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WO2023179366A1 - Dérivé d'oxadiazole, son procédé de préparation et son utilisation - Google Patents

Dérivé d'oxadiazole, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023179366A1
WO2023179366A1 PCT/CN2023/080355 CN2023080355W WO2023179366A1 WO 2023179366 A1 WO2023179366 A1 WO 2023179366A1 CN 2023080355 W CN2023080355 W CN 2023080355W WO 2023179366 A1 WO2023179366 A1 WO 2023179366A1
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WIPO (PCT)
Prior art keywords
chloro
compound
methyl
oxadiazol
amino
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PCT/CN2023/080355
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English (en)
Chinese (zh)
Inventor
邹武新
夏岩
张志清
马晓伟
仇运广
余春燕
陈雷
王丽君
安铎
徐展凯
柳俊宏
佘昱力
刘勇
李成涛
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星希尔生物科技(上海)有限公司
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Publication of WO2023179366A1 publication Critical patent/WO2023179366A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

Definitions

  • the application is based on the Chinese application with Chinese application number 202210328620.2 and the filing date is March 25, 2022, and claims its priority.
  • the disclosure content of the Chinese application is once again introduced into this application as a whole.
  • the invention belongs to the field of sphingosine 1-phosphate receptor agonists, and particularly relates to an oxadiazole derivative and its preparation method and use.
  • Sphingosine 1-phosphate is a phospholipid with a wide range of biological activities formed by the phosphorylation of sphingosine by sphingosine kinase.
  • S1P can cause a variety of cellular effects, including lymphocyte migration, cell proliferation, platelet aggregation, tumor cell infiltration, etc. Therefore, the S1P receptor has become an effective target for the treatment of tumors, cardiovascular diseases, and autoimmune diseases.
  • the biological activity of S1P is mediated by multiple receptor subtypes.
  • S1P1 The currently reported S1P receptor subtypes include: S1P1 (Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4 (Edg-6 ) and S1P5(Edg-8).
  • S1P1 is widely expressed. It stimulates S1P1 expressed on the surface of lymphocytes, causing endocytotic degradation of S1P1, thereby exerting a functional antagonistic effect, inducing "homing" of lymphocytes in the peripheral circulation system and thereby improving autoimmune diseases.
  • endothelial cell S1P1 and S1P3 receptors work together to regulate endothelial cell migration, differentiation, and vascular barrier function. Therefore, non-selective S1P receptors may cause toxic side effects such as transient bradycardia and hypertension.
  • FTY720 is a typical S1P agonist. Its phosphorylated metabolite FTY720-P can excite S1P receptors, induce "homing" of lymphocytes in the peripheral circulation system, reduce the number of lymphocytes in the peripheral blood circulation, thereby exerting immunity. Inhibitory effect, clinically used in the treatment of multiple sclerosis. However, in clinical practice, FTY720 can cause side effects such as bradycardia. It is generally believed that the occurrence of bradycardia is due to the agonistic effect of FTY720 on the S1P3 receptor.
  • Ozanimod is a second-generation oral highly selective S1P receptor modulator.
  • Ozanimod can selectively bind to S1P1 and S1P5 receptor subtypes, reduce the number of lymphocytes in the blood and lymph circulation, improve autoimmune diseases, and reduce side effects such as bradycardia and elevated blood pressure.
  • Ozanimod has been approved for use in adults. Treatment of relapsing forms of multiple sclerosis and ulcerative colitis.
  • Ozanimod still has problems such as complicated medication procedures and long lymphocyte recovery time after drug withdrawal.
  • S1P1 agonists examples include WO2008074821A1, WO2008023783A1, WO200807482A1.
  • S1P1 receptor agonist compounds with higher activity, selectivity or safety still need to be developed clinically.
  • the object of the present invention is to provide an oxadiazole derivative represented by Formula 1 or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable Salt,
  • n 1 or 2;
  • Q is selected from N or CH
  • X, Y or Z are each independently selected from CH, CR 9 or N;
  • R 1 is selected from aryl, heteroaryl, cycloalkyl, fused cycloalkyl or bridged cycloalkyl; wherein, R 1 is optionally substituted by one or more of the following substituents: halogen, alkyl, alkoxy Base, cycloalkyl, cycloalkoxy, cyano, nitro, haloalkyl, alkoxyalkyl, alkoxyalkoxy, amino, alkylamino, haloalkoxy, heterocyclyl, aryl, heteroaryl or aryloxy;
  • R 2 is selected from a substituted alkyl group or R 2 and R 3 together with their joint N form a substituted heterocyclyl group; wherein the substituted alkyl group or substituted heterocyclyl group is optionally replaced by one or more selected from the group consisting of hydroxyl, carboxyl or 5 -6-membered heteroaryl substituent substitution;
  • R 3 , R 4 or R 4' are each independently selected from hydrogen, alkyl or alkoxyalkyl; or R 4 , R 4' and the C connected thereto together form a cycloalkyl group;
  • R 5 or R 6 are each independently selected from hydrogen, alkyl, halogen or haloalkyl, or R 5 and R 6 together with the C connected thereto form a cycloalkyl group;
  • R 7 or R 8 are each independently selected from hydrogen, alkyl, halogen or haloalkyl, or R 7 and R 8 together with the C they are connected together form a cycloalkyl group;
  • R 9 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, heterocyclyl, hydroxyl, hydroxyalkyl, nitro, alkylaminoalkyl or Heterocyclyl.
  • Q is N; preferably, X, Y or Z are each independently selected from CH or CR9 ; preferably, R9 is selected from halogen, alkyl or haloalkyl.
  • R1 is selected from phenyl, pyridyl, pyrazolyl, Or C 5 -C 6 cycloalkyl; preferably, R 1 is phenyl or pyridyl; preferably, R 1 is optionally substituted by one or more of the following substituents: halogen, C 1 -C 4 alkyl , C 1 -C 4 alkoxy, phenoxy, C 3 -C 6 cycloalkoxy, cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy base, halogenated C 1 -C 4 alkyl group, (C 1 -C 3 alkyl) 2 amino group or 5-6 membered heterocyclyl group.
  • R 2 is selected from substituted C 2 -C 3 alkyl or R 2 and R 3 together with the N they are connected together form a substituted 4-6 membered heterocyclyl; preferably, substituted C 2 -C 3 alkyl or substituted 4-6 membered heterocyclyl is optionally substituted with one or more substituents selected from hydroxyl, carboxyl or tetrazolyl.
  • R 3 is H, C 1 -C 4 alkyl, C 1 -C 4oxy C 1 -C 4 alkyl; preferably, R 3 is hydrogen, methyl or methoxy Ethyl; preferably, R 4 is hydrogen or C 1 -C 3 alkyl; preferably, R 4' is H.
  • R 5 or R 6 is hydrogen or C 1 -C 3 alkyl; preferably, R 5 or R 6 are both hydrogen; preferably, R 7 is hydrogen or C 1 -C 3 alkyl; preferably, R 7 is hydrogen; preferably, R 8 is hydrogen, C 1 -C 3 alkyl, halogen or together with R 7 and the C attached thereto, form a cyclopropyl group.
  • Typical compounds represented by Formula 1 or their tautomers, racemates, enantiomers, diastereomers or pharmaceutically acceptable salts thereof, include but are not limited to the following compounds:
  • Another aspect of the present invention provides a method for preparing the oxadiazole derivative represented by formula 1 or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt method, when R 2 is substituted by carboxyl, R 4 and R 4' are both H,
  • the method includes the following steps:
  • R 2 is substituted by hydroxyl or heterocyclyl
  • R 4 and R 4' are both H
  • the method includes the following steps:
  • R 4 is not H, and R 4' is H
  • the method includes the following steps:
  • the preparation method of intermediate 3a includes the following steps: condensation reaction occurs between intermediate 1a and intermediate 2a to generate intermediate 3a;
  • the preparation method of intermediate 3a includes the following steps:
  • R q is H or Br
  • R w is the protecting group of amino group
  • n, Q, X, Y or Z and R 1 to R 8 are as defined in claim 1.
  • Another aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective dose of an oxadiazole derivative or its tautomer, racemate, enantiomer, diastereomer or Its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention also provides a method for preparing the above pharmaceutical composition, which includes preparing the oxadiazole derivative represented by Formula 1 or its tautomer, racemate, enantiomer, diastereomer, The form or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier or excipient.
  • the present invention further provides an oxadiazole derivative represented by Formula 1 or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, or comprising Its pharmaceutical composition and its use as a medicine.
  • the present invention further provides an oxadiazole derivative represented by Formula 1 or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, or comprising
  • the pharmaceutical composition thereof is used in the preparation of S1P1 agonist medicines.
  • the present invention further provides an oxadiazole derivative represented by Formula 1 or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, or comprising
  • the pharmaceutical composition thereof is used in the preparation of medicines for treating or preventing autoimmune diseases; preferably, the autoimmune diseases are selected from the group consisting of multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, specific Autoimmune diseases such as atopic dermatitis, graft-versus-host disease or psoriasis.
  • the present invention also provides a method for preventing and/or treating immune diseases, which includes administering a therapeutically effective dose of an oxadiazole derivative represented by Formula 1 or its tautomer as an S1P1 agonist to a patient in need thereof. isomers, racemates, enantiomers, diastereomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the oxadiazole derivative represented by Formula 1 as the active ingredient or its tautomer, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof can be prepared into a form suitable for administration by any suitable route, wherein the active ingredient is preferably in unit dosage form, or in such form that the patient may self-administer in single doses.
  • the unit dose of the active ingredient or composition of the present invention may be expressed in the form of tablets, capsules, granules, ointments, lozenges, suppositories or liquid preparations, etc.
  • the dosage of a compound or composition used in the treatment methods of the present invention will generally vary depending on the patient's weight, the severity of the disease, the compound changes depending on their relative effectiveness.
  • the general unit dose of the compound of the present invention is 0.1-1000 mg.
  • the pharmaceutical composition of the present invention may contain one or more carriers or excipients.
  • the carriers or excipients are selected from the following ingredients: fillers, disintegrants, binders, and wetting agents. Or lubricant, etc.
  • the pharmaceutical composition may contain 0.1-99% by weight of active ingredient.
  • compositions containing active ingredients may be in a form suitable for oral administration, such as tablets, capsules, granules, powders, suspensions or syrups, and the like.
  • Oral compositions may be prepared according to any method known in the art.
  • the tablets, capsules, granules, and powders in the oral composition include active ingredients and pharmaceutically acceptable excipients for mixing suitable for preparing the above oral composition.
  • These excipients can be fillers, disintegrating agents, etc.
  • Antidote, binder and lubricant; the oral composition may also contain the following carriers: sweeteners, flavoring agents, colorants and preservatives to improve taste and stability.
  • Suspensions contain the active substance and excipients suitable for the preparation of suspensions.
  • excipients include suspending, dispersing and wetting agents.
  • the suspension may also include preservatives, coloring or flavoring agents, and the like.
  • compositions of the invention may be in the form of sterile injectable aqueous solutions.
  • Excipients may include water, glycerin, sodium chloride and other solvents, preservatives, solubilizers, etc.
  • compositions of the present invention may be administered in the form of suppositories for rectal administration.
  • Excipients included in suppositories include bases, thickeners, antioxidants, hardeners, etc.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic group with a conjugated ⁇ electron system, preferably 6 to 10 members.
  • Non-limiting examples of aryl groups include: phenyl, naphthyl, wait.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from O, S, and N, and 5 to 10 ring atoms.
  • Non-limiting examples of heteroaryl include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine base, pyridazinyl, triazolyl, isoxazolyl or isothiazolyl, etc.
  • the heteroaryl ring includes a heteroaryl group fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include : wait.
  • cycloalkyl refers to a saturated or partially saturated cyclic hydrocarbon group.
  • the number of carbon atoms constituting the cycloalkyl group may be 3-15, such as 3-6.
  • Non-limiting examples of the cycloalkyl group include: cycloalkyl group Propyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, sharing an adjacent pair of carbon atoms between the rings, in which one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members; according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic, and the fused ring alkyl group is not limited sexual examples include: wait.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected. to contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, and tricyclic bridged cycloalkyl groups are preferred.
  • Non-limiting examples of bridged cycloalkyl groups include: wait.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • alkyl include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- Ethyl-2-methylpropyl.
  • alkoxy refers to a group with a "W-O-" structure, where W is an alkyl group.
  • alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy base or tert-butoxy group, etc.
  • cycloalkoxy refers to a group with the structure “Cyc-O-", where Cyc is cycloalkyl.
  • Non-limiting examples of cycloalkoxy include: cyclopropyloxy, cyclobutyloxy, Cyclopentyloxy or cyclohexyloxy, etc.
  • cyano refers to -CN.
  • haloalkyl refers to an alkyl group substituted by one or more halogens.
  • Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl, 1,3-difluoroisopropyl or trifluoro Propyl etc.
  • alkoxyalkyl refers to a group with a "W-O-W” structure, where W is an alkyl group.
  • alkoxyalkyl groups include: methoxymethyl, methoxyethyl or ethoxymethyl wait.
  • alkoxyalkoxy refers to a group having the structure "W-O-W-O", where W is an alkyl group.
  • alkoxyalkoxy include: methoxymethoxy, methoxyethoxy or Ethoxymethoxy etc.
  • amino refers to -NH2 .
  • alkylamino refers to a group having the structure "W-NH-" or "(W) 2 -N-", where W is an alkyl group.
  • alkylamino include: methylamino, dimethyl Amino, ethylamino or diethylamino, etc.
  • haloalkoxy refers to a group with a "W-O-" structure substituted by one or more halogens, where W is an alkyl group.
  • Non-limiting examples of haloalkoxy include: trifluoromethoxy, trifluoromethoxy Fluoroethoxy, 1,3-difluoroisopropoxy or trifluoropropoxy, etc.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from N, O or S , the remaining ring atoms are carbon; preferably it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms; most preferably it contains 3-8 ring atoms, and most preferably it contains 3-6 ring atoms, of which 1-2 are heteroatoms Heteroatom;
  • Non-limiting examples of heterocyclyl include dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or tetrahydrofuranyl, etc.
  • aryloxy refers to a group having the structure "Ph-O-", where Ph is phenyl or naphthyl.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to an alkyl group substituted by a hydroxyl group.
  • Non-limiting examples of hydroxyalkyl groups include: hydroxymethyl or hydroxyethyl.
  • nitro refers to -NO2 .
  • alkylaminoalkyl refers to a group having the structure "W-NH-W-" or "W 2 -NW-", where W is an alkyl group.
  • alkylaminoalkyl include: Aminomethyl, ethylaminomethyl or dimethylaminomethyl or diethylaminomethyl, etc.
  • substituted means that one or more hydrogen atoms in a group, preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents.
  • the substituents are only in their possible chemical positions, and a person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • composition means a composition containing one or more compounds described herein or in mixture with other chemical components, together with other ingredients such as pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • pharmaceutically acceptable salts refers to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.
  • the oxadiazole derivatives provided by the present invention have high agonistic activity on S1P1 and can be used as a treatment or prevention agent, for example, selected from the group consisting of multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, atopic dermatitis, and graft-versus-host disease. autoimmune diseases such as psoriasis or psoriasis.
  • Step 2 Synthesis of 3-bromo-5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (compound 1-3)
  • Step 4 3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde ( Synthesis of compound 1-6)
  • Step 5 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of -5-yl)methyl)amino)tert-butylpropionate (compound 1-7)
  • Step 6 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of -5-yl)methyl)amino)propionic acid (T01)
  • Step 1 1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde (compound 2- 1) synthesis
  • Step 2 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5- Synthesis of tert-butyl)methyl)amino)propionate (compound 2-2)
  • Step 3 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5- Synthesis of methyl)amino)propionic acid (T02)
  • Step 4 Synthesis of 3-chloro-6-fluoro-1H-indole-5-carbaldehyde (compound 3-5)
  • Step 5 3-Chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indole -Synthesis of 5-formaldehyde (compound 3-6)
  • Step 6 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-6-fluoro Synthesis of -1H-indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 3-7)
  • Step 7 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-6-fluoro Synthesis of -1H-indol-5-yl)methyl)amino)propionic acid (T03)
  • Step 1 3-(((3-chloro-1-(5-(3-chloro-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of tert-butyl indol-5-yl)methyl)(methyl)amino)propionate (compound 4-1)
  • Step 2 3-(((3-chloro-1-(5-(3-chloro-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)(methyl)amino)propionic acid (T04)
  • Step 5 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-fluoro-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 5-5)
  • Step 6 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-fluoro-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid (T05)
  • reaction solution was concentrated, and the crude product was prepared and purified by high-performance liquid chromatography to obtain compound 3-(((1-(5-(3-chloro-4-isopropoxyphenyl))-1,2,4-oxadiazole- 3-yl)-3-fluoro-1H-indol-5-yl)methyl)amino)propionic acid (T05, 40 mg), white solid, 43% yield.
  • Step 3 3-Chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methyl-1H-indole Synthesis of indole-5-carboxaldehyde (compound 6-3)
  • Step 4 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methyl Synthesis of tert-butyl-1H-indol-5-yl)amino)propionate (compound 6-4)
  • Step 5 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methyl Synthesis of 1H-indol-5-yl)methyl)amino)propionic acid (T06)
  • reaction solution was concentrated, and the crude product was prepared and purified by high-performance liquid chromatography to obtain compound 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl))-1,2, 4-oxadiazol-3-yl)-2-methyl-1H-indol-5-yl)methyl)amino)propionic acid (T06, 0.68 mg), white solid, 24% yield.
  • Step 5 Synthesis of 5-(3-bromo-1,2,4-oxadiazol-5-yl)-3-chloro-2-isopropoxypyridine (compound 7-5)
  • Step 6 3-Chloro-1-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-1H-indole- Synthesis of 5-formaldehyde (compound 7-6)
  • Step 7 3-(((3-chloro-1-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)- Synthesis of 1H-indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 7-7)
  • Step 8 3-(((3-chloro-1-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)- Synthesis of 1H-indol-5-yl)methyl)amino)propionic acid (T07)
  • Example 8 3-(((3-chloro-1-(5-(6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl) Synthesis of -1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid (T08)
  • Step 1 Synthesis of ethyl 2-(4,4-dimethyl-2-oxocyclohexyl)-2-oxoacetate (compound 8-1)
  • Step 2 Synthesis of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid ethyl ester (compound 8-2)
  • Step 3 Synthesis of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid (compound 8-3)
  • Step 4 3-(3-(5-bromo-3-chloro-1H-indol-1-yl)-1,2,4-oxadiazol-5-yl)-6,6-dimethyl- Synthesis of 4,5,6,7-tetrahydrobenzo[d]isoxazole (compound 8-4)
  • Step 5 3-Chloro-1-(5-(6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)-1,2,4 Synthesis of -oxadiazole-3-yl)-1H-indole-5-carbaldehyde (compound 8-5)
  • Step 6 3-(((3-chloro-1-(5-(6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)- Synthesis of 1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 8-6)
  • Step 7 3-(((3-chloro-1-(5-(6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)- Synthesis of 1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid (T08)
  • Step 3 3-(5-bromo-2,3-indolin-1-yl)-5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadis Synthesis of Azole (9-3)
  • Step 4 (((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline- Synthesis of tert-butyl 5-yl)methyl)amino)formate (compound 9-4)
  • reaction solution was cooled to room temperature, and the organic phase was concentrated in vacuo to obtain a crude product.
  • Step 5 (1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline-5- Synthesis of methylamine (compound 9-5)
  • Step 6 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 9-6)
  • Step 7 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of indol-5-yl)methyl)amino)propionic acid (T09)
  • reaction solution was concentrated, and the crude product was prepared and purified by high-performance liquid chromatography to obtain compound 3-(((1-(5-(3-chloro-4-isopropoxyphenyl))-1,2,4-oxadiazole- 3-yl)-2,3-indolin-5-yl)methyl)amino)propionic acid (T09, 12 mg), white solid, 54% yield.
  • Step 6 3-(5-bromo-3-methyl-2,3-indolin-1-yl)-5-(3-chloro-4-isopropoxyphenyl)-1,2, Synthesis of 4-oxadiazole (10-6)
  • Step 7 (((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methyl-2,3- Synthesis of indolin-5-yl)methyl)amino)formic acid tert-butyl ester (compound 10-7)
  • Step 8 (1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methyl-2,3-dihydro Synthesis of indole-5-yl)methanamine (compound 10-8)
  • Step 9 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methyl-2, Synthesis of tert-butyl 3-indolin-5-yl)methyl)amino)propionate (compound 10-9)
  • Step 10 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methyl-2, Synthesis of 3-indolin-5-yl)methyl)amino)propionic acid (T10)
  • reaction solution was concentrated, and the crude product was washed with 1,4-dioxane (3mL) and ethyl acetate (3mL*2) and dried to obtain compound 3-(((1-(5-(3-chloro-4- Isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methyl-2,3-indolin-5-yl)methyl)amino)propionic acid (T10 , 24 mg), white solid, yield 62%.
  • Step 1 Synthesis of 3-fluoro-4-isopropoxybenzoic acid isopropyl ester (compound 11-1)
  • Step 5 3-(((3-chloro-1-(5-(3-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 11-5)
  • Step 6 3-(((3-chloro-1-(5-(3-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid (T11)
  • reaction solution was extracted three times with water and ethyl acetate, 100 mL each time, and the organic phase was concentrated in vacuo to obtain a crude product.
  • Step 6 3-(((3-chloro-1-(5-(2-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 12-6)
  • Step 7 3-(((3-chloro-1-(5-(2-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid (T12)
  • Step 5 3-(((3-chloro-1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 13-6)
  • Step 6 3-(((3-chloro-1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole Synthesis of indol-5-yl)methyl)amino)propionic acid (T13)
  • Example 14 3-(((3-chloro-1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3) Synthesis of -1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid (T14)
  • Step 1 Synthesis of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (compound 14-1)
  • Step 2 Synthesis of 1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (compound 14-2)
  • Step 3 Synthesis of 1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (compound 14-3)
  • Step 4 3-(5-bromo-3-chloro-1H-indol-1-yl)-5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro Synthesis of -1H-indazol-3-yl)-1,2,4-oxadiazole (compound 14-4)
  • Benzotriazole (60.7mg, 0.45mmol, 1.0eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (86mg, 0.45mmol, 1.0eq), heated to 140°C , stir for 1 hour.
  • Step 5 3-Chloro-1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1,2 ,Synthesis of 4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde (compound 14-5)
  • Step 5 3-(((3-chloro-1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl Synthesis of )-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 14-6)
  • Step 6 3-(((3-chloro-1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl Synthesis of )-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propionic acid (T14)
  • Step 4 Synthesis of N-(4-methyl-5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetamide (compound 15-4)
  • Step 7 Synthesis of 5-(bromomethyl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (compound 15-7)
  • Step 8 Synthesis of 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-5-carbaldehyde (compound 15-8)
  • Step 11 3-Chloro-1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-6-(trifluoromethyl) -Synthesis of 1H-indole-5-carboxaldehyde (compound 15-11)
  • Step 12 3-(((3-chloro-1-(5-(3-chloro-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-6-( Synthesis of tert-butyl trifluoromethyl)-1H-indol-5-yl)methyl)amino)propionate (compound 15-12)
  • Step 13 3-(((3-chloro-1-(5-(3-chloro-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-6-( Synthesis of trifluoromethyl)-1H-indol-5-yl)methyl)amino)propionic acid (T15)
  • Step 5 3-(((1-(5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl Synthesis of tert-butyl)methyl)(methyl)amino)propionate (compound 16-5)
  • Step 6 3-(((1-(5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl )Synthesis of methyl)(methyl)amino)propionic acid (T16)
  • reaction was detected to be complete by LCMS and TLC. After vacuum concentration, flash column chromatography (5% methanol/dichloromethane) was used to obtain compound 3-(((3-chloro-1-(5-(3-chloro-4-isopropoxyphenyl))-1, 2,4-oxadiazol-3-yl)-1H-indol-5-yl)methyl)amino)propan-1-ol (T18, 39.07 mg), white solid, yield 56.49%.
  • reaction solution was extracted three times with water and ethyl acetate, 100 mL each time, and the organic phase was washed twice with 200 mL saturated brine. The organic phase was concentrated in vacuo to obtain crude product.
  • Step 3 3-(5-bromo-1H-indol-1-yl)-5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (compound 20- 3) synthesis
  • Step 5 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5- Synthesis of tert-butyl (methyl)(methyl)amino)propionate (compound 20-5)
  • Step 6 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5- Synthesis of (methyl)methyl)(methyl)amino)propionic acid (T20)
  • Step 3 5-(4-(benzyloxy)-3-chlorophenyl)-3-(5-bromo-1H-indol-1-yl)-1,2,4-oxadiazole (21- 3) synthesis
  • Step 4 1-(5-(4-(benzyloxy)-3-chlorophenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde (Compound 21 -4) synthesis
  • Step 5 Synthesis of 1-(5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde (21-5)
  • Step 6 1-(5-(3-chloro-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-5-carbaldehyde (compound 21-6) synthesis
  • Step 7 3-(((1-(5-(3-chloro-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indole- Synthesis of tert-butyl 5-yl)methyl)(methyl)amino)propionate (compound 21-7)
  • Step 8 3-(((1-(5-(3-chloro-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indole- 5-yl)methyl)(methyl)amino)propionic acid Synthesis of (T21)
  • Step 1 3-(((1-(5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl )Synthesis of tert-butyl methyl)amino)propionate (compound 22-1)
  • Step 2 3-(((1-(5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-5-yl )Synthesis of methyl)amino)propionic acid (T22)
  • Step 1 3-(((1-(5-(3-chloro-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indole- Synthesis of tert-butyl 5-yl)methyl)amino)propionate (23-1)
  • Step 2 3-(((1-(5-(3-chloro-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indole- Synthesis of 5-yl)methyl)amino)propionic acid (T23)
  • Step 7 1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3,3-dimethyl-2,3- Synthesis of indoline-5-carbaldehyde (compound 24-7)
  • Step 8 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3,3-dimethyl Synthesis of -tert-butyl 2,3-indolin-5-yl)methyl)amino)propionate (compound 24-8)
  • Step 9 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3,3-dimethyl Synthesis of -2,3-indolin-5-yl)methyl)amino)propionic acid (T24)
  • Step 4 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-5-(3-chloro-4-isopropoxyphenyl)-1,2,4- Synthesis of oxadiazole (compound 27-4)
  • Step 5 1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydroquinoline -Synthesis of 6-formaldehyde (compound 27-5)
  • Step 6 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4 -Synthesis of tert-butyl tetrahydroquinolin-6-yl)methyl)amino)propionate (compound 27-6)
  • Step 7 3-(((1-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4 -Synthesis of tetrahydroquinolin-6-yl)methyl)amino)propionic acid (T27)
  • Step 1 Synthesis of spiro(cyclopropane-1,3'-2,3-indoline)-2'-one (31-1)
  • Step 2 Synthesis of 5'-bromospiro(cyclopropane-1,3'-2,3-indolindole)-2'-one (compound 31-2)
  • Step 3 Synthesis of 5'-bromospirocycle (cyclopropane-1,3'-2,3-indoline) (compound 31-3)
  • Step 4 Synthesis of 5'-bromospiro(cyclopropane-1,3'-2,3-indoline)-1'-carbonitrile (compound 31-4)
  • reaction solution was extracted three times with water and ethyl acetate, 100 mL each time, and the organic phase was concentrated in vacuo to obtain a crude product.
  • Step 5 (Z)-5'-bromo-N'-hydroxyspiro(cyclopropane-1,3'-2,3-indoline)-1'-carboxyximamide (compound 31-5) synthesis
  • Step 6 3-(5'-bromospiro(cyclopropane-1,3'-2,3-indoline)-1'-yl)-5-(3-chloro-4-isopropoxy Synthesis of (phenyl)-1,2,4-oxadiazole (compound 31-6)
  • reaction solution was cooled to room temperature, 50 mL of water was added to the system to dilute, and extracted with ethyl acetate three times, 50 mL each time.
  • the organic phase was concentrated in vacuo to obtain a crude product.
  • Step 7 1'-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)spiro(cyclopropane-1,3'-2 ,Synthesis of 3-indoline)-5'-carbaldehyde (compound 31-7)
  • reaction solution After replacing the carbon monoxide gas, the temperature was raised to 99°C. Reaction time is 8 hours. TLC monitoring showed the reaction was complete. After the reaction solution cooled to room temperature, 30 mL of water was added to the system to dilute it, extracted three times with ethyl acetate, 30 mL each time, and the organic phase was concentrated in vacuo to obtain a crude product.
  • Step 8 3-(((1'-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)spiro(cyclopropane-1) ,Synthesis of tert-butyl 3'-2,3-indolin-5'-yl)methyl)amino)propionate (compound 31-8)
  • Step 9 3-(((1'-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)spiro(cyclopropane-1, Synthesis of 3'-2,3-indolin-5'-yl)methyl)amino)propionic acid (T31)
  • Step 1 3-(5-bromo-2,3-indolin-1-yl)-5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadis Synthesis of Azole (Compound 32-1)
  • Step 3 3-(((1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of tert-butyl indol-5-yl)methyl)amino)propionate (compound 32-3)
  • Step 4 3-(((1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of indol-5-yl)methyl)amino)propionic acid (T32)
  • Step 1 3-(((1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of tert-butyl indol-5-yl)methyl)(methyl)amino)propionate (compound 33-1)
  • Step 2 3-(((1-(5-(2-fluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline Synthesis of indol-5-yl)methyl)(methyl)amino)propionic acid (T33)
  • Step 1 5-(3-(5-bromo-2,3-indolin-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzene Synthesis of carbonitrile (compound 34-1)
  • Step 3 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of indol-5-yl)methyl)amino)propionic acid tert-butyl ester (compound 34-3)
  • Step 4 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of indol-5-yl)methyl)amino)propionic acid (compound T34)
  • Step 1 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of indol-5-yl)methyl)(methyl)amino)propionic acid tert-butyl ester (compound 35-1)
  • Step 2 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of indol-5-yl)methyl)(methyl)amino)propionic acid (T35)
  • Example 36 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3 -Synthesis of indolin-5-yl)methyl)(2-methoxyethyl)amino)propionic acid (T36)
  • Step 1 Synthesis of tert-butyl 3-((2-methoxyethyl)amino)propionate (compound 36-1)
  • Step 2 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of tert-butyl indol-5-yl)methyl)(2-methoxyethyl)amino)propionate (compound 36-2)
  • Step 3 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro Synthesis of indol-5-yl)methyl)(2-methoxyethyl)amino)propionic acid (T36)
  • Step 1 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-(1,1'-biphenyl)-4-carboxylic acid methyl ester (compound 37-1) synthesis
  • reaction solution was filtered and concentrated, and the residue was purified by silica gel chromatography to obtain the colorless compound 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-(1,1'-biphenyl )-4-carboxylic acid methyl ester (compound 37-1, 2.7g), oil, yield 89%.
  • Step 2 Synthesis of 4-cyclohexyl-3-(trifluoromethyl)benzoic acid methyl ester (compound 37-2)
  • Step 4 5-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-3-(-2,3-indolin-1-yl)-1,2,4-oxadiazole Synthesis of (compound 37-4)
  • reaction solution was introduced into water, extracted with ethyl acetate (3 ⁇ 20mL), and purified by column chromatography to obtain the product 5-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-3-(-2 , 3-indolin-1-yl)-1,2,4-oxadiazole (compound 37-4, 1.2g), as a yellow solid, yield 75.7%.
  • Step 5 1-(5-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)2,3-indoline-5 -Synthesis of formaldehyde (compound 37-5)
  • Step 6 1-((1-(5-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-di Synthesis of hydroindol-5-yl)methyl)azetidine-3-carboxylic acid tert-butyl ester (compound 37-6)
  • Step 7 1-((1-(5-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-di Synthesis of hydroindol-5-yl)methyl)azetidine-3-carboxylic acid (T37)
  • reaction solution was concentrated to obtain a crude product, which was then purified by preparative high performance liquid chromatography to obtain compound 5-(3-(5-((2-hydroxyethyl)amino)methyl)-2,3-indoline- 1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (T38, 17 mg), solid, 27.6% yield.
  • reaction solution was concentrated to obtain a crude product, which was then purified by preparative high performance liquid chromatography to obtain compound 5-(3-(5-(((2-hydroxyethyl)(methyl)amino)methyl)-2,3-di Hydroindol-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (T39, 6.4 mg), white solid, yield 10.6%.
  • Step 3 3-(5-bromo-2,3-indolin-1-yl)-5-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole Synthesis of -3-yl)-1,2,4-oxadiazole (compound 40-3)
  • Step 4 1-(5-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1,2,4-oxadiazole-3- Synthesis of -2,3-indoline-5-carbaldehyde (compound 40-4)
  • Step 5 1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1,2,4-oxa Synthesis of diazol-3-yl)-2,3-indoline-5-carbaldehyde (40-5)
  • Step 6 3-(((1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1, Synthesis of 2,4-oxadiazol-3-yl)-2,3-indolin-5-yl)methyl)amino)propionic acid tert-butyl ester (40-6)
  • Step 7 3-(((1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1, Synthesis of 2,4-oxadiazol-3-yl)-2,3-indolin-5-yl)methyl)amino)propionic acid (T40)
  • reaction was detected to be complete by LCMS and TLC. After vacuum concentration and purification using preparative liquid phase, compound 2-(((1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole- 3-yl)-1,2,4-oxadiazol-3-yl)-2,3-indolin-5-yl)methyl)amino)ethane-1-ol (T41) (8.3mg ), white solid, yield 7.44%.
  • Step 1 3-(((1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1, Synthesis of tert-butyl 2,4-oxadiazol-3-yl)-2,3-indolin-5-yl)methyl)(methyl)amino)propionate (compound 42-1)
  • Step 2 3-(((1-(5-(1-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1, Synthesis of 2,4-oxadiazol-3-yl)-2,3-indolin-5-yl)methyl)(methyl)amino)propionic acid (T42)
  • Step 1 5-(3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy Benzonitrile (compound 44-1)
  • N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (780.64 mg, 4.07 mmol, 1.1 eq), stir at 140°C for 3 hours. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*3).
  • Step 3 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of tert-butyl 4-tetrahydroquinolin-6-yl)methyl)amino)propionate (compound 44-3)
  • Step 4 3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of 4-tetrahydroquinolin-6-yl)methyl)amino)propionic acid (T44)
  • Step 1 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-5-(1-ethyl-1H-pyrazol-3-yl)-1,2,4 -Synthesis of oxadiazole (compound 45-1)
  • Step 3 3-(((1-(5-(1-ethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of tert-butyl 4-tetrahydroquinolin-6-yl)methyl)amino)propionate (compound 45-3)
  • Step 4 3-(((1-(5-(1-ethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of 4-tetrahydroquinolin-6-yl)methyl)amino)propionic acid (T45)
  • Step 1 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1,2,4 -Synthesis of oxadiazole (compound 46-1)
  • Triethylamine (20.3 mg, 0.2 mmol) and triethylsilane (54.37 mg, 0.468 mmol) were added sequentially to bistriphenylphosphine palladium dichloride (19 mg, 0.0267 mmol) and 3-(6-bromo-3 ,4-dihydroquinolin-1(2H)-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole (50 mg, 0.134 mmol) in dimethyl sulfoxide (3 mL).
  • the reaction mixture was heated at 100°C for 16 hours and cooled to room temperature.
  • Step 3 3-(((1-(5-(1-ethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of tert-butyl 4-tetrahydroquinolin-6-yl)methyl)amino)propionate (compound 46-3)
  • Step 4 3-(((1-(5-(1-ethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-1,2,3, Synthesis of 4-tetrahydroquinolin-6-yl)methyl)amino)propionic acid (T46)
  • Step 1 (R)-3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1, Synthesis of 2,3,4-tetrahydroquinolin-6-yl)methyl)amino)butyric acid methyl ester (compound 48-1)
  • Step 2 (R)-3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1, Synthesis of 2,3,4-tetrahydroquinolin-6-yl)methyl)amino)butyric acid (T48)
  • Step 1 (S)-3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1, Synthesis of 2,3,4-tetrahydroquinolin-6-yl)methyl)amino)butyric acid methyl ester (49-1)
  • Step 2 (S)-3-(((1-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1, Synthesis of 2,3,4-tetrahydroquinolin-6-yl)methyl)amino)butyric acid (T49)
  • Step 2 Synthesis of isopropyl 2,6-difluoro-4-isopropoxybenzoate (compound 50-2)
  • Step 4 3-(5-bromo-2,3-indolin-1-yl)-5-(2,6-difluoro-4-isopropoxyphenyl)-1,2,4 -Synthesis of oxadiazole (compound 50-4)
  • Step 5 1-(5-(2,6-difluoro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-indoline- Synthesis of 5-formaldehyde (compound 50-5)

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Abstract

L'invention concerne un dérivé d'oxadiazole, son procédé de préparation et son utilisation. Le dérivé d'oxadiazole a une structure telle que représentée dans la formule I. Le dérivé d'oxadiazole a un très bon effet agoniste sur S1P1, et peut être utilisé pour traiter ou prévenir des maladies auto-immunes telles que la sclérose en plaques, la maladie intestinale inflammatoire, la polyarthrite rhumatoïde, la dermatite atopique, la maladie du greffon contre l'hôte ou le psoriasis.
PCT/CN2023/080355 2022-03-25 2023-03-08 Dérivé d'oxadiazole, son procédé de préparation et son utilisation WO2023179366A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092638A1 (fr) * 2006-02-09 2007-08-16 University Of Virginia Patent Foundation Analogues de sphingosine 1-phosphate bicyclique
WO2008064320A2 (fr) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Analogues d'hydrindane ayant une activité agoniste de récepteur de sphingosine-1-phosphate
WO2008074820A1 (fr) * 2006-12-21 2008-06-26 Glaxo Group Limited Dérivés d'oxadiazole en tant qu'agonistes du récepteur s1p1
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
CN101611033A (zh) * 2006-12-21 2009-12-23 葛兰素集团有限公司 作为s1p1受体激动剂的吲哚衍生物
WO2010042998A1 (fr) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd Modulateurs des récepteurs s1p
CN103748087A (zh) * 2011-06-07 2014-04-23 大日本住友制药株式会社 吲唑和吡咯并吡啶衍生物和其药学用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092638A1 (fr) * 2006-02-09 2007-08-16 University Of Virginia Patent Foundation Analogues de sphingosine 1-phosphate bicyclique
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
WO2008064320A2 (fr) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Analogues d'hydrindane ayant une activité agoniste de récepteur de sphingosine-1-phosphate
WO2008074820A1 (fr) * 2006-12-21 2008-06-26 Glaxo Group Limited Dérivés d'oxadiazole en tant qu'agonistes du récepteur s1p1
CN101611033A (zh) * 2006-12-21 2009-12-23 葛兰素集团有限公司 作为s1p1受体激动剂的吲哚衍生物
WO2010042998A1 (fr) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd Modulateurs des récepteurs s1p
CN103748087A (zh) * 2011-06-07 2014-04-23 大日本住友制药株式会社 吲唑和吡咯并吡啶衍生物和其药学用途

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