)-1,2,4- oxadiazol-5-yl]-3,4-dihydro-2H-1- benzopyran-4-one 349.14 350.1
    Figure US20230234946A1-20230727-C01415
         		634 2-[(1-hydroxy-2-methylpropan-2- yl)amino]-5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 388.16 389.2
    Figure US20230234946A1-20230727-C01416
         		635 2-[(2,2-difluoro-3- hydroxypropyl)amino]-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile 410.13 411.2
    Figure US20230234946A1-20230727-C01417
         		636 4-{3-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 5-yl}-2,3-dihydro-1H-inden-1-ol 361.15 362
    Figure US20230234946A1-20230727-C01418
         		637 5-[5-(2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 361.12 362.2
    Figure US20230234946A1-20230727-C01419
         		638 5-[5-(1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]henzonitrile 373.15 374.2
    Figure US20230234946A1-20230727-C01420
         		639 2,2-diethyl-6-(3-(pyrimidin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351.1
    Figure US20230234946A1-20230727-C01421
         		640 2,2-diethyl-6-(3-(pyrimidin-2-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351.1
    Figure US20230234946A1-20230727-C01422
         		641 2-methyl-2-(5-(5-(3-methylpyrazin- 2-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 1-ol 351.14 352.2
    Figure US20230234946A1-20230727-C01423
         		642 2-(5-(5-(1H-benzo[d]imidazol-6- yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-o 375.14 376.1
    Figure US20230234946A1-20230727-C01424
         		643 2-(5-(5-(2-fluoropyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-1-ol 354.12 355.1
    Figure US20230234946A1-20230727-C01425
         		644 2-methyl-2-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl) propan-1-ol 404.12 405.2
    Figure US20230234946A1-20230727-C01426
         		645 7-[3-(1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl]-1,2,3,4- tetrahydroquinoxalin-2-one 282.09 281.1
    Figure US20230234946A1-20230727-C01427
         		646 1-(propan-2-yl)-5-[3-(1H-pyrazol- 4-yl)-1,2,4-oxadiazol-5-yl]-1H- 1,2,3-benzotriazole 295.12 296.2
    Figure US20230234946A1-20230727-C01428
         		647 1-{5-[3-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol 379.16 380.1
    Figure US20230234946A1-20230727-C01429
         		648 2,2-diethyl-6-(3-(pyridazin-4-yl)- 1,2,4-oxadiazol-5-yl)chroman-4- one 350.14 351
    Figure US20230234946A1-20230727-C01430
         		649 2-(isopropylamino)-5-(5-(pyridin- 3-yl)-1,3,4-oxadiazol-2- yl)benzonitrile 305.13 306.3
    Figure US20230234946A1-20230727-C01431
         		650 5-(3-(1-(1-hydroxy-2- methylpropan-2-yl)-1H- benzo[d][1,2,3]triazol-5-yl)-1,2,4- oxadiazol-5-yl)indolin-2-one 390.14 391.1
    Figure US20230234946A1-20230727-C01432
         		651 2-[(2,2-difluoroethyl)amino]-5-[5- (2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 383.08 384
    Figure US20230234946A1-20230727-C01433
         		652 2-[(2,2-difluoroethyl)amino]-5-[5- (1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl)-1,3,4- oxadiazol-2-yl}benzonitrile 395.12 396.1
    Figure US20230234946A1-20230727-C01434
         		653 2-methyl-1-{6-[3-(1H-pyrazol-4- yl)-1,2,4-oxadiazol-5-yl]-3H- indazol-3-yl}propan-2-ol 324.13 326.2
    Figure US20230234946A1-20230727-C01435
         		654 1-(5-(5-(4-methoxy-2- methylphenyl)-1,2,4-oxadiazol-3- yl)-1H-benzo[d][1,2,3]triazol-1-yl)- 2-methylpropan-2-ol 379.16 380.3
    Figure US20230234946A1-20230727-C01436
         		655 2-methyl-1-(5-(5-(3- methylthiophen-2-yl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 355.11 356.2
    Figure US20230234946A1-20230727-C01437
         		656 1-(5-(5-(2-methoxyphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)- 2-methylpropan-2-ol 365.15 366.2
    Figure US20230234946A1-20230727-C01438
         		657 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methoxypyridin-4-yl)-1,2,4- oxadiazole 336.13 337.1
    Figure US20230234946A1-20230727-C01439
         		662 1-{5-[3-(2-methoxy-4- methylphenyl)-1,2,4-oxadiazol-5- yl]-1H-1,2,3-benzotriazol-1-yl}-2- methylpropan-2-ol 379.16 380
    Figure US20230234946A1-20230727-C01440
         		663 2,2-diethyl-6-[5-(2-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one 363.16 364.1
    Figure US20230234946A1-20230727-C01441
         		664 2,2-diethyl-6-[5-(5-hydroxypyridin- 3-yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one 365.14 366.1
    Figure US20230234946A1-20230727-C01442
         		665 5-[5-(1-tert-butyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 400.2  401.3
    Figure US20230234946A1-20230727-C01443
         		666 2,2-diethyl-N-[(1E)- (hydroxyimino)[2- (trifluoromethyl)pyridin-3- yl]methyl]-4-oxo-3,4-dihydro-2H- 1-benzopyran-7-carboxamide 435.14 436.2
    Figure US20230234946A1-20230727-C01444
         		667 2-(isopropylamino)-5-(5-(pyridin- 4-yl)-1,3,4-oxadiazol-2- yl)benzonitrile 305.13 306.3
    Figure US20230234946A1-20230727-C01445
         		668 2-methyl-1-(5-(5-(3-methylpyrazin- 2-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 351.14 352.2
    Figure US20230234946A1-20230727-C01446
         		669 1-(5-(5-(2-chlorophenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-2-ol 369.1  369.9
    Figure US20230234946A1-20230727-C01447
         		670 1-(5-(5-(2-ethylphenyl)-1,2,4- oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)-2- methylpropan-2-ol 363.17 364
    Figure US20230234946A1-20230727-C01448
         		671 2-methyl-1-(5-(5-(4-methylpyridin- 3-yl)-1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 350.15 351.2
    Figure US20230234946A1-20230727-C01449
         		672 2-methyl-1-(5-(5-(3- (trifluoromethyl)pyridin-4-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 404.12 405.2
    Figure US20230234946A1-20230727-C01450
         		673 2-methyl-1-(5-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,2,4-oxadiazol-3-yl)-1H- benzo[d][1,2,3]triazol-1-yl)propan- 2-ol 404.12 405.2
    Figure US20230234946A1-20230727-C01451
         		675 1-{5-[3-(2,6-dimethylpyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1H-1,2,3- benzotriazol-1-yl}-2-methylpropan- 2-ol 364.16 365.1
    Figure US20230234946A1-20230727-C01452
         		676 5-[5-(1-tert-butyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile 422.17 423.1
    Figure US20230234946A1-20230727-C01453
         		677 2,2-diethyl-6-[3-(1-methyl-1H- indol-3-yl)-1,2,4-oxadiazol-5-yl]- 3,4-dihydro-2H-1-benzopyran-4- one 401.17 402.1
    Figure US20230234946A1-20230727-C01454
         		678 5-[3-(1-methyl-1H-indol-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 358.15 359.1
    Figure US20230234946A1-20230727-C01455
         		679 5-[3-(2,6-dimethylpyridin-3-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 334.15 335.1
    Figure US20230234946A1-20230727-C01456
         		680 2-methyl-1-{5-[3-(4-methyl-1,3- oxazol-5-yl)-1,2,4-oxadiazol-5-yl]- 1H-1,2,3-benzotriazol-1-yl}propan- 2-ol 340.13 341.1
    Figure US20230234946A1-20230727-C01457
         		681 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4- methoxypyridin-3-yl)-1,2,4- oxadiazole 336.13 337.3
    Figure US20230234946A1-20230727-C01458
         		682 5-[3-(1-methyl-1H-indol-3-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile 357.16 358.2
    Figure US20230234946A1-20230727-C01459
         		683 5-[3-(4-methyl-1,3-oxazol-5-yl)- 1,2,4-oxadiazol-5-yl]-1-(propan-2- yl)-1H-1,2,3-benzotriazole 310.12 311.1
    Figure US20230234946A1-20230727-C01460
         		684 2,2-diethyl-6-[3-(1-ethyl-1H-indol- 3-yl)-1,2,4-oxadiazol-5-yl]-3,4- dihydro-2H-1-benzopyran-4-one 415.19 416.2
    Figure US20230234946A1-20230727-C01461
         		685 5-[5-(1-methyl-1H-1,3- benzodiazol-4-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 358.15 359.2
    Figure US20230234946A1-20230727-C01462
         		686 2-[(2,2-difluoroethyl)amino]-5[5- (1-methyl-1H-1,3-benzodiazol-4- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 380.12 381.2
    Figure US20230234946A1-20230727-C01463
         		687 4-{5-[1-(propan-2-yl)-1H-1,2,3- benzotriazol-5-yl]-1,2,4-oxadiazol- 3-yl}-2,3-dihydro-1H-inden-1-one 359.14 360
    Figure US20230234946A1-20230727-C01464
         		688 2-((2,2-difluoroethyl)amino)-5-(5- (pyridin-4-yl)-1,3,4-oxadiazol-2- yl)benzonitrile 327.09 328.3
    Figure US20230234946A1-20230727-C01465
         		689 5-(5-(1H-pyrazol-4-yl)-1,3,4- oxadiazol-2-yl)-2- (isopropylamino)benzonitrile 294.12 295.3
    Figure US20230234946A1-20230727-C01466
         		690 3-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-5-(3- methylpyridin-2-yl)-1,2,4- oxadiazole 320.14 321.3
    Figure US20230234946A1-20230727-C01467
         		691 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(2- methylpyridin-3-yl)-1,2,4- oxadiazole 320.14 321.2 321.2
    Figure US20230234946A1-20230727-C01468
         		692 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methylpyridin-4-yl)-1,2,4- oxadiazole 320.14 321.2
    Figure US20230234946A1-20230727-C01469
         		693 5-(1-isopropyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(3- methylpyridin-2-yl)-1,2,4- oxadiazole 320.14 321.1
    Figure US20230234946A1-20230727-C01470
         		694 5-{5-[1-(propan-2-yl)-1H-1,3- benzodiazol-6-yl]-1,3,4-oxadiazol- 2-yl}-2-[(propan-2- yl)amino]benzonitrile 386.19 387.2
    Figure US20230234946A1-20230727-C01471
         		695 5-[5-(1-ethyl-1H-1,3-benzodiazol- 6-yl)-1,3,4-oxadiazol-2-yl]-2- [(propan-2-yl)amino]benzonitrile 372.17 373.1
    Figure US20230234946A1-20230727-C01472
         		696 2,2-diethyl-6-[5-(2- methoxypyridin-3-yl)-1,2,4- oxadiazol-3-yl]-3,4-dihydro-2H-1- benzopyran-4-one 379.15 380.2
    Figure US20230234946A1-20230727-C01473
         		697 2,2-diethyl-6-{5-[4- (trifluoromethyl)pyridin-3-yl]- 1,2,4-oxadiazol-3-yl}-3,4-dihydro- 2H-1-benzopyran-4-one 417.13 418.2
    Figure US20230234946A1-20230727-C01474
         		698 2,2-diethyl-6-[5-(2-fluoropyridin-3- yl)-1,2,4-oxadiazol-3-yl]-3,4- dihydro-2H-1-benzopyran-4-one 367.13 368.1
    Figure US20230234946A1-20230727-C01475
         		699 2,2-diethyl-6-{5-[2- (trifluoromethyl)pyridin-3-yl]- 1,2,4-oxadiazol-3-yl}-3,4-dihydro- 2H-1-benzopyran-4-one 417.13 418.1
    Figure US20230234946A1-20230727-C01476
         		700 6-[5-(5-aminopyridin-3-yl)-1,2,4- oxadiazol-3-yl]-2,2-diethyl-3,4- dihydro-2H-1-benzopyran-4-one 364.15 365.1
    Figure US20230234946A1-20230727-C01477
         		701 2-[(2,2-difluoroethyl)amino]-5-{5- [1-(propan-2-yl)-1H-1,3- benzodiazol-6-yl]-1,3,4-oxadiazol- 2-yl}benzonitrile 408.15 409.1
    Figure US20230234946A1-20230727-C01478
         		702 2-[(2,2-difluoroethyl)amino]-5-[5- (1-ethyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile 394.14 395.1
    Figure US20230234946A1-20230727-C01479
         		703 5-[3-(1-ethyl-1H-indol-3-yl)-1,2,4- oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile 371.17 372.1
    Figure US20230234946A1-20230727-C01480
         		704 2-[(2-fluoroethyl)amino]-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile 362.13 363.1
    Figure US20230234946A1-20230727-C01481
         		705 5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-1H-indazol-3-amine 331.12 332
    Figure US20230234946A1-20230727-C01482
         		706 2-[(2,2-difluoropropyl)aminol-5-[5- (1-methyl-1H-1,3-benzodiazol-6- yl)-1,3,4-oxadiazol-2- yl]benzonitrile 394.14 395.1
    Figure US20230234946A1-20230727-C01483
         		707 2-(cyclopropylamino)-5-[5-(1- methyl-1H-1,3-benzodiazol-6-yl)- 1,3,4-oxadiazol-2-yl]benzonitrile 356.14 357.1
    Figure US20230234946A1-20230727-C01484
         		708 2-[(1,3-difluoropropan-2- yl)amino]-5-[5-(1-methyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 394.14 395.1
    Figure US20230234946A1-20230727-C01485
         		709 5-[3-(3-methoxypyridin-4-yl)- 1,2,4-oxadiazol-5-yl]-1-(oxan-4- yl)-1H-1,2,3-benzotriazole 378.14 379.1
    Figure US20230234946A1-20230727-C01486
         		710 5-[5-(1,2-dimethyl-1H-1,3- benzodiazol-6-yl)-1,3,4-oxadiazol- 2-yl]-2-[(propan-2- yl)amino]benzonitrile 372.17 373.1
    .
    Figure US20230234946A1-20230727-C01487
         		711 2-[(2,2-difluoroethyl)amino]-5-[5- (1,2-dimethyl-1H-1,3-benzodiazol- 6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile 394.14 395.1
    Figure US20230234946A1-20230727-C01488
         		712 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2,2- trifluoroethyl)amino]benzonitrile 386.07 387
    Figure US20230234946A1-20230727-C01489
         		713 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2- fluoroethyl)amino]benzonitrile 350.09 351
    Figure US20230234946A1-20230727-C01490
         		718 2,2-diethyl-6-(5-(2-methylpyridin- 3-yl)-1,3,4-oxadiazol-2- yl)chroman-4-one 363.16 364.4
    Figure US20230234946A1-20230727-C01491
         		719 2,2-diethyl-6-(5-(2-methylpyridin- 3-yl)-1,3,4-thiadiazol-2- yl)chroman-4-one 379.14 380.2
    Figure US20230234946A1-20230727-C01492
         		720 2,2-diethyl-6-(5-(2-fluoropyridin-3- yl)-1,3,4-thiadiazol-2-yl)chroman- 4-one 383.11 384.2
    Figure US20230234946A1-20230727-C01493
         		721 5-(5-(1H-indol-5-yl)-1,3,4- oxadiazol-2-yl)-2- (isopropylamino)benzonitrile 343.14 344.4
    Figure US20230234946A1-20230727-C01494
         		724 2,2-diethyl-6-(5-(5-methylpyridin- 3-yl)-1,3,4-thiadiazol-2- yl)chroman-4-one 379.14 380.3
    Figure US20230234946A1-20230727-C01495
         		725 2,2-diethyl-6-(5-(4- (trifluoromethyl)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)chroman-4- one 433.11 434.3
    Figure US20230234946A1-20230727-C01496
         		726 2-(cyclopropylmethylamino)-5-[3- (2-oxo-3H-1,3-benzoxazol-6-yl)- 1,2,4-oxadiazol-5-yl]benzonitrile 373.12 374.1
    Figure US20230234946A1-20230727-C01497
         		727 2-((cyclopropylmethyl)amino)-5- (3-(1-oxoisoindolin-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 371.14 372.1
    Figure US20230234946A1-20230727-C01498
         		728 2-(isopropylamino)-5-(3-(2-oxo- 2,3-dihydro-1H-benzo[d]imidazol- 5-yl)-1,2,4-oxadiazol-5- yl)benzonitrile 360.13 361.1
    Figure US20230234946A1-20230727-C01499
         		729 2-((cyclopropylmethyparnino)-5- (3-(2-oxo-2,3-dihydro-1H- benzo[d]]imidazol-5-yl)-1,2,4- oxadiazol-5-yl)benzonitrile 372.13 373.1
    Figure US20230234946A1-20230727-C01500
         		730 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile 346.12 347.1
    Figure US20230234946A1-20230727-C01501
         		730 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(propan-2- yl)amino]benzonitrile 346.12 347.1
    Figure US20230234946A1-20230727-C01502
         		731 N-[4-(5-{3-cyano-4-[(propan-2- yl)amino]phenyl}-1,2,4-oxadiazol- 3-yl)-3-methoxyphenyl]acetamide 391.16 392.1
    Figure US20230234946A1-20230727-C01503
         		732 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2-[(2,2- difluoroethyl)amino]benzonitrile 358.12 369
    Figure US20230234946A1-20230727-C01504
         		733 2-[(2,2-difluoroethyl)amino]-5-[5- (isoquinolin-6-yl)-1,3,4-oxadiazol- 2-yl]benzonitrile 377.11 378.1
    Figure US20230234946A1-20230727-C01505
         		734 5-[3-(2,1,3-benzoxadiazol-5-yl)- 1,2,4-oxadiazol-5-yl]-2- [(cyclopropylmethyl)amino] benzonitrile 368.08 359
    Figure US20230234946A1-20230727-C01506
         		735 5-[5-(isoquinolin-6-yl)-1,3,4- oxadiazol-2-yl]-2-[(propan-2- yl)amino]benzonitrile 355.14 356.1
    Figure US20230234946A1-20230727-C01507
         		736 2-[(propan-2-yl)amino]-5-[5- (quinolin-6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile 355.14 356.1
    Figure US20230234946A1-20230727-C01508
         		736 2-[(propan-2-yl)amino]-5-[5- (quinolin-6-yl)-1,3,4-oxadiazol-2- yl]benzonitrile 355.14 356.1
    Figure US20230234946A1-20230727-C01509
         		737 2-(isopropylamino)-5-(5-(pyridin- 3-yl)pyrimidin-2-yl)benzonitrile 315.15 316
    Figure US20230234946A1-20230727-C01510
         		738 2-isopropoxy-5-(5-(pyridin-3- yl)pyrimidin-2-yl)benzonitrile 316.13 317
    Figure US20230234946A1-20230727-C01511
         		739 2-(isopropylamino)-5-(5-(pyridin- 4-yl)pyrimidin-2-yl)benzonitrile 315.15 316
    Figure US20230234946A1-20230727-C01512
         		740 2-isopropoxy-5-(5-(pyridin-4- yl)pyrimidin-2-yl)benzonitrile 316.13 317
    Figure US20230234946A1-20230727-C01513
         		741 2-(isopropylamino)-5-(5-(pyridin- 2-yl)pyrimidin-2-yl)benzonitrile 315.15 316
    Figure US20230234946A1-20230727-C01514
         		742 2-isopropoxy-5-(5-(pyridin-2- yl)pyrimidin-2-yl)benzonitrile 316.15 317
    Figure US20230234946A1-20230727-C01515
         		743 5-(5-(2-hydroxypyridin-4- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile 331.14 332
    Figure US20230234946A1-20230727-C01516
         		744 5-(5-(2-hydroxypyridin-4- yl)pyrimidin-2-yl)-2- isopropoxybenzonitrile 332.13 333
    Figure US20230234946A1-20230727-C01517
         		745 2-isopropoxy-5-(5-(2- methoxyphenyl)pyrimidin-2- yl)benzonitrile 345.15 346
    Figure US20230234946A1-20230727-C01518
         		746 5-(5-(2,2-diethyl-4-oxochroman-6- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile 440.22 441.4
    Figure US20230234946A1-20230727-C01519
         		747 2-(isopropylamino)-5-(5-(2- methoxyphenyl)pyrimidin-2- yl)benzonitrile 344.16 345.3
    Figure US20230234946A1-20230727-C01520
         		748 5-(5-(benzo[c][1,2,5]oxadiazol-5- yl)pyrimidin-2-yl)-2- isopropoxybenzonitrile 357.12 357.9
    Figure US20230234946A1-20230727-C01521
         		749 5-(5-(benzo[c][1,2,5]oxadiazol-5- yl)pyrimidin-2-yl)-2- (isopropylamino)benzonitrile 356.14 356.9
    Figure US20230234946A1-20230727-C01522
         		750 N-isopropyl-4-(5-(2- methoxyphenyl)pyrimidin-2-yl)-2- (trifluoromethyl)aniline 387.16 388
    Figure US20230234946A1-20230727-C01523
         		751 2-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5-(2- methoxyphenyl)pyrimidine 388.14 389
    Figure US20230234946A1-20230727-C01524
         		752 2-(4-isopropoxy-3- (trifluoromethyl)phenyl)-5- (pyridin-4-yl)pyrimidine 359.13 360
    Figure US20230234946A1-20230727-C01525
    • General Procedure A:
  • Figure US20230234946A1-20230727-C01526
    Figure US20230234946A1-20230727-C01527
    Figure US20230234946A1-20230727-C01528
    Figure US20230234946A1-20230727-C01529
    • Example 2
  • Figure US20230234946A1-20230727-C01530
    • Synthesis of Intermediate 2-2: N,2-dihydroxypyridine-3-carboximidamide
  • To a mixture of 2-1 (2-hydroxypyridine-3-carbonitrile)(200 mg, 1.67 mmol) in ethanol (10 mL) was added hydrochloride salt of hydroxylamine (174 mg, 2.50 mmol), diisopropylethylamine (430 mg, 3.33 mmol) at 20° C. The mixture was then heated to 90° C. and stirred for 16 hrs. The mixture was concentrated in vacuum to remove part of ethanol, the resulting mixture was filtered, and the solid was dried in vacuum which was used as the product in next step without further purification (185 mg, 69% yield).
  • 1H NMR (400 MHz, DMSO-d6) δ=12.06 (br, s, 1H), 9.50 (br, s, 1H), 7.95 (dd, J=7.2, 2.4 Hz, 1H), 7.51 (dd, J=6.0, 2.0 Hz, 1H), 6.3-6.30 (m, 3H).
    • General Procedure B Synthesis of Intermediate 3-2: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid
  • Figure US20230234946A1-20230727-C01531
    • Alternative Synthesis of Intermediate 4-4: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid
  • Figure US20230234946A1-20230727-C01532
    • Synthesis of 4-2: 6-bromo-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01533
  • To a solution of 1-(5-bromo-2-hydroxy-phenyl)ethanone (20 g, 93.0 mmol, 1 eq) in methanol (400 mL) was added pyrrolidine (7.94 g, 112 mmol, 1.2 eq) and pentan-3-one (9.61 g, 112 mmol, 1.2 eq). The mixture was stirred at 80° C. for 16 hr. The reaction mixture diluted with water (200 mL) and extracted with ethyl acetate (200 mL×2), the combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give the desired product 4-2 (12 g, 46% yield) as a yellow oil.
  • 1H NMR (400 MHz, CDCl3) δ=7.93 (d, J=2.5 Hz, 1H), 7.52 (dd, J=8.8, 2.6 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 2.70 (s, 2H), 1.86-1.62 (m, 4H), 0.92 (t, J=7.5 Hz, 6H).
    • Synthesis of Intermediate 4-3: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carbonitrile
  • Figure US20230234946A1-20230727-C01534
  • To a solution of 6-bromo-2,2-diethyl-chroman-4-one (10 g, 35.3 mmol, 1 eq) in DMF (100 mL) was added zinc cyanide (6.22 g, 53.0 mmol, 1.5 eq) and tetratriphenylphosphine palladium (4.08 g, 3.53 mmol, 0.1 eq). The mixture was stirred at 130° C. for 2 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether/ethyl acetate=100/1 to 1/1) to give the desired product 4-3 (8 g, 99% yield).
  • 1H NMR (400 MHz, DMSO-d6) δ=8.08 (d, J=1.9 Hz, 1H), 7.96 (dd, J=8.7, 2.0 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 2.88 (s, 2H), 1.86-1.59 (m, 4H), 0.86 (br, t, J=7.4 Hz, 6H).
    • Scheme 7 Synthesis of Intermediate 4-4: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid
  • Figure US20230234946A1-20230727-C01535
  • A suspension of 2,2-diethyl-4-oxo-chromane-6-carbonitrile (6.05 g, 26.4 mmol, 1 eq) in acetic acid (60 mL) and concentrated hydrochloride solution (60 mL) was stirred at 120° C. for 16 hr, The residue was triturated with water (500 mL), filtered and dried under vacuum to give the titled product 4-4 (5.8 g, 89% yield).
  • 1H NMR (400 MHz, DMSO-d6) δ=8.27 (d, J=1.9 Hz, 1H), 8.06 (dd, J=8.7, 2.0 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 2.85 (s, 2H), 1.77-1.68 (m, 4H), 0.87 (t, J=7.4 Hz, 6H).
    • General Procedure C:
  • Figure US20230234946A1-20230727-C01536
    • Synthesis of Compound 9α-1: 2,2-diethyl-6-(3-(2-hydroxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)chroman-4-one
  • Figure US20230234946A1-20230727-C01537
  • To a mixture of 4-4 (268 mg, 1.08 mmol) in N,N-dimethylformamide (6 mL) was added HOBt (159 mg, 1.18 mmol, 1.2 eq), EDCI (225 mg, 1.18 mmol, 1.2 eq) at 20° C. under nitrogen atmosphere. The mixture was stirred for 30 min, then, 2-2 (150 mg, 980 umol, 1 eq) was added, and the resultant mixture was then heated to 120° C. and stirred for 2 hrs. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3). The combined organic phase was washed by brine (50 mL), dried over sodium sulfate, concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 12 min) to give the product 9-1 as a white solid (20 mg, 6% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.23 (br, s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.33 (dd, J=7.2, 2.0 Hz, 1H), 8.28 (dd, J=8.8, 2.4 Hz, 1H), 7.68 (dd, J=6.0, 2.0 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.42 (t, J=6.8 Hz, 1H), 2.93 (s, 2H), 1.81-1.70 (m, 4H), 0.90 (t, J=7.2 Hz, 6H).
    • Synthesis of Compound: 2,2-diethyl-6-[3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]-3H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01538
  • To a solution of compound 4-4 (16.41 g, 66.08 mmol, 1 eq.) in DMF (50 mL) was added EDCI (15.20 g, 79.29 mmol, 1.2 eq.) and HOBt (8.93 g, 66.08 mmol, 1.0 eq.), stirred at 20° C. for 0.5 hour. Then compound 9b-1 (10 g, 79.29 mmol, 1.2 eq.) was added. The mixture was stirred at 20° C. for 0.5 hour, then heated to 120° C. and stirred for 2 hours. The mixture was diluted with water (100 mL), extracted with EtOAc (150 mL*3), dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give 9b-2 (7.2 g, yield: 30%) as white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=13.49 (br. s, 1H), 8.47 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.26 (dd, J=2.3, 8.8 Hz, 1H), 8.06 (s, 1H), 7.26 (d, J=8.7 Hz, 1H), 2.91 (s, 2H), 1.79-1.69 (m, 4H), 0.89 (t, J=7.4 Hz, 6H).
    • General Procedure D:
  • Figure US20230234946A1-20230727-C01539
    • Synthesis of 11-1: 3-bromo-5-(3-methoxyphenyl)-1,2,4-thiadiazole
  • Figure US20230234946A1-20230727-C01540
  • To a solution of (3-methoxyphenyl)boronic acid (247.25 mg, 1.63 mmol, 1 eq) in DME (5 mL) was added Pd(dppf)Cl2 (119.06 mg, 162.71 umol, 0.1 eq), K3PO4 (1.04 g, 4.88 mmol, 3 eq) and 10-1,3-bromo-5-chloro-1,2,4-thiadiazole (649.07 mg, 3.25 mmol, 2 eq). The mixture was stirred at 80° C. for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE/EA=10/1) to give 11-1 (3-bromo-5-(3-methoxyphenyl)-1,2,4-thiadiazole) (200 mg, 737.64 umol, 45% yield) as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.23 (dd, J=1.6, 7.8 Hz, 1H), 7.78-7.57 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 4.13 (s, 3H).
    • Synthesis of 12-1: 2,2-diethyl-6-[5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl]-3,4-ihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01541
  • To a solution of 3-bromo-5-(2-methoxyphenyl)-1,2,4-thiadiazole (100 mg, 368.82 umol, 1 eq) and 2,2-diethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one (146.15 mg, 442.59 umol, 1.2 eq) in DMF (1 mL) and H2O (0.5 mL) was added K3PO4 (234.87 mg, 1.11 mmol, 3 eq) and Pd(PPh3)4 (42.62 mg, 36.88 umol, 0.1 eq) and stirred at 120° C. for 0.25 h. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 70%-100%, 10 min) to give 2,2-diethyl-6-[5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl]chroman-4-one (34.5 mg, 87.46 umol, 23.71% yield, 100% purity) as a yellow solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.66 (d, J=2.1 Hz, 1H), 8.52-8.41 (m, 2H), 7.71-7.62 (m, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 4.14 (s, 3H), 2.88 (s, 2H), 1.76 (quint, J=7.2, 14.4 Hz, 4H), 0.90 (t, J=7.4 Hz, 6H).
    • Synthesis of 10-8: 2,2-diethyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01542
  • To a solution of 6-bromo-2,2-diethyl-chroman-4-one (1 g, 3.53 mmol, 1 eq) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (986.48 mg, 3.88 mmol, 1.1 eq), DPPF (195.78 mg, 353.16 umol, 0.1 eq), Pd(dppf)Cl2 (258.41 mg, 353.16 umol, 0.1 eq) and KOAc (415.92 mg, 4.24 mmol, 1.2 eq), the mixture was stirred at 100° C. for 4 h, The reaction mixture was diluted with water (100 mL) and extracted with (EA 100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE/EA=1/1) to give 2,2-diethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one (1 g, 3.03 mmol, 85.75% yield) as a white solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.26 (d, J=1.6 Hz, 1H), 7.86-7.75 (m, 1H), 6.85 (d, J=8.3 Hz, 1H), 2.64 (s, 2H), 1.82-1.58 (m, 4H), 1.32-1.21 (m, 12H), 0.85 (t, J=7.5 Hz, 6H).
    • Synthesis of 14-5: 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01543
    • Synthesis of 14-2: 4-bromo-2-nitro-N-(propan-2-yl)aniline
  • Figure US20230234946A1-20230727-C01544
  • To a solution of 4-bromo-1-fluoro-2-nitro-benzene (5 g, 22.73 mmol, 2.79 mL, 1.00 eq) and propan-2-amine (2.02 g, 34.09 mmol, 2.92 mL, 1.50 eq) in THF (250.00 mL) was added DIEA (7.34 g, 56.82 mmol, 9.90 mL, 2.50 eq) at 10° C. and stirred for 1 h, The reaction mixture was diluted with water (500 mL) and extracted with EA (500 mL×2). The combined organic layers were washed with NaHCO3(500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 4-bromo-N-isopropyl-2-nitro-aniline (3.2 g, 12.35 mmol, 54.34% yield) as yellow oil.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.14 (d, J=2.4 Hz, 1H), 7.88 (br d, J=7.5 Hz, 1H), 7.63 (dd, J=2.3, 9.3 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 3.92 (sxtd, J=6.5, 13.2 Hz, 1H), 1.25 (d, J=6.4 Hz, 6H).
    • Synthesis of 14-3: 4-bromo-1-N-(propan-2-yl)benzene-1,2-diamine
  • Figure US20230234946A1-20230727-C01545
  • To a solution of 4-bromo-N-isopropyl-2-nitro-aniline (2 g, 7.72 mmol, 1 eq) in EtOH (20 mL) was added SnCl2.2H2O (5.23 g, 23.16 mmol, 1.93 mL, 3 eq) and stirred at 80° C. for 16 h. The reaction mixture was quenched with aqueous NaOH (4 M, 50 mL), and then diluted with water (50 mL) and extracted with EA (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE/EA=100/1 to 1/1) to give 4-bromo-N-isopropyl-benzene-1,2-diamine (850 mg, 3.71 mmol, 48.06% yield) as a black-brown solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=6.82 (dd, J=2.1, 8.4 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 6.44 (d, J=8.3 Hz, 1H), 3.56-3.40 (m, 1H), 1.14 (d, J=6.4 Hz, 6H).
    • Synthesis of 14-4: 5-bromo-1-(propan-2-yl)-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01546
  • To a solution of 4-bromo-N-isopropyl-benzene-1,2-diamine (750 mg, 3.27 mmol, 1.00 eq) in HCl (5 mL, 6 M) was added NaNO2 (271.04 mg, 3.93 mmol, 213.42 uL, 1.20 eq) in H2O (2 mL) dropwise at 5° C. and stirred for 0.5 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (1/1) to give 5-bromo-1-isopropyl-benzotriazole (700 mg, 2.92 mmol, 89.06% yield) black-brown solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.32 (d, J=1.7 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.60-7.60 (m, 1H), 7.67 (dd, J=1.8, 8.9 Hz, 1H), 5.32-5.16 (m, 1H), 1.62 (d, J=6.7 Hz, 6H).
    • Synthesis of 14-5: 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01547
  • To a solution of 5-bromo-1-isopropyl-benzotriazole (700 mg, 2.92 mmol, 1 eq) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (814.38 mg, 3.21 mmol, 1.1 eq), DPPF (161.63 mg, 291.55 umol, 0.1 eq), Pd(dppf)Cl2 (213.33 mg, 291.55 umol, 0.1 eq) and KOAc (343.35 mg, 3.50 mmol, 1.2 eq), The mixture was stirred at 100° C. for 1 h, the mixture was diluted with water (100 mL) and extracted with (EA 100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE EA=100/1 to 1/1) to give 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazole (300 mg, 1.04 mmol, 35.83% yield) as a yellow solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.57 (s, 1H), 7.89 (dd, J=0.7, 8.3 Hz, 1H), 7.55 (dd, J=0.8, 8.4 Hz, 1H), 5.11 (spt, J=6.8 Hz, 1H), 1.75 (d, J=6.8 Hz, 6H), 1.47-1.34 (m, 12H).
    • General Procedure E:
  • Figure US20230234946A1-20230727-C01548
    • Synthesis of 19-6 and 19-7: 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-thiadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one; 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01549
    • Synthesis of 19-2: methyl 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carboxylate
  • Figure US20230234946A1-20230727-C01550
  • A mixture of 1-isopropylbenzotriazole-5-carbonitrile (1 g, 5.37 mmol, eq. in HCl/MeOH (20 mL, 4 M) was stirred at 80° C. for 2 h. The mixture was concentrated, diluted with water (20 mL), extracted with EA (20 mL×2), dried over Na2SO4 and concentrated to dry. The crude product methyl 1-isopropylbenzotriazole-5-carboxylate (0.9 g, 4.11 mmol, 76.44% yield) was used into the next step without further purification.
    • Synthesis of 19-3: 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbohydrazide
  • Figure US20230234946A1-20230727-C01551
  • A mixture of methyl 1-isopropylbenzotriazole-5-carboxylate (0.5 g, 2.28 mmol, 1 eq.) and NH2NH2·H2O (1.14 g, 22.81 mmol, 1.11 mL, 10 eq.) in EtOH (10 mL) was stirred at 80° C. for 2 h.
  • The mixture was concentrated to dry. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:1) to give 1-isopropyl Benzotriazole-5-carbohydrazide (0.38 g, 1.73 mmol, 76.00% yield) as a white solid.
    • Synthesis of 19-5: 2,2-diethyl-4-oxo-N′-[1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbonyl]-3,4-dihydro-2H-1-benzopyran-6-carbohydrazide
  • Figure US20230234946A1-20230727-C01552
  • To a mixture of 2,2-diethyl-4-oxo-chromane-6-carboxylic acid (274.04 mg, 1.10 mmol, 1.1 eq.) and 1-isopropylbenzotriazole-5-carbohydrazide (220 mg, 1.00 mmol, 1 eq.) in THF (10 mL) was added HATU (419.70 mg, 1.10 mmol, 1.1 eq.) and DIEA (142.66 mg, 1.10 mmol, 192.26 uL, 1.1 eq.), the mixture was stirred at 15° C. for 2 hr. The mixture was diluted with water (50 mL), extracted with EA (50 mL×2), dried over Na2SO4 and concentrated in vacuum. N′-(2,2-diethyl-4-oxo-chromane-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (420 mg, 934.37 umol, 93.12% yield) was obtained as yellow solid without further purification.
    • Synthesis of 19-7: 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-thiadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01553
  • A mixture of N′-(2,2-diethyl-4-oxo-chromane-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (200 mg, 444.94 umol, 1 eq.) and Lawesson's reagent (359.93 mg, 889.88 umol, 2 eq.) in THF (2 mL) was stirred at 80° C. for 2 h. The mixture was diluted with water (20 mL), extracted with EA (20 mL×2), dried over Na2SO4 and concentrated to dry. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 62%-92%, 13 min) to give 2,2-diethyl-6-[5-(1-isopropylbenzotriazol-5-yl)-1,3,4-thiadiazol-2-yl]chroman-4-one (61 mg, 29.99 umol, 6.74% yield, 22% purity) as a white solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.62 (d, J=0.6 Hz, 1H), 8.38-8.36 (m, 1H), 8.36-8.33 (m, 1H), 8.33-8.30 (m, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 5.22-5.11 (m, 1H), 2.82 (s, 2H), 1.95-1.83 (m, 4H), 1.82-1.80 (m, 6H), 0.99 (t, J=7.5 Hz, 6H).
    • Synthesis of 19-7: 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one
  • Figure US20230234946A1-20230727-C01554
  • A mixture of N′-(2,2-diethyl-4-oxo-chromane-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (200 mg, 444.94 umol, 1 eq.) and Burgess reagent (530.17 mg, 2.22 mmol, 5 eq.) in DCM (2 mL) was stirred at 15° C. for 2 h. The mixture was diluted with water (20 mL), extracted with EA (20 mL×2), dried over Na2SO4 and concentrated to dry. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 55%-85%, 12 min) to give 2,2-diethyl-6-[5-(1-isopropylbenzotriazol-5-yl)-1,3,4-oxadiazol-2-yl]chroman-4-one (56 mg, 129.78 umol, 29.17% yield, 100% purity) as a white solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.85 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.35 (t, J=2.1 Hz, 1H), 8.33 (t, J=2.1 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 5.24-5.11 (m, 1H), 2.84 (s, 2H), 1.94-1.85 (m, 2H), 1.82 (d, J=6.8 Hz, 5H), 1.80-1.75 (m, 2H), 1.00 (t, J=7.5 Hz, 6H) Synthesis of 25-2: 5-[5-(1H-1,3-benzodiazol-5-yl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzonitrile
  • Figure US20230234946A1-20230727-C01555
  • A suspension of 1 (N′-(1H-1,3-benzodiazole-5-carbonyl)-3-cyano-4-fluorobenzohydrazide, 541 mg, 1.67 mmol) in phosphorus oxychloride (10 mL, excess) was heated at 105° C. for 3 hours. The mixture was concentrated, and the residue was suspended in water with sonication/stirring. The resulting solid was collected, washed with sat'd NaHCO3and water, then dried under N2/vac in the filter funnel. The tan solid was suspended in MeCN and concentrated twice to remove residual water and dried under high vacuum to yield 25-2 (0.55 g, 107%). MH+=306.1.
    • Synthesis of 26-2: 6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-methyl-2,3-dihydro-1,3-benzoxazol-2-one
  • Figure US20230234946A1-20230727-C01556
  • To a suspension of 3 (6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,3-benzoxazol-2-one trifluoroacetate, 13 mg, 0.031 mmol) in DMF (1 mL) was added potassium carbonate (8.6 mg, 0.062 mmol) followed by methyl iodide (5.2 mg, 0.037 mmol) and the resulting white suspension heated to 100° C. for 45 min. The reaction was cooled to room temperature, filtered, and purified by reverse phase chromatography, 25%-75% MeCN/water/0.1% TFA. The product fractions lyophilized to yield 26-2 (1.6 mg, 12%). MH+=324.1. 1H NMR (400 MHz, DMSO) 7.93-7.91 (3H, m), 7.59-7.54 (1H, m), 7.44-7.41 (1H, m), 7.25-7.22 (1H, m), 7.11-7.07 (1H, m), 3.88 (3H, s); 3.45 (3H, s)
    • Synthesis of 27-3: methyl N-({6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl}sulfon yl)carbamate
  • Figure US20230234946A1-20230727-C01557
  • To a dry mixture of 27-1 (2-methoxyphenylhydrazide, 139 mg, 0.837 mmol), 27-2 (benzoxazol-2-one-6-carboxylic acid, 150 mg, 0.837 mmol), and HATU (318 mg, 0.837 mmol) was added THF (10 mL) to yield a hazy reddish solution. DIPEA (0.29 mL, 1.67 mmol) was added and the reaction was stirred at rt for 2 hr. Burgess reagent (499 mg, 2.09 mmol) was added one portion, and the reaction was heated to 60° C. overnight. An additional 499 mg Burgess reagent was added. and continued heating. After 4 hr, 2N KHSO4 (10 mL) was added and the resulting oily mixture was extracted 3×EtOAc. The combined organics were washed once with water, once with brine, filtered through cotton and concentrated to an orange solid which was purified by reverse phase chromatography, 20%-60% MeCN/water/0.1% TFA to yield 67 mg 27-3(18%) MH+=447.0. 1H NMR (400 MHz, DMSO) 8.02-7.97 (3H, m), 7.74 (1H, d, J=8.4 Hz), 7.64 (1H, t, J=8.2 Hz), 7.30 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=7.4 Hz), 3.95 (3H, s), 3.39 (3H, s).
    • Synthesis of 28-2: 2-[(2-fluoropropyl)amino]-5-[5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,3,4-oxadiazol-2-yl]benzonitrile
  • Figure US20230234946A1-20230727-C01558
  • To a nitrogen purged small Parr hydrogenation bottle was added 10% Pd/C (14 mg) and moistened with a small volume of EtOH. To 28-1 (2-[(2-fluoroprop-2-en-1-yl)amino]-5-[5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,3,4-oxadiazol-2-yl]benzonitrile trifluoroacetate, 70 mg, 0.139 mmol) was added EtOH (10 mL) and EtOAc (90 mL) to yield a milky mixture which was added to the hydrogenation bottle. The mixture was hydrogenated under 50 psi H2 for 24 hr. MeCN was added until the milky mixture clears, then filtered through Celite and concentrated. The residue was heated in a small volume of DMF, cooled, filtered, and purified by reverse phase chromatography, 30%-75% MeCN/water/0.10% TFA. The product fractions were lyophilized to yield 28-2 as a fluffy white solid (12.8 mg, 18%). MH+=392.1. 1H NMR (400 MHz, DMSO) 10.40 (1H, s), 8.25 (1H, d, J=2.1 Hz), 8.11 (1H, dd, J=2.0, 9.2 Hz), 7.92-7.81 (2H, m), 7.22 (1H, t, J=6.3 Hz), 7.11 (1H, d, J=9.2 Hz), 7.11 (1H, d, J=9.4 Hz), 7.02 (1H, d, J=8.7 Hz), 7.04-7.00 (1H, m), 5.00-4.80 (1H, m), 3.60-3.51 (2H, m), 3.01 (2H, t, J=7.4 Hz), 1.35 (3H, dd, J=6.2, 24.0 Hz).
    • Synthesis of 29-3: 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,3-dihydro-2,1-benzoxazol-3-one
  • Figure US20230234946A1-20230727-C01559
  • To a nitrogen purged hydrogenation bottle was added 10% Pd/C (12 mg), which was moistened with EtOH. A suspension of 29-1 (methyl 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2-nitrobenzoate, prepared according to Wuxi 1,3,4-oxadiazole experimental, 112 mg, 0.281) in EtOH (25 mL) and EtOAc (20 mL) was hydrogenated at 48 psi H2. After 30 minutes the reaction was filtered and concentrated to solid 29-2 (113 mg, 105%), which was used without further purification. MH+=342.1.
  • To a solution of 29-2 (47 mg, 0.132 mmol) in DMF (2 mL) was added triethylamine (0.1 mL) then water (0.2 mL) and the resulting solution stirred at rt for 60 hr. The reaction mixture was purified directly by reverse phase chromatography, 20%-65% MeCN/water/0.1% TFA to yield 8 mg 29-3 (14%). MH+=310.1. 1H NMR (400 MHz, DMSO) 12.52 (1H, s), 8.42-8.38 (2H, m), 8.03 (1H, d, J=6.9 Hz), 7.65 (1H, t, J=8.3 Hz), 7.57 (1H, d, J=7.6 Hz), 7.32 (1H, d, J=8.3 Hz), 7.17 (1H, t, J=6.9 Hz), 3.96 (3H, s).
    • Synthesis of 30-1: 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1-methyl-1,3-dihydro-2,1-benzoxazol-3-one
  • Figure US20230234946A1-20230727-C01560
  • To a solution of 29-2 (8 mg, 0.019 mmol) in DMF (0.5 mL) was added potassium carbonate (2.6 mg, 0.019 mmol) followed by methyl iodide (4.0 mg, 0.028 mmol) and the resulting solution heated to 100° C. for 15 minutes. The reaction was cooled to rt, filtered, and purified directly by reverse phase chromatography, 25%-75% MeCN/water/0.1% TFA to yield 5.3 mg 30-1 (64%) as a white solid. MH+=324.1. 1H NMR (400 MHz, DMSO) 8.40 (1H, d, J=8.7 Hz), 8.32 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=8.7 Hz), 7.58 (1H, t, J=8.3 Hz), 7.25 (1H, d, J=8.0 Hz), 7.10 (1H, t, J=7.7 Hz), 3.89 (3H, s), 3.49 (3H, s).
    • General Procedure F:
  • Figure US20230234946A1-20230727-C01561
    Figure US20230234946A1-20230727-C01562
    • Synthesis of 32-2: N-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carboximidamide
  • Figure US20230234946A1-20230727-C01563
  • To a mixture of 2-oxoindoline-5-carbonitrile (200 mg, 1.26 mmol, 1 eq) in ethanol (5 mL) was added hydrochloride salt of hydroxylamine (176 mg, 2.53 mmol, 2.0 eq), diisopropylethylamine (327 mg, 2.53 mmol, 2.0 eq) at 20° C. under nitrogen atmosphere. The mixture was then heated to 90° C. and stirred for 16 hrs. The mixture was concentrated in vacuum, and a white solid was precipitated out. The suspension was filtered, and the white solid was dried in vacuum to give the product 32-2 (210 mg, 83% yield).
  • 1H NMR (400 MHz, DMSO-d6) δ=10.46 (br, s, 1H), 9.45 (br, s, 1H), 7.51 (s, 1H), 7.50 (d, J=10.8 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.70 (br, s, 2H), 3.49 (s, 2H).
    • Synthesis of 33-1: 2-[(cyclopropylmethyl)amino]-5-[3-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl]benzonitrile
  • Figure US20230234946A1-20230727-C01564
  • To a mixture of 3-cyano-4-(cyclopropylmethylamino)benzoic acid (107 mg, 496 umol, 1.2 eq) in N,N-dimethylformamide (1 mL) was added HOBt (67.0 mg, 496 umol, 1.2 eq), EDCI (95.1 mg, 496 umol, 1.2 eq) at 20° C. The mixture was stirred for 30 min, then N-hydroxy-2-oxo-indoline-5-carboxamidine (79 mg, 413 umol, 1 eq) was added, and the resultant mixture then heated to 150° C. and stirred for 1 hour. The cooled reaction mixture was directly purified by prep-HPLC (column: Boston Green ODS 150×30 5 u; mobile phase: [water(0.225% FA)-ACN]; B %: 47%-77%, 10 min) to give the product 33-1 (20 mg, 12% yield).
  • 1H NMR (400 MHz, DMSO-d6) δ=10.73 (br, s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11 (dd, J=9.2, 2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.17 (t, J=6.4 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.61 (s, 2H), 3.20 (t, J=6.4 Hz, 2H), 1.16-1.13 (m, 1H), 0.52-0.47 (m, 2H), 0.33-0.29 (m, 2H).
    • General Procedure G:
  • Figure US20230234946A1-20230727-C01565
    • Synthesis of 35-2: 3-cyano-4-[(cyclopropylmethyl)amino]benzoic acid
  • Figure US20230234946A1-20230727-C01566
  • To a mixture of 3-cyano-4-fluoro-benzoic acid (5 g, 30.3 mmol, 1 eq) and cyclopropylmethanamine (5.38 g, 75.7 mmol, 2.5 eq) in dimethylsulfoxide (30 mL) was added potassium carbonate (12.6 g, 90.8 mmol, 3 eq) at 20° C. The mixture was then heated to 100° C. and stirred for 16 hours. The mixture was filtered, and the filtrate was diluted with water (50 mL), acidified by hydrochloride solution (2N) to pH=4-5. A yellow solid was precipitated out, the suspension was filtered, and the solid was washed by water (50 mL×3). The solid was dried in vacuum to give the desired product 35-2 (5 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ=7.95 (d, J=1.2 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 6.85-6.82 (m, 1H), 3.13 (t, J=6.0, 2H), 1.16-1.06 (m, 1H), 0.49-0.44 (m, 2H), 0.29-0.25 (m, 2H).
    • Synthesis of 36-2: 5-[3-(1H-indol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(prop-2-en-1-yl)amino]benzonitrile
  • Figure US20230234946A1-20230727-C01567
  • To a mixture of tert-butyl 5-[5-[4-(allylamino)-3-cyano-phenyl]-1,2,4-oxadiazol-3-yl]indole-1-carboxylate (60.0 mg, 136 umol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 50 eq) at 20° C. under nitrogen atmosphere. The mixture was stirred at 20° C. for 16 h. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (column: Gemini 150×25 5 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 47%-77%, 12 min) to give the product 36-2 (15 mg, 30% yield) as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.33 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.14 (dd, J=8.8, 2.0 Hz, 1H), 7.80 (dd, J=8.4, 1.2 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.48 (t, J=2.4 Hz, 1H), 7.39 (t, J=5.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.61 (s, 1H), 5.94-5.85 (m, 1H), 5.24-5.16 (m, 2H), 3.97 (s, 1H).
    • General Procedure H:
  • Figure US20230234946A1-20230727-C01568
    • Synthesis of 38-4: 1-cyclopentyl-N-hydroxy-1H-1,2,3-benzotriazole-5-carboximidamide
  • Figure US20230234946A1-20230727-C01569
    • Synthesis of 38-1: 4-(cyclopentylamino)-3-nitrobenzonitrile
  • Figure US20230234946A1-20230727-C01570
  • Preparation of 1: To a solution of 4-fluoro-3-nitro-benzonitrile (1.00 g, 6.02 mmol, 1.00 eq) and cyclopentanamine (767 mg, 9.03 mmol, 1.50 eq) in THF (20.00 mL) was added DIEA (1.95 g, 15.05 mmol, 2.63 mL, 2.50 eq) and the mixture was stirred at 10° C. for 16 hour. The mixture was evaporated to dry and diluted with H2O (50 mL), extracted with DCM (50 mL×2), dried over Na2SO4, filtered and concentrated to dry. Compound 4-(cyclopentylamino)-3-nitrobenzonitrile (1.36 g, 5.91 mmol, 98.10% yield) was obtained as a yellow solid which was used directly in next step.
    • Synthesis of 38-2: 3-amino-4-(cyclopentylamino)benzonitrile
  • Figure US20230234946A1-20230727-C01571
  • Preparation of 2: To a solution of 4-(cyclopentylamino)-3-nitro-benzonitrile (5.00 g, 21.62 mmol, 1.00 eq) in MeOH (150.00 mL) was added Pd/C (1.00 g, 4.32 mmol, 10% purity, 0.20 eq). Then the mixture was stirred for 12 hours at 20° C. under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to dry to get 3-amino-4-(cyclopentylamino)benzonitrile (4.20 g, 20.87 mmol, 96.52% yield) as black solid, which was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ=8.77 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 5.43 (m, 1H), 2.37-2.21 (m, 2H), 2.18-2.06 (m, 2H), 1.99-1.85 (m, 2H), 1.81-1.67 (m, 2H).
    • Synthesis of 38-4: 1-cyclopentyl-N-hydroxy-1H-1,2,3-benzotriazole-5-carboximidamide
  • Figure US20230234946A1-20230727-C01572
  • Preparation of 3: To a solution of 1-cyclopentylbenzotriazole-5-carbonitrile (1.50 g, 7.07 mmol) in ethanol (15.00 mL) was added hydroxylamine hydrochloride (736.64 mg, 10.60 mmol) and DIPEA (2.01 g, 15.55 mmol, 2.72 mL). Then the mixture was stirred at 70° C. for 4 hours. The mixture was filtered to get 1-cyclopentyl-N-hydroxy-benzotriazole-5-carboxamidine (1.20 g, 4.89 mmol, 69.20% yield) as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=9.77 (s, 1H), 8.31 (s, 1H), 7.97-7.89 (m, 1H), 7.87-7.79 (m, 1H), 5.98 (s, 2H), 5.34 (q, J=7.0 Hz, 1H), 2.36-2.21 (m, 2H), 2.19-2.07 (m, 2H), 1.99-1.84 (m, 2H), 1.81-1.67 (m, 2H).
    • General Procedure I:
  • Figure US20230234946A1-20230727-C01573
    Figure US20230234946A1-20230727-C01574
    • Synthesis of 42-2: 5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1-cyclopentyl-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01575
  • To a solution of 3-methylbenzoic acid (66.61 mg, 489.24 umol) in DMF (4.00 mL) was added EDCI (93.79 mg, 489.24 umol) and HOBt (66.11 mg, 489.24 umol). The mixture was stirred at 20° C. for 1 hour and 1-cyclopentyl-N-hydroxy-benzotriazole-5-carboxamidine (100.00 mg, 407.70 umol) was added to the mixture. Then the mixture was stirred at 120° C. for 12 hours under N2. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic layers were washed with brine (40 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by prep-HPLC (TFA) to get t 3-(1-cyclopentylbenzotriazol-5-yl)-5-(m-tolyl)-1,2,4-oxadiazole (96.00 mg, 277.94 umol, 68.17% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ=8.93 (s, 1H), 8.30 (dd, J=1.3, 8.7 Hz, 1H), 8.08 (s, 1H), 8.06 (br d, J=6.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.51-7.42 (m, 2H), 5.22 (quin, J=7.0 Hz, 1H), 2.50 (s, 3H), 2.43-2.32 (m, 4H), 2.15-2.01 (m, 2H), 1.92-1.81 (m, 2H).
    • Synthesis of 44-2: 2-{5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1H-1,2,3-benzotriazol-1-yl}acetic acid
  • Figure US20230234946A1-20230727-C01576
  • To a solution of methyl 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl] acetate (40.00 mg, 96.57 umol, 1.00 eq) in dioxane (2.00 mL) and H2O (2.00 mL) was added NaOH (15.45 mg, 386.28 umol, 4.00 eq). Then the mixture was stirred at 20° C. for 12 hours. The mixture was adjust to pH=2-3 with HCl (1N) and extracted with ethyl acetate (15 mL×2). The organic layers were dried over Na2SO4 and concentrated to give 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]acetic acid(17.30 mg, 43.23 umol, 44.76% yield) as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.70 (s, 1H), 8.26 (m, 3H), 7.93 (m, 2H), 7.66 (m, 2H), 5.24 (br s, 2H)
    • Synthesis of 45-1: 2-{5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1H-1,2,3-benzotriazol-1-yl}ethan-1-ol
  • Figure US20230234946A1-20230727-C01577
  • To a solution of methyl 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl] acetate (50.00 mg, 120.71 umol, 1.00 eq) in THF (1.00 mL) was added LiBH4 (5.26 mg, 241.42 umol, 2.00 eq) and stirred at 10° C. for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EA (30 mL×2), the combined organic layers were dried over Na2SO4, filtered and concentrated to dry. The residue was purified by prep-HPLC (TFA condition) to give 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]ethanol (10.00 mg, 25.89 umol, 21.45% yield) as a white solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.74 (s, 1H), 8.43 (br s, 1H), 8.25 (dd, J=1.1, 8.8 Hz, 1H), 8.17 (dd, J=1.9, 7.4 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.01-7.92 (m, 1H), 7.74-7.60 (m, 2H), 4.84 (t, J=5.1 Hz, 2H), 3.93 (t, J=5.1 Hz, 2H).
    • General Procedure J:
  • Figure US20230234946A1-20230727-C01578
    • Synthesis of 46-1: 3-(2-isopropoxyphenyl)-5-(1-isopropylindol-5-yl)-1,2,4-oxadiazole
  • Figure US20230234946A1-20230727-C01579
  • To a solution of N-hydroxy-2-isopropoxy-benzamidine (90.00 mg, 393.86 umol, 1.00 eq) in DMF (2.00 mL) was added 1-isopropylindole-5-carboxylic acid (80.05 mg, 393.86 umol, 1.00 eq), HOBt (63.86 mg, 472.63 umol, 1.20 eq) and EDCI (90.60 mg, 472.63 umol, 1.20 eq), the reaction was stirred at 120° C. for 12 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give 3-(2-isopropoxyphenyl)-5-(1-isopropylindol-5-yl)-1,2,4-oxadiazole (26.00 mg, 71.93 umol, 18.26% yield, 98.9% purity) as a yellow oil.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.56 (d, J=1.1 Hz, 1H), 8.10 (dt, J=1.7, 8.6 Hz, 2H), 7.53-7.43 (m, 2H), 7.35 (d, J=3.3 Hz, 1H), 7.14-7.07 (m, 2H), 6.69 (d, J=3.3 Hz, 1H), 4.81-4.65 (m, 2H), 1.60 (d, J=6.7 Hz, 7H), 1.46 (d, J=6.1 Hz, 6H).
    • Synthesis of 48-2: 5-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-(propan-2-yl)-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01580
  • To a solution of 1-isopropylbenzotriazole-5-carboxylic acid (100.00 mg, 487.31 umol, 1.00 eq) in DMF (1.00 mL) was added HOBt (79.01 mg, 584.77 umol, 1.20 eq) and EDCI (112.10 mg, 584.77 umol, 1.20 eq). The mixture was stirred at 10° C. for 0.5 h, then N-hydroxy-2-methoxy-benzamidine (80.98 mg, 487.31 umol, 1.00 eq) was added and stirred at 120° C. for 12 h. The mixture was diluted with H2O (20 mL) and extracted with EA (30 mL×2), the combined organic layers were dried over Na2SO4, filtered and concentrated to dry. The residue was purified by prep-HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 50%-80%, 13 min) to give 5-(1-isopropylbenzotriazol-5-yl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (110.00 mg, 328.01 umol, 67.31% yield) as a white solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.99 (s, 1H), 8.36 (dd, J=1.2, 8.7 Hz, 1H), 8.17 (dd, J=1.6, 7.7 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.59-7.48 (m, 1H), 7.20-7.05 (m, 2H), 5.16 (spt, J=6.8 Hz, 1H), 4.03 (s, 3H), 1.81 (d, J=6.8 Hz, 6H).
    • General Procedure K:
  • Figure US20230234946A1-20230727-C01581
    • Synthesis of 49-1: 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbothioamide
  • Figure US20230234946A1-20230727-C01582
  • To a solution of 1-isopropylbenzotriazole-5-carbonitrile (2 g, 10.74 mmol, 1 eq) in HCl/dioxane (100 mL, 4 M) was added thioacetamide (1.61 g, 21.48 mmol, 2 eq) and stirred at 110° C. for 2 h. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (PE/EA=2/1 to 1/1) to give 1-isopropylbenzotriazole-5-carbothioamide (2.1 g, 9.53 mmol, 88.76% yield) as a yellow solid.
    • Synthesis of 51-2: 5-{5-[2-(methyl-λ3-oxy)phenyl]-1,3-thiazol-2-yl}-1-(propan-2-yl)-1H-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01583
  • To a solution of 1-isopropylbenzotriazole-5-carbothioamide (300 mg, 1.36 mmol, 1 eq) in DMF (3 mL) was added Cs2CO3 (443.71 mg, 1.36 mmol, 1.00 eq) and 2-bromo-1-(2-methoxyphenyl)ethanone (311.95 mg, 1.36 mmol, 1 eq). The mixture was stirred at 100° C. for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 5 u; mobile phase: [water(10 mM NH4HCO3)-ACN]; B %: 60%-90%, 10 min) to give 2-(1-isopropylbenzotriazol-5-yl)-5-(2-methoxyphenyl)thiazole (190 mg, 509.65 umol, 37.42% yield, 94% purity) as a yellow solid.
  • 1H NMR (400 MHz, CHLOROFORM-d) 6=8.60 (s, 1H), 8.37 (dd, J=1.7, 7.8 Hz, 1H), 8.22 (dd, J=1.1, 8.8 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.31-7.23 (m, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 5.04 (spt, J=6.8 Hz, 1H), 3.92 (s, 3H), 1.70 (d, J=6.7 Hz, 6H).
    • General Procedure L:
  • Figure US20230234946A1-20230727-C01584
    • Synthesis of 52-1: 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carboxamide
  • To a solution of 46-1 (1.0 g, 5.4 mmol) in HOAc (10 mL) was added H2SO4 (0.5 mL) and reaction heated in MW 90 min at 120° C. Let cool overnight. Reaction mixture poured onto ice, neutralized and extracted with EtOAc. Solvent evaporated to give a dark solid. Silica gel chromatography (10-50% acetone in hexane) gave a residue which was triturated with a small amount of acetone and an off-white solid was collected by filtration to give the title compound (52-1) (0.5 g, 45%).
    • Synthesis of 52-3: 5-(4-phenyl-1,3-oxazol-2-yl)-1-(propan-2-yl)-1H-1,2,3-benzotriazole
  • To a mixture of 52-1 (50 mg, 0.25 mmol), 52-2 (51 mg, 0.25 mmol) was added AgSbF6 (86 0.25 mmol) and the mixture was heated to 90° C. for about 3 hrs then cool to rt. Reaction worked up with NaHCO3and CH2Cl2. Organic layer separated and evaporated to give a dark oil. Residue was chromatographed (0 to 5% MeOH in CH2Cl2) to give a residue which was further purified by reverse phase HPLC. Appropriate fractions combined and lyophilized to give the title compound as an off-white solid. (7 mg, 10%).
    • General Procedure M
  • Figure US20230234946A1-20230727-C01585
    • Synthesis of 5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-amine 53-2
  • To a solution of 53-1 (1.9 g, 10.0 mmol) in CH2Cl2 (50 mL) was added DMF (0.2 mL) followed by portion wise addition of oxalyl chloride (1.7 mL, 20.0 mmol) and the solution was stirred overnight at rt. Reaction mixture was evaporated in vacuum. To residue was added thiosemicarbazide (1.1 g, 15 mmol) followed by POCl3 (2.8 mL, 30 mmol) and the reaction mixture was heated to 90° C. After about 45 min to 1 hr, heat was turned off and allowed to cool overnight. Quench with ice and worked up with K2CO3 and EtOAc. Organic layer washed with sat'd NaHCO3and dried over Na2SO4. Filtered and evaporated to give a yellow residue which was triturated with CH2Cl2 and the title compound was collected as a beige solid (0.9 g, 43%). This material was used directly in the next step.
    • Synthesis of 2-bromo-5-(2-methoxyphenyl)-1,3,4-thiadiazole 53-3
  • A mixture of t-Bu-nitrite (0.9 mL, 9.6 mmol) and CuBr2 (2.2 g, 9.6 mmol) in MeCN (30 mL) was stirred for 10 min and then 53-2 (0.9 g, 1.76 mmol) was added in 2 portions. Stirred ˜1 hr and then solvent removed in vacuum. Residue was suspended in EtOAc, washed 2× with 1 N HCl, then brine and dried over Na2SO4. Filtered and evaporated to give the title compound as a yellow-orange solid (1 g, 86%).
    • Synthesis of 5-[5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl]-1-(propan-2-yl)-1H-1,2,3-benzotriazole 53-4
  • Combined 52-3 (95 mg, 0.25 mmol), 14-5 (45 mg, 0.3 mmol), K3PO4 (132 mg, 0.625 mmol) and Pd(Ph3P)4 (58 mg, 0.05 mmol) in a mixture of DMF (4 mL) and water (1 mL). Heated to 120° C. for 30 min in MW. Evap sol to give a residue which was chromatographed on silica (0 to 30% EtOAc in hex). Appropriate fraction were combined and solvent evaporated. This residue was further purified by reverse phase HPLC to give the title compound (30 mg, 20%) as an off-white solid.
    • Synthesis of 2-{3-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,2,4-thiadiazol-5-yl}phenol 53-5: 53-4
  • (40 mg, 0.11 mmol) was dissolved in HR and heated to 120° C. After ˜ 48 hrs starting material was gone. Neutralize with NaHCO3. Residue purified by reverse phase HPLC to give the title compound (10 mg, 22%). [M+H]+:338.0
    • General Procedure N
  • Figure US20230234946A1-20230727-C01586
    • Synthesis of 54-3: 4-amino-3-(3-ethyl-3-hydroxypent-1-yn-1-yl)benzonitrile
  • To a solution of compound 54-1 (1 g, 5.08 mmol, 1 eq.) in DMF (7 mL) and TEA (2.18 g, 21.55 mmol, 3 mL, 4.25 eq.) was added compound 54-2 (683.15 mg, 6.09 mmol, 783.43 uL, 1.2 eq.), CuI (48.33 mg, 253.77 umol, 0.05 eq.) and Pd(PPh3)2Cl2 (178.12 mg, 253.77 umol, 0.05 eq.). The mixture was stirred at 90° C. under nitrogen atmosphere for 3 hours. TLC showed a new one spot formed. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×2), washed with brine (20 mL), dried with sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography (PE:EA=5:1) to give compound 3 (1 g, yield: 86%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=7.52 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.6, 1.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 2.32 (s, 1H), 1.85-1.70 (m, 4H), 1.10 (t, J=7.4 Hz, 6H).
    • Synthesis of 54-4: 2,2-diethyl-4-oxo-1,3-dihydroquinoline-6-carboxylic acid
  • A mixture of compound 54-3 (300 mg, 1.31 mmol) in concentrated hydrochloric acid solution (1 mL) and acetic acid (1 mL) was stirred at 115° C. for 3 hours. The mixture was basified with 1 N sodium hydroxide solution to pH=10, washed with EtOAc (20 mL×3), the aqueous phase was acidized with 1 N hydrochloric acid solution to pH=3, filtered, the filtrate cake was washed with water (10 mL), dried under vacuum to give compound 54-4 (35 mg, yield: 11%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.08 (br. s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.52 (dd, J=2.0, 8.7 Hz, 1H), 7.14 (s, 1H), 6.58 (d, J=8.7 Hz, 1H), 1.73 (s, 1H), 1.36-1.19 (m, 4H), 0.58 (t, J=7.4 Hz, 6H).
    • Synthesis of 55-1: 2,2-diethyl-6-[3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl]-1,3-dihydroquinolin-4-one
  • Figure US20230234946A1-20230727-C01587
  • To a solution of compound 54-4 (100 mg, 404.39 umol, 1 eq.) in DMF (1 mL) was added HOBt (65.57 mg, 485.26 umol, 1.2 eq.) and EDCI (93.02 mg, 485.26 umol, 1.2 eq.). After stirring at 20° C. for 30 mins, compound 55-2 (63.24 mg, 444.82 umol, 1.1 eq.) was added, and stirred for another 30 mins. Then the mixture was heated to 120° C. and stirred for 2 hours. The mixture was triturated with EA (20 mL), filtered, washed with EA (10 mL), the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 50%-80%, 13 min) to give 55-1 (45 mg, yield: 29%) as orange solid. 1H NMR (400 MHz, DMSO-d6) δ=8.36-8.27 (m, 2H), 7.96 (dd, J=2.0, 8.8 Hz, 1H), 7.79 (dd, J=3.0, 5.0 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J=5.0 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 2.59 (s, 2H), 1.67-1.48 (m 4H), 0.86 (t, J=7.3 Hz, 6H).
    • General Procedure O
  • Figure US20230234946A1-20230727-C01588
    Figure US20230234946A1-20230727-C01589
    • Synthesis of 57-3: 5-(4-methoxy-1,3-benzoxazol-2-yl)-1-(2-methylpropyl)-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01590
    • Synthesis of 57-2: N-(2-hydroxy-6-methoxyphenyl)-1-(2-methylpropyl)-1,2,3-benzotriazole-5-carboxamide
  • To a solution of compound 57-1 (100 mg, 487.30 umol, 1 eq.) in DMF (3 mL) was added HOBt (65.85 mg, 487.30 umol, 1 eq.) and EDCI (112.10 mg, 584.76 umol, 1.2 eq.). After addition, the mixture was stirred at 20° C. for 0.5 hour, then compound 57-4 (81.37 mg, 584.76 umol, 1.2 eq.) was added, the mixture was stirred at 20° C. for further 12 hours. LCMS showed compound 57-1 consumed, and a major peak with desired MS detected. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL*2), washed with brine (20 mL), dried with sodium sulfate, filtered and concentrated, to give compound 57-2 (159 mg, crude) as brown oil, which was used in next step directly without further purification. LCMS: 327.2[M+1]
    • Synthesis of 57-3: 5-(4-methoxy-1,3-benzoxazol-2-yl)-1-(2-methylpropyl)-1,2,3-benzotriazole
  • To a solution of compound 57-2 (159 mg, crude) in xylene (10 mL) was added TsOH-H2O (370.70 mg, 1.95 mmol, 4 eq.). After addition, the mixture was stirred at 120° C. for 2 hours. LCMS showed compound 57-2 consumed, and a major peak with desired Ms detected. The mixture was concentrated, diluted with saturated sodium bicarbonate solution (20 mL), extracted with EtOAc (20 mL*2), dried with sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 42%-72%, 10 min) to give 57-3 (53 mg, yield: 35%) as grey solids.
  • 1H NMR (400 MHz, CDCl3) δ=8.95 (s, 1H), 8.51 (dd, J=1.1, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.37-7.31 (m, 1H), 7.28-7.27 (m, 1H), 6.85 (d, J=7.9 Hz, 1H), 5.18-5.08 (m, 1H), 4.10 (s, 3H), 1.80 (s, 3H), 1.78 (s, 3H)
    • Synthesis of 58-3: 1-isopropyl-5-(7-methoxy-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01591
    • Synthesis of 58-2: N-(2-bromo-3-methoxyphenyl)-1-isopropyl-1,2,3-benzotriazole-5-carboxamide
  • A mixture of compound 58-1 (200 mg, 989.86 umol, 1 eq.), compound 58-1 (243.76 mg, 1.19 mmol, 1.2 eq.) and EDCI (284.64 mg, 1.48 mmol, 1.5 eq.) in pyridine (3 mL) was stirred at 20° C. for 12 hours. The mixture was diluted with EtOAc (30 mL), washed with 1 N hydrochloric acid solution (20 mL*3), dried with sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (PE:EA=3:1) to give compound 58-2 (150 mg, yield: 38%) as brown oil. LCMS: 391.1 [M+1]
    • Synthesis of 58-3: 1-isopropyl-5-(7-methoxy-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole
  • A mixture of compound 58-2 (50 mg, 128.45 umol, 1 eq.), 1,10-phenanthroline (2.31 mg, 12.85 umol, 0.1 eq.), Cs2CO3 (62.78 mg, 192.68 umol, 1.5 eq.) and CuI (1.22 mg, 6.42 umol, 0.05 eq.) in DME (2 mL) was heated to 85° C. and stirred for 12 hours under nitrogen atmosphere. The mixture was diluted with EtOAc (20 mL), washed with water (10 mL), dried with sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 45%-75%, 12 min) to give 58-3 (8 mg, yield: 19%) as gray solid.
  • 1H NMR (400 MHz, DMSO-d6) δ=8.76 (s, 1H), 8.32 (dd, J=1.3, 8.8 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.44-7.28 (m, 2H), 7.07 (d, J=7.8 Hz, 1H), 5.29 (spt, J=6.7 Hz, 1H), 4.02 (s, 3H), 1.66 (d, J=6.6 Hz, 6H).
    • Synthesis of 59-3: 1-isopropyl-5-(6-methoxy-4-methyl-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole
  • Figure US20230234946A1-20230727-C01592
    • Synthesis of 59-3: 1-isopropyl-5-(6-methoxy-4-methyl-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole
  • To a solution of compound 59-2 (1-isopropyl-N-(4-methoxy-2-methylphenyl)-1,2,3-benzotriazole-5-carboxamide) prepared according to the procedure to prepare 58-2, (50 mg, 154.14 umol, 1 eq.) in o-xylene (2 mL) was added Cu(OTf)2 (11.12 mg, 30.83 umol, 0.2 eq.). The reaction was stirred at 130° C. under oxygen atmosphere for 16 hours. The mixture was diluted with water (20 mL), extracted with EtOAc (30 mL*3), dried with sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (PE:EA=4:1) to give 59-3 (1.1 mg, yield: 2%) as yellow solid.
  • 1H NMR (400 MHz, CDCl3) δ=8.80 (s, 1H), 8.33 (dd, J=1.4, 8.7 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.72 (d, J=1.5 Hz, 1H), 5.16-4.93 (m, 1H), 3.81 (s, 3H), 2.58 (s, 3H), 1.72 (d, J=6.8 Hz, 6H)
    • Example 2: In Vitro Activity of Compounds
  • Stable clonal Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA-β-arrestin2 and the human sphingosine-1-phosphate receptor 1 (NM_001400, S1P1) with a C-terminal Prolink™ tag were purchased from DiscoverX corporation (Cat #: 93-0207C2).
    • Cell Culturing and Assay Plating
  • Cell lines were cultured in AssayComplete™ Media 6 (DiscoverX Corporation, Cat #: 920018GF2) at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator. To begin assay plating, cells were washed with dulbecco's phosphate buffered saline (CellGro, Cat #: 21-031-CV) and lifted from the culturing flask by incubation (37° C., 5 min) with CellStripper (Cellgro, Cat #: 25-056-CI). Lifted cells were resuspended to 250,000 cells per milliliter in AssayComplete™ Cell Plating 11 Reagent (DiscoverX Corporation, Cat #: 93-0563R11B) and plated at 5,000 cells per well in white-opaque 384 well plates (Greiner Bio-One Item #: 20-784080). Plated cells were incubated overnight at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator.
  • Detecting Inhibition of cAMP Production
  • Agonist-promoted G-protein responses were determined by measuring changes in intracellular cAMP using the HTRF® cAMP HiRange kit (CisBio, Cat #: 62AM6PEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology. AssayComplete™ Cell Plating 11 Reagent was removed and replaced with Ham's F-12 (CellGro, Cat #: 10-080-CM) containing isobutyl-methyl-xanthine (IBMX; 500 μM; Tocris Bioscience, Cat #: 2845), and NKH-477 (1.5 μM; Tocris Bioscience, Cat #: 1603) along with test or control compounds at the desired concentrations. Following a 30-minute incubation at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator, the components of the cAMP HiRange kit were added as per the manufacturer's instructions. After an hour incubation at room temperature, plates were analyzed by a BMG PheraStar microplate reader. Responses were measured as the ratio of fluorescence emission at 665 nm to fluorescence emission at 620 nm.
    • β-Arrestin2 Recruitment Assay
  • Agonist-promoted 0-arrestin2 recruitment to the sphingosine-1-phosphate 1 receptor was determined using the β-arrestin PathHunter®) Detection kit (DiscoverX Corporation, Cat #: 93-0001). In this system, 0-arrestin2 is fused to an N-terminal deletion mutant of β-galactosidase (termed the enzyme acceptor or EA) and the C-terminus of the GPCR of interest is fused to a smaller (42 amino acids), weakly-complementing fragment 15 termed ProLink™. In cells that stably express these fusion proteins, stimulation with a cognate agonist results in the interaction of β-arrestin2 and the Prolink™-tagged GPCR. This allows the complementation of the two β-galactosidase fragments and results in the formation of a functional enzyme with β-galactosidase activity. AssayComplete™ Cell Plating 11 Reagent was removed and replaced with Ham's F-12 containing IBMX (500 μM), and NKH-477 (1.5 μM) along with test or control compounds at the desired concentrations. Following a 60 minute incubation at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator, the components of the β-arrestin PathHunter® Detection kit were added as per the manufacturer's instructions. After an hour incubation at room temperature, plates were analyzed by a BMG PheraStar microplate reader.
    • Activity Table
  • The compounds as indicated herein were able to modulate the activities (inhibition of cAMP production and β-arrestin2 recruitment) of the sphingosine-1-phosphate 1 receptor as indicated herein. The tables below include the efficacy of the compound as compared to a positive control, referred to as “SPAN”. These values are normalized to fingolimod, a known agonist of the sphingosine-1-phosphate 1 receptor. The tables also include potency values (pEC50) for modulating discrete receptor-mediated activities (inhibition of cAMP production and β-arrestin2 recruitment). This value represents the estimated concentration to promote half of the maximal efficacy (or SPAN) observed for each compound.
  • hS1P1 hS1P1 hS1P1 hS1P1
    Compound cAMP cAMP B-arrestin2 B-arrestin2
    Number pEC50 SPAN pEC50 SPAN
      1 <6.5 <75 <5 <75
      2 <6.5 >75 >5 <75
      3 >6.5 >75 >5 >75
      4 <6.5 <75 <5 <75
      5 <6.5 <75 <5 <75
      6 <6.5 <75 <5 <75
      7 <6.5 >75 <5 >75
      8 <6.5 <75 <5 <75
      9 <6.5 <75 <5 <75
     10 <6.5 <75 <5 <75
     11 <6.5 <75 <5 <75
     12 <6.5 <75 <5 <75
     13 >6.5 <75 >5 <75
     14 >6.5 <75 >5 <75
     15 <6.5 >75 <5 <75
     16 <6.5 <75 >5 >75
     17 >6.5 >75 >5 >75
     18 <6.5 <75 <5 <75
     19 <6.5 <75 >5 <75
     20 >6.5 >75 >5 >75
     21 <6.5 >75 <5 >75
     22 >6.5 >75 >5 >75
     23 <6.5 <75 <5 <75
     24 <6.5 >75 <5 <75
     25 <6.5 <75 <5 <75
     26 >6.5 >75 >5 >75
     26 >6.5 >75 >5 <75
     27 <6.5 >75 >5 <75
     28 <6.5 >75 <5 >75
     29 <6.5 <75 <5 <75
     30 <6.5 <75 <5 <75
     31 >6.5 >75 >5 >75
     32 >6.5 >75 >5 <75
     33 >6.5 >75 >5 >75
     34 <6.5 >75 >5 <75
     35 <6.5 >75 <5 >75
     36 <6.5 <75 <5 <75
     37 <6.5 <75 <5 <75
     38 <6.5 <75 <5 >75
     39 <6.5 <75 <5 <75
     40 >6.5 >75 >5 >75
     41 <6.5 <75 <5 <75
     41 <6.5 <75 <5 <75
     42 <6.5 >75 <5 >75
     43 >6.5 >75 >5 >75
     44 <6.5 <75 <5 <75
     45 <6.5 <75 <5 <75
     46 >6.5 >75 >5 >75
     47 <6.5 <75 <5 <75
     48 <6.5 <75 <5 <75
     49 <6.5 <75 <5 <75
     50 <6.5 <75 <5 <75
     51 <6.5 <75 <5 <75
     52 <6.5 <75 <5 <75
     53 <6.5 <75 <5 <75
     54 <6.5 <75 <5 >75
     55 >6.5 >75 >5 >75
     56 <6.5 <75 <5 <75
     57 <6.5 <75 <5 <75
     58 <6.5 <75 <5 <75
     59 >6.5 >75 >5 >75
     60 <6.5 <75 <5 <75
     61 >6.5 >75 >5 >75
     62 <6.5 >75 <5 >75
     63 >6.5 <75 <5 <75
     64 >6.5 >75 <5 >75
     65 <6.5 <75 <5 <75
     66 >6.5 >75 >5 >75
     67 <6.5 >75 >5 <75
     68 <6.5 <75 <5 <75
     69 <6.5 <75 >5 <75
     70 >6.5 <75 >5 <75
     71 <6.5 >75 <5 <75
     72 >6.5 >75 >5 >75
     73 <6.5 <75 >5 <75
     74 <6.5 <75 <5 <75
     75 >6.5 <75 >5 >75
     76 <6.5 <75 <5 <75
     77 <6.5 <75 <5 <75
     78 <6.5 <75 <5 <75
     79 >6.5 >75 >5 >75
     80 >6.5 <75 <5 <75
     81 <6.5 >75 <5 <75
     82 <6.5 <75 <5 <75
     83 >6.5 >75 >5 >75
     84 <6.5 <75 >5 >75
     85 <6.5 <75 <5 <75
     86 <6.5 <75 <5 >75
     87 <6.5 <75 <5 <75
     88 <6.5 <75 <5 <75
     89 <6.5 <75 <5 <75
     90 <6.5 >75 >5 >75
     91 <6.5 <75 <5 <75
     92 <6.5 <75 <5 <75
     93 <6.5 <75 <5 >75
     94 <6.5 >75 <5 >75
     95 <6.5 <75 <5 <75
     96 >6.5 >75 >5 >75
     97 <6.5 <75 <5 <75
     98 <6.5 >75 >5 >75
     99 >6.5 >75 >5 >75
    100 <6.5 <75 <5 <75
    101 >6.5 >75 >5 >75
    102 <6.5 <75 <5 <75
    103 >6.5 >75 >5 >75
    103 >6.5 >75 >5 >75
    103 >6.5 >75 >5 >75
    104 >6.5 >75 <5 >75
    105 <6.5 <75 <5 <75
    106 >6.5 >75 >5 >75
    107 >6.5 >75 >5 >75
    108 >6.5 <75 <5 <75
    109 <6.5 <75 >5 <75
    110 <6.5 <75 <5 <75
    111 <6.5 >75 <5 >75
    112 >6.5 >75 >5 >75
    113 <6.5 <75 <5 <75
    114 <6.5 <75 <5 <75
    115 >6.5 >75 >5 >75
    116 <6.5 <75 <5 <75
    117 <6.5 <75 <5 <75
    118 <6.5 <75 <5 <75
    119 <6.5 <75 <5 <75
    120 >6.5 >75 >5 >75
    121 <6.5 <75 <5 <75
    122 <6.5 <75 <5 <75
    123 >6.5 >75 >5 >75
    124 <6.5 <75 <5 <75
    125 <6.5 <75 <5 <75
    126 <6.5 <75 <5 <75
    127 <6.5 <75 <5 <75
    128 <6.5 <75 <5 <75
    129 <6.5 <75 <5 <75
    130 <6.5 <75 <5 <75
    131 <6.5 <75 <5 <75
    132 >6.5 >75 >5 >75
    133 <6.5 <75 <5 <75
    134 <6.5 <75 <5 <75
    135 <6.5 <75 <5 <75
    136 <6.5 <75 <5 <75
    137 >6.5 >75 <5 >75
    138 >6.5 >75 >5 >75
    139 >6.5 >75 >5 >75
    140 >6.5 >75 >5 >75
    141 >6.5 >75 >5 >75
    142 >6.5 >75 >5 >75
    143 <6.5 <75 <5 <75
    144 <6.5 >75 >5 <75
    145 >6.5 >75 >5 <75
    146 >6.5 >75 >5 <75
    147 >6.5 >75 >5 >75
    148 <6.5 <75 <5 <75
    149 >6.5 >75 >5 >75
    150 >6.5 >75 >5 >75
    151 <6.5 >75 <5 >75
    152 <6.5 >75 >5 >75
    153 <6.5 >75 >5 <75
    154 <6.5 <75 <5 <75
    155 <6.5 <75 <5 <75
    156 >6.5 >75 >5 >75
    157 <6.5 <75 <5 <75
    158 <6.5 <75 <5 <75
    159 <6.5 <75 <5 <75
    160 <6.5 <75 <5 <75
    161 <6.5 <75 <5 >75
    162 <6.5 >75 >5 >75
    163 >6.5 >75 >5 >75
    164 <6.5 <75 <5 <75
    165 <6.5 >75 <5 >75
    166 <6.5 <75 <5 >75
    167 <6.5 <75 <5 <75
    168 <6.5 <75 <5 <75
    169 >6.5 >75 >5 >75
    170 <6.5 <75 <5 <75
    171 >6.5 >75 >5 >75
    172 <6.5 <75 <5 <75
    173 >6.5 >75 >5 >75
    174 >6.5 >75 <5 >75
    175 >6.5 >75 >5 >75
    176 <6.5 >75 <5 <75
    177 >6.5 >75 >5 >75
    178 <6.5 >75 >5 <75
    179 >6.5 >75 >5 >75
    180 <6.5 >75 <5 >75
    181 <6.5 >75 <5 >75
    182 >6.5 >75 >5 <75
    183 >6.5 >75 >5 >75
    184 <6.5 >75 <5 <75
    185 >6.5 >75 >5 >75
    186 <6.5 <75 <5 <75
    187 <6.5 <75 <5 >75
    188 <6.5 <75 <5 <75
    189 >6.5 >75 >5 >75
    190 <6.5 <75 <5 <75
    192 <6.5 <75 <5 <75
    193 <6.5 <75 <5 <75
    194 <6.5 <75 <5 <75
    195 <6.5 <75 <5 <75
    196 <6.5 <75 <5 <75
    197 <6.5 <75 <5 <75
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    386 <6.5 >75 <5 <75
    387 <6.5 >75 >5 >75
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    392 <6.5 <75 <5 <75
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    399 >6.5 >75 >5 <75
    400 <6.5 <75 <5 <75
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    403 <6.5 <75 <5 <75
    404 <6.5 >75 <5 <75
    405 <6.5 <75 <5 <75
    406 >6.5 >75 >5 >75
    407 <6.5 >75 <5 <75
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    410 <6.5 <75 <5 <75
    411 <6.5 <75 <5 <75
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    416 >6.5 >75 >5 >75
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    423 >6.5 >75 >5 >75
    424 >6.5 >75 <5 >75
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    427 <6.5 >75 <5 >75
    428 <6.5 >75 <5 >75
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    430 <6.5 >75 <5 >75
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    460 <6.5 >75 <5 >75
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    466 <6.5 >75 <5 >75
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    468 >6.5 >75 >5 >75
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    470 <6.5 >75 <5 >75
    471 >6.5 >75 >5 >75
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    473 >6.5 >75 >5 >75
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    487 <6.5 >75 >5 >75
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    498 >6.5 >75 <5 <75
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    500 <6.5 <75 <5 <75
    501 <6.5 <75 <5 >75
    502 >6.5 >75 >5 >75
    503 <6.5 >75 <5 >75
    504 <6.5 >75 <5 <75
    505 <6.5 <75 <5 >75
    506 >6.5 <75 >5 <75
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    509 <6.5 <75 <5 >75
    510 >6.5 <75 >5 >75
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    512 >6.5 >75 >5 <75
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    520 >6.5 >75 >5 >75
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    538 >6.5 <75 >5 <75
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    540 <6.5 <75 <5 <75
    541 <6.5 <75 <5 <75
    542 <6.5 <75 >5 <75
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    546 <6.5 <75 <5 <75
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    548 <6.5 <75 <5 <75
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    550 <6.5 >75 >5 <75
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    556 >6.5 >75 >5 <75
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    560 >6.5 >75 >5 >75
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    567 <6.5 >75 <5 <75
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    569 <6.5 >75 <5 <75
    570 <6.5 <75 <5 <75
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    574 <6.5 >75 <5 >75
    575 >6.5 >75 >5 >75
    576 >6.5 >75 >5 <75
    577 <6.5 <75 >5 <75
    578 <6.5 >75 <5 <75
    579 >6.5 >75 >5 >75
    580 >6.5 >75 >5 >75
    581 <6.5 >75 <5 <75
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    583 <6.5 <75 <5 <75
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    585 >6.5 >75 >5 >75
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    587 <6.5 <75 <5 <75
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    590 <6.5 <75 <5 <75
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    594 >6.5 >75 >5 >75
    595 >6.5 >75 >5 >75
    596 >6.5 <75 >5 >75
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    599 >6.5 <75 >5 >75
    600 >6.5 >75 >5 >75
    601 <6.5 >75 >5 <75
    602 <6.5 <75 <5 >75
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    613 <6.5 <75 <5 <75
    614 <6.5 >75 <5 <75
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    617 <6.5 <75 <5 >75
    618 <6.5 <75 >5 <75
    619 >6.5 >75 >5 >75
    620 >6.5 <75 >5 >75
    621 <6.5 >75 <5 >75
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    624 <6.5 <75 <5 >75
    625 <6.5 <75 <5 <75
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    627 <6.5 >75 <5 >75
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    630 <6.5 <75 <5 <75
    633 <6.5 <75 <5 <75
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    640 <6.5 >75 <5 <75
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    647 >6.5 >75 >5 >75
    • Example 3: S1P1 Receptor are Effective to Treat Chemotherapeutic Induced Peripheral Neuropathy
  • Compounds were tested for efficacy in mouse models of chemotherapy induced peripheral neuropathy. The intraperitoneal (i.p.) injection of chemotherapeutics in rodents has been shown to induce sensory impairment and pain, similar to what is seen in humans where these sensations begin within days and last for several weeks. For these studies c57bl/6 mice are habituated to the test environment and baseline measurements of pain sensitivity are assessed. To determine mechanical responses, the threshold for responses to punctate mechanical stimuli (mechanical hyperalgesia) was tested according to the frequency method. In brief, the plantar surface of the animal hindpaw was stimulated with a single von Frey monofilament (0.4 g) for approximately 1-2 seconds. If there was a withdrawal response, it was recorded as a positive response. A response was defined as a lifting or shaking of the paw upon stimulation. This was repeated ten times for each mouse. The final measurement for each mouse is the % non-response to stimulation for the ten trials. The % non-response to stimulation is converted to a % MPE. For paclitaxel induced peripheral neuropathy, a series of injections of PAC (6 mg/kg, i.p.) on days 1, 3, 5 and 7 is used to induce peripheral neuropathy. After approximately 14 days from the initiation of PAC injections, animals are re-assessed for mechanical sensitivity. Animals that exhibit a 50% response rate and lower can be included in studies with test compounds. On test day animals are dosed with compounds either subcutaneously or orally and tested for mechanical response by the frequency method either 30 min (s.c.) or 60 min (p.o.) after drug administration. Data is presented as a % MPE. For oxaliplatin induced peripheral neuropathy, a series of injections of OXA (4 mg/kg, i.p.) on days 1-5 is used to induce peripheral neuropathy. After approximately 14 days from the initiation of PAC injections, animals are re-assessed for mechanical sensitivity. Animals that exhibit a 50% response rate and lower can be included in studies with test compounds. On test day animals are dosed with compounds subcutaneously and tested for mechanical response by the frequency method 30 min after drug administration. Data is presented as a % MPE. One or more of the compounds show reversal of chemotherapeutic induced peripheral neuropathy.
  • A compound was tested for the ability to prevent the development of OXA induced peripheral neuropathy. A concurrent with the OXA injections on Day 1-5, a compound was dosed (3 mg/kg, sc) every day for 15 days. On Day 16 animals were tested for mechanical allodynia. Animals treated with a test compound did not exhibit peripheral neuropathy. The data for exemplary compounds is provided below.
    • Reversal of Allodynia Induced by Oxaliplatin in Mice
  • Screen @
    Compound 3 mg/kg sc
    Number (% MPE)
    142 >50
    287 >50
     55 >50
    169 >50
    • Reversal of Allodynia Induced by Paclitaxel in Mice (s.c.)
  • Screen @
    Compound 1 mg/kg sc
    Number (% MPE)
    293 >50
    287 <50
     99 >50
     55 <50
    142 >50
      8 <50
    169 >50
     96 >50
    277 >50
    142 >50
    103 >50
    177 >50
     26 <50
    252 <50
    304 >50
    221 <50
     33 <50
    149 <50
    263 >50
    147 >50
    212 >50
    267 >50
    262 >50
    305 >50
    224 >50
    179 >50
    185 >50
    106 <50
    306 <50
    259 <50
    107 <50
    210 <50
    • Reversal of Allodynia Induced by Paclitaxel in Mice (p.o.)
  • Screen @
    Compound 3 mg/kg po
    Number (% MPE)
     26 <50
     99 >50
    103 >50
    142 >50
    179 >50
    262 >50
    263 >50
    348 >50
    354 >50
    355 >50
    356 >50
    358 >50
    359 >50
    415 <50
    423 >50
    435 >50
    442 >50
    455 >50
    469 >50
    471 <50
    472 >50
    489 >50
    497 <50
    502 >50
    513 <50
    514 >50
    519 <50
    520 >50
    531 >50
    547 >50
    558 >50
    560 >50
    562 >50
    563 <50
    564 >50
    568 <50
    579 >50
    580 >50
    584 >50
    585 <50
    586 <50
    598 <50
    600 <50
    606 >50
    607 >50
    608 <50
    615 >50
    636 <50
    637 >50
    726 >50
    727 >50
    728 >50
    729 >50
    730 >50
    731 >50
    732 >50
    733 >50
    734 >50
    735 <50
    736 >50
    • Example 4: The S1P1 Receptor Compounds can be Used to Treat Inflammation and Pain
  • Assessment of Tactile Allodynia Produced by Intraplantar Freund's Complete Adjuvant in Rats:
  • Animals were acclimated to the vivarium for at least 48 hr prior to behavioral testing. Inflammation was induced with the administration of an intraplantar (subcutaneous injection into the plantar surface of the hind paw, i.pl.) injection of 0.10 ml Freund's Complete Adjuvant (FCA).
  • The experiments were conducted 24 hours after CFA administration. Rats are tested for mechanical allodynia in a Randall-Selitto apparatus. The inflamed paw is put on a pedestal and a pointed force of increasing intensity (0 to 250 grams) is applied to the paw. When the animal struggles to withdraw from the force the test is stopped and the force to induce that struggle is recorded. Data is presented as mean grams of force to withdrawal or a percentage of the maximum possible effect.
  • Exemplary compounds in the CFA model are shown below.
  • Active Doses,
    Compound mg/kg sc
    Number (>50% MPE)
    103 ≥0.03
    293 ≥0.1
    142 ≥0.1
     26 ≥0.1
    212 ≥0.1
    469 ≥0.01
    • Example 5: Compounds Selective for S1P1 Receptor In Vitro Selectivity Assays
  • Stable clonal Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA-β-arrestin2 and the human sphingosine-1-phosphate receptor 2 (NM 004230.3, S1P2), human sphingosine-1-phosphate receptor 3 (NM_005226, S1P3) and sphingosine-1-phosphate receptor 5 (NM_001166215.1, S1P5) with a C-terminal Prolink™ tag were purchased from DiscoverX corporation (S1P2: Cat #93-0256C2, S1P3: Cat #93-0217C2, S1P5: Cat #93-0583C2).
    • Cell Culturing and Assay Plating
  • Cell lines were cultured in AssayComplete™ Media 6 (DiscoverX Corporation, Cat #: 920018GF2) at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator. To begin assay plating, cells were washed with dulbecco's phosphate buffered saline (CellGro, Cat #: 21-031-CV) and lifted from the culturing flask by incubation (37° C., 5 min) with CellStripper (Cellgro, Cat #: 25-056-CI). Lifted cells were resuspended to 250,000 cells per milliliter in either AssayComplete™ Cell Plating 11 Reagent (S1P5 cell line) (DiscoverX Corporation, Cat #: 93-0563R11B) or AssayComplete™ Cell Plating 2 Reagent (S1P2 and S1P3 cell line) (DiscoverX Corporation, Cat #: 93-0563R2B) and plated at 5000 cells per well (S1P3 cell line) or 7500 cells per well (S1P2 and S1P5 cell line) in white-opaque 384 well plates (Greiner Bio-One Item #: 20-784080). Plated cells were incubated overnight at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator.
  • Detecting Inhibition of cAMP Production
  • S1P3 and S1P5 Agonist-promoted G-protein responses were determined by measuring changes in intracellular cAMP using the HTRF® cAMP HiRange kit (CisBio, Cat #: 62AM6PEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology. AssayComplete™ Cell Plating 11 Reagent was removed and replaced with Ham's F-12 (CellGro, Cat #: 10-080-CM) containing isobutyl-methyl-xanthine (IBMX; 500 μM; Tocris Bioscience, Cat #: 2845), and NKH-477 (1.5 μM; Tocris Bioscience, Cat #: 1603) along with test or control compounds at the desired concentrations. Following a 30-minute room temperature incubation the components of the cAMP HiRange kit were added as per the manufacturer's instructions. After an hour incubation at room temperature, plates were analyzed by a BMG PheraStar microplate reader. Responses were measured as the ratio of signal over background, fluorescence emission at 665 nm to fluorescence emission at 620 nm.
    • Detecting Inositol Monophosphate Production
  • S1P2 Agonist-promoted G-protein responses were determined by measuring changes in intracellular inositol monophosphate using the IP-one TB kit (CisBio, Cat #: 62IPAPEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology. AssayComplete™ Cell Plating 2 Reagent was removed and replaced with 1×IP-one stimulation buffer (as per manufacturer's instructions) along with test or control compounds at the desired concentrations. Following a 60-minute incubation at 37° C. and 5% CO2 in a humidified CO2 and temperature-controlled incubator, the components of the IP-one TB kit were added as per the manufacturer's instructions. After an hour incubation at room temperature, plates were analyzed by a BMG PheraStar microplate reader. Responses were measured as the ratio of signal over background, fluorescence emission at 665 nm to fluorescence emission at 620 nm.
    • Activity Table
  • The compounds were able to modulate the activities (inhibition of cAMP production or accumulation of inositol monophosphate) of the sphingosine-1-phosphate 2, sphingosine-1-phosphate 3, sphingosine-1-phosphate 5 receptor as indicated herein. The tables below include the efficacy of the compound as compared to a positive control, referred to as “SPAN”. These values are normalized to fingolimod, a known agonist of the sphingosine-1-phosphate 3 and 5 receptor or CYM5520, a known agonist of the sphingosine-1-phosphate 2 receptor. The tables also include potency values (pEC50) for modulating discrete receptor-mediated activities (inhibition of cAMP production or inositol monophosphate accumulation). This value represents the estimated concentration to promote half of the maximal efficacy (or SPAN) observed for each compound. Exemplary compounds that were found to be selective are shown below.
  • hS1P2 hS1P2 hS1P3 hS1P3 hS1P5 hS1P5
    Compound IP-one IP-one cAMP cAMP cAMP cAMP
    number pEC50 SPAN pEC50 SPAN pEC50 SPAN
    22 >5.0 <50 <5.0 <50 >5.0 <50
    26 <5.0 <50 <5.0 <50 <5.0 <50
    32 <5.0 <50 <5.0 <50 <5.0 <50
    99 <5.0 <50 <5.0 <50 <5.0 >50
    103 <5.0 <50 <5.0 <50 <5.0 <50
    141 <5.0 <50 >5.0 >50 >5.0 >50
    147 <5.0 <50 <5.0 <50 >5.0 <50
    149 <5.0 <50 >5.0 >50 >5.0 >50
    152 <5.0 <50 <5.0 <50 <5.0 <50
    177 <5.0 <50 >5.0 >50 >5.0 >50
    185 <5.0 <50 <5.0 <50 <5.0 >50
    212 <5.0 <50 <5.0 <50 <5.0 <50
    219 >5.0 <50 <5.0 <50 <5.0 <50
    221 <5.0 <50 >5.0 <50 >5.0 <50
    252 >5.0 <50 >5.0 <50 >5.0 >50
    259 <5.0 <50 <5.0 <50 <5.0 <50
    262 <5.0 >50 <5.0 <50 <5.0 <50
    263 <5.0 <50 <5.0 <50 <5.0 <50
    267 <5.0 <50 <5.0 <50 <5.0 <50
    277 <5.0 >50 <5.0 <50 <5.0 <50
    287 <5.0 <50 <5.0 <50 <5.0 <50
    293 <5.0 <50 <5.0 <50 <5.0 >50
    304 <5.0 <50 >5.0 <50 <5.0 <50
    391 >5.0 <50 >5.0 >50 >5.0 <50
    398 <5.0 <50 <5.0 <50 <5.0 <50
    406 <5.0 <50 <5.0 <50 <5.0 <50
    417 >5.0 <50 <5.0 <50 <5.0 <50
    422 >5.0 <50 >5.0 <50
    423 >5.0 <50 >5.0 <50
    445 >5.0 <50 <5.0 <50
    455 <5.0 <50 <5.0 <50
    496 <5.0 <50 <5.0 <50

    Thus, the compounds were found to be sufficiently selective for S1P1.
    • Example 6: The S1P1 Receptor Compounds can be Used to Treat Diabetic Neuropathy
  • Assessment of Tactile Allodynia and Thermal Hyperalgesia in a Rodent Model of Diabetic Neuropathy—Streptozotocin-Induced (STZ)
  • A cohort of 48 male Sprague Dawley rats, weighing 225-250 g at arrival, was group housed under constant temperature, humidity and a 12-hour light-dark cycle. Following acclimation to the animal colony, the animals were tested for baseline withdrawal responses to mechanical allodynia and thermal hyperalgesia using the methods described below in Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. and Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53: 55-63, 1994; Joris, J. L., Dubner, R. and Hargreaves, K. M. Opioid analgesia at Peripheral Sites: a Target for Opioids Released during Stress and Inflammation? Anesthesia and Analgesia 66(12), 1277-81, 1987; and Morrow, T. J. Animal Models of Painful Diabetic Neuropathy: The STZ rat model. Current Protocols in Neuroscience, November; Chapter 9, Unit 9.18, 2004.
  • A diabetic-like state was induced with a single intraperitoneal (IP) injection of streptozotocin STZ (50 mg/kg) freshly dissolved in 10 mM citric acid buffer was injected intraperitoneally (IP) on Day 1. Two days later (on Day 3), hyperglycermia was confirmed by existence of blood glucose >350 mg/dL as measured by glucometer, and the animal health was monitored biweekly for 12 days.
  • For measures of mechanical allodynia, rats were preselected for experimentation only if the pain threshold 7-14 days after STZ injection (pre-treatment) was reduced by 10 grams of force relative to the response of the individual paw before STZ challenge (pre-induction), namely, with clear presence of allodynia. The rats were randomized based on pre-dose mechanical allodynia scores to balanced treatment groups. The animals were tested prior to study inclusion for mechanical allodynia by the manual von Frey test on Day 20 (Chaplan up/down method using von Frey filaments on the plantar surface of the paw). The manual von Frey test was repeated at 0.5 or 1 hr following administrations of test articles, vehicle, and reference compound via the specified route(s) and on Day 21 post-surgery.
  • For measures of thermal hyperalgesia, rats were pre-selected for experimentation only if the pain threshold 7-14 days after STZ injection (pre-treatment) was reduced by 75% relative to the response of the individual paw before STZ challenge (pre-induction), namely, with clear presence of hyperalgesia. The rats were randomized based on pre-dose thermal hyperalgesia scores to balanced treatment groups. Rats were preselected (with clear presence of thermal hyperalgesia) on Day 20. Thermal hyperalgesia was measured at 1 or 1.5 hr after dosing of test articles, vehicle, and reference compound via the specified route(s) on Day 21. Each rat was placed within a plastic box atop a glass floor for 20 to 30 minutes. A light beam under the floor was aimed at the plantar surface of the left hind paw. The time was measured automatically when the paw was withdrawn away from the thermal stimulus. A cut-off latency of 23 sec was imposed. The latency to withdrawal was obtained for each rat and defined as the heat pain threshold.
  • Mean thresholds and withdrawal latencies were analyzed via Two Way ANOVA followed by Dunnett's Multiple Comparison tests to STZ+VEH group with differences considered significant at p<0.05.
  • Exemplary compounds, but not limited to these, that were effective in this animal model are described below. For example, compounds 103 and 293 were tested and found to have active doses between 50 and 100 mg/kg in both mechanical allodynia and thermal hyperalgesia.
  • Active Doses in STZ Active Doses in STZ
    Diabetic Neuropathy Diabetic Neuropathy
    Model (mg/kg, po) Model (mg/kg, po)
    (p < 0.05 compared to (p < 0.05 compared to
    STZ + VEH treated STZ + VEH treated
    Compound mice) mice)
    # MECHANICAL THERMAL
    103 <100 <100
    293 <100 <100
    469 <100 <100
    • Example 7: The S1P1 Receptor Compounds can be Used to Treat Peripheral Neuropathy
  • Assessment of Tactile Allodynia and Thermal Hyperalgesia in a Rodent Model of Peripheral Neuropathy—Spinal Nerve Ligation (SNL)
  • A cohort of 48 male Sprague Dawley rats, weighing 225-250 g at arrival, was group housed under constant temperature, humidity and a 12-hour light-dark cycle. Following acclimation to the animal colony, the animals were tested for baseline withdrawal responses to mechanical allodynia and thermal hyperalgesia using the methods described in. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. and Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53: 55-63, 1994; Joris, J. L., Dubner, R. and Hargreaves, K. M. Opioid analgesia at Peripheral Sites: a Target for Opioids Released during Stress and Inflammation? Anesthesia and Analgesia 66(12), 1277-81, 1987; and Kim, S. H. and Chung, J. M. An experimental model of peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50: 335-63, 1992.
  • Animals (n=40) were anesthetized with an intraperitoneal (IP) injection of Pentobarbital (50 mg/kg). Spinal nerve ligation (SNL) was performed by first separating the left paraspinal muscles from the spinous processes (L4-S2). The L6-S1 facet joint was nipped. The transverse process of L6 was removed to identify the locations of the L5 and L6 spinal nerve. The left L5 and L6 spinal nerves were isolated and tightly ligated with 6.0 silk sutures. Another 8 animals were underwent sham surgery only (anesthesia, surgical opening and skin suture).
  • For measures of mechanical allodynia, rats were preselected for experimentation only if the pain threshold 7-14 days after SNL surgery (pre-treatment) was reduced by 10 grams of force relative to the response of the individual paw before surgery (pre-induction), namely, with clear presence of allodynia. The rats were randomized based on pre-dose mechanical allodynia scores to balanced treatment groups. The animals were tested prior to study inclusion for mechanical allodynia by the manual von Frey test on Day 20 (Chaplan up/down method using von Frey filaments on the plantar surface of the paw). The manual von Frey test was repeated at 0.5 or 1 hr following administrations of test articles, vehicle, and reference compound via the specified route(s) and on Day 21 post-surgery.
  • For measures of thermal hyperalgesia, rats were pre-selected for experimentation only if the pain threshold 7-14 days after spinal surgery (pre-treatment) was reduced by 75% relative to the response of the individual paw before surgery (pre-induction), namely, with clear presence of hyperalgesia. The rats were randomized based on pre-dose thermal hyperalgesia scores to balanced treatment groups. Rats were preselected (with clear presence of thermal hyperalgesia) on Day 20. Thermal hyperalgesia was measured at 1 or 1.5 hr after dosing of test articles, vehicle, and reference compound via the specified route(s) on Day 21. Each rat was placed within a plastic box atop a glass floor for 20 to 30 minutes. A light beam under the floor was aimed at the plantar surface of the left hind paw. The time was measured automatically when the paw was withdrawn away from the thermal stimulus. A cut-off latency of 23 sec was imposed. The latency to withdrawal was obtained for each rat and defined as the heat pain threshold.
  • Mean thresholds and withdrawal latencies were analyzed via Two Way ANOVA followed by Dunnett's Multiple Comparison tests to SNL+VEH group with differences considered significant at p<0.05.
  • Exemplary compounds, but not limited to these, that were effective in this animal model are described below. For example, compound 103 was tested and found to have active doses between 50 and 100 mg/kg.
  • Active Doses in SNL Active Doses in SNL
    Neuropathy Model Neuropathy Model
    (mg/kg) (mg/kg)
    (p < 0.05 compared to (p < 0.05 compared to
    SNL + VEH treated SNL + VEH treated
    Compound mice) mice)
    # MECHANICAL THERMAL
    103 <100 <100
    • Example 8: Compounds do not Inhibit hERG Channel Activity
  • The standard Automated Qpatch patch-clamp assay have been used and the selective hERG inhibitor E4031, serves as a positive control.
  • Compound IC50
    number (μM)
    E4031 0.013
     26 >10
    304 >10
    469 >10
    497 >10
    520 >10
    730 >10
    738 >10
    742 >10
    743 >10
    744 >10
    • Example 9: Compounds do not Cause Lymphopenia
  • Compounds were tested for changes in peripheral blood lymphocytes in c57bl/6 mice. In acute studies, animals (n=5/group) were dosed subcutaneously with test compound at a dose of 3 mg/kg. Animals were sacrificed at specific time points and 500 μl of whole blood was collected in EDTA (K2) Eppendorf tubes. Blood was stored on ice and shipped immediately overnight delivery to Charles River Laboratories for analysis. CRL ran samples through their WBC/differential panel on an Advia 120 instrument. We received peripheral lymphocyte counts (103 cells/μl) for each blood sample. Treatment group means were compared to a vehicle treatment group for statistical significance. In chronic studies, animals (n=6-8/group) were dosed subcutaneously with test compound either in a dose response paradigm (highest dose of 3 mg/kg) or in a screening paradigm at 6 mg/kg for seven days. On the seventh day, animals were sacrificed 45 minutes after the final dose. Whole blood was collected and analyzed as described for acute studies. None of the compounds showed statistically significant decreases in peripheral blood lymphocytes in acute or chronic studies. Non-limiting exemplary data is provided below.
  • Lymphopenia—c57bl/6 Mice
  • Compound
    Number Effect and Doses, mg/kg, sc
      8 no change: 6 mg/kg, 7 days
     19 no change: 6 mg/kg, 7 days
     22 no change: 3 mg/kg, 7 days
     32 no change: 6 mg/kg, 7 days
     55 no change: 6 mg/kg, 7 days
     59 no change: 6 mg/kg, 7 days
     96 no change: 6 mg/kg, 7 days
     99 no change: 6 mg/kg, 7 days
    103 no change: 6 mg/kg, 7 days
    142 no change: 6 mg/kg, 7 days
    147 no change: 6 mg/kg, 7 days
    169 no change: 6 mg/kg, 7 days
    234 no change: 6 mg/kg, 7 days
    287 no change: 6 mg/kg, 7 days
    293 no change: 6 mg/kg, 7 days
    304 no change: 6 mg/kg, 7 days
    355 no change: 6 mg/kg, 7 days
    356 no change: 6 mg/kg, 7 days
    384 no change: 3 mg/kg; 45 min and 2 hr
    423 no change: 6 mg/kg, 7 days
    455 no change: 6 mg/kg, 7 days
    469 −28% not stat sig: 6 mg/kg, 7 days
    520 no change: 6 mg/kg, 7 days
    531 no change: 6 mg/kg, 7 days
    730 no change: 6 mg/kg, 7 days
    731 −78% stat sig: 6 mg/kg, 7 days
    737 −40% not stat sig: 6 mg/kg, 7 days
    • Example 10: Compounds Inhibit Tumor Growth and Prolong Survival in Tumor Model
  • Female athymic nude mice (Crl:NU(NCr)-Foxn1nu, Charles River Laboratories) were implanted with A2780 human ovarian carcinoma cells to initiate tumor growth.
  • Each mouse received 1×107 cells (0.1 mL cell suspension) subcutaneously in the right flank, and tumors were monitored as their volumes approached the target range of 100 to 150 mm3. Fourteen days later, designated as Day 1 of the study, mice were sorted into six groups of ten each. The individual tumor volumes ranged from 108 to 196 mm3 and group mean tumor volumes were 148 mm3. Tumors were measured twice weekly for the study duration.
  • Paclitaxel dosing solutions were prepared in 5% ethanol, 5% Cremophor EL in D5W (Vehicle 1). Ozanimod and Compound 103 dosing solutions were prepared in 10% dimethylacetamide, 10% Cremophor EL, 80% sterile water with 10% β-cyclodextrin (Vehicle 2). Starting on Day 1 of the study, six groups (n=10) of female athymic nude mice with established A2780 tumors were treated according to the following plan. Treatments were administered either by intravenous injection (i.v.) or oral gavage (p.o.) and were adjusted to the body weight of the individual animal. Group 1 received Vehicle 1, i.v., once every other day for five doses (qod×5) and Vehicle 2, p.o., once daily to the end of the study (qd to end), and served as the control group for efficacy analysis. Group 2, the paclitaxel monotherapy group, received paclitaxel i.v., qod×5 plus Vehicle 2, p.o., qd to end. Group 3, the ozanimod monotherapy group, received ozanimod p.o., qd to end plus Vehicle 1, i.v., qod×5. Combination Group 4 received ozanimod p.o., qd to end plus paclitaxel i.v., qod×5. Group 5, the Compound 103 monotherapy group, received Compound 103 p.o., qd to end plus Vehicle 1, i.v., qod×5. Combination Group 6 received Compound 103 p.o., qd to end plus paclitaxel i.v., qod×5.
  • Animals were monitored individually, and each mouse was euthanized when its tumor reached the endpoint volume of 2000 mm3 or on the final day, whichever came first. The time to endpoint (TTE) was calculated for each mouse. Treatment outcome was determined from percent tumor growth delay (% TGD), defined as the percent increase in median TTE for treated versus control mice, with differences in TTE values between groups deemed statistically significant at P<0.05 using logrank survival analysis. Mice were also monitored for complete regression (CR) and partial regression (PR) responses. An animal with a CR at the end of the study was additionally classified as a tumor-free survivor (TFS). Treatment tolerability was assessed by body weight measurements and frequent observation for clinical signs of treatment-related side effects.
  • All regimens were acceptably-tolerated based. Control tumors exhibited progressive growth, attaining the 2000 mm3 endpoint in a median 9.8 days, establishing a maximum possible TGD of 50.2 days (512%) for the 60-day study. Paclitaxel as monotherapy provided significant (P<0.001) survival benefit (128% TGD) compared to controls, whereas the ozanimod and Compound 103 monotherapy regimens were associated with non-significant (P>0.05) TGD of 31% and 15%, respectively, compared with the control. One animal receiving Compound 103 monotherapy survived the study with a sub-endpoint tumor. The combination of paclitaxel and ozanimod was associated with 185% TGD, providing statistically significant survival benefit over either of the corresponding monotherapies, and one study survivor with a CR/TFS tumor regression response. The combination of paclitaxel and Compound 103 provided 193% TGD, a significant result compared with paclitaxel monotherapy, but not statistically different (P>0.05) from the result for ozanimod monotherapy.
    • SUMMARY
  • The present example evaluated test agents ozanimod and Compound 103 each in combination with paclitaxel for efficacy in the A2780 human ovarian carcinoma model in female athymic mice. All regimens were acceptably-tolerated. Control tumors exhibited progressive growth, attaining the 2000 mm3 endpoint in a median 9.8 days, establishing a maximum possible TGD of 50.2 days (512%) for the 60-day study. Paclitaxel as monotherapy provided significant (P≤0.05) survival benefit (128% TGD) compared to controls, whereas the ozanimod and Compound 103 monotherapy regimens were associated with non-significant (P>0.05) TGD of 31% and 15%, respectively, compared with the control. One animal receiving Compound 103 monotherapy survived the study with a sub-endpoint tumor. The combination of paclitaxel and ozanimod was associated with 185% TGD, providing statistically significant survival benefit over either of the corresponding monotherapies, and one study survivor with a CR/TFS tumor regression response. The combination of paclitaxel and Compound 103 provided 193% TGD, a significant result compared with paclitaxel monotherapy and more than additive as compared with the corresponding monotherapies.
  • Thus, these results demonstrate that the compounds provided herein can be used to treat cancers, such as breast or ovarian cancer.
  • The examples and data provided herein demonstrate the unexpected properties and advantages of the compounds and pharmaceutical compositions provided herein. These properties could not have been predicted.

Claims (18)

1-124. (canceled)
125. A compound having Formula I, or a pharmaceutically acceptable salt thereof:
Figure US20230234946A1-20230727-C01593
wherein:
AA is
Figure US20230234946A1-20230727-C01594
W is O, S, or NR1;
X is O, S, or NR4;
Z is CHR42 or NR43;
n is 0, 1, 2, 3, or 4;
B1 and D1 together have a formula of
Figure US20230234946A1-20230727-C01595
B2, B3, and B4 are independently CR38 or N;
D1 is H, OH, NH2, NO2, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl;
R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or R2 and R3 are together optionally substituted cycloalkyl, or together form
Figure US20230234946A1-20230727-C01596
R1, R4, R38, and R43 are independently H, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
R42 is independently Br, Cl, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
126. The compound of claim 125, or a pharmaceutically acceptable salt thereof, wherein AA is
Figure US20230234946A1-20230727-C01597
127. The compound of claim 126, or a pharmaceutically acceptable salt thereof, wherein AA is
Figure US20230234946A1-20230727-C01598
128. The compound of claim 127, or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are Et.
129. The compound of claim 126, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01599
wherein:
Z6 is O, S, NR40, or CHR37;
Z7, Z8, Z9 and Z10 are independently N or CR41;
R24, R25, and R26 are each independently H, OH, NH2, NO2, carbocycle, heterocycle, heteroaryl, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylsulfanyl; or two of R24, R25, and R26 together form a carbocycle, heterocycle, aryl, heteroaryl that is attached to one or more of the atoms of D1; and
R35, R36, R37, R40, and R41 are each independently H, OH, NH2, carbocycle, heterocycle, aryl, heteroaryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R35 and R36 together form a carbocycle, heterocycle, aryl, or heteroaryl that is attached to one or more of the atoms of D1.
130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01600
131. The compound of claim 126, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01601
wherein R21, R22, R23 are each independently optionally substituted C1-C6 alkyl or H, OH, NH2, NO2, carbocycle, heterocycle, aryl, heteroaryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R21, R22, and R23 together form a carbocycle, heterocycle, aryl, or heteroaryl that is attached to one or more of the atoms of D1.
132. The compound of claim 131, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01602
133. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01603
wherein:
Z6 is O, S, NR40, or CHR37;
Z7, Z8, Z9, and Z10 are independently N or CR41;
R35, R36, R37, R40, and R41 are each independently H, OH, NH2, carbocycle, heterocycle, heteroaryl, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R35 and R36 together form an aryl, carbocycle, heterocycle, or heteroaryl that is attached to one or more of the atoms of D1.
134. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein D1 is
Figure US20230234946A1-20230727-C01604
135. The compound of claim 125 having the formula of:
Figure US20230234946A1-20230727-C01605
or a pharmaceutically acceptable salt thereof.
136. A pharmaceutical composition comprising a compound of claim 125, or a pharmaceutically acceptable salt thereof.
137. A method of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, HIV-related neuropathy or pain associated with HIV-related neuropathy, pain or neuropathy resulting from spinal chord injury, nerve lesions, tissue injury, MS, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex region pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof in a subject comprising administering to the subject a compound of any one of claim 125, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
138. A method of treating or preventing neuropathy, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy in a subject in need thereof, the method comprising administering to the subject a compound of claim 125 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
139. A method of treating or preventing chemotherapy induced neuropathic pain in a subject in need thereof, the method comprising administering to the subject a compound of claim 125 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
140. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of claim 125, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
141. The method of claim 140, wherein the cancer is ovarian, breast, lung, brain, colon, prostate, esophageal, pancreatic, brain, glioblastoma, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer.
US18/296,018 2017-06-14 2023-04-05 Compounds for modulating s1p1 activity and methods of using the same Pending US20230234946A1 (en)

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