CN102459202B - As the inhibitor isoxazoline of fatty acid amide hydrolase - Google Patents

As the inhibitor isoxazoline of fatty acid amide hydrolase Download PDF

Info

Publication number
CN102459202B
CN102459202B CN201080032435.4A CN201080032435A CN102459202B CN 102459202 B CN102459202 B CN 102459202B CN 201080032435 A CN201080032435 A CN 201080032435A CN 102459202 B CN102459202 B CN 102459202B
Authority
CN
China
Prior art keywords
certain embodiments
alkyl
group
compound
unit
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201080032435.4A
Other languages
Chinese (zh)
Other versions
CN102459202A (en
Inventor
马克·L·本克
阿尔弗雷多·C·卡斯特罗
劳伦斯·K·陈
凯瑟琳·A·埃文斯
路易斯·格勒涅尔
迈克尔·J·格罗根
伊夫·勒布朗
刘涛
斯特凡·佩卢索
丹尼尔·A·斯奈德
托马斯·T·帝比茨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Infinity Pharmaceuticals Inc
Original Assignee
Infinity Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Infinity Pharmaceuticals Inc filed Critical Infinity Pharmaceuticals Inc
Publication of CN102459202A publication Critical patent/CN102459202A/en
Application granted granted Critical
Publication of CN102459202B publication Critical patent/CN102459202B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/04—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • 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
    • 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
    • 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
    • C07D498/10—Spiro-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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems

Abstract

The invention provides formula (I) isoxazoline FAAH inhibitor or its pharmaceutically acceptable form, wherein each G, R a, R b, R cand R das defined herein.The present invention also provides the pharmaceutical composition of compound containing formula (I) or its pharmaceutically acceptable form and pharmaceutically acceptable vehicle.The present invention also provides the method for the illness for the treatment of FAAH mediation, comprises the compound to the formula (I) of individual administering therapeutic significant quantity in need or its pharmaceutically acceptable form.

Description

As the inhibitor isoxazoline of fatty acid amide hydrolase
The cross reference of related application
The application advocates the right of priority of the U.S. Provisional Patent Application sequence number 61/179,280,61/179,283 and 61/179,285 submitted on May 18th, 2009, is incorporated herein by reference at this full content by them.
Background
Fatty acid amide hydrolase (FAAH, also referred to as amine hydroxybenzene lytic enzyme and anandamide hydroamidase) be a kind of AQP-CHIP regulating fatty acid amide (FAA) for being hydrolyzed several important endogenous neural comprising anandamide, Oleoyl monoethanolamide and Palmitylethanolamide, and with its regulation and control close association.Because these FAA and cannaboid and capsaicin receptor interact, therefore they are often called as " Endocannabinoids " or " endogenous capsaicine ".Research and development FAAH inhibitor is concentrated on to increase the effect of FAA and to ease the pain in the initial interest in this field.Further research finds, FAAH inhibitor can be used for treating various illness by FAA and the interaction of unique extracellular and intracellular receptor, includes but not limited to inflammation, metabolism disorder (such as, relevant with obesity illness and expendable illness are as emaciation and apocleisis), disorder (such as, relevant to neurotoxicity and/or the nerve injury disorder of central nervous system, apoplexy, multiple sclerosis, Spinal injury, dyskinesia is as disorderly in basal ganglion, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, mental disorder is as anxiety, depressed, learning disorder and schizophrenia, somnopathy is as insomnia, feel sick and/or vomit and take drugs), heart disease (such as, hypertension, the recycle system is suffered a shock, myocardial ischemia-reperfusion injury and atherosclerosis) and glaucoma (people such as Pacher, " TheEndocannabinoidSystemasanEmergingTargetofPharmacother apy " PharmacologicalReviews (2006) 58:389-462, the people such as Pillarisetti, " PainandBeyond:FattyAcidAmidesandFattyAcidAmideHydrolasei nCardiovascularandMetabolicDiseases " DrugDiscoveryToday (2009) 597:1-14).Summary
The invention provides formula (I) isoxazoline FAAH inhibitor compound:
Or its pharmaceutically acceptable form,
Wherein:
(i) each R a, R band R cindependently selected from H, C 1-10alkyl and C 1-10whole haloalkyl, R dbe group-L-Z, and Z is selected from C 6-14aryl;
(ii) each R a, R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl, R dbe group-L-Z, and Z is selected from 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl;
(iii) R aand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical condensed ring, and R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl; Or
(iv) R cand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical spiral shell condensed ring, and R aand R bindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl;
L is covalent linkage or divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more oxygen, sulphur or nitrogen-atoms independently;
G is selected from-CN ,-NO 2,-S (=O) R e,-SO 2r e,-SO 2nR fr e,-PO 2r e,-PO 2oR e,-PO 2nR fr e,-(C=O) R e,-(C=O) OR e,-(C=O) NR fr e,-Br ,-I ,-F ,-Cl ,-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-SR e,-OSO 2r e,-NR fsO 2r e,-OPO 2r e,-OPO 2oR e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fr e,-O (C=O) R e,-O (C=O) OR e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr e,-NR f(C=NR f) OR e,-[N (R f) 2r e] +x -, wherein X -counter ion;
Each R ebe selected from C 1-10alkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl; The each R be connected with nitrogen-atoms findependently selected from-H, C 1-10alkyl or amino protecting group; Or R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring.
The present invention also provides the pharmaceutical composition of compound containing formula (I) or its pharmaceutically acceptable form and pharmaceutically acceptable vehicle.
The present invention also provides the method for the illness of FAAH mediation in treatment individuality, comprises the compound to the formula (I) of individual administering therapeutic significant quantity in need or its pharmaceutically acceptable form.
The details of other embodiments of the present invention is illustrated in detailed description hereafter and embodiment.Other features of the present invention, object and advantage will be apparent from detailed description and claims.
Definition
Hereafter the definition of particular functional group and the technical term of chemistry will be described in more detail.Chemical element is according to the periodic table of elements, and CAS version, HandbookofChemistryandPhysics, in the 75th edition, page is differentiated, and particular functional group is generally by definition described herein.In addition, vitochemical General Principle and particular functional part and reactivity are described in in Publication about Document: OrganicChemistry, ThomasSorrell, UniversltyScienceBooks, Sausalito, 1999; Smith and MarchMarch ' sAdvancedOrganicChemistry, the 5th edition, JohnWiley & Sons, Inc., NewYork, 2001; Larock, ComprehensiveOrganicTransformations, VCHPublishers, Inc., NewYork, 1989; And Carruthers, SomeModernMethodsofOrganicSynthesis, the 3rd edition, CambridgeUniversityPress, Cambridge, 1987.
Some compound of the present invention can comprise one or more asymmetric center, therefore can exist with various isomeric forms such as such as enantiomer and/or diastereomer etc.Therefore, compound provided herein can be the form of single enantiomer, diastereomer or geometrical isomer, can be maybe the form of stereoisomer mixture, comprises the mixture of racemic mixture and one or more steric isomer enrichments.In certain embodiments, compound of the present invention is enantiopure compound.In certain other embodiments, the mixture of steric isomer is provided.
In addition, unless otherwise noted, some compound can have one or more double bond as described herein, it can exist as cis or trans or E or Z isomer.The compound as the single isomer that there is no other isomer is also contained in the present invention, and as the compound of various isomer mixture (such as, the racemic mixture of E or Z isomer or the mixture of a kind of E or Z isomer enrichment).
Term " enantiomer enrichment ", " enantiomeric pure " and " non-racemic " exchange use in this article, refer to such composition, wherein a kind of weight percent of enantiomer is greater than the weight percent (such as, being greater than 1: 1 by weight) in the control mixture that this enantiomer forms in racemize.Such as, (S) preparation of the enantiomer enrichment of-enantiomer, refers to relative to (R)-enantiomer, the compound formulation that (S)-enantiomer is greater than 50 % by weight, more preferably at least 75 % by weight, more more preferably at least 80 % by weight.In some embodiments, enrichment can much larger than 80 % by weight, thus " substantially enantiomer enrichment ", " substantially enantiomeric pure " or " substantially non-racemic " preparation are provided, this preparation refers to relative to another kind of enantiomer, a kind of enantiomer at least accounts for 85 % by weight of composition, more preferably at least 90 % by weight, more more preferably at least 95 % by weight preparation.In preferred embodiments, with regard to the therepic use of unit mass, the racemic mixture of this composition of ratio of components of enantiomer enrichment has higher effect.Can by well known by persons skilled in the art any method of the formation and crystallization that comprise Chiral high pressure liquid chromatography (HPLC) and chirality salt from mixture separation enantiomer; Or preferred enantiomer can be prepared by asymmetric synthesis.See, such as, the people such as Jacques, Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); The people such as Wilen, S.H., Tetrahedron33:2725 (1977); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); And Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972).
When listing the scope of numerical value, be intended to be included in each value within the scope of this and subrange.Such as, " C 1-6alkyl " be intended to comprise C 1, C 2, C 3, C 4, C 5, C 6, C 1-6, C 1-5, C 1-4, C 1-3, C 1-3, C 2-6, C 2-5, C 2-4, C 2-3, C 3-6, C 3-5, C 3-4, C 4-6, C 4-5and C 5-6alkyl.
Used herein, " direct key " or " covalent linkage " refer to the singly-bound of connection two groups.
Used herein, independent or as the part of another group, " halo " and " halogen " refers to fluorine (fluoro ,-F), chlorine (chloro ,-Cl), bromine (bromo ,-Br) or iodine (iodo ,-I).
Used herein, independent or as the part of another group, " alkyl " refers to the univalent perssad (" C of the saturated hydrocarbyl of the straight or branched with 1-10 carbon atom 1-10alkyl ").In some embodiments, alkyl has 1-9 carbon atom (" C 1-9alkyl ").In some embodiments, alkyl has 1-8 carbon atom (" C 1-8alkyl ").In some embodiments, alkyl has 1-7 carbon atom (" C 1-7alkyl ").In some embodiments, alkyl has 1-6 carbon atom (" C 1-6alkyl ").In some embodiments, alkyl has 1-5 carbon atom (" C 1-5alkyl ").In some embodiments, alkyl has 1-4 carbon atom (" C 1-4alkyl ").In some embodiments, alkyl has 1-3 carbon atom (" C 1-3alkyl ").In some embodiments, alkyl has 1-2 carbon atom (" C 1-2alkyl ").In some embodiments, alkyl has 1 carbon atom (" C 1alkyl ").In some embodiments, alkyl has 2-6 carbon atom (" C 2-6alkyl ").C 1-6the example of alkyl comprises methyl (C 1), ethyl (C 2), n-propyl (C 3), sec.-propyl (C 3), normal-butyl (C 4), the tertiary butyl (C 4), sec-butyl (C 4), isobutyl-(C 4), n-pentyl (C 5), 3-amyl group (C 5), amyl group (C 5), neo-pentyl (C 5), 3-methyl-2-butyl (C 5), tert-pentyl (C 5) and n-hexyl (C 6).The additional examples of alkyl comprises n-heptyl (C 7), n-octyl (C 8) etc.Except as otherwise noted, each alkyl be independently unsubstituted (" unsubstituted alkyl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" alkyl of replacement ").In certain embodiments, alkyl is unsubstituted C 1-10alkyl (such as ,-CH 3).In certain embodiments, alkyl is the C replaced 1-10alkyl.
" whole haloalkyl " defined herein refers to wherein all each alkyl (" C with 1-10 carbon atom using halogen (such as, being selected from fluorine, bromine, chlorine or iodine) to replace independently of hydrogen atom 1-10whole haloalkyl ").In some embodiments, moieties has 1-8 carbon atom (" C 1-8whole haloalkyl ").In some embodiments, moieties has 1-6 carbon atom (" C 1-6whole haloalkyl ").In some embodiments, moieties has 1-4 carbon atom (" C 1-4whole haloalkyl ").In some embodiments, moieties has 1-3 carbon atom (" C 1-3whole haloalkyl ").In some embodiments, moieties has 1-2 carbon atom (" C 1-2whole haloalkyl ").In some embodiments, whole hydrogen atom each replace with fluoro.In some embodiments, whole hydrogen atom each replace with chloro.The example of whole haloalkyl comprises-CF 3,-CF 2cF 3,-CF 2cF 2cF 3,-CCl 3,-CFCl 2,-CF 2cl etc.
Used herein, independent or as the part of another group, " thiazolinyl " refers to the univalent perssad (" C of the alkyl of the straight or branched with 2-10 carbon atom and one or more carbon-carbon double bond 2-10thiazolinyl ").In some embodiments, thiazolinyl has 2-9 carbon atom (" C 2-9thiazolinyl ").In some embodiments, thiazolinyl has 2-8 carbon atom (" C 2-8thiazolinyl ").In some embodiments, thiazolinyl has 2-7 carbon atom (" C 2-7thiazolinyl ").In some embodiments, thiazolinyl has 2-6 carbon atom (" C 2-6thiazolinyl ").In some embodiments, thiazolinyl has 2-5 carbon atom (" C 2-5thiazolinyl ").In some embodiments, thiazolinyl has 2-4 carbon atom (" C 2-4thiazolinyl ").In some embodiments, thiazolinyl has 2-3 carbon atom (" C 2-3thiazolinyl ").In some embodiments, thiazolinyl has 2 carbon atom (" C 2thiazolinyl ").One or more carbon-carbon double bond can in inner (as in crotyl) or in end (as in 1-butylene base).C 2-4the example of thiazolinyl comprises vinyl (C 2), 1-propenyl (C 3), 2-propenyl (C 3), 1-butylene base (C 4), crotyl (C 4), butadienyl (C 4) etc.C 2-6the example of thiazolinyl comprises aforementioned C 2-4thiazolinyl and pentenyl (C 5), pentadienyl (C 5), hexenyl (C 6) etc.The additional examples of thiazolinyl comprises heptenyl (C 7), octenyl (C 8), sarohornene base (C 8) etc.Except as otherwise noted, each thiazolinyl be independently unsubstituted (" unsubstituted thiazolinyl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" thiazolinyl of replacement ").In certain embodiments, thiazolinyl is unsubstituted C 2-10thiazolinyl.In certain embodiments, thiazolinyl is the C replaced 2-10thiazolinyl.
Used herein, independent or as the part of another group, " alkynyl " refers to the univalent perssad (" C of the alkyl of the straight or branched with 2-10 carbon atom and one or more carbon carbon triple bond 2-10alkynyl ").In some embodiments, alkynyl has 2-9 carbon atom (" C 2-9alkynyl ").In some embodiments, alkynyl has 2-8 carbon atom (" C 2-8alkynyl ").In some embodiments, alkynyl has 2-7 carbon atom (" C 2-7alkynyl ").In some embodiments, alkynyl has 2-6 carbon atom (" C 2-6alkynyl ").In some embodiments, alkynyl has 2-5 carbon atom (" C 2-5alkynyl ").In some embodiments, alkynyl has 2-4 carbon atom (" C 2-4alkynyl ").In some embodiments, alkynyl has 2-3 carbon atom (" C 2-3alkynyl ").In some embodiments, alkynyl has 2 carbon atom (" C 2alkynyl ").One or more carbon carbon triple bond can in inner (as in 2-butyne base) or in end (as in ethyl acetylene base).C 2-4the example of alkynyl includes but not limited to ethynyl (C 2), 1-proyl (C 3), 2-propynyl (C 3), ethyl acetylene base (C 4), 2-butyne base (C 4) etc.C 2-6the example of thiazolinyl comprises aforementioned C 2-4alkynyl and pentynyl (C 5), hexin base (C 6) etc.The additional examples of alkynyl comprises heptyne base (C 7), octyne base (C 8) etc.Except as otherwise noted, each alkynyl be independently unsubstituted (" unsubstituted alkynyl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" alkynyl of replacement ").In certain embodiments, alkynyl is unsubstituted C 2-10alkynyl.In certain embodiments, alkynyl is the C replaced 2-10alkynyl.
" divalence C 1-6alkyl " be divalence C 1-6alkyl, divalence C 1-6thiazolinyl or divalence C 1-6alkynyl, wherein 1,2 or 3 MU (methylene unit) (-CH of hydrocarbon chain 2-) optionally and replace with one or more oxygen, sulphur or nitrogen-atoms independently.In certain embodiments, divalence C 1-6alkyl is divalence C 1-6alkyl.In certain embodiments, divalence C 1-6alkyl is unsubstituted divalence C 1-6alkyl (such as, unsubstituted divalence C 1-6alkyl).
Used herein, independent or as the part of another group, " alkoxyl group " refers to the alkyl defined herein replaced with Sauerstoffatom, and wherein tie point is Sauerstoffatom.In certain embodiments, alkyl has 1-10 carbon atom (" C 1-10alkoxyl group ").In some embodiments, alkyl has 1-8 carbon atom (" C 1-8alkoxyl group ").In some embodiments, alkyl has 1-6 carbon atom (" C 1-6alkoxyl group ").In some embodiments, alkyl has 1-4 carbon atom (" C 1-4alkoxyl group ").C 1-4the example of alkoxyl group comprises methoxyl group (C 1), oxyethyl group (C 2), propoxy-(C 3), isopropoxy (C 3), butoxy (C 4), tert.-butoxy (C 5) etc.C 1-6the example of alkoxyl group comprises aforementioned C 1-4alkoxyl group and pentyloxy (C 5), isopentyloxy (C 5), neopentyl oxygen (C 5), hexyloxy (C 6) etc.The additional examples of alkoxyl group comprises oxygen base (C in heptan 7), octyloxy (C 8) etc.Except as otherwise noted, the moieties of each alkoxyl group be independently unsubstituted (" unsubstituted alkoxyl group ") or replace by 1,2,3,4 or 5 substituting group as described herein (" alkoxyl group of replacement ").In certain embodiments, alkoxyl group is unsubstituted C 2-10alkoxyl group (such as ,-OCH 3).In certain embodiments, alkoxyl group is the C replaced 2-10alkoxyl group (such as, perhaloalkoxy groups defined herein).
" perhaloalkoxy groups " refer to wherein all hydrogen atom each independently with the alkoxyl group that the halogen atom being selected from fluorine, chlorine, bromine and iodine replaces.In certain embodiments, moieties has 1-10 carbon atom (" C 1-10perhaloalkoxy groups ").In some embodiments, moieties has 1-8 carbon atom (" C 1-8perhaloalkoxy groups ").In some embodiments, moieties has 1-6 carbon atom (" C 1-6perhaloalkoxy groups ").In some embodiments, moieties has 1-4 carbon atom (" C 1-4perhaloalkoxy groups ").In some embodiments, moieties has 1-3 carbon atom (" C 1-3perhaloalkoxy groups ").In some embodiments, moieties has 1-2 carbon atom (" C 1-2perhaloalkoxy groups ").In some embodiments, whole hydrogen atom each replace with fluoro.In some embodiments, whole hydrogen atom each replace with chloro.The example of perhaloalkoxy groups includes but not limited to-OCF 3,-OCF2CF 3,-OCF 2cF 2cF 3,-OCCl 3,-OCFCl 2,-OCF 2cl etc.
Used herein, independent or as the part of another group, " carbocylic radical " refers to the non-aromatic cyclic hydrocarbon base with 3-10 ring carbon atom and in non-aromatic ring system, has 0 heteroatomic group (" C 3-10carbocylic radical ").In some embodiments, carbocylic radical has 3-8 ring carbon atom (" C 3-8carbocylic radical ").In some embodiments, carbocylic radical has 3-6 ring carbon atom (" C 3-6carbocylic radical ").In some embodiments, carbocylic radical has 3-6 ring carbon atom (" C 3-6carbocylic radical ").In some embodiments, carbocylic radical has 5-10 ring carbon atom (" C 5-10carbocylic radical ").C 3-6the example of carbocylic radical includes but not limited to cyclopropyl (C 3), cyclobutyl (C 4), cyclopentyl (C 5), cyclopentenyl (C 5), cyclohexyl (C 6), cyclohexenyl (C 6), cyclohexadienyl (C 6) etc.C 3-8the example of carbocylic radical comprises aforementioned C 3-6carbocylic radical and suberyl (C 7), cycloheptadiene base (C 7), cycloheptatriene base (C 7), ring octyl group (C 8), dicyclo [2.2.1] heptane, dicyclo [2.2.2] octane etc.C 3-10the example of carbocylic radical comprises aforementioned C 3-8carbocylic radical and octahydro-1H-indenyl, decahydro naphthyl, spiral shell [4.5] decyl etc.As previous examples illustrates, in certain embodiments, carbocylic radical be monocycle (" monocyclic carbocyclyl residues ") or many rings (such as, containing condensing, bridge joint or spiro system, as bicyclic ring system (" bicyclic carbocyclic group ") or three ring systems (" three ring carbocylic radicals ")), and can be saturated, or can one or more carbon-carbon double bond or triple bond be contained." carbocylic radical " also comprises wherein as carbocyclic ring basic ring as defined above and one or more aryl or the heteroaryl-condensed and wherein ring system of tie point on carbocyclic ring basic ring.Except as otherwise noted, each carbocylic radical be independently unsubstituted (" unsubstituted carbocylic radical ") or replace by 1,2,3,4 or 5 substituting group as described herein (" carbocylic radical of replacement ").In certain embodiments, carbocylic radical is unsubstituted C 3-10carbocylic radical.In certain embodiments, carbocylic radical is the C replaced 3-10carbocylic radical.
In some embodiments, " carbocylic radical " has the monocycle of 3-10 ring carbon atom, saturated carbocylic radical (" C 3-10cycloalkyl ").In some embodiments, cycloalkyl has 3-8 ring carbon atom (" C 3-8cycloalkyl ").In some embodiments, cycloalkyl has 3-6 ring carbon atom (" C 3-6cycloalkyl ").In some embodiments, cycloalkyl has 5-6 ring carbon atom (" C 5-6cycloalkyl ").In some embodiments, cycloalkyl has 5-10 ring carbon atom (" C 5-10cycloalkyl ").C 5-6the example of cycloalkyl comprises cyclopentyl (C 5) and cyclohexyl (C 6).C 3-6the example of cycloalkyl comprises aforementioned C 5-6cycloalkyl and cyclopropyl (C 3) and cyclobutyl (C 4).C 3-8the example of cycloalkyl comprises aforementioned C 3-6cycloalkyl and suberyl (C 7) and ring octyl group (C 8).Except as otherwise noted, each cycloalkyl be independently unsubstituted (" unsubstituted cycloalkyl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" cycloalkyl of replacement ").In certain embodiments, cycloalkyl is unsubstituted C 3-10cycloalkyl.In certain embodiments, cycloalkyl is the C replaced 3-10cycloalkyl.
Used herein, independent or as the part of another group, " heterocyclic radical " refers to the group (" 3-14 unit heterocyclic radical ") of the 3-14 unit non-aromatic ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur.In the heterocyclic radical containing one or more nitrogen-atoms, if valence state allows, tie point can be carbon or nitrogen-atoms.Heterocyclic radical can be monocycle (" monocyclic heterocycles base ") or many rings (such as, condense, bridge joint or spiro system, as bicyclic ring system (" bicyclic heterocyclic radical ") or three ring systems (" tricyclic heterocyclic base ")), and can be saturated or can one or more carbon-carbon double bond or triple bond be contained.Heterocyclic radical many rings ring system can comprise one or more heteroatoms at a ring or two rings." heterocyclic radical " also comprises wherein as heterocyclic ring as defined above and one or more carbocylic radical condense and the wherein ring system of tie point on carbocylic radical or heterocyclic ring or wherein as heterocyclic ring as defined above and one or more aryl or the heteroaryl-condensed and wherein ring system of tie point on heterocyclic ring.In some embodiments, heterocyclic radical is the 5-10 unit non-aromatic ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-10 unit heterocyclic radical ").In some embodiments, heterocyclic radical is the 5-8 unit non-aromatic ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-8 unit heterocyclic radical ").In some embodiments, heterocyclic radical is the 5-6 unit non-aromatic ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-6 unit heterocyclic radical ").In some embodiments, 5-6 unit heterocyclic radical has 1-3 the ring hetero atom being selected from nitrogen, oxygen and sulphur.In some embodiments, 5-6 unit heterocyclic radical has 1-2 the ring hetero atom being selected from nitrogen, oxygen and sulphur.In some embodiments, 5-6 unit heterocyclic radical has 1 ring hetero atom being selected from nitrogen, oxygen and sulphur.Exemplaryly contain 1 heteroatomic 3-unit heterocyclic radical and include but not limited to aziridinyl, Oxyranyle, thiorenyl.Exemplaryly contain 1 heteroatomic 4-unit heterocyclic radical and include but not limited to azelidinyl, oxetanylmethoxy and thietanyl.Exemplaryly contain 1 heteroatomic 5-unit heterocyclic radical and include but not limited to tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, pyrrolidyl, pyrrolin base and pyrryl-2,5-diketone.Exemplaryly contain 2 heteroatomic 5-unit heterocyclic radicals and include but not limited to dioxolanyl, oxygen thia penta cyclic group and dithia penta cyclic group.Exemplaryly contain 3 heteroatomic 5-unit heterocyclic radicals and include but not limited to triazoline base, 4-oxadiazole quinoline base and thia bisoxazoline base.Exemplaryly contain 1 heteroatomic 6-unit heterocyclic radical and include but not limited to piperidyl, THP trtrahydropyranyl, dihydropyridine base and thiophene alkyl.Exemplaryly contain 2 heteroatomic 6-unit heterocyclic radicals and include but not limited to piperazinyl, morpholinyl, dithiane base, alkyl dioxin.Exemplaryly contain 2 heteroatomic 6-unit heterocyclic radicals and include but not limited to triazinyl.Exemplaryly contain 1 heteroatomic 7-unit heterocyclic radical and include but not limited to diazepine base, oxygen azatropylidene base and sulphur azatropylidene base.Exemplaryly contain 1 heteroatomic 8-unit heterocyclic radical and include but not limited to azocanyl, oxecanyl and thiocanyl.Exemplary bicyclic heterocyclic radical includes but not limited to indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, tetrahydro benzo thienyl, tetrahydrochysene benzfuran base, tetrahydro indole base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, octahydro chromenyl, the heterochromatic thiazolinyl of octahydro, decahydro naphthyridinyl, decahydro-1,8-naphthyridinyl, octahydro pyrrolo-[3,2-b] pyrroles, indoline base, phthaloyl imino, naphthalimido, chromanyl, chromenyl, 1H-benzo [e] [Isosorbide-5-Nitrae] diazepinyl, Isosorbide-5-Nitrae, 5,7-tetrahydropyrans is [3,4-b] pyrryl also, 5,6-dihydro-4H-furo [3,2-b] pyrryl, 6,7-dihydro-5H-furo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno-[2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo-[2,3-b] pyridyl, 2,3 dihydro furan is [2,3-b] pyridyl also, 4,5,6,7-tetrahydro-1 H-pyrrolo is [2,3-b] pyridyl also, 4,5,6,7-tetrahydrofuran (THF) is [3,2-c] pyridyl also, 4,5,6,7-tetramethylene sulfide is [3,2-b] pyridyl also, 1,2,3,4-tetrahydrochysene-1,6-naphthyridinyl etc.Except as otherwise noted, each heterocyclic radical be independently unsubstituted (" unsubstituted heterocyclic radical ") or replace by 1,2,3,4 or 5 substituting group as described herein (" heterocyclic radical of replacement ").In certain embodiments, heterocyclic radical is unsubstituted 3-14 unit heterocyclic radical.In certain embodiments, heterocyclic radical is the 3-14 unit heterocyclic radical replaced.
Used herein, independent or as the part of another group, " aryl " refers to have 6-14 ring carbon atom and 0 heteroatomic monocycle or many rings (such as in aromatic series ring system, dicyclo or three rings) the group (" C of aromatic series ring system (such as, sharing 6,10 or 14 π-electrons in ring) 6-14aryl ").In some embodiments, aryl has 6 ring carbon atom (" C 6aryl "; Such as, phenyl).In some embodiments, aryl has 10 ring carbon atom (" C 10aryl "; Such as, naphthyl, as 1-naphthyl and 2-naphthyl).In some embodiments, aryl has 14 ring carbon atom (" C 14aryl "; Such as, anthryl)." aryl " also comprises wherein as the ring system that aryl rings as defined above and one or more carbocylic radical or heterocyclic radical condense, and wherein linking group or tie point are in aryl rings.Except as otherwise noted, each aryl be independently unsubstituted (" unsubstituted aryl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" aryl of replacement ").In certain embodiments, aryl is unsubstituted C 6-14aryl.In certain embodiments, aryl is the C replaced 6-14aryl.
" aralkyl " is the subset of " alkyl ", and refer to the alkyl defined herein that replaces by aryl defined herein, wherein tie point is on moieties.
Used herein, independent or as the part of another group, " heteroaryl " refer to there is ring carbon atom and 1-4 ring hetero atom in aromatic series ring system 5-14 unit monocycle or many rings (such as, dicyclo or three rings) aromatic series ring system is (such as, in ring, share 6,10 or 14 π-electrons) group (" 5-14 unit heteroaryl "), wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur.In the heteroaryl containing one or more nitrogen-atoms, if valence state allows, tie point can be carbon or nitrogen-atoms.Heteroaryl many rings ring system can comprise one or more heteroatoms at one or two ring." heteroaryl " also comprise wherein as heteroaryl ring as defined above with one or more aryl-condensed and wherein the ring system of tie point on aryl or on heteroaryl ring or wherein as heteroaryl ring as defined above and one or more carbocylic radical or heterocyclic radical condense and the wherein ring system of tie point on heteroaryl ring.For one of them ring containing heteroatomic polyheteroaromatic (not such as, indyl, quinolyl, carbazyl etc.), tie point can on arbitrary ring, namely, or with heteroatomic ring (such as, 2-indyl) go up or do not containing on heteroatomic ring (such as, 5-indyl).In some embodiments, heteroaryl is the 5-10 unit aromatic series ring system in aromatic series ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-10 unit heteroaryl ").In some embodiments, heteroaryl is the 5-8 unit aromatic series ring system in aromatic series ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-8 unit heteroaryl ").In some embodiments, heteroaryl is the 5-6 unit aromatic series ring system in aromatic series ring system with ring carbon atom and 1-4 ring hetero atom, and wherein each heteroatoms is independently selected from nitrogen, oxygen and sulphur (" 5-6 unit heteroaryl ").In some embodiments, 5-6 unit heteroaryl has 1-3 the ring hetero atom being selected from nitrogen, oxygen and sulphur.In some embodiments, 5-6 unit heteroaryl has 1-2 the ring hetero atom being selected from nitrogen, oxygen and sulphur.In some embodiments, 5-6 unit heteroaryl has 1 ring hetero atom being selected from nitrogen, oxygen and sulphur.Exemplaryly contain 1 heteroatomic 5-unit heteroaryl and include but not limited to pyrryl, furyl and thienyl.Exemplaryly contain 2 heteroatomic 5-unit heteroaryls and include but not limited to imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.Exemplaryly contain 3 heteroatomic 5-unit heteroaryls and include but not limited to triazolyl, oxadiazolyl, thiadiazolyl group.Exemplaryly contain 4 heteroatomic 5-unit heteroaryls and include but not limited to tetrazyl.Exemplaryly contain 1 heteroatomic 6-unit heteroaryl and include but not limited to pyridyl.Exemplaryly contain 2 heteroatomic 6-unit heteroaryls and include but not limited to pyridazinyl, pyrimidyl and pyrazinyl.Exemplaryly contain 3 or 4 heteroatomic 6-unit heteroaryls and include but not limited to triazinyl and tetrazine base respectively.Exemplaryly contain 1 heteroatomic 7 yuan of heteroaryl and include but not limited to azepinyl, oxepinyl and thiepinyl.Exemplary 5,6-bicyclic heteroaryls include but not limited to indyl, pseudoindoyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuryl, benzisoxa furyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, Ben Bing oxadiazolyl, benzothiazolyl, benzisothiazole base, diazosulfide base, indolizinyl and purine radicals.Exemplary 6,6-bicyclic heteroaryls include but not limited to naphthyridinyl, pteridyl, quinolyl, isoquinolyl, cinnolines base, quinoxalinyl, phthalazinyl and quinazolyl.Exemplary tricyclic heteroaryl includes but not limited to phenanthridinyl, dibenzofuran group, carbazyl, acridyl, phenothiazinyl, phenoxazinyl and phenazinyl.Except as otherwise noted, each heteroaryl be independently unsubstituted (" unsubstituted heteroaryl ") or replace by 1,2,3,4 or 5 substituting group as described herein (" heteroaryl of replacement ").In certain embodiments, heteroaryl is unsubstituted 5-14 unit heteroaryl.In certain embodiments, heteroaryl is the 5-14 unit heteroaryl replaced.
" heteroaralkyl " is the subset of " alkyl ", and refer to the alkyl defined herein that replaces by heteroaryl defined herein, wherein tie point is on moieties.
Used herein, term " part is undersaturated " refers to the loop section comprising at least one double bond or triple bond.Term " part is undersaturated " is intended to contain the ring with multiple unsaturated sites, but does not attempt to comprise aromatic group as herein defined (such as, aryl or heteroaryl moieties).
Alkyl defined herein, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl are optional replacements (such as, " replacement " or " unsubstituted " alkyl, " replacement " or " unsubstituted " thiazolinyl, " replacement " or " unsubstituted " alkynyl, " replacement " or " unsubstituted " carbocylic radical, " replacement " or " unsubstituted " heterocyclic radical, " replacement " or " unsubstituted " aryl or " replacement " or " unsubstituted " heteroaryl).In general, no matter exist before or there is not term " optionally ", term " replacement " meaning all refers at group (such as, carbon or nitrogen-atoms etc.) at least one hydrogen replace with admissible substituting group, such as, be substituted the substituting group generating stable compound, the compound of such as, can not spontaneously change (as by rearrangement, cyclisation, elimination or other reactions).Except as otherwise noted, " replacement " group has can have substituting group in the position of substitution place the one or more of group, and when the more than one position in any specified structure is substituted, the substituting group at each position place is identical or different.
Exemplary carbon atom substituting group includes but not limited to halogen (that is, fluorine (-F), bromine (-Br), chlorine (-C1) and iodine (-I)) ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR aa,-ON (R bb) 2,-N (R bb) 2,-N (R bb) 3 +x -,-N (OR cc) R bb,-SH ,-SR aa,-SSR cc,-C (=O) R aa,-CO 2h ,-CHO ,-C (OR cc) 2,-CO 2r aa,-OC (=O) R aa,-OCO 2r aa,-C (=O) N (R bb) 2,-OC (=O) N (R bb) 2,-NR bbc (=O) R aa,-NR bbcO 2r aa,-NR bbc (=O) N (R bb) 2,-C (=NR bb) R aa,-C (=NR bb) OR aa,-OC (=NR bb) R aa,-OC (=NR bb) OR aa,-C (=NR bb) N (R bb) 2,-OC (=NR bb) N (R bb) 2, NR bbc (=NR bb) N (R bb) 2,-C (=O) NR bbsO 2r aa,-NR bbsO 2r aa,-SO 2n (R bb) 2,-SO 2r aa,-SO 2oR aa,-OSO 2r aa,-S (=O) R aa,-OS (=O) R aa,-Si (R aa) 3,-OSi (R aa) 3-C (=S) N (R bb) 2,-C (=O) SR aa,-C (=S) SR aa,-SC (S) SR aa,-P (=O) 2r aa,-OP (=O) 2r aa,-P (=O) (R aa) 2,-OP (=O) (R aa) 2,-OP (=O) (OR cc) 2,-P (=O) 2n (R bb) 2,-OP (=O) 2n (R bb) 2,-P (=O) (NR bb) 2,-OP (=O) (NR bb) 2,-NR bbp (=O) (OR cc) 2,-NR bbp (=O) (NR bb) 2,-P (R cc) 2,-P (R cc) 3,-OP (R cc) 2,-OP (R cc) 3,-B (OR cc) 2,-BR aa(OR cc), C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-14carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced;
Or on carbon atom two together with hydrogen by group=O ,=S ,=NN (R bb) 2,=NNR bbc (=O) R aa,=NNR bbc (=O) OR aa,=NNR bbs (=O) 2r aa,=NR bb,=NOR ccreplace;
Each R aaindependently selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced;
Each R bbindependently selected from hydrogen ,-OH ,-OR aa,-N (R cc) 2,-CN ,-C (=O) R aa,-C (=O) N (R cc) 2,-CO 2r aa,-SO 2r aa,-C (=NR cc) OR aa,-C (=NR cc) N (R cc) 2,-SO 2n (R cc) 2,-SO 2r cc,-SO 2oR cc,-SOR aa,-C (=S) N (R cc) 2,-C (=O) SR cc,-C (=S) SR cc,-P (=O) 2r aa,-P (=O) (R aa) 2,-P (=O) 2n (R cc) 2,-P (=O) (NR cc) 2, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms ccgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced;
Each R ccindependently selected from hydrogen, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms ccgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced;
Each R ddindependent selected from halo ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR ee,-ON (R ff) 2,-N (R ff) 2,-N (R ff) 3 +x -,-N (OR ee) R ff,-SH ,-SR ee,-SSR ee,-C (=O) R ee,-CO 2h ,-CO 2r ee,-OC (=O) R ee,-OCO 2r ee,-C (=O) N (R ff) 2,-OC (=O) N (R ff) 2,-NR ffc (=O) R ee,-NR ffcO 2r ee,-NR ffc (=O) N (R ff) 2,-C (=NR ff) OR ee,-OC (=NR ff) R ee,-OC (=NR ff) OR ee,-C (=NR ff) N (R ff) 2,-OC (=NR ff) N (R ff) 2,-NR ffc (=NR ff) N (R ff) 2,-NR ffsO 2r ee,-SO 2n (R ff) 2,-SO 2r ee,-SO 2oR ee,-OSO 2r ee,-S (=O) R ee,-Si (R ee) 3,-OSi (R ee) 3,-C (=S) N (R ff) 2,-C (=O) SR ee,-C (=S) SR ee,-SC (=S) SR ee,-P (=O) 2r ee,-P (=O) (R ee) 2,-OP (=O) (R ee) 2,-OP (=O) (OR ee) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-10 unit heterocyclic radical, C 6-10aryl, 5-10 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently gggroup replaced, or two together with R ddsubstituting group can form=O or=S jointly;
Each R eeindependently selected from C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-10aryl, 3-10 unit's heterocyclic radical and 3-10 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently gggroup replaced;
Each R ffindependently selected from hydrogen, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-10 unit heterocyclic radical, C 6-10aryl and 5-10 unit heteroaryl, or two R be connected with nitrogen-atoms ffgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently gggroup replaced; With
Each R gghalogen ,-CN ,-NO independently 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OC 1-6alkyl ,-ON (C 1-6alkyl) 2,-N (C 1-6alkyl) 2,-N (C 1-6alkyl) 3x ,-NH (C 1-6alkyl) 2x ,-NH 2(C 1-6alkyl) X ,-NH 3x ,-N (OC 1-6alkyl) (C 1-6alkyl) ,-N (OH) (C 1-6alkyl) ,-NH (OH) ,-SH ,-SC 1-6alkyl ,-SS (C 1-6alkyl) ,-C (=O) (C 1-6alkyl) ,-CO 2h ,-CO 2(C 1-6alkyl) ,-OC (=O) (C 1-6alkyl) ,-OCO 2(C 1-6alkyl) ,-C (=O) NH 2,-C (=O) N (C 1-6alkyl) 2,-OC (=O) NH (C 1-6alkyl) ,-NHC (=O) (C 1-6alkyl) ,-N (C 1-6alkyl) C (=O) (C 1-6alkyl) ,-NHCO 2(C 1-6alkyl) ,-NHC (=O) N (C 1-6alkyl) 2,-NHC (=O) NH (C 1-6alkyl) ,-NHC (=O) NH 2,-C (=NH) O (C 1-6alkyl) ,-OC (=NH) (C 1-6alkyl) ,-OC (=NH) OC 1-6alkyl ,-C (=NH) N (C 1-6alkyl) 2,-C (=NH) NH (C 1-6alkyl) ,-C (=NH) NH 2,-OC (=NH) N (C 1-6alkyl) 2,-OC (NH) NH (C 1-6alkyl) ,-OC (NH) NH 2,-NHC (NH) N (C 1-6alkyl) 2,-NHC (=NH) NH 2,-NHSO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-SO 2nH 2,-SO 2c 1-6alkyl ,-SO 2oC 1-6alkyl ,-OSO 2c 1-6alkyl ,-SOC 1-6alkyl ,-Si (C 1-6alkyl) 3,-OSi (C 1-6alkyl) 3, C (=S) N (C 1-6alkyl) 2, C (=S) NH (C 1-6alkyl), C (=S) NH 2,-C (=O) S (C 1-6alkyl) ,-C (=S) SC 1-6alkyl ,-SC (=S) SC 1-6alkyl ,-P (=O) 2(C 1-6alkyl) ,-P (=O) (C 1-6alkyl) 2,-OP (=O) (C 1-6alkyl) 2,-OP (=O) (OC 1-6alkyl) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-10aryl, 3-10 unit heterocyclic radical, 5-10 unit heteroaryl; Or two together with R ggsubstituting group can form=O or=S jointly;
Wherein X -counter ion.
Used herein, " counter ion " are connected with positively charged quaternary amine to keep electroneutral electronegative group.Exemplary counter ion comprise halogen ion (such as, F -, Cl-, Br -, I -), NO 3 -, ClO 4 -, OH -, H 2pO 4 -, HSO 4 -, sulfonate ion (such as, methanesulfonic root, trifluoromethayl sulfonic acid root, tosic acid root, Phenylsulfonic acid root, 10-camphorsulfonic acid root, naphthalene-2-sulfonic acid root, naphthalene-1-sulfonic acid-5-sulfonate radical, ethane-1-sulfonic acid-2-sulfonate radical etc.) and carboxylic acid ion (such as, acetate, acetate moiety, propionate, benzoate anion, glycerine acid group, lactate, tartrate anion, ethanol acid group etc.).
If valence state allows, nitrogen-atoms can be substituted or not be substituted, and comprises primary, secondary, uncle and quaternary nitrogen atoms.Exemplary nitrogen-atoms substituting group includes but not limited to hydrogen ,-OH ,-OR aa,-N (R cc) 2,-CN ,-C (=O) R aa,-C (=O) N (R cc) 2,-CO 2r aa,-SO 2r aa,-C (=NR bb) R aa,-C (=NR cc) OR aa,-C (=NR cc) N (R cc) 2,-SO 2n (R cc) 2,-SO 2r cc,-SO 2oR cc,-SOR aa,-C (=S) N (R cc) 2,-C (=O) SR cc,-C (=S) SR cc,-P (=O) 2r aa,-P (=O) (R aa) 2,-P (=O) 2n (R cc) 2,-P (=O) (NR cc) 2, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms ccgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced, and wherein R aa, R bb, R ccand R ddas defined above.
In certain embodiments, substituting group nitrogen-atoms existed is amino protecting group.Amino protecting group includes but not limited to-OH ,-OR aa,-N (R cc) 2,-C (=O) R aa,-C (=O) N (R cc) 2,-CO 2r aa,-SO 2r^ ,-C (=NR cc) R aa,-C (=NR cc) OR aa,-C (=NR cc) N (R cc) 2,-SO 2n (R cc) 2,-SO 2r cc,-SO 2oR cc,-SOR aa,-C (=S) N (R cc) 2,-C (=O) SR cc,-C (=S) SR cc, C 1-10alkyl (such as, aralkyl), C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aralkyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently ddgroup replaced, and wherein R aa, R bb, R ccand R ddas defined above.Amino protecting group is well-known in the art, and is included in ProtectingGroupsinOrganicSynthesis, T.W.Greene and P.G.M.Wuts; 3rd edition; JohnWiley & Sons, record in detail in 1999 those, be incorporated to the document as a reference at this.
Such as, amino protecting group is as amide group (such as ,-C (=O) R aa) include but not limited to methane amide, ethanamide, chlor(o)acetamide, trichloroacetamide, trifluoroacetamide, phenyl-acetamides, 3-Phenylpropionamide, picoline acid amides, 3-pyridinyl carboxamide, N-benzoyl phenylalanyl derivative, benzamide, to phenylbenzamaide, ortho-nitrophenyl yl acetamide, ortho-nitrophenyl oxygen yl acetamide, aceto-acetamide, (N '-dithiobenzyloxycarbonylamino) ethanamide, 3-(o-hydroxy-phenyl) propionic acid amide, 3-(O-Nitrophenylfluorone) propionic acid amide, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionic acid amide, 2-methyl-2-(adjacent phenylazo phenoxy group) propionic acid amide, 4-chlorobutamide, 3-methyl-3-nitro butyramide, adjacent nitrocinnamyl acid amides, N-ethanoyl methionine(Met) derivative, ortho-nitrophenyl methane amide and adjacent (benzoyl oxygen ylmethyl) benzamide.
Amino protecting group is as carbamate groups (such as ,-C (=O) OR aa) include but not limited to Urethylane, urethanum, carboxylamine 9-fluorenyl methyl ester (Fmoc), carboxylamine 9-(2-sulfonic group) fluorenyl methyl ester, carboxylamine 9-(2,7-dibromo) fluorenyl methyl ester, carboxylamine 2,7-bis--tertiary butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrochysene thioxanthene base)] methyl esters (DBD-Tmoc), carboxylamine 4-anisoyl methyl esters (Phenoc), carboxylamine 2,2,2-trichloro ethyl ester (Troc), carboxylamine 2-trimethylsilylethyl (Teoc), carboxylamine 2-phenyl chlorocarbonate (hZ), carboxylamine 1-(1-adamantyl)-1-Methylethyl (Adpoc), carboxylamine 1,1-dimethyl-2-halogen ethyl ester, carboxylamine 1,1-dimethyl-2,2-dibromo ethyl ester (DB-t-BOC), carboxylamine 1,1-dimethyl-2,2,2-trichloro ethyl ester (TCBOC), carboxylamine 1-methyl isophthalic acid-(4-xenyl) ethyl ester (Bpoc), carboxylamine 1-(3,5-, bis--tert-butyl-phenyl)-1-Methylethyl (t-Bumeoc), carboxylamine 2-(2 '-and 4 '-pyridyl) ethyl ester (Pyoc), carboxylamine 2-(N, N-dicyclohexyl formamido group) ethyl ester, t-butyl carbamate (BOC), carboxylamine 1-diamantane ester (Adoc), carboxylamine ethene ester (Voc), allyl carbamate (Alloc), carboxylamine 1-sec.-propyl allyl ester (Ipaoc), carboxylamine cinnamic ester (Coc), carboxylamine 4-nitrocinnamyl ester (Noc), carboxylamine 8-quinoline ester, carboxylamine N-hydroxy piperidine ester, dithiocarbamic acid alkyl ester, benzyl carbamate (Cbz), carboxylamine is to methoxy benzyl ester (Moz), carboxylamine is to p-Nitrobenzyl, carboxylamine is to bromobenzyl ester, carboxylamine is to benzyl chloride ester, carboxylamine 2,4-benzyl dichloride ester, carboxylamine 4-methylsulfinyl benzyl ester (Msz), carboxylamine 9-anthrylmethyl, carboxylamine phenylbenzene methyl esters, carboxylamine 2-methylthio group ethyl ester, carboxylamine 2-methyl sulphonyl ethyl ester, carboxylamine 2-(p-toluenesulfonyl) ethyl ester, carboxylamine [2-(1,3-dithiane base)] methyl esters (Dmoc), carboxylamine 4-thiotolene ester (Mtpc), carboxylamine 2,4-thioxene ester (Bmpc), carboxylamine 2-phosphonate group ethyl ester (Peoc), carboxylamine 2-triphenylphosphine acidic group isopropyl ester (Ppoc), carboxylamine 1,1-dimethyl-2-cyanaoethyl methacrylate, chloro-to acyloxy benzyl ester between carboxylamine, carboxylamine is to (dihydroxyl boryl) benzyl ester, carboxylamine 5-benzoisoxazole base methyl esters, carboxylamine 2-(trifluoromethyl)-6-look onylmethyl (Tcroc), carboxylamine m-nitro ester, carboxylamine 3,5-dimethoxy benzyl ester, the adjacent p-Nitrobenzyl of carboxylamine, carboxylamine 3,4-dimethoxy-6-p-Nitrobenzyl, carboxylamine phenyl (O-Nitrophenylfluorone) methyl esters, tert.-amyl carbamate, thiocarbamate S-benzyl ester, carboxylamine is to cyano group benzyl ester, carboxylamine ring butyl ester, carbamic acid cyclohexyl ester, carboxylamine ring pentyl ester, carboxylamine cyclopropylmethyl ester, carboxylamine is to oxygen base benzyl ester in the last of the ten Heavenly stems, carboxylamine 2,2-benzhydryloxycarbonyl vinyl acetate, carboxylamine neighbour (N, N-dimethylformamide base) benzyl ester, carboxylamine 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl ester, carboxylamine 1,1-dimethyl propynyl ester, carboxylamine two (2-pyridyl) methyl esters, carboxylamine 2-furyl methyl esters, carboxylamine 2-iodo-ethyl ester, carboxylamine isobornyl thiocyanoacetate, isobutyl carbamate, carboxylamine isonicotine ester, carboxylamine is to (p '-p-methoxy-phenyl azo) benzyl ester, carboxylamine 1-methyl ring butyl ester, carboxylamine 1-methyl cyclohexyl, carboxylamine 1-methyl isophthalic acid-cyclopropylmethyl ester, carboxylamine 1-methyl isophthalic acid-(3,5-Dimethoxyphenyl) ethyl ester, carboxylamine 1-methyl isophthalic acid-(to phenylazo phenyl) ethyl ester, carboxylamine 1-methyl isophthalic acid-phenethyl ester, carboxylamine 1-methyl isophthalic acid-(4-pyridyl) ethyl ester, phenyl carbamate, carboxylamine is to (phenylazo) benzyl ester, carboxylamine 2,4,6-tri--tertiary butyl phenyl ester, carboxylamine 4-(trimethyl ammonium) benzyl ester and carboxylamine 2,4,6-trimethylammonium benzyl ester.
Amino protecting group is as sulfuryl amine group (such as ,-S (=O) 2r aa) include but not limited to para toluene sulfonamide (Ts), benzsulfamide, 2, 3, 6,-trimethylammonium-4-methoxybenzenesulphoismide (Mtr), 2, 4, 6-triimethoxvbenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulphoismide (Pme), 2, 3, 5, 6-tetramethyl--4-methoxybenzenesulphoismide (Mte), 4-methoxybenzenesulphoismide (Mbs), 2, 4, 6-trimethylbenzene sulfonamide (Mts), 2, 6-dimethoxy-4 '-methyl benzenesulfonamide (iMds), 2, 2, 5, 7, 8-pentamethyl-chroman-6-sulphonamide (Pmc), amsacrine (Ms), β-trimethyl silyl ethane sulphonamide (SES), 9-anthracene sulphonamide, 4-(4 ', 8 '-dimethoxy naphthyl methyl) benzsulfamide (DNMBS), benzyl sulphonamide, trimethyl fluoride sulfonyl amine and phenylacetyl sulphonamide.
Other amino protecting groups include but not limited to phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonyl aminocarbonyl derivatives, N '-phenylaminothiocarbonyl derivative, N-benzoyl phenylalanyl derivative, N-ethanoyl methionine(Met) derivative, 4,5-phenylbenzene-3-oxazoline-2-ketone, N phlhalimide, N-dithia succinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethyl pyrrole, N-1, Isosorbide-5-Nitrae, 4-tetramethyl xylene silylation aza-cyclopentane adducts (STABASE), 1,3-dimethyl-1,3, the 5-tri-azepine hexamethylene-2-ketone that 5-replaces, 1,3-dibenzyl-1,3, the 5-tri-azepine hexamethylene-2-ketone that 5-replaces, 3, the 5-dinitrobenzene-4-pyridones that 1-replaces, N-methylamine, N-allyl amine, N-[2-(trimethyl silyl) oxyethyl group] methylamine (SEM), N-3-acetoxyl group propylamine, N-(1-sec.-propyl-4-nitro-2-oxo-3-pyrroline-3-base) amine, quaternary ammonium salt, N-benzylamine, N-bis-(4-p-methoxy-phenyl) methylamine, N-5-dibenzo cycloheptylamine, N-triphenyl methylamine (Tr), N-[(4-p-methoxy-phenyl) diphenyl methyl] amine (MMTr), N-9-phenylfluorenyl amine (PhF), N-2,7-bis-chloro-9-fluorenyl methylene amine, N-ferrocenyl methylamino (Fcm), N-2-picolyl amino N '-oxide compound, N-1,1-dimethyl sulphur-based methylene amine, N-benzal amine, N-is to methoxyl group benzal amine, N-phenylbenzene methylene amine, N-[(2-pyridyl) trimethylphenyl] methylene amine, N-(N ', N '-dimethylamino methylene) amine, N, N '-isopropylidene diamines, N-is to the sub-Phenoxybenzamine of nitro, N-salicylidene amine, N-5-chlorine salicylidene amine, N-(5-chlorine-2-hydroxyl phenyl) phenyl methylidene amine, N-cyclohexylidene amine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivative, N-diphenyl-borinic acids derivative, N-[phenyl (pentacarbonyl chromium or tungsten) carbonyl] amine, N-copper chelate, N-chelates of zinc, N-nitra-amine, N-nitrosamine, amine n-oxide, diphenylphosphine acid amides (Dpp), dimethyl thio phosphonic amide (Mpt), phenylbenzene sulfo-phosphonic amide (Ppt), phosphoramidic acid dialkyl, phosphoramidic acid dibenzyl ester, phosphoramidic acid diphenyl ester, phenylsulfinyl amine, ortho-nitrophenyl sulfinyl amine (Nps), 2,4-dinitrobenzene sulfinyl amine, pentachlorobenzene sulfinyl amine, 2-nitro-4-anisole sulfinyl amine, trityl group sulfinyl amine, 3-nitropyridine sulfinyl amine (Npys).
Used herein, " leavings group " is the intelligible term in this area, refers to the molecule fragment that pair of electrons leaves in heterolytic fission process, and wherein said molecule fragment is negatively charged ion or neutral molecule.See, such as, Smith, MarchAdvancedOrganicChemistry the 6th edition (501-502).
These and other illustrative substituents are documented in embodiment, experimental example and claims in more detail.The present invention is not intended to the illustrative substituents list be limited to by any way above.
Used herein, " its pharmaceutically acceptable form " comprise as hereafter with the pharmacy acceptable salt of the compounds of this invention as defined herein, hydrate, solvate, prodrug, tautomer, isomer and/or polymorphic form.
Used herein, term " pharmacy acceptable salt " refers in the scope that judges in rational medicine, is suitable for using with compared with lower animal contact tissue with the mankind and invariably when toxicity, stimulation, anaphylaxis etc. and with rational benefit/risk than the salt conformed to.Pharmacy acceptable salt is well-known in the art.Such as, the people such as S.M.Berge, at J.PharmaceuticalSciences, describe pharmacy acceptable salt in detail in 1977,66,1-19.The pharmacy acceptable salt of the compounds of this invention comprises the salt derived from suitable inorganic and organic bronsted lowry acids and bases bronsted lowry.The example of pharmaceutically acceptable non-toxic acid addition salts be amino with all example hydrochloric acids, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid etc. mineral acid or the salt that formed with the organic acid such as such as acetic acid, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid, or the salt by using the additive methods used in the art such as such as ion exchange method to be formed.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodide, 2-hydroxy-ethanesulfonate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, methane sulfonates, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, embonate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, tosilate, undecane hydrochlorate, valerate etc.Salt derived from suitable alkali comprises an alkali metal salt, alkaline earth salt, ammonium salt and N +(C 1-4alkyl) 4salt.Representative basic metal or alkaline earth salt comprise sodium salt, lithium salts, sylvite, calcium salt, magnesium salts etc.Time suitable, other pharmacy acceptable salts comprise nontoxic ammonium, quaternary ammonium and the amine positively charged ion that counter ion such as using such as halogen ion, hydroxide radical, carboxylate radical, sulfate radical, phosphate radical, nitrate radical, loweralkyl sulfonate and aryl sulfonic acid root are formed.
In certain embodiments, its pharmaceutically acceptable form is isomer.Used herein, term " isomer " comprises any and all geometrical isomers and steric isomer.Such as, " isomer " comprises cis-and trans-isomer, E-and Z-isomer, R-and S-enantiomer, diastereomer, (D)-isomer, (L)-isomer, its racemic mixture and other mixtures, these all within the scope of the present invention.
In certain embodiments, its pharmaceutically acceptable form is tautomer.Used herein, term " tautomer " comprises two or more compound that can mutually transform, it is changed (such as by least one form migration of hydrogen atom and at least one valence state, singly-bound becomes double bond, triple bond becomes singly-bound, or double bond becomes singly-bound, singly-bound becomes triple bond) produce.The definite ratio of tautomer is depending on comprising the some questions of temperature, solvent and pH value.Tautomerization (that is, the reaction providing tautomerism right) can by acid or base catalysis.Exemplary tautomerization comprises ketone to enol, acid amides to imide, lactan to lactim, enamine to imines and enamine to the tautomerization of (difference) enamine.
In certain embodiments, its pharmaceutically acceptable form is hydrate or solvate.Used herein, term " hydrate " refers to the compound with one or more water molecules non-covalent linking.Equally, " solvate " refers to the compound with one or more organic solvent non-covalent linking.
In certain embodiments, its pharmaceutically acceptable form is prodrug.Used herein, term " prodrug " refers to be needed to transform in vivo to discharge the derivative of the parent compound of parent compound.In some cases, prodrug has physics and/or the delivery characteristics of the improvement being better than parent compound.Prodrug is usually designed to and can strengthens relevant to the parent compound characteristic based on pharmacology and/or pharmacokinetics.The benefit of prodrug may be its physical property, as used for parenteral, compares the water-soluble of parent compound enhancing under at physiological ph; Or it can strengthen gastral absorption; Or it can strengthen the stability of medicine prolonged storage.
In certain embodiments, its pharmaceutically acceptable form is polymorphic form.Used herein, " polymorphic form " refers to the compound had more than a kind of crystalline texture, and such as, it is produced by the packing of molecules of solid compounds and/or the difference of molecular conformation.
Recognition sequence number
SEQ.ID.NO.: homo sapiens FAAH aminoacid sequence:
MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQR
QRAGLENMDRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVL
FTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFT
YKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYD
CSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSSF
CGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALL
CEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLE
TKQSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPC
LGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEI
EVYRKTVIAQWRALDLDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCL
DFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVA
VQCVALPWQEELCLRPMREVERLMTPEKQSS
Describe in detail
I. compound
The invention provides the compound of isoxazoline FAAH inhibitor formula (I):
Or its pharmaceutically acceptable form,
Wherein:
(i) each R a, R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl, R dbe group-L-Z, and Z is selected from C 6-14aryl;
(ii) each R a, R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl, R dbe group-L-Z, and Z is selected from 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl;
(iii) R aand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical condensed ring, and R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl; Or
(iv) R cand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical spiral shell condensed ring, and R aand R bindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl;
L is covalent linkage or divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more oxygen, sulphur or nitrogen-atoms independently;
G is selected from-CN ,-NO 2,-S (=O) R e,-SO 2r e,-SO 2nR fr e,-PO 2r e,-PO 2oR e,-PO 2nR fr e,-(C=O) R e,-(C=O) OR e,-(C=O) NR fr e,-Br ,-I ,-F ,-Cl ,-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-SR e,-OSO 2r e,-NR fsO 2r e,-OPO 2r e,-OPO 2oR e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fp e,-O (C=O) R e,-O (C=O) OR e,-NR fp e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fp e,-NR f(C=NR f) NR fp e,-O (C=NR f) NR fp e,-NR f(C=NR f) OR e,-[N (R f) 2r e] +x -, wherein X -counter ion; With
Each R ebe selected from C 1-10alkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl; The each R be connected with nitrogen-atoms findependently selected from-H, C 1-10alkyl or amino protecting group; Or R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring.
group G
As defined above, G is selected from-CN ,-NO 2,-S (=O) R e,-SO 2r e,-SO 2nR fr e,-PO 2r e,-PO 2oR e,-PO 2nR fr e,-(C=O) R e,-(C=O) OR e,-(C=O) NR fr e,-Br ,-I ,-F ,-Cl ,-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-SR e,-OSO 2r e,-NR fsO 2r e,-OPO 2r e,-OPO 2oR e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fr e,-O (C=O) R e,-O (C=O) OR e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr e,-NR f(C=NR f) OR e,-[N (R f) 2r e] +x -, wherein X -counter ion; With
Wherein R ebe selected from C 1-10alkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl; The each R be connected with nitrogen-atoms findependently selected from-H, C 1-10alkyl or amino protecting group; Or R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring.
In certain embodiments, G is not leavings group, and such as, G is selected from-F ,-CN ,-NO 2,-S (=O) R e,-SO 2r e,-SO 2nR fr e,-PO 2r e,-PO 2oR e,-PO 2nR fr e,-(C=O) R e,-(C=O) OR ewith-(C=O) NR fr e.
In certain embodiments, G is selected from-CN and-NO 2.In certain embodiments, G is-CN.In certain embodiments, G is-NO 2.
In certain embodiments, G is selected from-S (=O) R e,-SO 2r ewith-SO 2nR fr e.In certain embodiments, G is-S (=O) R e.In certain embodiments, G is-SO 2r e.In certain embodiments, G is-SO 2nR fr e.
In certain embodiments, G is selected from-PO 2r e,-PO 2oR ewith-PO 2nR fr e.In certain embodiments, G is-PO 2r e.In certain embodiments, G is-PO 2oR e.In certain embodiments, G is-PO 2nR fr e.
In certain embodiments, G is selected from-(C=O) R e,-(C=O) OR ewith-(C=O) NR fr e.In certain embodiments, G is-(C=O) R e.In certain embodiments, G is-(C=O) OR e.In certain embodiments, G is-(C=O) NR fr e.
Such as, but in certain embodiments, G is leavings group, and, G is selected from-Cl ,-Br ,-I ,-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-SR e,-OSO 2r e,-NR fsO 2r e,-OPO 2r e,-OPO 2oR e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fr e,-O (C=O) R e,-O (C=O) OR e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr e,-NR f(C=NR f) OR ewith-[N (R f) 2r e] +x -, wherein X -counter ion.
In certain embodiments, G is halogen; That is ,-F ,-Cl ,-Br and-I is selected from.In certain embodiments, G is-F.In certain embodiments, G is-Br.In certain embodiments, G is-I.In certain embodiments, G is-Cl.But in certain embodiments, G is not halogen.Such as, in certain embodiments, G is not-Br.In certain embodiments, G is not-I.In certain embodiments, G is not-F.In certain embodiments, G is not-Cl.
In certain embodiments, G is selected from-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-OSO 2r e,-OPO 2r e,-OPO 2oR e,-OPO 2nR fr e,-O (C=O) R e,-O (C=O) OR e,-O (C=O) NR fr ewith-O (C=NR f) NR fr e.In certain embodiments, G is selected from-OR e,-O (C=O) R e,-O (C=O) OR e,-O (C=O) NR fr ewith-O (C=NR f) NR fr e.In certain embodiments, G is selected from-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-OPO 2nR fr e,-O (C=O) NR fr ewith-O (C=NR f) NR fr e.In certain embodiments, G is-OR e.In certain embodiments, G is-ONR fr e.In certain embodiments, G is-ONR f(C=O) R e.In certain embodiments, G is-ONR fsO 2r e.In certain embodiments, G is-ONR fpO 2r e.In certain embodiments, G is-ONR fpO 2oR e.In certain embodiments, G is-OSO 2r e.In certain embodiments, G is-OPO 2r e.In certain embodiments, G is-OPO 2oR e.In certain embodiments, G is-OPO 2nR fr e.In certain embodiments, G is-O (C=O) R e.In certain embodiments, G is-O (C=O) OR e.In certain embodiments, G is-O (C=O) NR fr e.In certain embodiments, G is-O (C=NR f) NR fr e.
In certain embodiments, G is selected from-OR ewith-SR e.In certain embodiments, G is selected from-OR e.In certain embodiments, G is-SR e.
In certain embodiments, G is selected from-NR fsO 2r e,-NR fpO 2r e,-NR fpO 2oR e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-NR f(C=NR f) NR fr e,-NR f(C=NR f) OR ewith-[N (R f) 2r e] +x -, wherein X -counter ion.In certain embodiments, G is selected from-NR fsO 2r e,-NR fpO 2r e,-NR fpO 2oR e,-NR fr e,-NR f(C=O) R ewith-NR f(C=O) OR e.In certain embodiments, G is selected from-NR fsO 2r e,-NR fr e,-NR f(C=O) R ewith-NR f(C=O) OR e.In certain embodiments, G is-NR fsO 2r e.In certain embodiments, G is-NR fpO 2r e.In certain embodiments, G is-NR fpO 2oR e.In certain embodiments, G is-NR fr e.In certain embodiments, G is-NR f(C=O) R e.In certain embodiments, G is-NR f(C=O) OR e.In certain embodiments, G is-NR f(C=NR f) NR fr e.In certain embodiments, G is-NR f(C=NR f) OR e.In certain embodiments, G is-[N (R f) 2r e] +x -, wherein X -counter ion.
Below with the Additional embodiments providing G herein, be included in radicals R eand R fexplanation in and illustrate in form and embodiment.
the R of group G e
As general definition above, in certain embodiments, wherein G is selected from-S (=O) R e,-SO 2r e,-SO 2nR fr e,-PO 2r e,-PO 2oR e,-PO 2nR fr e,-(C=O) R e,-(C=O) OR e,-(C=O) NR fr e,-OR e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-SR e,-OSO 2r e,-NR fsO 2r e,-OPO 2r e,-OPO 2oR e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fr e,-O (C=O) R e,-O (C=O) OR e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr e,-NR f(C=NR f) OR ewith-[N (R f) 2r e] +x -, wherein X -counter ion, R ebe selected from C 1-10alkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl.
In certain embodiments, R ebe selected from C 1-10alkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl, wherein alkyl, thiazolinyl, alkynyl, carbocylic radical, aryl, heterocyclic radical and heteroaryl 0,1,2,3,4 or 5 R hgroup replaced, as defined below and herein.
In certain embodiments, R ec 1-10alkyl.In certain embodiments, R ec 1-6alkyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 1-6alkyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 1-5alkyl.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe C that group replaces 1-4alkyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe C that group replaces 1-3alkyl.In certain embodiments, R ewith 0,1 or 2 R hthe C that group replaces 1-2alkyl.Exemplary alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl and hexyl, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
In certain embodiments, R ec 1-6whole haloalkyl.In certain embodiments, R ec 1-5whole haloalkyl.In certain embodiments, R ec 1-4whole haloalkyl.In certain embodiments, R ec 1-3whole haloalkyl.In certain embodiments, R ec 1-2whole haloalkyl.Exemplary R ewhole haloalkyl includes but not limited to-CF 3,-CF 2cF 3,-CF 2cF 2cF 3,-CCl 3,-CFCl 2with-CF 2cl.
In certain embodiments, R ec 2-10thiazolinyl.In certain embodiments, R ec 2-6thiazolinyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 2-6thiazolinyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 2-5thiazolinyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe C that group replaces 2-3thiazolinyl.Exemplary alkenyl groups includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, butadienyl, pentenyl, pentadienyl and hexenyl, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
In certain embodiments, R ec 2-10alkynyl.In certain embodiments, R ec 2-6alkynyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 2-6alkynyl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 2-5alkynyl.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe C that group replaces 2-4alkynyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe C that group replaces 2-3alkynyl.Exemplary R ealkynyl includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, pentynyl and hexin base, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
But, in certain embodiments, when G is-OR etime, R enot C 1-6alkyl (such as, methyl, ethyl, propyl group, sec.-propyl, aralkyl).In certain embodiments, when G is-ORe, R enot C 2-6thiazolinyl (such as, allyl group).
In certain embodiments, when G is-S, R enot C 1-6alkyl (such as, methyl, ethyl, propyl group, sec.-propyl, aralkyl).
In certain embodiments, when G is-NR er fand R f-H or C 1-3time alkyl (such as, methyl, ethyl, aralkyl), R enot C 1-6alkyl.
In certain embodiments, R ec 6-14aryl.In certain embodiments, R ec 6-10aryl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 6-10aryl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 6aryl (such as, phenyl).In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 10aryl (such as, naphthyl).
In certain embodiments, R eit is phenyl.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe phenyl that group replaces.In certain embodiments, R ewith 0,1,2 or 3 R hthe phenyl that group replaces.In certain embodiments, R ewith 0,1 or 2 R hthe phenyl that group replaces.In certain embodiments, R ewith 0 or 1 R hthe phenyl that group replaces.In certain embodiments, R ethat dibasic phenyl is (that is, with 2 R hgroup replaces).In certain embodiments, R ethat mono-substituted phenyl is (that is, with 1 R hgroup replaces).In certain embodiments, R ethat unsubstituted phenyl is (that is, with 0 R hgroup replaces).
In certain embodiments, R ewith at least one adjacent R hthe phenyl that group replaces.In certain embodiments, R ewith at least one R hthe phenyl that group replaces.In certain embodiments, R eto R with at least one hthe phenyl that group replaces.
In certain embodiments, R ethe phenyl of following formula:
Wherein x is 0,1,2,3,4 or 5, and R has defined below and herein.In certain embodiments, x is 0,1,2,3 or 4.In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.In certain embodiments, x is 3.In certain embodiments, R edibasic phenyl (that is, wherein x is 2).In certain embodiments, R emono-substituted phenyl (that is, wherein x is 1).In certain embodiments, R eunsubstituted phenyl (that is, wherein x is 0).
Such as, in certain embodiments, R eany one substituted or unsubstituted phenyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is naphthyl.In certain embodiments, R eany one naphthyl in following formula:
Wherein x is 0,1,2,3,4 or 5, and R has defined below and herein.In certain embodiments, x is 0,1,2,3 or 4.In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.In certain embodiments, R etrisubstituted naphthyl (that is, wherein x is 3).In certain embodiments, R edibasic naphthyl (that is, wherein x is 2).In certain embodiments, R emono-substituted naphthyl (that is, wherein x is 1).In certain embodiments, R eunsubstituted naphthyl (that is, wherein x is 0).
Such as, in certain embodiments, R eany one substituted or unsubstituted 1-naphthyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 2-naphthyl in following formula:
Wherein R has defined below and herein.
But, in certain embodiments, when G is-OR etime, R enot C 10aryl (such as, 1-naphthyl, 2-naphthyl).
In certain embodiments, R eit is 5-14 unit heteroaryl.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 5-10 unit heteroaryl that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 5-8 unit heteroaryl that group replaces.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe 5-6 unit heteroaryl that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 9-10 unit heteroaryl that group replaces.
Exemplary R eheteroaryl includes but not limited to pyrryl, furyl and thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group, tetrazyl, pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (such as, 3-pyridazinyl, 4-pyridazinyl), pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl), pyrazinyl, triazinyl, tetrazine base, azepinyl, oxepinyl, thiepinyl, indyl, pseudoindoyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuryl, benzisoxa furyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, Ben Bing oxadiazolyl, benzothiazolyl, benzisothiazole base, diazosulfide base, indolizinyl, purine radicals, naphthyridinyl, pteridyl, quinolyl, isoquinolyl, cinnolines base, quinoxalinyl, phthalazinyl, quinazolyl, phenanthridinyl, dibenzofuran group, carbazyl, acridyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein these groups are with 0, 1, 2, 3, 4 or 5 R hgroup replaces.
In certain embodiments, R eit is 5-unit heteroaryl.In certain embodiments, R ewith 0,1,2 or 3 R hthe 5-unit heteroaryl that group replaces.In certain embodiments, R ethe 5-unit heteroaryl, wherein these groups 0,1,2 or 3 R that are selected from pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group and tetrazyl hgroup replaces.
Such as, in certain embodiments, R ethe 5-unit heteroaryl of following formula:
Wherein Y a, Y b, Y cand Y dindependently selected from CH, CR h, O, S, N or NR k, condition is Y a, Y b, Y cand Y din at least one be O, S, N or NR k, and wherein R hand R kbelow and define herein.
In some embodiment of above formula (i-d), Y ao, S, N or NR k, and Y b, Y cand Y dindependently selected from CH, CR h, NR kor N.In some embodiment of above formula (i-d), Y ao, S, N or NR k, and Y b, Y cand Y dindependently selected from CH or CR h.In some embodiment of above formula (i-d), Y ao, S or NR k, Y cn, and Y band Y dindependently selected from CH or CR h.
In some embodiment of above formula (i-d), Y bo, S or NR k, and Y a, Y cand Y dindependently selected from CH, CR hor N.In some embodiment of above formula (i-d), Y bo, S or NR k, and Y a, Y cand Y dindependently selected from CH or CR h.In some embodiment of above formula (i-d), Y bo, S or NR k, Y dn, and Y aand Y cindependently selected from CH or CR h.
In certain embodiments, R ethe first heteroaryl of the substituted or unsubstituted 5-of any one in following formula:
Wherein x is 0,1 or 2, and wherein R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5-unit's heteroaryl (that is, wherein x is 0).In certain embodiments, R e5-unit's heteroaryl (such as, wherein x is 1 or 2) replaced.In certain embodiments, R emono-substituted 5-unit's heteroaryl (that is, wherein x is 1).In certain embodiments, R edibasic 5-unit's heteroaryl (that is, wherein x is 2).In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
But, in certain embodiments, when G is-OR e+time, R ethe thiazolyl of such as following formula:
Wherein x is 0,1 or 2, and wherein R hand R kbelow and define herein.
In certain embodiments, R eit is 6-unit heteroaryl.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe 6-unit heteroaryl that group replaces.In certain embodiments, R ebe selected from pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (such as, 3-pyridazinyl, 4-pyridazinyl), pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl), 6-unit heteroaryl, wherein these groups 0,1,2,3 or 4 R of pyrazinyl, triazinyl and tetrazine base hgroup replaces.
Such as, in certain embodiments, R ethe 6-unit heteroaryl of following formula:
Wherein W a, W b, W c, W dand W eindependently selected from CH, CR hor N, condition is W a, W b, W c, W dand W ein at least one be N, and wherein R has defined below and herein.
In certain embodiments, R eit is pyridyl.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe pyridyl that group replaces.Such as, in certain embodiments, R ethe pyridyl of following formula:
Wherein x is 0,1,2,3 or 4, and R has defined below and herein.In certain embodiments, R eunsubstituted pyridyl (that is, wherein x is 0).In certain embodiments, R eit is the pyridyl (such as, wherein x is 1,2,3 or 4) replaced.In certain embodiments, R emono-substituted pyridyl (that is, wherein x is 1).In certain embodiments, R edisubstituted pyridine base (that is, wherein x is 2).In certain embodiments, R etrisubstituted pyridyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe 2-pyridyl of such as formula (i-e), wherein W abe N and W b, W c, W dand W ecH or CR independently h.In certain embodiments, R ethe 3-pyridyl of such as formula (i-e), wherein W bn, and W a, W c, W dand W ecH or CR independently h.In certain embodiments, R ethe 4-pyridyl of such as formula (i-e), wherein W cn, and W a, W b, W dand W ecH or CR independently h.
In certain embodiments, R eany one substituted or unsubstituted 2-pyridyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 3-pyridyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 4-pyridyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is pyridazinyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe pyridazinyl that group replaces.Such as, in certain embodiments, R ethe pyridazinyl of following formula:
Wherein x is 0,1,2 or 3, and R has defined below and herein.In certain embodiments, R eunsubstituted pyridazinyl (that is, wherein x is 0).In certain embodiments, R eit is the pyridazinyl (such as, wherein x is 1,2 or 3) replaced.In certain embodiments, R emono-substituted pyridazinyl (that is, wherein x is 1).In certain embodiments, R edibasic pyridazinyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted pyridazinyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe 3-pyridazinyl of such as formula (i-e), wherein W aand W bn, and W c, W dand W ecH or CR independently h.In certain embodiments, R ethe 4-pyridazinyl of such as formula (i-e), wherein W band W cn, and W a, W dand W ecH or CR independently h.
In certain embodiments, R eany one substituted or unsubstituted 3-pyridazinyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 4-pyridazinyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is pyrimidyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe pyrimidyl that group replaces.Such as, in certain embodiments, R ethe pyrimidyl of following formula:
Wherein x is 0,1,2 or 3, and R has defined below and herein.In certain embodiments, R eunsubstituted pyrimidyl (that is, wherein x is 0).In certain embodiments, R eit is the pyrimidyl (such as, wherein x is 1,2 or 3) replaced.In certain embodiments, R emono-substituted pyrimidyl (that is, wherein x is 1).In certain embodiments, R edibasic pyridazinyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted pyrimidine base (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe 2-pyrimidyl of such as formula (i-e), wherein W aand W en, and W b, W cand W dcH or CR independently h.In certain embodiments, R ethe 4-pyrimidyl of such as formula (i-e), wherein W aand W cn, and W b, W dand W ecH or CR independently h.In certain embodiments, R ethe 5-pyrimidyl of such as formula (i-e), wherein W band W dn, and W a, W cand W ecH or CR independently h.
In certain embodiments, R eany one substituted or unsubstituted 2-pyrimidyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 4-pyrimidyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eany one substituted or unsubstituted 5-pyrimidyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is pyrazinyl.In certain embodiments, R ewith 0,1,2 or 3 R hthe pyrazinyl that group replaces.Such as, in certain embodiments, R ethe pyrazinyl of following formula:
Wherein x is 0,1,2 or 3, and R has defined below and herein.In certain embodiments, R eunsubstituted pyrazinyl (that is, wherein x is 0).In certain embodiments, R eit is the pyrazinyl (such as, wherein x is 1,2 or 3) replaced.In certain embodiments, R emono-substituted pyrazinyl (that is, wherein x is 1).In certain embodiments, R edibasic pyrazinyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted pyrazinyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R eany one substituted or unsubstituted pyrazinyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is triazinyl.In certain embodiments, R ewith 0,1 or 2 R hthe triazinyl that group replaces.Such as, in certain embodiments, R ethe triazinyl of following formula:
Wherein x is 0,1 or 2, and R has defined below and herein.In certain embodiments, R eunsubstituted pyrazinyl (that is, wherein x is 0).In certain embodiments, R eit is the pyrazinyl (such as, wherein x is 1 or 2) replaced.In certain embodiments, R emono-substituted pyrazinyl (that is, wherein x is 1).In certain embodiments, R edibasic pyrazinyl (that is, wherein x is 2).In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R eany one substituted or unsubstituted triazinyl in following formula:
Wherein R has defined below and herein.
In certain embodiments, R eit is tetrazine base.In certain embodiments, R ewith 0 or 1 R hthe tetrazine base that group replaces.Such as, in certain embodiments, R ethe tetrazine base of following formula:
Wherein x is 0 or 1, and R has defined below and herein.In certain embodiments, R eunsubstituted pyrazinyl (that is, wherein x is 0).In certain embodiments, R eit is the pyrazinyl (such as, wherein x is 1) replaced.In certain embodiments, x is 0 or 1.
In certain embodiments, R eany one substituted or unsubstituted tetrazine base in following formula:
Wherein R has defined below and herein.
In certain embodiments, R e9-unit's heteroaryl (such as, 5,6-bicyclic heteroaryl).In certain embodiments, R ewith 0,1,2,3,4 or 5 R h5, the 6-bicyclic heteroaryls that group replaces.In certain embodiments, R ebe selected from indyl, pseudoindoyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuryl, benzisoxa furyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, Ben Bing oxadiazolyl, benzothiazolyl, benzisothiazole base, diazosulfide base, indolizinyl and purine radicals 5,6-bicyclic heteroaryl, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
Such as, in certain embodiments, R e5,6-bicyclic heteroaryls of following formula:
Wherein Y e, Y f, Y g, Y i, Y j, Y kand Y mc, CH, CR independently h, O, S, N or NR k, and Y nbe C or N, condition is middle Y e, Y f, Y gat least one be selected from O, S, N or NR k, wherein R hand R kas defined below and herein.
In certain embodiments, R e5,6-bicyclic heteroaryls of formula (i-f), wherein Y ebe selected from O, S or NR k, Y nc, and Y f, Y g, Y i, Y j, Y kand Y mc, CH or CR independently h.Such as, in certain embodiments, R e5,6-bicyclic heteroaryls of following formula:
Wherein x is 0,1,2,3,4 or 5, and R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 0).In certain embodiments, R e5, the 6-bicyclic heteroaryls (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted 5,6-bicyclic heteroaryls (that is, wherein x is 1).In certain embodiments, R edibasic 5,6-bicyclic heteroaryls (that is, wherein x is 2).In certain embodiments, R etrisubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R e5,6-bicyclic heteroaryl, wherein Y ebe selected from O, S or NR k; Y gn; Y nc; Y fc, CH or CR hor N, and Y i, Y j, Y kand Y mc, CH or CR independently h.Such as, in certain embodiments, R e5,6-bicyclic heteroaryls of following formula:
Wherein x is 0,1,2,3,4 or 5, and R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 0).In certain embodiments, R e5, the 6-bicyclic heteroaryls (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted 5,6-bicyclic heteroaryls (that is, wherein x is 1).In certain embodiments, R edibasic 5,6-bicyclic heteroaryls (that is, wherein x is 2).In certain embodiments, R etrisubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R e5,6-bicyclic heteroaryl, wherein Y enR k, S or O; Y mn; Y nc; And Y f, Y g, Y i, Y jand Y kc, CH or CR independently h.Such as, in certain embodiments, R e5,6-bicyclic heteroaryl following formula:
Wherein x is 0,1,2,3,4 or 5, and R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 0).In certain embodiments, R e5, the 6-bicyclic heteroaryls (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted 5,6-bicyclic heteroaryls (that is, wherein x is 1).In certain embodiments, R edibasic 5,6-bicyclic heteroaryls (that is, wherein x is 2).In certain embodiments, R etrisubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R e5,6-bicyclic heteroaryl wherein Y go, S or NR k; Y mn; Y nc; And Y e, Y f, Y i, Y jand Y kc, CH or CR independently h.Such as, in certain embodiments, R e5,6-bicyclic heteroaryls of following formula:
Wherein x is 0,1,2,3,4 or 5, and R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 0).In certain embodiments, R e5, the 6-bicyclic heteroaryls (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted 5,6-bicyclic heteroaryls (that is, wherein x is 1).In certain embodiments, R edibasic 5,6-bicyclic heteroaryls (that is, wherein x is 2).In certain embodiments, R etrisubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R e5,6-bicyclic heteroaryl, wherein Y ebe selected from N; Y nn; And Y f, Y i, Y j, Y kand Y mc, CH or CR independently h.Such as, in certain embodiments, R e5,6-bicyclic heteroaryls of following formula:
Wherein x is 0,1,2,3,4 or 5, and R hand R kbelow and define herein.In certain embodiments, R eunsubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 0).In certain embodiments, R e5, the 6-bicyclic heteroaryls (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted 5,6-bicyclic heteroaryls (that is, wherein x is 1).In certain embodiments, R edibasic 5,6-bicyclic heteroaryls (that is, wherein x is 2).In certain embodiments, R etrisubstituted 5,6-bicyclic heteroaryls (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R e10-unit's heteroaryl (such as, 6,6-bicyclic heteroaryl).In certain embodiments, R ewith 0,1,2,3,4 or 5 R h6, the 6-bicyclic heteroaryls that group replaces.In certain embodiments, R e6, the 6-bicyclic heteroaryls being selected from naphthyridinyl, pteridyl, quinolyl, isoquinolyl, cinnolines base, quinoxalinyl, phthalazinyl and quinazolyl, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
Such as, in certain embodiments, R e6,6-bicyclic heteroaryls of following formula:
Wherein W f, W g, W h, W i, W j, W k, W mand W nindependently selected from C, CH, CR hor N, condition is middle W f, W g, W h, W i, W j, W k, W mand W nat least one be N, and wherein R has defined below and herein.
In certain embodiments, R ethe quinolyl of such as formula (i-g), wherein W ibe N and W g, W h, W f, W j, W k, W mand W nc, CH or CR independently h.Such as, in certain embodiments, R ethe quinolyl of following formula:
Wherein x is 0,1,2,3,4 or 5, and R has defined below and herein.In certain embodiments, R eunsubstituted quinolines base (that is, wherein x is 0).In certain embodiments, R eit is the quinolyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted quinolyl (that is, wherein x is 1).In certain embodiments, R edibasic quinolyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted quinolyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe isoquinolyl of such as formula (i-g), wherein W hn, and W f, W g, W i, W j, W k, W mand W nc, CH or CR independently h.Such as, in certain embodiments, R ethe isoquinolyl of following formula:
Wherein x is 0,1,2,3,4 or 5, and R has defined below and herein.In certain embodiments, R eunsubstituted isoquinolyl (that is, wherein x is 0).In certain embodiments, R eit is the isoquinolyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted isoquinolyl (that is, wherein x is 1).In certain embodiments, R edisubstituted isoquinilone base (that is, wherein x is 2).In certain embodiments, R etrisubstituted isoquinolyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe quinoxalinyl of such as formula (i-g), wherein W fand W in, and W g, W h, W j, W k, W mand W nc, CH or CR independently h.Such as, in certain embodiments, R ethe quinoxalinyl of following formula:
Wherein x is 0,1,2,3,4 or 5, and R has defined below and herein.In certain embodiments, R eunsubstituted quinoxalinyl (that is, wherein x is 0).In certain embodiments, R eit is the quinoxalinyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted quinoxalinyl (that is, wherein x is 1).In certain embodiments, R edibasic quinoxalinyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted quinoxalinyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R eit is 3-14 unit heterocyclic radical.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 3-14 unit heterocyclic radical that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 5-10 unit heterocyclic radical that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 5-8 unit heterocyclic radical that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 5-6 unit heterocyclic radical that group replaces.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 9-10 unit heterocyclic radical that group replaces.
Exemplary heterocyclic groups R egroup includes but not limited to aziridinyl, Oxyranyle, thiorenyl, azelidinyl, oxetanylmethoxy, thietanyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, pyrrolidyl, pyrrolin base, pyrryl-2,5-diketone, dioxolanyl, oxygen thia penta cyclic group, dithia penta cyclic group, triazoline base, 4-oxadiazole quinoline base, thia bisoxazoline base, piperidyl, THP trtrahydropyranyl, dihydropyridine base, thiophene alkyl, piperazinyl, morpholinyl, dithiane base, alkyl dioxin, triazinyl, diazepine base, oxygen azatropylidene base, sulphur azatropylidene base, azocanyl, oxecanyl, thiocanyl, indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, tetrahydro benzo thienyl, tetrahydrochysene benzfuran base, tetrahydro indole base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, octahydro chromenyl, the heterochromatic thiazolinyl of octahydro, decahydro naphthyridinyl, decahydro-1,8-naphthyridinyl, octahydro pyrrolo-[3,2-b] pyrroles, indoline base, phthaloyl imino, naphthalimido, chromanyl, chromenyl, 1H-benzo [e] [Isosorbide-5-Nitrae] diazepinyl, Isosorbide-5-Nitrae, 5,7-ttetrahydro-pyran is [3,4-b] pyrryl also, 5,6-dihydro-4H-furo [3,2-b] pyrryl, 6,7-dihydro-5H-furo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno-[2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo-[2,3-b] pyridyl, 2,3 dihydro furan is [2,3-b] pyridyl also, 4,5,6,7-tetrahydro-1 H-pyrrolo is [2,3-b] pyridyl also, 4,5,6,7-tetrahydrofuran (THF) is [3,2-c] pyridyl also, with 4,5,6,7-tetramethylene sulfide also [3,2-b] pyridyl, 1,2,3,4-tetrahydrochysene-1,6-naphthyridinyl, wherein these groups are with 0, 1, 2, 3, 4 or 5 R hgroup replaces.
In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe 6-unit heterocyclic radical that group replaces.In certain embodiments, R ethe 6-unit heterocyclic radical, wherein these groups 0,1,2,3,4 or 5 R that are selected from piperidyl, THP trtrahydropyranyl, dihydropyridine base, thiophene alkyl, piperazinyl, morpholinyl, dithiane base, alkyl dioxin and triazinyl hgroup replaces.
Such as, in certain embodiments, R ethe 6-unit heterocyclic radical of following formula:
Wherein W o, W p, W q, W rand W sindependently selected from CH 2, CHR h, C (R h) 2, NR k, O or S, and W tn, CH, CR h, condition is W o, W p, W q, W rand W sin at least one be selected from N, NR k, O or S, and wherein R hand R kbelow and define herein.
In certain embodiments, R eit is piperidyl.In certain embodiments, R euse 0,1,2,3,4 or 5 R of such as following formula hthe piperidyl that group replaces:
Wherein x is 0,1,2,3,4 or 5, and R nand R kas defined below and herein.In certain embodiments, R eunsubstituted piperidyl (that is, wherein x is 0).In certain embodiments, R eit is the piperidyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted piperidyl (that is, wherein x is 1).In certain embodiments, R edisubstituted piperidine base (that is, wherein x is 2).In certain embodiments, R etrisubstituted piperidyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe piperidino of such as formula (i-h), wherein W tn, and W o, W p, W q, W rand W sindependently selected from CH 2, CHR h, C (R h) 2.In certain embodiments, R ethe 2-piperidyl of such as formula (i-h), wherein W onR k; W p, W q, W rand W scHR independently h, C (R h) 2or CH 2; And W tcH or CR h.In certain embodiments, R ethe 3-piperidyl of such as formula (i-h), wherein W pnR k; W o, W q, W rand W scHR independently h, C (R h) 2or CH 2; And W tcH or CR h.In certain embodiments, R ethe 4-piperidyl of such as formula (i-h), wherein W qnR k; W o, W p, W rand W scHR independently h, C (R h) 2or CH 2; And W tcH or CR h.
In certain embodiments, R eit is piperazinyl.In certain embodiments, R euse 0,1,2,3 or 4 R of such as following formula hthe piperazinyl that group replaces:
Wherein x is 0,1,2,3,4 or 5, and R hand R kas defined below and herein.In certain embodiments, R eunsubstituted piperazinyl (that is, wherein x is 0).In certain embodiments, R eit is the piperazinyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted piperazinyl (that is, wherein x is 1).In certain embodiments, R edisubstituted piperazines base (that is, wherein x is 2).In certain embodiments, R etrisubstituted piperazinyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe 1-piperazinyl of such as formula (i-h), wherein W tn, W qnR k, and W o, W p, W rand W sindependently selected from CH 2, CHR h, C (R h) 2.In certain embodiments, R ethe 2-piperazinyl of such as formula (i-h), wherein W oand W rnR independently k, and W p, W q, W rand W scHR independently h, C (R h) 2or CH 2; And W tcH or CR h.
In certain embodiments, R eit is morpholinyl.In certain embodiments, R euse 0,1,2,3 or 4 R of such as following formula hthe morpholinyl that group replaces:
Wherein x is 0,1,2,3,4 or 5, and R hand R kas defined below and herein.In certain embodiments, R eunsubstituted morpholinyl (that is, wherein x is 0).In certain embodiments, R eit is the morpholinyl (such as, wherein x is 1,2,3,4 or 5) replaced.In certain embodiments, R emono-substituted morpholinyl (that is, wherein x is 1).In certain embodiments, R edibasic morpholinyl (that is, wherein x is 2).In certain embodiments, R etrisubstituted morpholinyl (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R ethe morpholinyl of formula (i-h), wherein W tn, W qo, and W o, W p, W rand W sindependently selected from CH 2, CHR h, C (R h) 2.
In certain embodiments, R eshi alkyl dioxin.In certain embodiments, R euse 0,1,2,3 or 4 R of such as following formula hgroup replaces alkyl dioxin:
Wherein x is 0,1,2,3,4 or 5, and R hand R kas defined below and herein.In certain embodiments, R eunsubstituted alkyl dioxin (that is, wherein x is 0).In certain embodiments, R ereplace alkyl dioxin (such as, wherein x is 1,2,3,4 or 5).In certain embodiments, R emono-substituted alkyl dioxin (that is, wherein x is 1).In certain embodiments, R edibasic alkyl dioxin (that is, wherein x is 2).In certain embodiments, R etrisubstituted alkyl dioxin (that is, wherein x is 3).In certain embodiments, x is 0,1,2 or 3.In certain embodiments, x is 0,1 or 2.In certain embodiments, x is 0 or 1.
In certain embodiments, R esuch as formula (i-h) alkyl dioxin, wherein W oand W ro, and W p, W q, W rand W scHR independently h, C (R h) 2or CH 2; And W tcH or CR h.
Other 6-units heterocyclic radical R that formula (i-h) comprises egroup comprises monose, such as, is selected from the pyranoside of ribose, pectinose, wood sugar, lyxose, allose, altrose, glucose, seminose, gulose, idose, semi-lactosi and talose.
In certain embodiments, R ec 3-10carbocylic radical.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 3-10carbocylic radical.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 5-8carbocylic radical.In certain embodiments, R ewith 0,1,2,3 or 4 R hthe C that group replaces 5-6carbocylic radical.In certain embodiments, R ewith 0,1,2,3,4 or 5 R hthe C that group replaces 9-10carbocylic radical.
Exemplary R ec 3-10carbocylic radical, includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl and cycloheptadiene base, wherein these groups 0,1,2,3,4 or 5 R hgroup replaces.
the R of group G f
As general definition above, in certain embodiments, wherein G is selected from-SO 2nR fr e,-PO 2nR fr e,-(C=O) NR fr e,-ONR fr e,-ONR f(C=O) R e,-ONR fsO 2r e,-ONR fpO 2r e,-ONR fpO 2oR e,-NR fsO 2r e,-NR fpO 2r e,-NR fpO 2oR e,-OPO 2nR fr e,-NR fr e,-NR f(C=O) R e,-NR f(C=O) OR e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr e,-NR f(C=NR f) OR ewith-[N (R f) 2r e] +x -, wherein X -counter ion, each R be connected with nitrogen-atoms findependently selected from-H or C 1-10alkyl or amino protecting group, or R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring.
In certain embodiments, R fh or C 1-10alkyl.
In certain embodiments, R fh.
In certain embodiments, R fc 1-10alkyl.In certain embodiments, R fwith 0,1,2,3,4 or 5 R hthe C that group replaces 1-10alkyl.Exemplary R falkyl includes but not limited to methyl, ethyl, propyl group, allyl group, and benzyl.In certain embodiments, R funsubstituted methyl, i.e.-CH 3.In certain embodiments, R funsubstituted ethyl, i.e.-CH 2cH 3.
In certain embodiments, R fit is amino protecting group.Such as, in certain embodiments, R fbe selected from-OH ,-OR i,-N (R k) 2,-C (=O) R i,-C (=O) N (R k) 2,-CO 2r i,-SO 2r i,-C (=NR k) R i,-C (=NR k) OR i,-C (=NR k) N (R k) 2,-SO 2n (R k) 2,-SO 2r i,-SO 2oR i,-SOR i,-C (=S) N (R k) 2,-C (=O) SR i,-C (=S) SR i, C 1-10alkyl (such as, aralkyl), C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aralkyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces, wherein R i, R k, R mas defined below and herein.
But, in certain embodiments, when G is-NR er fand R f-H or C 1-3during alkyl, R enot C 1-6alkyl or thiazolyl.
In addition, in certain embodiments, when G is-OC (=O) NR ftime, R eand R fnot all-CH 3.
Selectively, in certain embodiments, R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring; Such as, when G is-SO 2nR fr e,-PO 2nR fr e,-(C=O) NR fr e,-ONR fr e,-OPO 2nR fr e,-NR fr e,-O (C=O) NR fr e,-NR f(C=NR f) NR fr e,-O (C=NR f) NR fr ewith-[N (R f) 2r e] +x -time, wherein X -counter ion.In certain embodiments, wherein R eand R fbe connected to form 3-14 unit's heterocyclic ring or 5-14 unit heteroaryl ring, heterocyclic ring or heteroaryl ring 0,1,2,3,4 or 5 R hgroup replaces, as defined below and herein.
In certain embodiments, R eand R fbe connected to form 3-14 unit heterocyclic ring.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 3-14 unit heterocyclic ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 5-10 unit heterocyclic ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 5-8 unit heterocyclic ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2 or 3 R hthe 5-6 unit heterocyclic ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 9-10 unit heterocyclic ring that group replaces.
In certain embodiments, R eand R fbe connected to form heterocyclic radical, described heterocyclic radical is selected from aziridinyl, azelidinyl, pyrrolidyl, pyrrolin base, pyrryl-2, 5-diketone, triazoline base, 4-oxadiazole quinoline base, thia bisoxazoline base, piperidyl, dihydropyridine base, thiophene alkyl, piperazinyl, morpholinyl, triazinyl, diazepine base, oxygen azatropylidene base, sulphur azatropylidene base, azocanyl, indoline base, isoindoline base, tetrahydro benzo-thienyl, tetrahydro indole base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, indoline base and phthaloyl imino, wherein these groups are with 0, 1, 2, 3, 4 or 5 R hgroup replaces.
Such as, in certain embodiments, R eand R fbe connected to form the 5-unit heterocyclic ring being selected from following group:
Wherein x is 0,1,2 or 3, wherein R hand R kas defined below and herein.
In certain embodiments, R eand R fbe connected to form the 6-unit heterocyclic ring being selected from following group:
Wherein x is 0,1,2 or 3, wherein R hand R kas defined below and herein.
But, in certain embodiments, when G is-NR er ftime, R eand R fbe not connected to form pyrrolidyl, piperidyl or diazepine basic ring.
In certain embodiments, R eand R fbe connected to form 5-14 unit heteroaryl ring.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 5-14 unit heteroaryl ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 5-10 unit heteroaryl ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3 or 4 R hthe 5-8 unit heteroaryl ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3 or 4 R hthe 5-6 unit heteroaryl ring that group replaces.In certain embodiments, R eand R fbe connected to form with 0,1,2,3,4 or 5 R hthe 9-10 unit heteroaryl ring that group replaces.
In certain embodiments, R eand R fbe connected to form the 5-unit heteroaryl ring being selected from following group:
Wherein x is 0,1 or 2, and R hand R kas defined below and herein.
But, in certain embodiments, when G is-NR ftime, R eand R fbe not connected to form 1,2,4-triazole basic ring of such as following formula:
Wherein x is 0 or 1, and R has defined below and herein.
In certain embodiments, R eand R fbe connected to form 9-unit's heteroaryl ring (" 5,6-bicyclic heteroaryl ") being selected from following group:
Wherein x is 0,1,2 or 3, and R hand R kas defined below and herein.
group G substituting group
r h embodiment
As defined above and herein, each R hindependent selected from halo (fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I)) ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR i,-ON (R k) 2,-N (R k) 2,-N (R k) 3 +x -,-N (OR j) R k,-SH ,-SR i,-SSR j,-C (=O) R i,-CO 2h ,-CHO ,-CO 2r i,-OC (=O) R i,-OCO 2r i,-C (=O) N (R k) 2,-OC (=O) N (R k) 2,-NR kc (=O) R i,-NR kcO 2r i,-NR kc (=O) N (R k) 2,-C (=NR k) R i,-C (=NR k) OR i,-OC (=NR k) R i,-OC (=NR k) OR i,-C (=NR k) N (R k) 2,-OC (=NR k) N (R k) 2,-NR kc (=NR k) N (R k) 2,-C (=O) NR ksO 2r i,-NR ksO 2r i,-SO 2n (R k) 2,-SO 2r i,-SO 2oR i,-OSO 2r i,-S (=O) R i,-OS (=O) R i,-Si (R i) 3,-OS (R i) 3,-C (=S) N (R k) 2,-C (=O) SR i,-C (=S) SR i,-SC (S) SR i,-P (=O) 2r i,-OP (=O) 2r i,-P (=O) (R i) 2,-OP (=O) (R i) 2,-OP (=O) (OR j) 2,-P (=O) 2n (R k) 2,-OP (=O) 2n (R k) 2,-P (=O) (NR k) 2,-OP (=O) (NR k) 2,-NR kp (=O) (OR) 2,-NR kp (=O) (NR k) 2,-P (R j) 2,-P (R j) 3,-OP (R j) 2,-OP (R j) 3,-B (OR j) 2,-BR i(OR j), C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-14carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces;
Each R iindependently selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces;
Each R kindependently selected from hydrogen ,-OH ,-OR i,-N (R j) 2,-CN ,-C (=O) R i,-C (=O) N (R j) 2,-CO 2r i,-SO 2r i,-C (=NR j) OR i,-C (=NR j) N (R j) 2,-SO 2n (R j) 2,-SO 2r j,-SO 2oR j,-SOR i,-C (=S) N (R j) 2,-C (=O) SR j,-C (=S) SR j,-P (=O) 2r i,-P (=O) (R j) 2,-P (=O) 2n (R j) 2,-P (=O) (NR j) 2, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms jgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces;
Each R jindependently selected from hydrogen, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms jgroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces;
Each R mindependently selected from fluorine (-F), bromine (-Br), chlorine (-C1) and iodine (-I) ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR o,-ON (R n) 2,-N (R n) 2,-N (R n) 3 +x -,-N (OR o) R n,-SH ,-SR o,-SSR o,-C (O) R o,-CO 2h ,-CO 2r o,-OC (O) R o,-OCO 2r o,-C (=O) N (R n) 2,-OC (=O) N (R n) 2,-NR nc (=O) R o,-NR ncO 2r o,-NR nc (=O) N (R n) 2,-C (=NR n) OR o,-OC (=NR n) R o,-OC (=NR n) OR o,-C (=NR n) N (R n) 2,-OC (=NR n) N (R n) 2,-NR nc (=NR n) N (R n) 2,-NR nsO 2r o,-SO 2n (R n) 2,-SO 2r o,-SO 2oR o,-OSO 2r o,-S (O) R o,-Si (R o) 3,-OSi (R o) 3,-C (=S) N (R n) 2,-C (=O) SR o,-C (=S) SR o,-SC (=S) SR o,-P (=O) 2r o,-P (=O) (R o) 2,-OP (=O) (R o) 2,-OP (=O) (OR o) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl, 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently pgroup replaces, or two together with R msubstituting group can form=O or=S jointly;
Each R oindependently selected from C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-10aryl, 3-10 unit's heterocyclic radical and 3-10 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently pgroup replaces;
Each R nindependently selected from hydrogen, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-10 unit heterocyclic radical, C 6-10aryl and 5-10 unit heteroaryl, or two R be connected with nitrogen-atoms ngroup is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently pgroup replaces; With
Each R pfluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-CN ,-NO independently 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OC 1-6alkyl ,-ON (C 1-6alkyl) 2,-N (C 1-6alkyl) 2,-N (C 1-6alkyl) 3x ,-NH (C 1-6alkyl) 2x ,-NH 2(C 1-6alkyl) X ,-NH 3x ,-N (OC 1-6alkyl) (C 1-6alkyl) ,-N (OH) (C 1-6alkyl) ,-NH (OH) ,-SH ,-SC 1-6alkyl ,-SS (C 1-6alkyl) ,-C (=O) (C 1-6alkyl) ,-CO 2h ,-CO 2(C 1-6alkyl) ,-OC (=O) (C 1-6alkyl) ,-OCO 2(C 1-6alkyl) ,-C (=O) NH 2,-C (=O) N (C 1-6alkyl) 2,-OC (=O) NH (C 1-6alkyl) ,-NHC (=O) (C 1-6alkyl) ,-N (C 1-6alkyl) C (=O) (C 1-6alkyl) ,-NHCO 2(C 1-6alkyl) ,-NHC (=O) N (C 1-6alkyl) 2,-NHC (=O) NH (C 1-6alkyl) ,-NHC (=O) NH 2,-C (=NH) O (C 1-6alkyl) ,-OC (=NH) (C 1-6alkyl) ,-OC (=NH) OC 1-6alkyl ,-C (=NH) N (C 1-6alkyl) 2,-C (=NH) NH (C 1-6alkyl) ,-C (=NH) NH 2,-OC (=NH) N (C 1-6alkyl) 2,-OC (NH) NH (C 1-6alkyl) ,-OC (NH) NH 2,-NHC (NH) N (C 1-6alkyl) 2,-NHC (=NH) NH 2,-NHSO 2(C1 -6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-SO 2nH 2,-SO 2c 1-6alkyl ,-SO 2oC 1-6alkyl ,-OSO 2c 1-6alkyl ,-SOC 1-6alkyl ,-Si (C 1-6alkyl) 3,-OSi (C 1-6alkyl) 3,-C (=S) N (C 1-6alkyl) 2, C (=S) NH (C 1-6alkyl), C (=S) NH 2,-C (O) S (C 1-6alkyl), C (=S) SC 1-6alkyl ,-SC (=S) SC 1-6alkyl ,-P (=O) 2(C 1-6alkyl) ,-P (=O) (C 1-6alkyl) 2,-OP (=O) (C 1-6alkyl) 2,-OP (=O) (OC 1-6alkyl) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-14 unit heterocyclic radical, 5-14 unit heteroaryl; Or two together with R psubstituting group can form=O or=S jointly;
Wherein X -counter ion.
In certain embodiments, R hbe selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-CN ,-NO 2,-OH ,-OR i,-SR i,-SO 2h ,-SO 3h ,-N (R k) 2,-N (R k) 3 +x -,-C (=O) R i,-CO 2h ,-CHO ,-CO 2r i,-OC (O) R i,-OCO 2r i,-C (=O) N (R k) 2,-OC (=O) N (R k) 2,-NR kc (=O) R i,-NR kcO 2r i,-NR kc (=O) N (R k) 2,-C (=NR k) R i,-C (=NR k) OR i,-OC (=NR k) R i,-OC (=NR k) OR i,-C (=NR k) N (R k) 2,-OC (=NR k) N (R k) 2,-NR kc (=NR k) N (R k) 2,-C (O) NR ksO 2r i,-NR ksO 2r i,-SO 2n (R k) 2,-SO 2r i,-SO 2oR i,-OSO 2r i,-S (O) R i,-OS (O) R i,-C (=S) N (R k) 2,-C (=O) SR i,-C (=S) SR i,-SC (S) SR i,-P (=O) 2r i,-OP (=O) 2r ,-P (=O) (R i) 2,-OP (=O) (R i) 2,-OP (=O) (OR j) 2,-P (=O) 2n (R k) 2,-OP (=O) 2n (R k) 2,-P (=O) (NR k) 2,-OP (=O) (NR k) 2,-NR kp (=O) (OR j) 2,-NR kp (=O) (NR k) 2,-B (OR j) 2,-BR i(OR j), C 1-10alkyl ,-C 1-10whole haloalkyl, C 3-14carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces; Wherein X -counter ion.
In certain embodiments, R hbe selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-CN ,-NO 2,-OH ,-OR i,-SR i,-N (R k) 2,-N (R k) 3 +x -,-C (=O) R i,-CO 2r i,-CO 2h ,-OC (=O) R i,-OCO 2r i,-C (=O) N (R k) 2,-OC (=O) N (R k) 2,-NR kc (=O) R i,-NR kcO 2r i,-NR kc (=O) N (R k) 2,-C (=O) NR ksO 2r i,-NR ksO 2r i,-SO 2n (R k) 2,-SO 2r i, C 1-10alkyl, C 6aryl and 5-6 unit heteroaryl, wherein each alkyl, aryl and heteroaryl use 0,1,2,3 or 4 R independently mgroup replaces; Wherein X -counter ion.
In certain embodiments, R h-OR i, such as, be selected from-OCH 3,-OCF 3,-OCH 2cH 3,-OCH 2cF 3,-OiPr and-OnBu.
In certain embodiments, R h-SR i, such as, be selected from-SCH 3.
In certain embodiments, R h-N (R k) 2or-N (R k) 3 +x -, such as, be selected from-NH 2with-NH 3 +x -.
In certain embodiments, R h-C (=O) R i, such as, be selected from-C (=O) CH 3.
In certain embodiments, R h-CO 2r i, such as, be selected from-CO 2cH 3.
In certain embodiments, R h-C (=O) N (R k) 2, such as, be selected from
-C (=O) NHOH-C (=O) NH 2,-C (=O) NHCH 3,-C (=O) N (CH 3) 2,-C (=O) NHCH 2cH 3,-C (=O) NHCH 2cF 3-,-C (=O) NH (CH 2) 1-6nH 3 +x -,-C (=O) NHCH 2c (=O) OCH 3,-C (=O) NHCH 2c (=O) OH and-C (=O) NHCH 2cH 2oH.
In certain embodiments, R h-OC (=O) R i, such as, be selected from-OC (=O) CH 3.
In certain embodiments, R h-OCO 2r i, such as, be selected from-OCO 2cH 3.
In certain embodiments, R h-OC (=O) N (R k) 2, such as, be selected from-OC (=O) NH 2.
In certain embodiments, R h-NR kc (=O) R i, such as, be selected from-NHC (=O) CH 3.
In certain embodiments, R h-NR kcO 2r i, such as, be selected from-NHC (=O) OCH 3with-NHC (=O) OtBu.
In certain embodiments, R h-NR kc (=O) N (R k) 2, such as, be selected from-NHC (=O) NH 2.
In certain embodiments, R h-C (=O) NR ksO 2r i, such as, be selected from-C (=O) NHSO 2cH 3,-C (=O) NHSO 2cH 2cH 3,-C (=O) NHSO 2c 5h 9with-C (=O) NHSO 2iBu.
In certain embodiments, R h-NR ksO 2r i, such as, be selected from-NHSO 2cH 3.
In certain embodiments, R h-SO 2n (R k) 2, such as, be selected from-SO 2nH 2,-SO 2n (CH 3) 2.
In certain embodiments, R h-SO 2r i, such as, be selected from-SO 2cH 3,-SO 2cH 2cH 3,-SO 2c 5h 9with-SO 2 ibu.
In certain embodiments, R hc 1-10alkyl, such as, is selected from-CH 3,-CH 2cH 3,-iPr ,-nBu ,-CF 3,-CH 2cH 2cO 2me ,-CH 2cH 2cO 2h and-CH 2cH 2cO 2nH 2.
In certain embodiments, R hbe selected from-C (=O) R i,-CO 2h and-SO 2r i.In certain embodiments, R h-C (=O) R i.In certain embodiments, R h-SO 2r i.In certain embodiments, R h-CO 2h or-SO 2cH 3.In certain embodiments, R h-CO 2h.In certain embodiments, R h-SO 2cH 3.
In certain embodiments, each R hindependently selected from fluorine (-F), bromine (-Br), chlorine (-Cl), iodine (-I) ,-NH 2,-NH 3 +x -,-CN ,-NO 2,-SO 2cH 3,-SO 2cH 2cH 3,-SO 2c 5h 9,-SO 2iBu ,-SO 2nH 2,-SO 2n (CH 3) 2,-C (=O) NHSO 2cH 3,-C (=O) NHSO 2cH 2cH 3,-C (=O) NHSO 2c 5h 9,-C (=O) NHSO 2iBu ,-C (=O) CH 3,-CO 2h ,-CO 2cH 3,-OC (=O) CH 3,-OCO 2cH 3,-C (=O) NHOH ,-C (=O) NH 2,-C (=O) NHCH 3,-C (=O) N (CH 3) 2,-C (=O) NHCH 2cH 3,-C (=O) NHCH 2cF 3,-C (=O) NH (CH 2) 1-6nH 3 +x -,-OC (O) NH 2,-NHC (=O) CH 3,-NHC (=O) OCH 3,-NHC (=O) OtBu ,-NHC (=O) NH 2,-NHSO 2cH 3,-CH 3,-CH 2cH 3,-iPr ,-nBu ,-CF 3,-OH ,-OCH 3,-SCH 3,-OCF 3,-OCH 2cH 3,-OCH 2cF 3,-OiPr ,-OnBu ,-CH 2cH 2cO 2me ,-CH 2cH 2cO 2h ,-CH 2cH 2cO 2nH 2,-C (=O) NHCH 2c (=O) OCH 3,-C (=O) NHCH 2c (=O) OH ,-C (=O) NHCH 2cH 2oH, with 0,1 or 2 R mthe C that group replaces 6aryl and with 0,1 or 2 R mthe 5-6 unit heteroaryl that group replaces; Wherein X -counter ion.
In certain embodiments, R hwith 0,1 or 2 R mthe C that M group replaces 6aryl (such as, phenyl).In certain embodiments, R hwith 1 R mthe C that group replaces 6aryl (such as, phenyl), and R m-CO 2h ,-CO 2cH 3,-CO 2cH 2cH 3with-C (=O) NH 2.
In certain embodiments, R hwith 0,1 or 2 R mthe 5-6 unit heteroaryl that group replaces.In certain embodiments, R hwith 0,1 or 2 R m5 yuan of heteroaryls that group replaces.Exemplary 5 yuan of heteroaryl R hgroup includes but not limited to pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group and tetrazyl, wherein these groups 0 or 1 R mgroup replaces.In certain embodiments, R hbe selected from pyrazolyl with 5 yuan of heteroaryls of oxadiazolyl, wherein these groups 0 or 1 R mgroup replaces.
R iembodiment
In certain embodiments, each R iindependently selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl are unsubstituted.
In certain embodiments, R iunsubstituted C 1-10alkyl.In certain embodiments, R ic 1-10whole haloalkyl.In certain embodiments, R iunsubstituted C 2-10thiazolinyl.In certain embodiments, R iunsubstituted C 2-10alkynyl.In certain embodiments, R iunsubstituted C 3-10carbocylic radical.In certain embodiments, R iit is unsubstituted 3-14 unit heterocyclic radical.In certain embodiments, R iunsubstituted C 6-14aryl.In certain embodiments, R iit is unsubstituted 5-14 unit heteroaryl.
R membodiment
In certain embodiments, each R mindependently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-CN ,-NO 2,-SO 2h ,-SO 3h ,-OH ,-OR o,-ON (R n) 2,-N (R n) 2,-N (R n) 3 +x -,-N (OR o) R n,-SH ,-SR o,-SSR o,-C (=O) R o,-CO 2h ,-CO 2r o,-OC (=O) R o,-OCO 2r o,-C (=O) N (R n) 2,-OC (=O) N (R n) 2,-NR nc (=O) R o,-NR ncO 2r o,-NR nc (=O) N (R n) 2,-C (=NR n) OR o,-OC (=NR n) R o,-OC (=NR n) OR o,-C (=NR n) N (R n) 2,-OC (=NR n) N (R n) 2,-NR nc (=NR n) N (R n) 2,-NR nsO 2r o,-SO 2n (R n) 2,-SO 2r o,-SO 2oR o,-OSO 2r o,-S (=O) R o,-C (=S) N (R n) 2,-C (=O) SR o,-C (=S) SR o,-SC (=S) SR o,-P (=O) 2r o,-P (=O) (R o) 2,-OP (=O) (R o) 2,-OP (=O) (OR o) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl, 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently pgroup replaces.
In certain embodiments, each R mindependently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-CN ,-NO 2,-SO 2h ,-SO 3h ,-OH ,-OR o,-ON (R n) 2,-N (R n) 2,-N (R n) 3 +x -,-N (OR o) R n,-SH ,-SR o,-SSR o,-C (=O) R o,-CO 2h ,-CO 2r o,-OC (=O) R o,-OCO 2r o,-C (=O) N (R n) 2,-OC (=O) N (R n) 2,-NR nc (=O) R o,-NR ncO 2r o,-NR nc (=O) N (R n) 2,-C (=NR n) OR o,-OC (=NR n) R o,-OC (=NR n) OR o,-C (=NR n) N (R n) 2,-OC (=NR n) N (R n) 2,-NR nc (=NR n) N (R n) 2,-NR nsO 2r o,-SO 2n (R n) 2,-SO 2r o,-SO 2oR o,-OSO 2r o,-S (=O) R o,-C (=S) N (R n) 2,-C (=O) SR o,-C (=S) SR o,-SC (=S) SR o,-P (=O) 2r o,-P (=O) (R o) 2,-OP (=O) (R o) 2,-OP (=O) (OR o) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl, 5-14 unit heteroaryl.
In certain embodiments, R mbe selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-NH 2,-NH 3 +x -,-CN ,-NO 2,-SO 2cH 3,-SO 2cH 2cH 3,-SO 2c 5h 9,-SO 2iBu ,-SO 2nH 2,-SO 2n (CH 3) 2,-C (=O) NHSO 2cH 3,-C (=O) NHSO 2cH 2cH 3,-C (=O) NHSO 2c 5h 9,-C (=O) NHSO 2iBu ,-C (=O) CH 3,-CO 2h ,-CO 2cH 3,-OC (=O) CH 3,-OCO 2cH 3,-C (=O) NHOH ,-C (=O) NH 2,-C (=O) NHCH 3,-C (=O) N (CH 3) 2,-C (=O) NHCH 2cH 3,-C (=O) NHCH 2cF 3-,-C (=O) NH (CH 2) 1-6nH 3 +x -,-OC (O) NH 2,-NHC (=O) CH 3,-NHC (=O) OCH 3,-NHC (=O) OtBu ,-NHC (=O) NH 2,-NHSO 2cH 3,-CH 3,-CH 2cH 3,-iPr ,-nBu ,-CF 3,-OH ,-OCH 3,-OCF 3,-OCH 2cH 3,-OCH 2cF 3,-OiPr ,-OnBu ,-CH 2cH 2cO 2me ,-CH 2cH 2cO 2h ,-CH 2cH 2cO 2nH 2,-C (=O) NHCH 2c (=O) OCH 3,-C (=O) NHCH 2c (=O) OH and-C (=O) NHCH 2cH 2oH.
R kembodiment
As defined above and herein, each R kindependently selected from-H ,-OH ,-OR i,-N (R k) 2,-C (=O) R i,-C (=O) N (R k) 2,-CO 2r i,-SO 2r i,-C (=NR k) R i,-C (=NR k) OR i,-C (=NR k) N (R k) 2,-SO 2n (R k) 2,-SO 2r i,-SO 2oR i,-SOR i,-C (=S) N (R k) 2,-C (=O) SR i,-C (=S) Sri, C 1-10alkyl (such as, aralkyl), C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14 virtuebase and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aralkyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently mgroup replaces, wherein R i, R k, R mas defined above and herein.
In certain embodiments, each R kindependently selected from-H ,-C (=O) R i,-C (=O) OR i,-SO 2r ior C 1-6alkyl.In certain embodiments, each R kindependently selected from-H or C 1-6alkyl.In certain embodiments, each R kindependently selected from-H and-CH 3.In certain embodiments, each R kindependently selected from-H.In certain embodiments, each R kindependently selected from-CH 3.
radicals R a , R b and R c
As general definition, wherein R above dgroup-L-Z, each R a, R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl.
In certain embodiments, each R a, R band R cindependently selected from-H, C 1-6alkyl and C 1-6whole haloalkyl.In certain embodiments, each R a, R band R cindependently selected from-H, C 1-3alkyl and C 1-3whole haloalkyl.In certain embodiments, each R a, R band R cindependently selected from-H ,-CH 3,-CH 2cH 3with-CF 3.In certain embodiments, each R a, R band R cindependently selected from-H ,-CH 3with-CF 3.
In certain embodiments, R aand R bh, and R cbe selected from C 1-3alkyl and C 1-3whole haloalkyl.In certain embodiments, R aand R bh, and R cbe selected from-CH 3with-CF 3.In certain embodiments, R aand R bh, and R c-CH 3.In certain embodiments, R aand R bh, and R c-CF 3.
In certain embodiments, R band R ch, and R abe selected from C 1-3alkyl and C 1-3whole haloalkyl.In certain embodiments, R band R ch, and R abe selected from-CH 3with-CF 3.In certain embodiments, R band R ch, and R a-CH 3.In certain embodiments, R band R ch, and R a-CF 3.
In certain embodiments, each R a, R band R cindependently selected from H ,-CH 3with-CF 3.In certain embodiments, each R a, R band R cindependently selected from H or-CH 3.In certain embodiments, each R a, R band R ch.
radicals R d
As general definition above, in certain embodiments, R dgroup-L-Z,
Wherein L is covalent linkage or divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more oxygen, sulphur or nitrogen-atoms independently, and
Z is selected from C 6-10aryl, 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl.
r d group L
As general definition above, L is covalent linkage or divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more oxygen, sulphur or nitrogen-atoms independently.
In certain embodiments, L is covalent linkage.
In certain embodiments, L is divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and independently with one or more oxygen (-O-), sulphur (-S-) or nitrogen (such as ,-NR 1-) atom replacement.
In certain embodiments, L is divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more oxygen (-O-) atom independently.
In certain embodiments, L is divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and replace with one or more sulphur (-S-) atom independently.
In certain embodiments, L is divalence C 1-6alkyl, wherein 1,2 of L or 3 MU (methylene unit) are optionally and independently with one or more nitrogen (-NR 1-) atom replacement.But, in certain embodiments, when L is the divalence C comprising 1,2 or 3 nitrogen-atoms 1-6during alkyl, L is unsubstituted divalence C 1-6alkyl, and L is not group-CH 2nR 1, wherein R 1h, C 1-6alkyl or amino protecting group.
In certain embodiments, L is divalence C 1-6alkyl, wherein 1 MU (methylene unit) of L replaces with oxygen, sulphur or nitrogen-atoms optionally and independently.In certain embodiments, L is divalence C 1-6alkyl, wherein 1 MU (methylene unit) of L optionally and replace with Sauerstoffatom independently.In certain embodiments, L is divalence C 1-6alkyl, wherein 1 MU (methylene unit) of L optionally and replace with sulphur atom independently.In certain embodiments, L is divalence C 1-6alkyl, wherein 1 MU (methylene unit) of L optionally and replace with nitrogen-atoms independently.
In some embodiment of L, divalence C 1-6alkyl is unsubstituted divalence C 1-6alkyl.In some embodiment of L, divalence C 1-6alkyl contains 1 oxygen, sulphur or nitrogen-atoms.In certain embodiments, divalence C 1-6alkyl is unsubstituted divalence C 1-6alkyl (such as, unsubstituted divalence C 1-6alkyl).
Such as, in certain embodiments, L is unsubstituted divalence C 1-6alkyl, wherein 1 MU (methylene unit) oxygen, sulphur or the nitrogen-atoms of L replace.In certain embodiments, L is unsubstituted divalence C 1-6alkyl, wherein 1 MU (methylene unit) Sauerstoffatom of L replaces.In certain embodiments, L is unsubstituted divalence C 1-6alkyl, wherein 1 MU (methylene unit) sulphur atom of L replaces.In certain embodiments, L is unsubstituted divalence C 1-6alkyl, wherein 1 MU (methylene unit) nitrogen-atoms of L replaces.But, in certain embodiments, when L is unsubstituted divalence C 1-6during alkyl, L is not group-CH 2nR 1, wherein R 1h, C 1-6alkyl or amino protecting group.
In certain embodiments, L is divalence C 1alkyl, wherein 1 MU (methylene unit) oxygen, sulphur or the nitrogen-atoms of L replace, and such as, L is selected from oxygen (-O-), sulphur (-S-) or nitrogen (such as ,-NR 1-).In certain embodiments, L is oxygen (-O-).In certain embodiments, L is sulphur (-S-).In certain embodiments, L is nitrogen (such as ,-NR 1-).
In certain embodiments, L is selected from-(C (R 10) 2) m-,-(C (R 11) 2) m-O-(C (R 12) 2) n-,-(C (R 11) 2) m-S-(C (R 12) 2) n-or-(C (R 11) 2) m-NR 1-(C (R 12) 2) n-, wherein m and n is 0,1,2,3,4,5 or 6 independently, and each R 10, R 11and R 12independently selected from H, halogen or C 1-6alkyl.In certain embodiments, each R 10, R 11and R 12-H.
In certain embodiments, L is-(C (R 10) 2) m-.In certain embodiments, L is selected from-CH 2-,-CH 2cH 2-,-CH 2cH 2cH 2-,-CH 2cH 2cH 2cH 2-,-CH 2cH 2cH 2cH 2cH 2-and-CH 2cH 2cH 2cH 2cH 2cH 2-.
In certain embodiments, L is-(C (R 11) 2) m-O-(C (R 12) 2) n-.In certain embodiments, L is selected from-O-,-CH 2o-,-OCH 2-,-OCH 2cH 2-,-OCH 2cH 2-,-OCH 2cH 2cH 2-,-CH 2cH 2cH 2o-,-CH 2oCH 2cH 2-and-CH 2cH 2oCH 2-.
In certain embodiments, L is-(C (R 11) 2) m-S-(C (R 12) 2) n-.In certain embodiments, L is selected from-S-,-CH 2s-,-SCH 2-,-SCH 2cH 2-,-CH 2cH 2s-,-SCH 2cH 2cH 2-,-CH 2cH 2cH 2s-,-CH 2sCH 2cH 2-and-CH 2cH 2sCH 2-.
In certain embodiments, L is-(C (R 11) 2) m-NR 1-(C (R 12) 2) n-.In certain embodiments, L is selected from-NR 1-,-CH 2nR 1-,-NR 1cH 2-,-NR 1cH 2cH 2-,-CH 2cH 2nR 1-,-NR 1cH 2cH 2cH 2-,-CH 2cH 2cH 2nR 1-,-CH 2nR 1cH 2cH 2-and-CH 2cH 2nR 1cH 2-, wherein R 1be selected from H, C 1-6alkyl or amino protecting group.
In certain embodiments, R 1be selected from H or C 1-6alkyl.In certain embodiments, R 1hydrogen.In certain embodiments, R 1-CH 3.
wherein R d group Z be the embodiment of aryl
As general definition above, in certain embodiments, Z is C 6-14aryl.
In certain embodiments, Z is C 6-14aryl.In certain embodiments, Z is C 6-14aryl.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 6-14aryl.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 6aryl (such as, phenyl).In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 10aryl (such as, naphthyl).
In certain embodiments, Z is phenyl.In certain embodiments, Z is with 0,1,2,3 or 4 R 15the phenyl that group replaces.In certain embodiments, Z is with 0,1,2 or 3 R 15the phenyl that group replaces.In certain embodiments, Z is with 0,1 or 2 R 15the phenyl that group replaces.In certain embodiments, Z is with 0 or 1 R 15the phenyl that group replaces.In certain embodiments, Z is that dibasic phenyl is (that is, with 2 R 15group replaces).In certain embodiments, Z is that mono-substituted phenyl is (that is, with 1 R 15group replaces).In certain embodiments, Z is that unsubstituted phenyl is (that is, with 0 R 15group replaces).
In certain embodiments, Z is with at least one adjacent R 15the phenyl that group replaces.In certain embodiments, Z is with at least one R 15the phenyl that group replaces.In certain embodiments, Z is to R with at least one 15the phenyl that group replaces.
In certain embodiments, Z is with 1 adjacent R 15the mono-substituted phenyl that group replaces.In certain embodiments, Z is with R between 1 15the mono-substituted phenyl that group replaces.In certain embodiments, Z is to R with 1 15the mono-substituted phenyl that group replaces.
In certain embodiments, Z uses adjacent R 15group and a R 15dibasic phenyl that group replaces.In certain embodiments, Z uses adjacent R 15group and to R 15dibasic phenyl that group replaces.In certain embodiments, Z is R between use 15group and to R 15dibasic phenyl that group replaces.In certain embodiments, Z is with R between 2 15dibasic phenyl that group replaces.
In certain embodiments, Z is the phenyl of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, z is 0,1,2,3 or 4.In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.In certain embodiments, z is 3.In certain embodiments, Z is dibasic phenyl (that is, wherein z is 2).In certain embodiments, Z is mono-substituted phenyl (that is, wherein z is 1).In certain embodiments, Z is unsubstituted phenyl (that is, wherein z is 0).
Such as, in certain embodiments, Z is any one substituted or unsubstituted phenyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is naphthyl.In certain embodiments, Z is any one naphthyl in following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, z is 0,1,2,3 or 4.In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.In certain embodiments, Z is trisubstituted naphthyl (that is, wherein z is 3).In certain embodiments, Z is dibasic naphthyl (that is, wherein z is 2).In certain embodiments, Z is mono-substituted naphthyl (that is, wherein z is 1).In certain embodiments, Z is unsubstituted naphthyl (that is, wherein z is 0).
Such as, in certain embodiments, Z is any one substituted or unsubstituted 1-naphthyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is any one substituted or unsubstituted 2-naphthyl in following formula:
Wherein R 15as defined below and herein.
wherein R d group Z be the embodiment of heterocyclic radical or heteroaryl
As general definition above, in certain embodiments, Z is selected from 3-14 unit's heterocyclic radical and 5-14 unit heteroaryl.
In certain embodiments, Z is 5-14 unit heteroaryl.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 5-10 unit heteroaryl that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 5-8 unit heteroaryl that group replaces.In certain embodiments, Z is with 0,1,2,3 or 4 R 15the 5-6 unit heteroaryl that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 9-10 unit heteroaryl that group replaces.
Exemplary Z heteroaryl includes but not limited to pyrryl, furyl and thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group, tetrazyl, pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (such as, 3-pyridazinyl, 4-pyridazinyl), pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl), pyrazinyl, triazinyl, tetrazine base, azepinyl, oxepinyl, thiepinyl, indyl, pseudoindoyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuryl, benzisoxa furyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, Ben Bing oxadiazolyl, benzothiazolyl, benzisothiazole base, diazosulfide base, indolizinyl, purine radicals, naphthyridinyl, pteridyl, quinolyl, isoquinolyl, cinnolines base, quinoxalinyl, phthalazinyl, quinazolyl, phenanthridinyl, dibenzofuran group, carbazyl, acridyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein these groups are with 0, 1, 2, 3, 4 or 5 R 15group replaces.
In certain embodiments, Z is with 0,1,2 or 3 R 15the 5-unit heteroaryl that group replaces.In certain embodiments, Z is the 5-unit heteroaryl, wherein these groups 0,1,2 or 3 R that are selected from pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group and tetrazyl 15group replaces.
Such as, in certain embodiments, Z is the 5-unit heteroaryl of following formula:
Wherein Y 1, Y 2, Y 3and Y 4independently selected from CH, CR 15, O, S, N or NR 18, condition is Y 1, Y 2, Y 3and Y 4in at least one be selected from O, S, N or NR 18, and wherein R 15and R 18below and define herein.
In some embodiment of above formula (ii-d), Y 1o, S or NR 18, and Y 2, Y 3and Y 4independently selected from CH, CR 15or N.In some embodiment of above formula (ii-d), Y 1o, S or NR 18, and Y 2, Y 3and Y 4independently selected from CH or CR 15.In some embodiment of above formula (ii-d), Y 1o, S or NR 18, Y 3n, and Y 2and Y 4independently selected from CH or CR 15.In some embodiment of above formula (ii-d), Y 1s, Y 3n, and Y 2and Y 4cH or CR 15.In some embodiment of above formula (ii-d), Y 1s, Y 3n, Y 2cR 15, and Y 4cH.In some embodiment of above formula (ii-d), Y 1s, and Y 2, Y 3and Y 4cH or CR 15.
In some embodiment of above formula (ii-d), Y 2o, S or NR 18, and Y 1, Y 3and Y 4independently selected from CH, CR 15or N.In some embodiment of above formula (ii-d), Y 2o, S or NR 18, and Y 1, Y 3and Y 4independently selected from CH or CR 15.In some embodiment of above formula (ii-d), Y 2o, S or NR 18, Y 4n, and Y 1and Y 3independently selected from CH or CR 15.
In certain embodiments, Z is the first heteroaryl of the 5-of any one in following formula:
Wherein z is 0,1 or 2, and R 15and R 18as defined below and herein.In certain embodiments, Z is unsubstituted 5-unit's heteroaryl (that is, wherein z is 0).In certain embodiments, Z is 5-unit's heteroaryl (such as, wherein z is 1 or 2) replaced.In certain embodiments, Z is mono-substituted 5-unit's heteroaryl (that is, wherein z is 1).In certain embodiments, Z is dibasic 5-unit's heteroaryl (that is, wherein z is 2).In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is with 0,1,2,3 or 4 R hthe 6-unit heteroaryl that group replaces.In certain embodiments, Z is selected from pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (such as, 3-pyridazinyl, 4-pyridazinyl), pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl), 6-unit heteroaryl, wherein these groups 0,1,2,3 or 4 R of pyrazinyl, triazinyl and tetrazine base 15group replaces.
Such as, in certain embodiments, Z is the 6-unit heteroaryl of following formula:
Wherein W 1, W 2, W 3, W 4and W 5independently selected from CH, CR 15or N, condition is W 1, W 2, W 3, W 4and W 5in at least one be N, and wherein R 15as defined below and herein.
In certain embodiments, Z is pyridyl.In certain embodiments, Z is with 0,1,2,3 or 4 R 15the pyridyl that group replaces.Such as, in certain embodiments, Z is the pyridyl of following formula:
Wherein z is 0,1,2,3 or 4, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyridyl (that is, wherein z is 0).In certain embodiments, Z is the pyridyl (such as, wherein z is 1,2,3 or 4) replaced.In certain embodiments, Z is mono-substituted pyridyl (that is, wherein z is 1).In certain embodiments, Z is Disubstituted pyridine base (that is, wherein z is 2).In certain embodiments, Z is trisubstituted pyridyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the 2-pyridyl of such as formula (ii-e), wherein W 1n, and W 2, W 3, W 4and W 5cH or CR independently 15.In certain embodiments, Z is the 3-pyridyl of such as formula (ii-e), wherein W 2n, and W 1, W 3, W 4and W 5cH or CR independently 15.In certain embodiments, Z is the 4-pyridyl of such as formula (ii-e), wherein W 3n, and W 1, W 2, W 4and W 5cH or CR independently 15.
In certain embodiments, R eany one substituted or unsubstituted 2-pyridyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is any one substituted or unsubstituted 3-pyridyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is the substituted or unsubstituted 4-pyridyl of following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is pyridazinyl.In certain embodiments, Z is with 0,1,2 or 3 R 15the pyridazinyl that group replaces.Such as, in certain embodiments, Z is the pyridazinyl of following formula:
Wherein z is 0,1,2 or 3, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyridazinyl (that is, wherein z is 0).In certain embodiments, Z is the pyridazinyl (such as, wherein z is 1,2 or 3) replaced.In certain embodiments, Z is mono-substituted pyridazinyl (that is, wherein z is 1).In certain embodiments, Z is dibasic pyridazinyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted pyridazinyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the 3-pyridazinyl of such as formula (ii-e), wherein W 1and W 2n, and W 3, W 4and W 5cH or CR independently 15.In certain embodiments, Z is the 4-pyridazinyl of such as formula (ii-e), wherein W 2and W 3n, and W 1, W 4and W 5cH or CR independently 15.
In certain embodiments, Z is any one substituted or unsubstituted 3-pyridazinyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is any one substituted or unsubstituted 4-pyridazinyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is pyrimidyl.In certain embodiments, Z is with 0,1,2 or 3 R 15the pyrimidyl that group replaces.Such as, in certain embodiments, Z is the pyrimidyl of following formula:
Wherein z is 0,1,2 or 3, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyrimidyl (that is, wherein z is 0).In certain embodiments, Z is the pyrimidyl (such as, wherein z is 1,2 or 3) replaced.In certain embodiments, Z is mono-substituted pyrimidyl (that is, wherein z is 1).In certain embodiments, Z is dibasic pyridazinyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted pyrimidine base (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the 2-pyrimidyl of such as formula (ii-e), wherein W 1and W 5n, and W 2, W 3and W 4cH or CR independently 15.In certain embodiments, Z is the 4-pyrimidyl of such as formula (ii-e), wherein W 1and W 3n, and W 2, W 4and W 5cH or CR independently 15.In certain embodiments, Z is the 5-pyrimidyl of such as formula (ii-e), wherein W 2and W 4n, and W 1, W 3and W 5cH or CR independently 15.
In certain embodiments, Z is any one 2-pyrimidyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is any one 4-pyrimidyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is any one 5-pyrimidyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is pyrazinyl.In certain embodiments, Z is with 0,1,2 or 3 R 15the pyrazinyl that group replaces.Such as, in certain embodiments, Z is the pyrazinyl of following formula:
Wherein z is 0,1,2 or 3, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyrazinyl (that is, wherein z is 0).In certain embodiments, Z is the pyrazinyl (such as, wherein z is 1,2 or 3) replaced.In certain embodiments, Z is mono-substituted pyrazinyl (that is, wherein z is 1).In certain embodiments, Z is dibasic pyrazinyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted pyrazinyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is any one pyrazinyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is triazinyl.In certain embodiments, Z is with 0,1 or 2 R 15the triazinyl that group replaces.Such as, in certain embodiments, Z is the triazinyl of following formula:
Wherein z is 0,1 or 2, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyrazinyl (that is, wherein z is 0).In certain embodiments, Z is the pyrazinyl (such as, wherein z is 1 or 2) replaced.In certain embodiments, Z is mono-substituted pyrazinyl (that is, wherein z is 1).In certain embodiments, Z is dibasic pyrazinyl (that is, wherein z is 2).In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is any one substituted or unsubstituted triazinyl in following formula:
Wherein R 15as defined below and herein.
In certain embodiments, Z is tetrazine base.In certain embodiments, Z is with 0 or 1 R 15the tetrazine base that group replaces.Such as, in certain embodiments, Z is the tetrazine base of following formula:
Wherein z is 0 or 1, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted pyrazinyl (that is, wherein z is 0).In certain embodiments, Z is the pyrazinyl (such as, wherein z is 1) replaced.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is any one tetrazine base in following formula:
Wherein R 15below and define herein.
In certain embodiments, Z is 9-unit's heteroaryl (such as, 5,6-bicyclic heteroaryl).In certain embodiments, Z is with 0,1,2,3,4 or 5 R 155, the 6-bicyclic heteroaryls that group replaces.In certain embodiments, Z is be selected from indyl, pseudoindoyl, indazolyl, benzotriazole base, benzothienyl, isobenzo-thienyl, benzofuryl, benzisoxa furyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, Ben Bing oxadiazolyl, benzothiazolyl, benzisothiazole base, diazosulfide base, indolizinyl and purine radicals 5,6-bicyclic heteroaryl, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein Y 5, Y 6, Y 7, Y 9, Y 10, Y 11and Y 12c, CH, CR independently 15, O, S, N or NR 18,and Y 13be C or N, condition is Y 5, Y 6, Y 7in at least one be selected from O, S, N or NR 18, and wherein R 15and R 18as defined herein.
In certain embodiments, Z is 5,6-bicyclic heteroaryls of formula (ii-f), wherein Y 5be selected from O, S or NR 18, Y 13c, and Y 6, Y 7, Y 9, Y 10, Y 11and Y 12c, CH or CR independently 15.Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18below and define herein.In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 0).In certain embodiments, Z is 5, the 6-bicyclic heteroaryls (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted 5,6-bicyclic heteroaryls (that is, wherein z is 1).In certain embodiments, Z is dibasic 5,6-bicyclic heteroaryls (that is, wherein z is 2).In certain embodiments, Z is trisubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y 5be selected from O, S or NR 18; Y 7n; Y 13c; Y 6c, CH or CR 15or N, and Y 9, Y 10, Y 11and Y 12c, CH or CR independently 15.Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18below and define herein.In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 0).In certain embodiments, Z is 5, the 6-bicyclic heteroaryls (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted 5,6-bicyclic heteroaryls (that is, wherein z is 1).In certain embodiments, Z is dibasic 5,6-bicyclic heteroaryls (that is, wherein z is 2).In certain embodiments, Z is trisubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y 5nR k, S or O; Y 12n; Y 13c; And Y 6, Y 7, Y 9, Y 10and Y 11c, CH or CR independently 15.Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18below and define herein.In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 0).In certain embodiments, Z is 5, the 6-bicyclic heteroaryls (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted 5,6-bicyclic heteroaryls (that is, wherein z is 1).In certain embodiments, Z is dibasic 5,6-bicyclic heteroaryls (that is, wherein z is 2).In certain embodiments, Z is trisubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y 7o, S or NR k; Y 12n; Y 13c; And Y 5, Y 6, Y 9, Y 10and Y 11c, CH or CR independently 15.Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18below and define herein.In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 0).In certain embodiments, Z is 5, the 6-bicyclic heteroaryls (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted 5,6-bicyclic heteroaryls (that is, wherein z is 1).In certain embodiments, Z is dibasic 5,6-bicyclic heteroaryls (that is, wherein z is 2).In certain embodiments, Z is trisubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y 5be selected from O, S or NR 18; Y 13n; And Y 6, Y 7, Y 8, Y 9and Y 10c, CH or CR independently 15.Such as, in certain embodiments, Z is 5,6-bicyclic heteroaryls of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18below and define herein.In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 0).In certain embodiments, Z is 5, the 6-bicyclic heteroaryls (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted 5,6-bicyclic heteroaryls (that is, wherein z is 1).In certain embodiments, Z is dibasic 5,6-bicyclic heteroaryls (that is, wherein z is 2).In certain embodiments, Z is trisubstituted 5,6-bicyclic heteroaryls (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 10-unit's heteroaryl (such as, 6,6-bicyclic heteroaryl).In certain embodiments, Z is with 0,1,2,3,4 or 5 R 156, the 6-bicyclic heteroaryls that group replaces.In certain embodiments, Z is 6, the 6-bicyclic heteroaryls being selected from naphthyridinyl, pteridyl, quinolyl, isoquinolyl, cinnolines base, quinoxalinyl, phthalazinyl and quinazolyl, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
Such as, in certain embodiments, Z is 6,6-bicyclic heteroaryl following formula:
Wherein W 6, W 7, W 8, W 9, W 10, W 11, W 12and W 13independently selected from C, CH, CR 15or N, condition is W 6, W 7, W 8, W 9, W 10, W 11, W 12and W 13in at least one be N, and wherein R 15as defined below and herein.
In certain embodiments, Z is the quinolyl of such as formula (ii-g), wherein W 9n, and W 6, W 7, W 8, W 10, W 11, W 12and W 13c, CH or CR independently 15.Such as, in certain embodiments, Z is the quinolyl of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted quinolines base (that is, wherein z is 0).In certain embodiments, Z is the quinolyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted quinolyl (that is, wherein z is 1).In certain embodiments, Z is dibasic quinolyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted quinolyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the isoquinolyl of such as formula (ii-g), wherein W 8n, and W 6, W 7, W 9, W 10, W 11, W 12and W 13c, CH or CR independently 15.Such as, in certain embodiments, Z is the isoquinolyl of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted isoquinolyl (that is, wherein z is 0).In certain embodiments, Z is the isoquinolyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted isoquinolyl (that is, wherein z is 1).In certain embodiments, Z is disubstituted isoquinilone base (that is, wherein z is 2).In certain embodiments, Z is trisubstituted isoquinolyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the quinoxalinyl of such as formula (ii-g), wherein W 6and W 9n, and W 7, W 8, W 10, W 11, W 12and W 13c, CH or CR independently 15.Such as, in certain embodiments, Z is the quinoxalinyl of following formula:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted quinoxalinyl (that is, wherein z is 0).In certain embodiments, Z is the quinoxalinyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted quinoxalinyl (that is, wherein z is 1).In certain embodiments, Z is dibasic quinoxalinyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted quinoxalinyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is 3-14 unit heterocyclic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 3-14 unit heterocyclic radical that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 5-10 unit heterocyclic radical that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 5-8 unit heterocyclic radical that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 5-6 unit heterocyclic radical that group replaces.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 9-10 unit heterocyclic radical that group replaces.
Exemplary heterocyclic groups Z group includes but not limited to aziridinyl, Oxyranyle, thiorenyl, azelidinyl, oxetanylmethoxy, thietanyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, pyrrolidyl, pyrrolin base, pyrryl-2,5-diketone, dioxolanyl, oxygen thia penta cyclic group, dithia penta cyclic group, triazoline base, 4-oxadiazole quinoline base, thia bisoxazoline base, piperidyl, THP trtrahydropyranyl, dihydropyridine base, thiophene alkyl, piperazinyl, morpholinyl, dithiane base, alkyl dioxin, triazinyl, diazepine base, oxygen azatropylidene base, sulphur azatropylidene base, azocanyl, oxecanyl, thiocanyl, indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, tetrahydro benzo thienyl, tetrahydrochysene benzfuran base, tetrahydro indole base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, octahydro chromenyl, the heterochromatic thiazolinyl of octahydro, decahydro naphthyridinyl, decahydro-1,8-naphthyridinyl, octahydro pyrrolo-[3,2-b] pyrroles, indoline base, phthaloyl imino, naphthalimido, chromanyl, chromenyl, 1H-benzo [e] [Isosorbide-5-Nitrae] diazepinyl, Isosorbide-5-Nitrae, 5,7-ttetrahydro-pyran is [3,4-b] pyrryl also, 5,6-dihydro-4H-furo [3,2-b] pyrryl, 6,7-dihydro-5H-furo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno-[2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo-[2,3-b] pyridyl, 2,3 dihydro furan is [2,3-b] pyridyl also, 4,5,6,7-tetrahydro-1 H-pyrrolo is [2,3-b] pyridyl also, 4,5,6,7-tetrahydrofuran (THF) is [3,2-c] pyridyl also, with 4,5,6,7-tetramethylene sulfide also [3,2-b] pyridyl, 1,2,3,4-tetrahydrochysene-1,6-naphthyridinyl, wherein these groups are with 0, 1, 2, 3, 4 or 5 R 15group replaces.
In certain embodiments, Z is 6-unit heterocyclic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the 6-unit heterocyclic radical that group replaces.In certain embodiments, Z is the 6-unit heterocyclic radical, wherein these groups 0,1,2,3,4 or 5 R that are selected from piperidyl, THP trtrahydropyranyl, dihydropyridine base, thiophene alkyl, piperazinyl, morpholinyl, dithiane base, alkyl dioxin and triazinyl 15group replaces.
Such as, in certain embodiments, Z is the 6-unit heterocyclic radical of following formula:
Wherein W 14, W 15, W 16, W 17, W 18cH independently 2, CHR 15, C (R 15) 2, NR 18, O or S, and W 19n, CH or CR 15, condition is W 14, W 15, W 16, W 17, W 18and W 19in at least one be N, NR 18, O or S, and wherein R 15and R 18below and define herein.
In certain embodiments, Z is piperidyl.In certain embodiments, Z is use 0,1,2,3,4 or 5 R of such as following formula 15the piperidyl that group replaces:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18as defined below and herein.In certain embodiments, Z is unsubstituted piperidyl (that is, wherein z is 0).In certain embodiments, Z is the piperidyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted piperidyl (that is, wherein z is 1).In certain embodiments, Z is disubstituted piperidine base (that is, wherein z is 2).In certain embodiments, Z is trisubstituted piperidyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the piperidino of such as formula (ii-h), wherein W 19n, and W 14, W 15, W 16, W 17and W 18independently selected from CH 2, CHR 15, C (R 15) 2.In certain embodiments, Z is the 2-piperidyl of such as formula (ii-h), wherein W 14nR 18; W 15, W 16, W 17and W 18cHR independently 15, C (R 15) 2or CH 2; And W 19cH or CR 15.In certain embodiments, Z is the 3-piperidyl of such as formula (ii-h), wherein W 15nR 18; W 14, W 16, W 17and W 18cHR independently 15, C (R 15) 2or CH 2; And W 19cH or CR 15.In certain embodiments, Z is the 4-piperidyl of such as formula (ii-h), wherein W 16nR 18; W 14, W 15, W 17and W 18cHR independently 15, C (R 15) 2or CH 2; And W 19cH or CR 15.
In certain embodiments, Z is piperazinyl.In certain embodiments, Z is use 0,1,2,3 or 4 R of such as following formula 15the piperazinyl that group replaces:
Wherein x is 0,1,2,3,4 or 5, and R 15and R 18as defined below and herein.In certain embodiments, Z is unsubstituted piperazinyl (that is, wherein z is 0).In certain embodiments, Z is the piperazinyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted piperazinyl (that is, wherein z is 1).In certain embodiments, Z is disubstituted piperazines base (that is, wherein z is 2).In certain embodiments, Z is trisubstituted piperazinyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the piperazinyl of such as formula (ii-h), wherein W 19n, W 16nR 18, and W 14, W 15, W 16, W 17and W 18cHR independently 15, C (R 15) 2or CH 2.In certain embodiments, Z is piperazinyl, wherein W 19cH or CR 15, W 14and W 17nR independently 18, and W 15, W 16and W 18cHR independently 15, C (R 15) 2or CH 2.
In certain embodiments, Z is use 0,1,2,3 or 4 R of such as following formula 15the morpholinyl that group replaces:
Wherein z is 0,1,2,3,4 or 5, and R 15and R 18as defined below and herein.In certain embodiments, Z is unsubstituted morpholinyl (that is, wherein z is 0).In certain embodiments, Z is the morpholinyl (such as, wherein z is 1,2,3,4 or 5) replaced.In certain embodiments, Z is mono-substituted morpholinyl (that is, wherein z is 1).In certain embodiments, Z is dibasic morpholinyl (that is, wherein z is 2).In certain embodiments, Z is trisubstituted morpholinyl (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is the morpholinyl of such as formula (ii-h), wherein W 19n, W 16o, and W 14, W 15, W 16and W 17independently selected from CH 2, CHR 15, C (R 15) 2.In certain embodiments, Z is morpholinyl, wherein W 19cH or CR 15, W 14and W 17independently selected from O and NR 18, and W 15, W 16and W 18cHR independently 15, C (R 15) 2or CH 2.
In certain embodiments, Z Shi alkyl dioxin.In certain embodiments, Z is use 0,1,2,3 or 4 R of such as following formula 15group replaces alkyl dioxin:
Wherein z is 0,1,2,3,4 or 5, and R 15as defined below and herein.In certain embodiments, Z is unsubstituted alkyl dioxin (that is, wherein z is 0).In certain embodiments, Z replaces alkyl dioxin (such as, wherein z is 1,2,3,4 or 5).In certain embodiments, Z is mono-substituted alkyl dioxin (that is, wherein z is 1).In certain embodiments, Z is dibasic alkyl dioxin (that is, wherein z is 2).In certain embodiments, Z is trisubstituted alkyl dioxin (that is, wherein z is 3).In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 0 or 1.
In certain embodiments, Z is such as formula (ii-h) alkyl dioxin, wherein W 14and W 17o, and W 15, W 16and W 18cHR independently 15, C (R 15) 2or CH 2; And W 19cH or CR 15.In certain embodiments, Z Shi alkyl dioxin, wherein W 19cH or CR 16, W 14and W 16independently selected from O, and W 15, W 17and W 18cHR independently 15, C (R 15) 2or CH 2.In certain embodiments, Z Shi alkyl dioxin, wherein W 19cH or CR 15, W 15and W 17independently selected from O, and W 14, W 16and W 18cHR independently 15, C (R 15) 2or CH 2.
In certain embodiments, Z is C 3-10carbocylic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 3-10carbocylic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 5-8carbocylic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 5-6carbocylic radical.In certain embodiments, Z is with 0,1,2,3,4 or 5 R 15the C that group replaces 9-10carbocylic radical.
wherein R a and R d connect the embodiment of (condensing)
As general definition above, in certain embodiments, R aand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical condensed ring, and R band R cindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl.
In certain embodiments, each R band R cindependently selected from-H, C 1-6alkyl and C 1-6whole haloalkyl.In certain embodiments, each R band R cindependently selected from-H, C 1-3alkyl and C 1-3whole haloalkyl.In certain embodiments, each R band R cindependently selected from-H, C 1alkyl and C 1whole haloalkyl.In certain embodiments, each R band R cindependently selected from-H ,-CH 3with-CF 3.In certain embodiments, each R band R cindependently selected from-H and-CH 3.In certain embodiments, each R band R cindependently selected from-H and-CF 3.In certain embodiments, R band R call-H.
In certain embodiments, R aand R dbe connected to form C 5-7carbocylic radical or 5-7 unit heterocyclic radical condensed ring.In certain embodiments, R aand R dbe connected to form the C of following formula 5-7carbocylic radical or 5-7 unit heterocyclic radical condensed ring:
Wherein W 20, W 21, W 22and W 23cH independently 2, CHR 15, C (R 15) 2or NR 18, R 15and R 18as defined below and herein, s is 0,1 or 2, and represented by dotted arrows ring condenses.
In certain embodiments, R aand R dbe connected to form C 5-7carbocylic radical condensed ring.Such as, in some embodiment of formula (ii-j), W 20, W 21, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.Exemplary R aand R dthe C that can be connected to form 5-7carbocylic radical includes but not limited to cyclopentyl, cyclohexyl and suberyl, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
In certain embodiments, R aand R dbe connected to form 5-7 unit heterocyclic radical condensed ring.Such as, in some embodiment of formula (ii-j), W 20nR 18, and W 21, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.In some embodiment of formula (ii-j), W 21nR 18, and W 20, W 22, and W 23cH independently 2, CHR 15or C (R 15) 2.In some embodiment of formula (ii-j), W 22nR 18, and W 20, W 21and W 23cH independently 2, CHR 15or C (R 15) 2.Exemplary R aand R dthe 5-7 unit heterocyclic radical that can be connected to form includes but not limited to pyrrolidyl, pyrazolidyl, imidazolidyl, piperidyl, piperazinyl and diazepine base, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
In certain embodiments, wherein s is 0, R aand R dbe connected to form the C of following formula 5carbocylic radical or 5-unit heterocyclic radical condensed ring:
Wherein W 20, W 21and W 22cH independently 2, CHR 15, C (R 15) 2or NR 18, R 15and R 18as defined below and herein, represented by dotted arrows ring condenses.
In some embodiment of formula (ii-k), R aand R dsuch as be connected to form C 5carbocylic radical condensed ring (that is, cyclopentyl), wherein W 20, W 21and W 22cH independently 2, CHR 15, C (R 15) 2.
In some embodiment of formula (ii-k), R aand R dsuch as be connected to form 5-unit's heterocyclic radical condensed ring (such as, pyrrolidyl), wherein W 21nR 18, and W 20, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.In some embodiment of formula (ii-k), R aand R dsuch as be connected to form 5-unit's heterocyclic radical condensed ring (such as, pyrrolidyl), wherein W 20nR 18, and W 21, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein s is 1, R aand R dbe connected to form the C of following formula 6carbocylic radical or 6-unit heterocyclic radical condensed ring:
Wherein W 20, W 21, W 22and W 23cH independently 2, CHR 15, C (R 15) 2or NR 18, R 15and R 18as defined below and herein, represented by dotted arrows ring condenses.
In some embodiment of formula (ii-m), R aand R dsuch as be connected to form C 6carbocylic radical condensed ring (that is, cyclohexyl), wherein W 20, W 21, W 22and W 23cH independently 2, CHR 15, C (R 15) 2.
In some embodiment of formula (ii-m), R aand R dsuch as be connected to form 6-unit's heterocyclic radical condensed ring (such as, piperidyl), wherein W 21nR, and W 20, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.In some embodiment of formula (ii-m), R aand R dbe connected to form 6-unit's heterocyclic radical condensed ring (such as, piperidyl), such as, wherein W 20nR 18, and W 21, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein s is 2, R aand R dbe connected to form the C of following formula 7carbocylic radical or 7-unit heterocyclic ring:
Wherein W 20, W 21, W 22and W 23cH independently 2, CHR 15, C (R 15) 2or NR 18, R 15and R 18as defined below and herein, represented by dotted arrows ring condenses.
In some embodiment of formula (ii-n), R aand R dsuch as be connected to form C 7carbocylic radical (that is, suberyl), wherein W 20, W 21, W 22and W 23cH independently 2, CHR 15, C (R 15) 2.
In some embodiment of formula (ii-n), R aand R dsuch as be connected to form 7-unit's heterocyclic ring (such as, diazepine base), wherein W 21nR 18, and W 20, W 22and W 23cH independently 2, CHR 15or C (R 15) 2.In some embodiment of formula (ii-n), R aand R dsuch as be connected to form 7-unit's heterocyclic ring (such as, diazepine base), wherein W 22nR 18, and W 20, W 21and W 23cH independently 2, CHR 15or C (R 15) 2.
wherein R c and R d connect the embodiment of (spiral shell-condense)
As general definition above, in certain embodiments, R cand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical spiral shell condensed ring, and R aand R bindependently selected from-H, C 1-10alkyl and C 1-10whole haloalkyl.
In certain embodiments, each R aand R bindependently selected from-H, C 1-6alkyl and C 1-6whole haloalkyl.In certain embodiments, each R aand R bindependently selected from-H, C 1-3alkyl and C 1-3whole haloalkyl.In certain embodiments, each R aand R bindependently selected from-H, C 1alkyl and C 1whole haloalkyl.In certain embodiments, each R aand R bindependently selected from-H ,-CH 3with-CF 3.In certain embodiments, each R aand R bindependently selected from-H and-CH 3.In certain embodiments, each R aand R bindependently selected from-H and-CF 3.In certain embodiments, R aand R ball-H.
In certain embodiments, R cand R dbe connected to form C 5-7carbocylic radical, 5-7 unit heterocyclic radical, 5,6-bicyclic carbocyclic group, 6,6-bicyclic carbocyclic group, 5,6-bicyclic heterocyclic radicals or 6,6-bicyclic heterocyclic radical spiral shell condensed ring.
Such as, in certain embodiments, R cand R dbe connected to form the C of following formula 5-7carbocylic radical, 5-7 unit heterocyclic radical, 5,6-bicyclic carbocyclic group or 5,6-bicyclic heterocyclic radical spiral shell condensed ring:
Wherein W 24, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15, C (R 15) 2or NR 18, optionally wherein W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace; T and v is 0 or 1 independently; And R 15and R 18as defined below and herein.In certain embodiments, t be 0 and v be 0.In certain embodiments, t be 0 and v be 1.In certain embodiments, t be 1 and v be 0.In certain embodiments, t be 1 and v be 1.
In certain embodiments, R cand R dbe connected to form C 5-7carbocylic radical spiral shell condensed ring.Such as, in some embodiment of formula (iii-a), W 24, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.Exemplary R cand R dthe C that can be connected to form 5-7carbocylic radical includes but not limited to cyclopentyl, cyclohexyl and suberyl, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
In certain embodiments, R cand R dbe connected to form 5-7 unit heterocyclic radical spiral shell condensed ring.Such as, in some embodiment of formula (iii-a), W 25nR 18, and W 26, W 27, W 28and W 29cH independently 2, CHR 15, C (R 15) 2.In some embodiment of formula (iii-a), W 26nR 18, and W 24, W 25, W 27, W 28and W 29cH independently 2, CHR 15, C (R 15) 2.In some embodiment of formula (iii-a), W 27nR 18, and W 24, W 25, W 26, W 28and W 29cH independently 2, CHR 15, C (R 15) 2.Exemplary R cand R dthe 5-7 unit heterocyclic radical that can be connected to form includes but not limited to pyrrolidyl, pyrazolidyl, imidazolidyl, piperidyl, piperazinyl and diazepine base, wherein these groups 0,1,2,3,4 or 5 R 15group replaces.
In certain embodiments, wherein t be 0 and v be 0, R cand R dbe connected to form the C of following formula 5carbocylic radical or 5-unit heterocyclic radical spiral shell condensed ring:
Wherein W 25, W 26, W 27and W 28cH independently 2, CHR 15, C (R 15) 2or NR 18, and R 15and R 18as defined below and herein.
In certain embodiments, R cand R dbe connected to form the C of such as formula (iii-b) 5carbocylic radical spiral shell condensed ring (such as, cyclopentyl), wherein W 25nR 18, and W 26, W 27and W 28cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, R cand R dbe connected to form the 5-unit heterocyclic radical spiral shell condensed ring of such as formula (iii-b), wherein W 26nR 18, and W 25, W 27and W 28cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein t be 0 and v be 1, R cand R dbe connected to form the C of following formula 6carbocylic radical or 6-unit heterocyclic radical spiral shell condensed ring:
Wherein W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15, C (R 15) 2or NR 18, and R 15and R 18as defined below and herein.
In certain embodiments, R cand R dbe connected to form the C of such as formula (iii-c) 6carbocylic radical spiral shell condensed ring (such as, cyclohexyl), wherein W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 16) 2.
In certain embodiments, R cand R dbe connected to form the 5-unit heterocyclic radical spiral shell condensed ring of such as formula (iii-c), wherein W 26nR 18, and W 25, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, R cand R dbe connected to form the 5-unit heterocyclic radical spiral shell condensed ring of formula (iii-c), wherein W 27nR 18, and W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein t be 1 and v be 1, R cand R dbe connected to form the C of following formula 7carbocylic radical or 7-unit heterocyclic radical spiral shell condensed ring:
Wherein W 24, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15, C (R 15) 2or NR 18, and R 15and R 18as defined below and herein.
In certain embodiments, R cand R dbe connected to form the C of such as formula (iii-d) 7carbocylic radical spiral shell condensed ring (such as, suberyl), wherein W 24, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, R cand R dbe connected to form the 7-unit heterocyclic radical spiral shell condensed ring of such as formula (iii-d), wherein W 25nR 18, and W 24, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, R cand R dbe connected to form 7-unit heterocyclic radical spiral shell condensed ring, wherein W 26nR 18, and W 24, W 25, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, R cand R dbe connected to form 7-unit heterocyclic radical spiral shell condensed ring, wherein W 27nR 18, and W 24, W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, R cand R dbe connected to form 5,6-bicyclic carbocyclic group spiral shell condensed ring or 5,6-bicyclic heterocyclic radical spiral shell condensed ring.Such as, in some embodiment of formula (iii-a), t and v is all 0, W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace, W 27cH 2, CHR 15, C (R 15) 2and NR 18, and W 28cH 2, CHR 15or C (R 15) 2.In some embodiment of formula (iii-a), R cand R dbe connected to form 5,6-bicyclic carbocyclic group spiral shell condensed ring, such as, wherein t and v is all 0, W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace, and W 27and W 28cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 25and W 26with the C condensed 6aryl rings replaces.
Such as, in certain embodiments, wherein t and v is all 0 and W 25and W 26with the C condensed 6aryl rings replaces, R cand R dbe connected to form 5,6-bicyclic carbocyclic group spiral shell condensed ring of following formula:
Wherein W 27and W 28cH independently 2, CHR 15with C (R 15) 2, z is 0,1,2,3 or 4; And R 15as defined below and herein.In certain embodiments, W 27and W 28all CH 2group.In certain embodiments, z is 0,1,2,3 or 4.In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 2.In certain embodiments, z is 1.In certain embodiments, z is 0.
In certain embodiments, R cand R dbe connected to form 6,6-bicyclic carbocyclic group spiral shell condensed ring or 6,6-bicyclic heterocyclic radical spiral shell condensed ring.Such as, in some embodiment of formula (iii-a), t be 0 and v be 1, W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace, W 27and W 28cH independently 2, CHR 15, C (R 15) 2and NR 18, and W 29cH 2, CHR 15, C (R 15) 2.In some embodiment of formula (iii-a), R cand R dbe connected to form 6,6-bicyclic carbocyclic group spiral shell condensed ring, such as, wherein t be 0 and v be 1, W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace, and W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 25and W 26with the C condensed 6aryl rings replaces.
Such as, in certain embodiments, wherein t be 0 and v be 1 and W 25and W 26with the C condensed 6aryl rings replaces, R cand R dbe connected to form 6,6-bicyclic carbocyclic group spiral shell condensed ring of following formula:
Wherein W 27, W 28and W 29cH independently 2, CHR 15with C (R 15) 2, z is 0,1,2,3 or 4, and R 15as defined below and herein.In certain embodiments, W 27, W 28and W 29each is CH 2group.In certain embodiments, z is 0,1,2,3 or 4.In certain embodiments, z is 0,1,2 or 3.In certain embodiments, z is 0,1 or 2.In certain embodiments, z is 2.In certain embodiments, z is 1.In certain embodiments, z is 0.
In yet another aspect, R cand R dbe connected to form the carbocylic radical of the bridge joint of following formula or the heterocyclic radical spiral shell condensed ring of bridge joint:
Wherein W 30, W 31, W 32, W 33and W 36cH independently 2, CHR 15, C (R 15) 2or NR 18; And W 34and W 35cH or CR independently 15, and R 15and R 18as defined below and herein.
In some embodiment of formula (iii-f), W 30, W 31, W 32, W 33cH independently 2, CHR 15or C (R 15) 2; W 36nR 18; And W 34and W 35cH or CR independently 15.In some embodiment of formula (iii-f), W 30, W 31, W 32, W 33and W 36cH independently 2, CHR 15or C (R 15) 2; And W 34and W 35cH or CR independently 15.In some embodiment of formula (iii-f), W 34and W 35cH.
r 15 group
Used herein, each R 15independent selected from halo (that is, fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I)) ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR 16,-ON (R 18) 2,-N (R 18) 2,-N (R 18) 3 +x -,-N (OR 17) R 18,-SH ,-SR 16,-SSR 17,-C (O) R 16,-CO 2h ,-CHO ,-CO 2r 16,-OC (=O) R 16,-OCO 2r 16,-C (=O) N (R 18) 2,-OC (=O) N (R 18) 2,-NR 18c (=O) R 16,-NR 18cO 2r 16,-NR 18c (=O) N (R 18) 2,-C (=NR 18) R 16,-C (=NR 18) OR 16,-OC (=NR 18) R 16,-OC (=NR 18) OR 16,-C (=NR 18) N (R 18) 2,-OC (=NR 18) N (R 18) 2, NR 18c (=NR 18) N (R 18) 2,-C (=O) NR 18sO 2r 16,-NR 18sO 2r 16,-SO 2n (R 18) 2,-SO 2r 16,-SO 2oR 16,-OSO 2r 16,-S (=O) R 16,-OS (=O) R 16,-Si (R 16) 3,-OSi (R 16) 3,-C (=S) N (R 18) 2,-C (=O) SR 16,-C (=S) SR 16,-SC (S) SR 16,-P (=O) 2r 16,-OP (=O) 2r 16,-P (=O) (R 16) 2,-OP (=O) (R 16) 2,-OP (=O) (OR 17) 2,-P (=O) 2n (R 18) 2,-OP (=O) 2n (R 18) 2,-P (=O) (NR 18) 2,-OP (=O) (NR 18) 2,-NR 18p (=O) (OR 17) 2,-NR 18p (=O) (NR 18) 2,-P (R 17) 2,-P (R 17) 3,-OP (R 17) 2,-OP (R 17) 3,-B (OR 17) 2,-BR 16(OR 17), C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-14carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces; Or two adjacent R 15group group-O (C (R 2) 2) 1-2o-replaces, wherein each R 2h, C independently 1-6alkyl or halogen;
Each R 16independently selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces;
Each R 18independently selected from hydrogen ,-OH ,-OR 16,-N (R 17) 2,-CN ,-C (=O) R 16,-C (=O) N (R 17) 2,-CO 2r 16,-SO 2r 16,-C (=NR 17) OR 16,-C (=NR 17) N (R 17) 2,-SO 2n (R 17) 2,-SO 2r 17,-SO 2oR 17,-SOR 16,-C (=S) N (R 17) 2,-C (=O) SR 17,-C (=S) SR 17,-P (=O) 2r 16,-P (=O) (R 16) 2,-P (=O) 2n (R 17) 2,-P (=O) (NR 17) 2, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms 17group is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces;
Each R 17independently selected from hydrogen, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, or two R be connected with nitrogen-atoms 17group is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces;
Each R 19independent selected from halo ,-CN ,-NO 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OR 20,-ON (R 21) 2,-N (R 21) 2,-N (R 21) 3 +x -,-N (OR 20) R 21,-SH ,-SR 20,-SSR 20,-C (=O) R 20,-CO 2h ,-CO 2r 20,-OC (=O) R 20,-OCO 2r 20,-C (=O) N (R 21) 2,-OC (=O) N (R 21) 2,-NR 21c (=O) R 20,-NR 21cO 2r 20,-NR 21c (=O) N (R 21) 2,-C (=NR 21) OR 20,-OC (=NR 21) R 20,-OC (=NR 21) OR 20,-C (=NR 21) N (R 21) 2,-OC (=NR 21) N (R 21) 2,-NR 21c (=NR 21) N (R 21) 2,-NR 21sO 2r 20,-SO 2n (R 21) 2,-SO 2r 20,-SO 2oR 20,-OSO 2r 20,-S (=O) R 20,-Si (R 20) 3,-OSi (R 20) 3,-C (=S) N (R 21) 2,-C (=O) SR 20,-C (=S) SR 20,-SC (=S) SR 20,-P (=O) 2r 20,-P (=O) (R 20) 2,-OP (=O) (R 20) 2,-OP (=O) (OR 20) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-10 unit heterocyclic radical, C 6-10aryl, 5-10 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 22group replaces, or two together with R 19substituting group can form=O or=S jointly;
Each R 20independently selected from C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-10aryl, 3-10 unit's heterocyclic radical and 3-10 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 22group replaces;
Each R 21independently selected from hydrogen, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, 3-10 unit heterocyclic radical, C 6-10aryl and 5-10 unit heteroaryl, or two R be connected with nitrogen-atoms 21group is connected to form 3-14 unit's heterocyclic radical or 5-14 unit heteroaryl ring, and wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 22group replaces; With
Each R 22halogen ,-CN ,-NO independently 2,-N 3,-SO 2h ,-SO 3h ,-OH ,-OC 1-6alkyl ,-ON (C 1-6alkyl) 2,-N (C 1-6alkyl) 2,-N (C 1-6alkyl) 3x ,-NH (C 1-6alkyl) 2x ,-NH 2(C 1-6alkyl) X ,-NH 3x ,-N (OC 1-6alkyl) (C 1-6alkyl) ,-N (OH) (C 1-6alkyl) ,-NH (OH) ,-SH ,-SC 1-6alkyl ,-SS (C 1-6alkyl) ,-C (=O) (C 1-6alkyl) ,-CO 2h ,-CO 2(C 1-6alkyl) ,-OC (=O) (C 1-6alkyl) ,-OCO 2(C 1-6alkyl) ,-C (=O) NH 2,-C (=O) N (C 1-6alkyl) 2,-OC (=O) NH (C 1-6alkyl) ,-NHC (=O) (C 1-6alkyl) ,-N (C 1-6alkyl) C (=O) (C 1-6alkyl) ,-NHCO 2(C 1-6alkyl) ,-NHC (=O) N (C 1-6alkyl) 2,-NHC (=O) NH (C 1-6alkyl) ,-NHC (=O) NH 2,-C (=NH) O (C 1-6alkyl) ,-OC (=NH) (C 1-6alkyl) ,-OC (=NH) OC 1-6alkyl ,-C (=NH) N (C 1-6alkyl) 2,-C (=NH) NH (C 1-6alkyl) ,-C (=NH) NH 2,-OC (=NH) N (C 1-6alkyl) 2,-OC (NH) NH (C 1-6alkyl) ,-OC (NH) NH 2,-NHC (NH) N (C 1-6alkyl) 2,-NHC (=NH) NH 2,-NHSO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-SO 2nH 2,-SO 2c 1-6alkyl ,-SO 2oC 1-6alkyl ,-OSO 2c 1-6alkyl ,-SOC 1-6alkyl ,-Si (C 1-6alkyl) 3,-OSi (C 1-6alkyl) 3,-C (=S) N (C 1-6alkyl) 2, C (=S) NH (C 1-6alkyl), C (=S) NH 2,-C (O) S (C 1-6alkyl), C (=S) SC 1-6alkyl ,-SC (=S) SC 1-6alkyl ,-P (=O) 2(C 1-6alkyl) ,-P (=O) (C 1-6alkyl) 2,-OP (=O) (C 1-6alkyl) 2,-OP (=O) (OC 1-6alkyl) 2, C 1-6alkyl, C 1-6whole haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-10carbocylic radical, C 6-14aryl, 3-10 unit heterocyclic radical, 5-10 unit heteroaryl; Or two together with R 22substituting group can form=O or=S jointly; Wherein X -counter ion.
In certain embodiments, each R 15independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-OR 16,-C (=O) N (R 18) 2,-SO 2n (R 18) 2, C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces.
In certain embodiments, R 15independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) ,-OR 16, and C 1-10whole haloalkyl.In certain embodiments, R 15independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) and-OR 16.In certain embodiments, R 15independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) and C 1-10whole haloalkyl.
In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
In certain embodiments, R 15-OR 16.In certain embodiments, R 16be selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 6-10aryl and 5-6 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces.
In certain embodiments, R 15-OR 16and R 16be selected from C 1-10alkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-6alkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-4alkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-2alkyl.In certain embodiments, R 15-OR 16, and R 16-CH 3,-Et ,-iPr ,-nBu ,-n-pentyl.In certain embodiments, R 15-OR 16and R 16-CH 3.
In certain embodiments, R 15-OR 16and R 16be selected from C 1-10whole haloalkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-6whole haloalkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-4whole haloalkyl.In certain embodiments, R 15-OR 16and R 16be selected from C 1-2whole haloalkyl.In certain embodiments, R 15-OR 16and R 16-CF 3,-CF 2cF 3,-CF 2cF 2cF 3,-CCl 3,-CFCl 2or-CF 2cl.In certain embodiments, R 15-OR 16and R 16-CF 3.
In certain embodiments, R 15-OR 16and R 16be selected from C 2-10thiazolinyl.In certain embodiments, R 15-OR 16and R 16be selected from C 2-6thiazolinyl.In certain embodiments, R 15-OR 16and R 16be selected from C 2-4thiazolinyl.In certain embodiments, R 15-OR 16and R 16be selected from-CH 2cHCH 2(that is, allyl group).
In certain embodiments, R 15-OR 16and R 16be selected from C 2-10alkynyl.In certain embodiments, R 15-OR 16and R 16be selected from C 2-6alkynyl.In certain embodiments, R 15-OR 16and R 16be selected from C 2-4alkynyl.In certain embodiments, R 15-OR 16and R 16be selected from-CH 2cCH (that is, propargyl).
In certain embodiments, R 15-OR 16and R 16be selected from 0,1,2,3 or 4 R 19the C that group replaces 6aryl (such as, phenyl).In certain embodiments, R 15-OR 16and R 16with 0,1 or 2 R 19the phenyl that group replaces.In certain embodiments, R 15-OR 16and R 16with 1 R 19the phenyl that group replaces.In certain embodiments, R 15-OR 16and R 16with 0 R 19phenyl (that is ,-C that group replaces 6h 5).
In certain embodiments, R 15-OR 16and R 16be selected from 0,1,2,3 or 4 R 19the 5-6 unit heteroaryl that group replaces.In certain embodiments, R 15-OR 16and R 16be selected from 0,1,2,3 or 4 R 196 yuan of heteroaryls that group replaces.In certain embodiments, R 15-OR 16and R 16be selected from 0,1,2,3 or 4 R 19the pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl) that group replaces.In certain embodiments, R 15-OR 16and R 16be selected from 0,1,2 or 3 R 19the pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl) that group replaces.
In certain embodiments, R 15-C (=O) N (R 18) 2.
In certain embodiments, R 15-SO 2n (R 18) 2.
In certain embodiments, R 15c 1-10whole haloalkyl.In certain embodiments, R 15c 1-6whole haloalkyl.In certain embodiments, R 15c 1-4whole haloalkyl.In certain embodiments, R 15c 1-2whole haloalkyl.In certain embodiments, R 15be selected from-CF 3,-CF 2cF 3,-CF 2cF 2cF 3,-CCl 3,-CFCl 2with-CF 2cl.In certain embodiments, R 15be selected from-CF 3.
In certain embodiments, R 15with 0,1,2,3,4 or 5 R 19the C that group replaces 1-10alkyl.In certain embodiments, R 15with 0,1,2,3,4 or 5 R 19the C that group replaces 1-6alkyl.R 15with 0,1,2,3,4 or 5 R 19that group replaces is C 1-4alkyl.In certain embodiments, R 15alkyl is unsubstituted (0 R 19group).In certain embodiments, R 15-CH 3,-Et ,-iPr ,-nBu ,-n-pentyl.
In certain embodiments, R 15with 0,1,2,3,4 or 5 R 19the C that group replaces 2-10thiazolinyl.In certain embodiments, R 15with 0,1,2,3 or 4 R 19the C that group replaces 2-6thiazolinyl.In certain embodiments, R 15with 0,1,2 or 3 R 19the C that group replaces 2-4thiazolinyl.In certain embodiments, R 15thiazolinyl is unsubstituted (0 R 19group).In certain embodiments, R 15-CH 2cHCH 2(that is, allyl group).
In certain embodiments, R 15with 0,1,2,3,4 or 5 R 19the C that group replaces 2-10alkynyl.In certain embodiments, R 15with 0,1,2 or 3 R 19the C that group replaces 2-6alkynyl.In certain embodiments, R 15with 0,1 or 2 R 19the C that group replaces 2-4alkynyl.In certain embodiments, R 15alkynyl is unsubstituted (0 R 19group).In certain embodiments, R 15-CH 2cCH (that is, propargyl).
In certain embodiments, R 15c 6-14aryl.In certain embodiments, R 15be selected from 0,1,2,3 or 4 R 19the C that group replaces 6aryl (such as, phenyl).In certain embodiments, R 15it is unsubstituted phenyl.In certain embodiments, R 15that mono-substituted phenyl is (that is, with 1 R 19group replaces).
In certain embodiments, R 15with 0,1,2,3,4 or 5 R 19the 5-14 unit heteroaryl that group replaces.In certain embodiments, R 15with 0,1,2,3 or 4 R 19the 5-6 unit heteroaryl that group replaces.In certain embodiments, R 15with 0,1,2,3 or 4 R 19the 6-unit heteroaryl that group replaces.In certain embodiments, R 15with 0,1,2,3 or 4 R 19the pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl) that group replaces.In certain embodiments, R 15with 0,1,2 or 3 R 19the pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl) that group replaces.In certain embodiments, R 15heteroaryl is unsubstituted (0 R 19group).
r 18 group
In certain embodiments, each R 18independently selected from-H ,-OH ,-OR 16,-N (R 17) 2,-C (=O) R 16,-C (=O) N (R 17) 2,-CO 2r 16,-SO 2r 16,-C (=NR 17) R 16,-C (=NR 17) OR 16,-C (=NR 17) N (R 17) 2,-SO 2n (R 17) 2,-SO 2r 16,-SO 2oR 16,-SOR 16,-C (=S) N (R 17) 2,-C (=O) SR 16,-C (=S) SR 16, C 1-10alkyl (such as, aralkyl), C 2-10thiazolinyl, C 2-10alkynyl, C 3-10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl, wherein each alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aralkyl, aryl and heteroaryl use 0,1,2,3,4 or 5 R independently 19group replaces, wherein R 16, R 17, R 19as defined above and herein.
In certain embodiments, each R 17independently selected from-H ,-C (=O) R 16,-C (=O) OR 16,-SO 2r 16or C 1-6alkyl.In certain embodiments, each R 17independently selected from-H or C 1-6alkyl.In certain embodiments, each R 17independently selected from-H and-CH 3.In certain embodiments, each R 17independently selected from-H.In certain embodiments, each R 17independently selected from-CH 3.
other embodiments of formula (I) compound
As general definition above, the invention provides the compound of formula (I):
Or its pharmaceutically acceptable form, wherein G, R a, R b, R cand R das defined herein.
In one aspect, wherein R a, R b, R ceach is H, and R dbe group Z, the invention provides the compound of formula (II):
Or its pharmaceutically acceptable form, wherein G and Z is as defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
Such as, in certain embodiments, wherein L is covalent linkage, R a, R b, R ceach is H, and G is group-OR e; The invention provides the compound of formula (II-a):
Or its pharmaceutically acceptable form, wherein R eas defined herein with Z.
In certain embodiments, wherein Z is benzyl ring, the invention provides the compound of formula (II-b):
Or its pharmaceutically acceptable form, wherein G, L, R a, R b, R c, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, z is 2 and R 15in a position and contraposition.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
Such as, in certain embodiments, z is 1 and R 15in contraposition, provide the compound of formula (II-c):
Or its pharmaceutically acceptable form, wherein G, L, R a, R b, R c, R 15as defined herein with z.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
Such as, in certain embodiments, z is 2, and a R 15at a position and last R 15in contraposition, provide the compound of formula (II-c):
Or its pharmaceutically acceptable form, wherein G, L, R a, R b, R c, R 15as defined herein with z.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
Such as, in certain embodiments, wherein Z is benzyl ring, and G is group-OR e; The invention provides the compound of formula (II-d):
Or its pharmaceutically acceptable form, wherein L, R a, R b, R c, R 15, R eas defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, L is covalent linkage.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
In certain embodiments, wherein Z is benzyl ring, and G is group-OR e, and R ebe benzyl ring, the invention provides the compound of formula (II-e):
Or its pharmaceutically acceptable form, wherein L, R a, R b, R c, R 15, R h, x and z be as defined herein.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, L is covalent linkage.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
In certain embodiments, wherein Z is benzyl ring, and G is group-OR e, and R ebe 5-unit heteroaryl ring, the invention provides the compound of formula (II-f):
Or its pharmaceutically acceptable form, wherein Y a, Y b, Y c, Y d, L, R a, R b, R c, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, L is covalent linkage.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
In certain embodiments, wherein Z is benzyl ring, and G is group-OR e, and R ebe 6-unit heteroaryl ring, the invention provides the compound of formula (II-g):
Or its pharmaceutically acceptable form, wherein W a, W b, W c, W d, W e, L, R a, R b, R c, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.In certain embodiments, L is covalent linkage.In certain embodiments, W bn, and W a, W c, W dand W ebe selected from CH or CR h.In certain embodiments, in certain embodiments, W bn, W ccR h, and W a, W c, W dand W eeach is CH.In certain embodiments, W band W dn, and W a, W c, W dand W ebe selected from CH or CR h.
In certain embodiments, wherein Z is benzyl ring, and G is group-OR e, and R ebe 9-unit heteroaryl ring, the invention provides the compound of formula (II-h):
Or its pharmaceutically acceptable form, wherein Y e, Y f, Y g, Y i, Y j, Y k, Y m, Y n, L, R a, R b, R c, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.In certain embodiments, L is covalent linkage.
In certain embodiments, wherein Z is benzyl ring, and G is group-OR e, and R ebe 10-unit heteroaryl ring, the invention provides the compound of formula (II-i):
Or its pharmaceutically acceptable form, wherein W f, W g, W h, W i, W j, W k, W m, W n, L, R a, R b, R c, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.In certain embodiments, L is covalent linkage.
In certain embodiments, wherein Z is benzyl ring and G is group-NR er f, the invention provides the compound of formula (II-j):
Or its pharmaceutically acceptable form, wherein L, R a, R b, R c, R e, R f, R 15as defined herein with z.Such as, in certain embodiments, z is 1 and R 15at ortho position.In certain embodiments, z is 1 and R 15in a position.In certain embodiments, z is 1 and R 15in contraposition.In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.In certain embodiments, L is covalent linkage.In certain embodiments, R eand R fbe connected to form 3-10 unit heterocyclic ring.In certain embodiments, R eand R fbe connected to form 5-14 unit heteroaryl ring.
In some embodiment of formula (II), wherein Z is 5-unit heteroaryl ring, the invention provides the compound of formula (III-a):
Or its pharmaceutically acceptable form, wherein Y 1, Y 2, Y 3, Y 4, G, L, R a, R band R cas defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, Y 1s, Y 2cR 15, Y 3n, and Y 4cH or CR 15, wherein R 15as defined above and herein.In certain embodiments, Y 4cH.In certain embodiments, Y 2on substituting group be C 6aryl (such as, phenyl).
In certain embodiments, wherein Z is 6-unit heteroaryl ring, the invention provides the compound of formula (III-b):
Or its pharmaceutically acceptable form, wherein W 1, W 2, W 3, W 4, G, L, R a, R band R cas defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, 6-unit heteroaryl ring is pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl) or pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl).
In certain embodiments, wherein Z is 9-unit heteroaryl ring, the invention provides the compound of formula (III-c):
Or its pharmaceutically acceptable form, wherein Y 5, Y 6, Y 7, Y 9, Y 10, Y 11, Y 12, Y 13, G, L, R a, R band R cas defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein Z is 10-unit heteroaryl ring, the invention provides the compound of formula (III-e):
Or its pharmaceutically acceptable form, wherein W 6, W 7, W 8, W 9, W 10, W 11, W 12, W 13, G, L, R a, R band R cas defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein Z is 6-unit heterocyclic radical, the invention provides the compound of formula (III-f):
Or its pharmaceutically acceptable form, wherein W 14, W 15, W 16, W 17, W 18, W 19, G, L, R a, R band R cas defined herein.In certain embodiments, L is covalent linkage.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In yet another aspect, wherein R aand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic radical, the invention provides the compound of formula (IV):
Or its pharmaceutically acceptable form, wherein s is 0,1 or 2, and W 20, W 21, W 22, W 23, G, R c, R d, R 15and R 18as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 0, the invention provides the compound of formula (IV-a):
Or its pharmaceutically acceptable form, wherein G, R b, R c, W 20, W 21and W 22as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 0, W 21nR 18, and W 20, W 22and W 23cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (IV-b):
Or its pharmaceutically acceptable form, wherein G, R b, R c, R 18and R 15as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 1, the invention provides the compound of formula (IV-c):
Or its pharmaceutically acceptable form, wherein G, R b, R c, W 20, W 21, W 22and W 23as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 1, W 21nR 18, and W 20, W 22and W 23cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (IV-d):
Or its pharmaceutically acceptable form, wherein G, R b, R c, R 18and R 15as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 1, W 22nR 18, and W 20, W 21and W 23cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (IV-e):
Or its pharmaceutically acceptable form, wherein G, R b, R c, R 18and R 15as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 2, the invention provides the compound of formula (IV-f):
Or its pharmaceutically acceptable form, wherein G, R b, R c, W 20, W 21, W 22and W 23as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein s is 2, W 22nR 18, and W 20, W 21and W 23cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (IV-g):
Or its pharmaceutically acceptable form, wherein G, R b, R c, R 18and R 15as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In yet another aspect, wherein R cand R dbe connected to form C 3-10carbocylic radical or 3-14 unit heterocyclic ring, the invention provides the compound of formula (V):
Or its pharmaceutically acceptable form, wherein W 24, W 26, W 27, W 28and W 30cH independently 2, CHR 15, C (R 15) 2or NR 18, optionally wherein W 25and W 26with the C condensed 6aryl rings or the 6-unit heteroaryl ring condensed replace; T and v is 0 or 1 independently; Wherein G, R a, R b, R 15and R 18as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, t be 0 and v be 0.In certain embodiments, t be 0 and v be 1.In certain embodiments, t be 1 and v be 0.In certain embodiments, t be 1 and v be 1.
In certain embodiments, wherein t be 0 and v be 0, Formula provided by the invention (V-a):
Or its pharmaceutically acceptable form, wherein G, R a, R b, W 25, W 26, W 27and W 28as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, W 27nR 18, and W 25, W 26and W 28cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 25, W 26, W 27and W 28cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein t is 0, v is 0, W 27nR 18, and W 25, W 26and W 28cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (V-b):
Or its pharmaceutically acceptable form, wherein G, R a, R b, R 15and R 18as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein t be 0 and v be 1, Formula provided by the invention (V-c):
Or its pharmaceutically acceptable form, wherein G, R a, R b, W 25, W 26, W 27, W 28and W 29as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, W 26nR 18, and W 25, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 27nR 18, and W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein t is 0, v is 1, W 27nR 18, and W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (V-d):
Or its pharmaceutically acceptable form, wherein G, R a, R b, R 15and R 18as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein t be 1 and v be 1, the invention provides the compound of formula (V-e):
Or its pharmaceutically acceptable form, wherein G, R a, R b, W 24, W 25, W 26, W 27, W 28and W 29as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, W 25nR 18, and W 24, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 26nR 18, and W 24, W 25, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 27nR 18, and W 24, W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.In certain embodiments, W 24, W 25, W 26, W 27, W 28and W 29cH independently 2, CHR 15or C (R 15) 2.
In certain embodiments, wherein t is 1, v is 1, W 27nR 18, and W 24, W 25, W 26, W 28and W 29cH independently 2, CHR 15or C (R 15) 2, the invention provides the compound of formula (V-f):
Or its pharmaceutically acceptable form, wherein G, R a, R b, R 15and R 18as defined above and herein.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).
In certain embodiments, wherein t is 0, v is 0, W 27and W 28cH independently 2, CHR 15with C (R 15) 2, and W 25and W 26with the C condensed 6aryl rings replaces, R cand R dbe connected to form 5,6-bicyclic carbocyclic group spiral shell condensed ring of formula (V-g):
Or its pharmaceutically acceptable form, wherein G, R a, R band R 15as defined above and herein.In certain embodiments, R aand R b-H.In certain embodiments, z is 1.In certain embodiments, G is-OR e.In certain embodiments, G is-Br.But in certain embodiments, G is not halogen (such as ,-Br ,-Cl ,-I).In certain embodiments, R 15be selected from-OR 16and C 1-10whole haloalkyl.
exemplary compound of the present invention
The exemplary compounds of formula (I) and (II) and subclass thereof is shown in following table 1a-1m, and is also recorded in more detail in embodiment 1-253 provided herein.Use the compound of methods analyst as the inhibitor of mankind FAAH of record in detail in embodiment 351.
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1a:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1b:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1c:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1d:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1e:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1f:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1g:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1h:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1i:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1j:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1k:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 11:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 1m:
Other exemplary compounds of formula (I), (II), (III) and subclass thereof are shown in following table 2a-2e, and are also recorded in more detail in embodiment 254-284 provided herein.Use the compound of methods analyst as the inhibitor of mankind FAAH of record in detail in embodiment 351.
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 2a:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 2b:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 2c:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 2d:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 2e:
Other exemplary compounds of formula (I), (IV) and (V) and subclass thereof are shown in following table table 3a-3d, and are also recorded in more detail in embodiment 285-350 provided herein.Use the compound of methods analyst as the inhibitor of mankind FAAH of record in detail in embodiment 351.
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 3a:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 3b:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 3c:
In certain embodiments, described compound is any one compound or its pharmaceutically acceptable form of providing in table 3d:
But in some embodiment of formula (I) and (II) or its subclass, any one in following compound is specifically foreclosed:
In formula (I), (II) and (III) or some embodiment of its subclass, any one in following compound is specifically foreclosed, wherein R 18as defined herein:
In some embodiment of formula (I), (IV) and (V) or its subclass, any one in following compound is specifically foreclosed, wherein R 18as defined herein and R 15-OCH 3,-CN ,-CO 2h ,-CO 2cH 3,-CO 2cH 2cH 3:
II. pharmaceutical composition
In certain embodiments, the invention provides the pharmaceutical composition of compound containing formula (I) or its pharmaceutically acceptable form and pharmaceutically acceptable vehicle.
Pharmaceutically acceptable vehicle comprises any one and all solvents, thinner or other liquid vehicle, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc. that are suitable for required particular dosage form.Such as, Remington ' sPharmaceuticalSciences, 16th edition, E.W.Martin (MackPublishingCo., Easton, Pa., 1980) and Remington:TheScienceandPracticeofPharmacy, the general remark of formula about pharmaceutical composition and/or preparation is disclosed in 21st edition (LippincottWilliams & Wilkins, 2005).
Pharmaceutical composition as herein described can by any method preparation known in field of pharmacology.In general, described preparation method comprises the following steps: activeconstituents is mixed with carrier and/or one or more other ancillary components, then, if desired and/or optionally, makes product be shaped and/or be packaged into required single dosage unit or multiple doses unit.
Pharmaceutical composition can with in batch, form preparation, the packaging of single unitary dose and/or multiple single unitary dose and/or sell.Used herein, " unitary dose " is the discrete magnitude of the pharmaceutical composition of activeconstituents containing predetermined amount.The amount of activeconstituents generally equals the dosage of activeconstituents used individuality and/or a part for described appropriate dosage, the half or 1/3rd of such as described dosage.
The relative quantity of the activeconstituents in pharmaceutical composition of the present invention, pharmaceutically acceptable carrier and/or any other composition along with treated individuality identity, physique and/or illness and in addition the approach of applying said compositions is changed.For example, composition can contain the activeconstituents of 0.1%-100% (w/w).
Pharmaceutically acceptable vehicle for the manufacture of provided pharmaceutical composition comprises inert diluent, dispersion agent and/or granulating agent, tensio-active agent and/or emulsifying agent, disintegrating agent, binding agent, sanitas, buffer reagent, lubricant and/or oil.Also can there is the vehicle such as such as theobroma oil and suppository wax, tinting material, coating agent, sweeting agent, seasonings and perfume compound in composition.
Exemplary thinning agents comprises calcium carbonate, sodium carbonate, calcium phosphate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, secondary calcium phosphate, sodium phosphate lactose, sucrose, Mierocrystalline cellulose, Microcrystalline Cellulose, kaolin, mannitol, Sorbitol Powder, inositol, sodium-chlor, dry starch, W-Gum, Icing Sugar etc. and combination thereof.
Exemplary granulating agent and/or dispersion agent comprise yam starch, W-Gum, tapioca (flour), sodium starch glycollate, clay, Lalgine, guar gum, citrus pulp, agar, wilkinite, Mierocrystalline cellulose and woodwork, natural sponge, Zeo-karb, calcium carbonate, silicate, sodium carbonate, crosslinked PVP (polyvinylpolypyrrolidone), sodium starch glycolate (sodium starch glycollate), carboxymethyl cellulose, croscarmellose sodium (croscarmellose), methylcellulose gum, pregelatinized Starch (starch 1500), Microcrystalline Starch, water-insoluble starch, calcium carboxymethylcellulose, neusilin (Wei Gemu (Veegum)), Sodium Lauryl Sulphate BP/USP, quaternary ammonium compound etc. and combination thereof.
Exemplary surfactants and/or emulsifying agent comprise naturally occurring emulsifying agent (such as, gum arabic, agar, Lalgine, sodium alginate, tragacanth, carrageen (chondrux), cholesterol, xanthan gum, pectin, gelatin, yolk, casein, lanolin, cholesterol, wax and Yelkin TTS), Colloidal Clay (such as, wilkinite [pure aluminium silicate] and Wei Gemu [neusilin]), long chain amino acid derivative, high molecular weight alcohol (such as, stearyl alcohol, hexadecanol, oleyl alcohol, Stearinsaeure triactin, Unister E 275, glyceryl monostearate, propylene glycol monostearate, polyvinyl alcohol), carbomer (carbomer) (such as, carboxyvinyl polymer, polyacrylic acid, acrylate copolymer and carboxyvinyl polymer), carrageenin, derivatived cellulose (such as, Xylo-Mucine, powdery cellulose, Walocel MT 20.000PV, hydroxypropylcellulose, Vltra tears, methylcellulose gum), sorbitan-fatty acid ester (such as, Polyoxyethylene sorbitan mono-laurate [Tween20], Polyoxyethylene sorbitan [Tween60], polyoxyethylene sorbitan monooleate [Tween80], sorbitan monopalmitate [Span40], sorbitan monostearate [Span60], sorbitan tristearate [Span65], XU 61518.10, sorbitan monooleate [Span80]), polyoxyethylene ester (such as, polyoxyethylene monostearate ester [Myri45], polyoxyethylene hydrogenated castor oil, GREMAPHOR GS32, polyoxymethylene stearate and Suo Luotuo (Solutol)), sucrose fatty ester, cithrol (such as, crin not Buddhist (Cremophor)), polyoxyethylene ether (such as, polyoxyethylene lauryl ether [Brij30]), PVP, Diethylene Glycol mono-laurate, Emulphor FM, sodium oleate, potassium oleate, ethyl oleate, oleic acid, Laurate ethyl, Sodium Lauryl Sulphate BP/USP, PluronicF68, Poloxamer188, Cetrimonium Bromide, cetylpyridinium chloride, benzalkonium chloride, Docusate Sodium etc. and/or its combination.
Exemplary binder comprises starch (such as, W-Gum and starch paste), gelatin, sugar (such as, sucrose, glucose, dextrose, dextrin, molasses, lactose, Saccharum lactis, mannitol etc.), natural and synthetical glue (such as, gum arabic, sodium alginate, sea moss extract, panwar glue, gum ghatti, the mucus of isapol skin, carboxymethyl cellulose, methylcellulose gum, ethyl cellulose, Natvosol, hydroxypropylcellulose, Vltra tears, Microcrystalline Cellulose, rhodia, PVP, neusilin (Veegum) and tamarack gather arabogalactan), alginates, polyethylene oxide, polyoxyethylene glycol, inorganic calcium salt, silicic acid, polymethacrylate, wax, water, alcohol etc. and/or its combination.
Exemplary preservative comprises antioxidant, sequestrant, antibiotic antiseptic, antimycotic preservative, alcohol sanitas, acid sanitas and other sanitass.
Exemplary antioxidants comprises alpha-tocopherol, xitix, Quicifal, butylated hydroxy anisole, butylhydroxy toluene, MTG, potassium pyrosulfite, propionic acid, Tenox PG, sodium ascorbate, sodium bisulfite, Sodium Pyrosulfite and S-WAT.
Exemplary chelators comprises ethylenediamine tetraacetic acid (EDTA) (EDTA) and salt and hydrate thereof (such as, sodium ethylene diamine tetracetate, disodium ethylene diamine tetraacetate, trisodium EDTA, Sormetal, EDTA-2K etc.), citric acid and salt thereof and hydrate (such as, single citric acid monohydrate), fumaric acid and salt thereof and hydrate, oxysuccinic acid and salt thereof and hydrate, phosphoric acid and salt thereof and hydrate and tartrate and salt thereof and hydrate.Exemplary antibiotic antiseptic comprises benzalkonium chloride, benzyl rope chloramines, phenylcarbinol, cloth sieve Bo Er, Cetrimonium Bromide, cetylpyridinium chloride, chlorhexidine, butylene-chlorohydrin, parachlorometacresol, chloroxylenol, cresols, ethanol, glycerine, hexetidine, imidazolidine urea, phenol, phenoxyethyl alcohol, phenylethyl alcohol, Phenylmercurinitrate, propylene glycol and Thiomersalate.
Exemplary antimycotic preservative comprises butyl p-hydroxybenzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propylparaben, phenylformic acid, hydroxy-benzoic acid, potassium benzoate, potassium sorbate, Sodium Benzoate, Sodium Propionate and Sorbic Acid.
Exemplary alcohols sanitas comprises ethanol, polyoxyethylene glycol, phenol, phenol system compound, bis-phenol, butylene-chlorohydrin, hydroxybenzoate and phenylethyl alcohol.
Illustrative acid sanitas comprises vitamin A, vitamins C, vitamin-E, β-carotene, citric acid, acetic acid, dehydroacetic acid (DHA), xitix, Sorbic Acid and phytic acid.
Other sanitass comprise tocopherol, VITAMIN E ACETATE, methylsulfonic acid Di Teaoximu (deteroximemesylate), Cetrimonium Bromide, butylated hydroxy anisole (BHA), butylhydroxy toluene (BHT), quadrol, Sodium Lauryl Sulphate BP/USP (SLS), SODIUM LAURYL ETHER SULPHATE (SLES), sodium bisulfite, Sodium Pyrosulfite, potassium sulfite, potassium pyrosulfite, GlydantPlus, phenol resistance to (Phenonip), methyl p-hydroxybenzoate, Germall115, GermabenII, Ni Aolong (Neolone), Kathon CG (Kathon) and excellent this (Euxyl).In certain embodiments, sanitas is antioxidant.In other embodiments, sanitas is sequestrant.
Examples of buffers comprises citrate buffer, acetate buffer, phosphate buffered saline buffer, ammonium chloride, calcium carbonate, calcium chloride, citrate of lime, Neo-Calglucon, Glucoheptonic Acid Calcium salt, calcium gluconate, D-glyconic acid, neurosin, calcium lactate, propionic acid, calcium levulinate, valeric acid, Si Liaodengji dicalcium phosphate feed grade, phosphoric acid, tricalcium phosphate, alkali calcium phosphate, potassium acetate, Repone K, potassium gluconate, potassium mixture, dipotassium hydrogen phosphate, potassium primary phosphate, potassiumphosphate mixture, sodium acetate, sodium bicarbonate, sodium-chlor, Trisodium Citrate, Sodium.alpha.-hydroxypropionate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, sodium phosphate mixture, Trometamol, magnesium hydroxide, aluminium hydroxide, Lalgine, pyrogen-free matter water, isotonic physiological saline, Ringer's solution, ethanol etc. and combination thereof.
Exemplary lubricants comprises Magnesium Stearate, calcium stearate, stearic acid, silicon-dioxide, talcum, Fructus Hordei Germinatus, Glyceryl Behenate, hydrogenated vegetable oil, polyoxyethylene glycol, Sodium Benzoate, sodium acetate, sodium-chlor, leucine, lauryl magnesium sulfate, Sodium Lauryl Sulphate BP/USP etc. and combination thereof.
Exemplary oil comprises Prunus amygdalus oil, almond fruit oil, Lipoval A, babassu oil, Oils, bergamot peel, seed of black currant oil, borage oil, oleum alchitri, chamomile oil, Canola oil, Oleum Cari, babassu oil, Viscotrol C, Oleum Cinnamomi, theobroma oil, Oleum Cocois, Oils,glyceridic,cod-liver, coffee oil, Semen Maydis oil, Oleum Gossypii semen, fat of Oromaius norvaehollandeae, Oil of Eucalyptus, Oenothera oil, fish oil, linseed oil, Geraniol, calaba oil, raisin seed oil, hazelnut oil, oil of hyssop, isopropyl myristate, jojoba oil, Hawaii kernel oil, lavandin oil, oleum lavendulae, lemon oil, litsea cubeba oil, macadimia nut oil, high mallow oil, mango seed oil, Bai Manghua seed oil, ermine oil, ucuhuba oil, sweet oil, orange oil, tilapia oil, plam oil, palm-kernel oil, persic oil, peanut oil, seed of Papaver somniferum L. powder, Semen Cucurbitae oil, rapeseed oil, Rice pollard oil, rosemary oil, Thistle oil, santal oil, Camellia oil, savory oil, Oleum Hippophae, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, Ji oil, camellia caul-fat, vetiver oil, walnut oil and wheatgerm oil.Exemplary oil includes but not limited to butyl stearate, sad Witepsol W-S 55, capric acid Witepsol W-S 55, cyclomethicone, ethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, Standamul G, oleyl alcohol, silicone oil and combination thereof.
The liquid dosage form used for oral and parenteral comprises pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active component, liquid dosage form can also containing inert diluent conventional in this area, such as water or other solvents, solubilizing agent and emulsifying agent (such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (such as, Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitan-fatty acid ester and its mixture.Except inert diluent, oral compositions can also contain adjuvant, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, seasonings and perfume compound.In some embodiment that parenteral is used, mixed by concatenator of the present invention with solubilizing agent, described solubilizing agent is such as crin not Buddhist, alcohols, oils, modification oils, glycols, polysorbate, cyclodextrin, polymkeric substance and combination thereof.
Suitable dispersion agent or wetting agent and suspension agent can be used to allocate injectable formulation according to known technology, such as sterile injectable water-based or oily suspensions.Sterile injectable preparation can be sterile injectable solution, suspension or emulsion in the acceptable thinner of nontoxic parenteral or solvent, such as, solution in 1,3 butylene glycol.Operable acceptable mediator and solvent are water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, usually sterile non-volatile oils is used as solvent or suspension medium.For this reason, the nonvolatile oil comprising any gentleness of synthetic glycerine one ester or triglyceride can use.In addition, lipid acid (such as oleic acid) also can be used for preparing injectable thing.
Such as, can by the filtration of bacteria retaining filter, or pass through to add disinfectant with the aseptic solid composite form that can be dissolved or dispersed in before use in sterilized water or other sterile injectable medium, by injectable formulation sterilizing.
For prolong drug effect, usually need to slow down the absorption of the medicine from subcutaneous or intramuscular injection.This can realize by using the liquid suspension of water-soluble weak crystallization or amorphous substance.The uptake rate of medicine is then depending on its dissolution rate, and its dissolution rate is determined by crystalline size and crystalline form.Or, by by medicine dissolution or be suspended in the delayed absorption realizing the medicament forms that parenteral is used in oily mediator.
The composition of per rectum or vaginal application is generally suppository, its by by concatenator of the present invention with for solid but under body temperature in rectum or vaginal canal, therefore melt the suitable nonirritant excipient of also release of active ingredients or carrier (such as theobroma oil, polyoxyethylene glycol or suppository wax) mixes and prepares for liquid at ambient temperature.
Orally administered solid dosage comprises capsule, tablet, pill, powder and granule.In described solid dosage, the pharmaceutically acceptable vehicle of activeconstituents and at least one inertia or carrier (such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade) and/or following material are mixed: a) weighting agent or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent, such as carboxymethyl cellulose, alginic acid ester, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) heat preserving agent, such as glycerine; D) disintegrating agent, such as agar, calcium carbonate, yam starch or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) resistance solvent, such as paraffin; F) accelerator, such as quaternary ammonium compound is absorbed; G) wetting agent, such as hexadecanol and glyceryl monostearate; H) sorbent material, such as kaolin and wilkinite; And i) lubricant, such as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP; With its mixture.When capsule, tablet and pill, formulation can contain buffer reagent.
Use such as lactose or the vehicle such as toffee and high molecular weight polyethylene glycol, also the solids composition of similar type can be used as the weighting material in soft hard-filled gelatin capsule.Tablet, lozenge, capsule, pill and the granule solid dosage with dressing and shell (in such as casing and field of pharmaceutical preparations other dressings well-known) can be prepared.They optionally can have only or preferential optional to delay the composition of mode release of active ingredients in certain part of enteron aisle containing opacifying agent.The example of operable embedding composition comprises polymeric material and wax.Use such as lactose or the vehicle such as toffee and high molecular weight polyethylene glycol, also the solids composition of similar type can be used as the weighting material in soft hard-filled gelatin capsule.
Activeconstituents can be the form of micropackaging together with one or more vehicle as described above.Tablet, lozenge, capsule, pill and the granule solid dosage with dressing and shell (in such as casing, controlled release coat and field of pharmaceutical preparations other dressings well-known) can be prepared.In described solid dosage, activeconstituents can be mixed with at least one inert diluents such as such as sucrose, lactose or starch.When normally producing, described formulation can contain other materials besides inert diluents, such as, and tableting lubricant and other compression aids, such as Magnesium Stearate and Microcrystalline Cellulose.When capsule, tablet and pill, formulation can contain buffer reagent.They optionally can have only or preferential optional to delay the composition of mode release of active ingredients in certain part of enteron aisle containing opacifying agent.The example of operable embedding composition comprises polymeric material and wax.
Local and/or the transdermal administration formulation of the compounds of this invention can comprise ointment, paste, emulsifiable paste, washing lotion, gel, powder, solution, sprays, inhalation and/or paster.In general, aseptically, by activeconstituents and pharmaceutically acceptable carrier and/or when needing any required sanitas and/or buffer reagent mix.In addition, use percutaneous plaster is contained in the present invention, and it has the additional advantage making activeconstituents controlled delivery to health usually.Such as, can by by solubilize active ingredients and/or be scattered in suitable medium and prepare described formulation.Selectively or in addition, can by providing rate controlling membranes and/or carrying out speed control by being scattered in polymeric matrix and/or gel by activeconstituents.
Appropriate device for Intradermal delivery pharmaceutical composition as herein described comprises hour hand device, such as United States Patent (USP) 4, and 886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; With 5,417, those devices described in 662.The device that can enter effective penetration length of skin by limiting pin uses intracutaneous composition, such as open those devices described in WO99/34850 of PCT and its functional equivalent.Jet injection device is applicable, and aqueous vaccine is delivered to corium via liquid jet injector and/or via thrusting stratum corneum and producing the pin of jet arriving corium by it.Jet injection device is such as described in United States Patent (USP) 5, and 480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; With in open WO97/37705 and WO97/13537 of PCT.Medicinal powder/the particle delivery device using pressurized gas the vaccine of powder type to be accelerated across skin outer layer arrival corium is suitable.Selectively or in addition, conventional syringe can be used in the classical Man Tuofa of intradermal administration.
The preparation being suitable for topical application comprises liquid and/or semi-liquid preparations, such as liniment, washing lotion, oil-in-water and/or water-in-oil emulsion (such as emulsifiable paste, ointment and/or paste) and/or solution and/or suspension.Can the formulation example of topical application as can containing the activeconstituents of the 1%-10% that has an appointment (w/w), but the concentration of activeconstituents may be up to activeconstituents solubility limit in a solvent.The preparation of topical application can also contain one or more other compositions as herein described.
Pharmaceutical composition of the present invention can be suitable for preparing via the dosage form of oral cavity pulmonary administration, pack and/or selling.Described preparation can contain dried particles, and it contains activeconstituents and has the diameter of about 0.5-7 nanometer or about 1-6 nanometer.Described composition is expediently for being suitable for using the device (the described dry powder reservoir that propellant flow can be led is to make powder dispersion) comprising dry powder reservoir and/or the dry powder form using self-propelled solvent/powder dispense container (such as, containing the device dissolving and/or be suspended in the activeconstituents in low boiling propellant in sealed vessel) to use.Described powder contains particle, and wherein the particle of at least 98 % by weight has the diameter that is greater than 0.5 nanometer and the particle of at least 95 quantity % has the diameter being less than 7 nanometers.Or the particle of at least 95 % by weight has the diameter that is greater than 1 nanometer and the particle of at least 90 quantity % has the diameter being less than 6 nanometers.Dry powder composite can contain the solid fines thinners such as such as sugar and it normally provides with unit dosage.
Low boiling propellant generally comprises boiling point at atmosheric pressure lower than the liquid propellant of 65 °F.In general, propelling agent can account for the 50-99.9% (w/w) of composition, and activeconstituents can account for the 0.1-20% (w/w) of composition.Propelling agent can also contain other compositions, as liquid non-ionic and/or solid anionic tensio-active agent, and/or solid diluent (it can have the granularity with the particle same order containing activeconstituents).
The pharmaceutical composition of the present invention that preparation is used for sending through lung can provide the activeconstituents of the drops of solution and/or suspension.Described preparation can contain optionally aseptic water-based and/or dilute alcohol solution and/or form of suspension preparation, the packaging of activeconstituents and/or sell, and any spraying and/or atomisation unit can be used expediently to use.Described preparation can also contain one or more other compositions, comprises seasonings (such as soluble saccharin), ethereal oil, buffer reagent, tensio-active agent and/or sanitas (as methyl hydroxybenzoate).The drop that this route of administration provides can have the mean diameter of about 0.1-200 nanometer.
Preparation as can be used for sending through lung described herein can be used for intranasal delivery pharmaceutical composition of the present invention.The another kind of preparation being suitable for intranasal administration is containing activeconstituents and has the meal of the average grain of about 0.2-500 micron.By being aspirated through nasal meatus rapidly from the powder container remained near nostril, use described preparation.
Be suitable for the formulation example of nasal administration as lacked to 0.1% (w/w) and the activeconstituents of height to 100% (w/w) containing having an appointment, and can one or more other compositions as herein described be contained.Pharmaceutical composition of the present invention can be suitable for dosage form preparation, packaging that direct oral cavity uses and/or sell.Described formulation example is as the form that can be tablet and/or the lozenge using ordinary method to obtain, and such as can contain the activeconstituents of 0.1-20% (w/w), surplus comprises oral solubilized and/or degradable composition and chooses any one kind of them or multiple other compositions as herein described.In addition, be suitable for preparation that direct oral cavity uses and can comprise powder containing activeconstituents and/or aerosolization and/or atomized soln and/or suspension.When described Powdered, aerosolization and/or atomization preparation dispersion, it can have at the average grain of about 0.1-200 nanometer and/or drop size, and can also contain one or more other compositions as herein described.
The dosage form that pharmaceutical composition of the present invention can be suitable for using through eye is prepared, packs and/or is sold.Described formulation example is as the form that can be eye drop, and it is such as containing solution in water-based or oily liquid carrier of the activeconstituents of 0.1/1.0% (w/w) and/or suspension.Described dropping liquid can also contain buffer reagent, salt and/or one or more other compositions as herein described.Other useful preparations can used through eye comprise the preparation of the activeconstituents containing microcrystalline form and/or Liposomal formulation form.Expection [Dan and/or eye drop will within the scope of the invention.
Although the description of pharmaceutical composition provided in this article relates generally to the pharmaceutical composition being suitable for using the mankind, it will be apparent to those skilled in the art that described composition is generally suitable for using the animal of all kinds.Change the pharmaceutical composition being suitable for using the mankind to be fully understood to make described composition be suitable for using various animal, and general veterinary drug pharmacologist can utilize normal experiment design and/or perform this change.About the preparation of pharmaceutical composition and/or the general provisions of manufacture can see such as Remington:TheScienceandPracticeofPharmacy the 21st edition, LippincottWilliams & Wilkins, 2005.
The present invention also comprises cartridge bag and/or test kit further.The cartridge bag provided and/or test kit can comprise the composition and container (such as, bottle, ampoule, bottle, syringe and/or distribution bag, or other suitable containers) that provide.In some embodiments, the test kit provided optionally comprises second container further, and it comprises the suitable aqueous carrier for making preparation use individual composition dilution or suspend.In some embodiments, the content of the preparation container provided and solvent container combines and forms at least one unit dosage.
In some embodiments, use together with pain relieving (PCA) equipment that composition provided by the invention can be controlled with individuality, if wherein require Pain management, then individuality can use such as opium analgesics.
Optionally, single container can comprise the one or more rooms containing the composition provided and/or suitable suspension or diluting water carrier.In some embodiments, single container can be suitable for amendment, makes this container can accept physics and changes, to allow the component combination of each room and/or each room.Such as, paper tinsel or plastics bag can comprise two or more rooms of being separated by aperture seal bar, and sealed strip can break, thus once produce the signal making sealed strip break, allow the content combination of two independent rooms.Therefore, cartridge bag or test kit can comprise this multichamber vessel, containing the composition provided and suitable solvent and/or suitable suspension use carrier.
Optionally, in this test kit of the present invention, also operation instruction is provided.This explanation generally can provide such as relevant dosage and the instruction of using.In other embodiments, the more details that can also provide about the special instruction to special container and/or administration system are described.In addition, the special instruction that can provide and use together with other treatment and/or combinationally use is described.In a non-limitative example, preparation of the present invention can be used with opium analgesics and be combined, this optionally can comprise pain relieving (PCA) equipment using individuality controlled, therefore, the operation instruction of the preparation provided can comprise the operation instruction combinationally using PCA application equipment.
III. use and methods for the treatment of
The invention provides the method for the illness for the treatment of FAAH mediation, comprise the compound to the formula (I) of individual administering therapeutic significant quantity in need or its pharmaceutically acceptable form.
The present invention also provides the method suppressing FAAH in individuality, comprises compound from the formula (I) of significant quantity to individual treatment in need or its pharmaceutically acceptable form of using.
The present invention also provides a kind of method of activation of external or in vitro suppression FAAH path, comprises and FAAH albumen is contacted with formula (I) compound presenting in an amount at least sufficient to reduce FAAH Pathway Activation.
The present invention also provides the compound of formula (I) to be used for the treatment of the purposes of the illness of FAAH mediation in individuality.
The present invention also provides the purposes of compound for the manufacture of medicine of formula (I).In certain embodiments, described medicine is used for the treatment of the illness of FAAH mediation.
Expect that " individuality " be applied includes but not limited to that the mankind (namely, the sex of any age bracket, such as, the pediatrics department individuality (such as, baby, children and adolescents) or adult individu is (such as, youngster, the elderly or old man etc.)) and/or other primates (such as, macaque, rhesus monkey); Mammals, comprises commercial relevant Mammals, as ox, pig, horse, sheep, cat and/or dog; And/or birds, comprise commercial relevant birds, as chicken, duck, goose and/or turkey.
Used herein, except as otherwise noted, term " treatment " refer to individuality suffer from specified disease, disorder or illness time the effect that occurs, refer to the severity reducing disease, disorder or illness, or delay or slow down the progress of disease, disorder or illness.
Used herein, except as otherwise noted, term " prevention " refers to the effect occurred before individuality starts to suffer from specified disease, disorder or illness, refers to the severity suppressing or reduce disease, disorder or illness.
Used herein, except as otherwise noted, term " control " is included in the individuality suffering from specified disease, disorder or illness the recurrence preventing disease, disorder or illness, and/or extend suffered from specified disease, the individuality of disorder or illness keeps time of alleviating.This term comprises regulation and control disease, the threshold value of disorder or illness, development and/or time, or change individual response disease, disorder or illness mode.
Used herein, except as otherwise noted, " the treatment significant quantity " of compound is its amount in the treatment of disease, disorder or illness or is enough to provide treatment benefit in controlling, or is enough to delay or minimizes one or more symptoms relevant to disease, disorder or illness.The compound for the treatment of significant quantity refer to separately or the therapeutical agent co-administered with other treatment amount disease, disorder or illness treatment or provide treatment benefit in controlling.Term " treatment significant quantity " can comprise and improves whole treatment, reduce or avoid the symptom of disease or illness or the amount of the cause of disease, or strengthens the amount of therapeutic efficiency of another kind of therapeutical agent.
Used herein, except as otherwise noted, " the prevention significant quantity " of compound is one or more symptoms of being enough to prevent disease, disorder or illness relevant to disease, disorder or illness or prevents its amount recurred.The compound of prevention significant quantity refers to separately or the amount of therapeutical agent used with other agents provides prevention benefit in the prevention of disease, disorder or illness.Term " prevention significant quantity " can comprise the amount of the prevention effects improved whole prevention or strengthen another kind of preventive.
Used herein, " suppression " and " inhibitor " etc. refer to relative to carrier, and compound reduces, slows down, stops or preventing the ability of the activity (such as, FAAH activity) of specific bioprocess in cell.
Used herein, " illness of FAAH mediation " refers to by suppressing the medicable disease of FAAH activity, disorder or illness." disease ", " disorder " or " illness " are used interchangeably herein.The illness of FAAH mediation includes but not limited to the disorder of antalgesic, inflammatory conditions, immunologic derangement, central nervous system, metabolism disorder, heart disease and glaucoma.
In certain embodiments, the illness of FAAH mediation is antalgesic.Used herein, " antalgesic " includes but not limited to neuropathic pain (such as, peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (such as, chronic pain pain and other forms of chronic pain, as post-operative pain, such as, stern, the pain occurred after knee or other transplantations), preoperative pain, the stimulation (painful pain) of pain receptor, acute pain (such as, illusion and temporary acute pain), non-inflammatory pain, inflammatory pain, the pain that cancer is relevant, trauma pain, burn pain, post-operative pain, the pain that medical procedures is relevant, the pain caused of scratching where it itches, painful bladder syndrome, premenstrual irritated disorderly relevant pain and/or premenstrual syndrome, the pain that chronic fatigue syndrome is relevant, the pain that premature labor is relevant, dopy gives up the relevant pain of syndrome, arthralgia, arthritis ache (the pain that such as, crystalline arthritis is relevant, osteoarthritis, psoriasis arthropathica, urarthritis, reactive arthritis, rheumatoid arthritis or Reiter sacroiliitis), lumbus sacrum pain, musculoskeletal pain, headache, migraine, myalgia, back pain, cervicodynia, toothache, tooth/Orofacial pain, visceral pain etc.
One or more antalgesics of expecting herein can comprise the mixing (such as, painful pain, inflammatory pain, neuropathic pain etc.) of all kinds pain above-mentioned and as herein described.In some embodiments, specific pain in the highest flight.In other embodiments, antalgesic comprises the pain of two or more type, does not have one in the highest flight.Clinician can determine to realize the dosage for the treatment significant quantity of the particular individual of antalgesic.
In certain embodiments, antalgesic is neuropathic pain.Term " neuropathic pain " refers to the pain caused by nerve injury.Neuropathic pain is different from painful pain, and painful pain is the pain caused by the acute tissue injury of the little cutaneous nerve related in muscle or reticular tissue or nervelet.Neuropathic pain is generally long-term or chronic, and usually after initial acute tissue injury, develops a couple of days or several months.Neuropathic pain may relate to lasting idiopathic pain and paralgesia (it is the pain reaction to usually not causing the stimulation of pain).Neuropathic pain can also with hyperpathia (wherein there is the reaction of the aggravation to the usually small pain stimulation thing such as such as pinprick) for feature.Neuropathic pain disorders may develop after nerve injury and the pain produced may even still periods of months or several years after damage is originally cured.Neuronal damage can occur in some region of nerve, Dorsal root, spinal cord or brain around.Neuropathic pain disorders includes but not limited to: diabetic neuropathy (such as, diabetic peripheral neuropathy), sciatica, non-specific back pain, multiple sclerosis pain, carpal tunnel syndrome, fibromyalgia, HIV associated neurological disease, neurodynia (such as, postherpetic neuralgia and trigeminal neuralgia), the pain caused by physical trauma (such as, amputation, operation, intrusive mood medical procedures, toxin, burn, infect), the pain that cancer or chemotherapy cause (such as, the pain that chemotherapy causes, peripheral neuropathy as chemotherapy causes), and the pain that inflammatory conditions causes (such as, chronic inflammatory disorder).Neuropathic pain can be caused by peripheral nerve disorders such as such as neuroma, Nerve entrapments, Crushed nerve, neutral stretch or incomplete Nerve Transection, mononeuropathy or polyneuropathys.Neuropathic pain also can be oppressed by such as dorsal root ganglion; Spinal cord inflammation; The contusion of spinal cord, tumour or hemisection; The tumour of brain stem, thalamus or cortex; Or the disorder such as the wound of brain stem, thalamus or cortex causes.
The symptom of neuropathic pain is different and is usually described as spontaneous shouting pain and lancinate pain or ongoing burning pain.In addition, also exist usually do not cause the relevant pain of the sensation of pain (paresthesia and sensory disturbance) with such as " numbness and uncomfortableness " etc., (oxypathy), noxious stimulation are increased to the susceptibility touched after pain perception (dynamic, static state or thermalgesia are extremely), (hot, cold, mechanical hyperalgesia) is increased to the susceptibility of noxious stimulation, remove and stimulate rear constant pain to feel that (hyperpathia) or selectivity feel that path does not exist or lacks (hypalgia).
In certain embodiments, antalgesic is non-inflammatory pain.The type of non-inflammatory pain includes but not limited to that peripheral neuropathic pain (such as, the pain caused by peripheral nervous system lesions or malfunction), central pain (such as, the pain caused by central nervous system injury or malfunction), deafferentiation pain (such as, because being delivered to the pain that the sensory deprivation in central nervous system causes), chronic pain pain (such as, the cancer pain of some type), the noxious stimulation of pain receptor (such as, the pain of response tissue injury or imminent tissue injury and perception), phantom pain (such as, the pain of a part for the health no longer existed of institute's perception, limbs as excised), the pain of mental patient institute perception (such as, pain when there is not physical reason) and migrans pain is (such as, wherein pain repeatedly changes position in health).
In certain embodiments, antalgesic is inflammatory pain.In certain embodiments, antalgesic (such as, inflammatory pain) is relevant to inflammatory conditions and/or immunologic derangement.
In certain embodiments, the illness of FAAH mediation is inflammatory conditions.Term " inflammatory conditions " refers to pain (grieved, by generation objectionable impurities and nerve stimulation cause), heat (scorching hot, caused by vasorelaxation), rubescent (flush, caused by vasorelaxation and blood flow increase), swelling (tumour, caused by the excessive inflow of fluid or finite exit boundaries) and/or afunction (dysfunction, its can be partially or completely, provisional or persistent) sign be those diseases of feature, disorder or illness.Inflammation presents various ways, includes but not limited to acute, tackiness, atrophic, Catarrhal, chronic, hardening, diffusivity, dissemination, exudative, fibering, fibrosis, Focal, granulomatous, proliferative, hypertrophica, chromic fibrous, transitivity, gangrenosum acne, occlusive, substance, shaping, Hypertrophic, proliferative, pseudomembranous, suppurative, hardening, serofibrinous, serosity, pure, specificity, subacute, suppurative, toxic, traumatic and/or ulcerative inflammation.
Exemplary inflammatory conditions includes but not limited to the inflammation that acne is relevant, anemia (such as, aplastic anemia, hemolytic autoimmunity anemia), asthma, arteritis (such as, polyarteritis, temporal arteritis, periarteritis, Takayasu arteritis), sacroiliitis (such as, crystalline arthritis, osteoarthritis, psoriasis arthropathica, urarthritis, reactive arthritis, rheumatoid arthritis and Reiter sacroiliitis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune disorders, allergy or anaphylaxis, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (such as, type i diabetes, type ii diabetes), skin disorder (such as, psoriatic, eczema, burn, dermatitis, pruritus (sending out overworked)), endometriosis, Guillain-Barre syndrome, infect, ischemic heart disease, Kawasaki is sick, glomerulonephritis, gingivitis, irritated, headache (such as, migraine, headache, tension headache), intestinal obstruction (such as, postoperative ileus and the intestinal obstruction in septicemia), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal dysfunction (such as, is selected from peptide ulceration, region enteritis, diverticulitis, gastrointestinal hemorrhage, eosinophil driven's gastrointestinal dysfunction (such as, eosinophil driven's granulocytic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophil driven's colitis), gastritis, diarrhoea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel (IBD) (such as, Crohn's disease, ulcerative colitis, collagenous colitis, lymphatic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, uncertain colitis) and inflammatory bowel irritable syndrome (IBS)), lupus, multiple sclerosis, scleroderma, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus, pernicious anemia, stomach ulcer, polymyositis, primary biliary cirrhosis, relevant neuroinflamation (such as, Parkinson's disease disorderly to brain, lymphogranulomatosis and Alzheimer's disease), prostatitis, the chronic inflammatory diseases that brain radiotherapy damage is relevant, pelvic disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematous, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren syndrome, thyroiditis, graft-rejection, tendinitis, wound or damage (such as, frostbite, chemical irritant, toxin, scar, burn, personal injury), vasculitis, vitiligo and Wegener granulomatosis.In certain embodiments, inflammatory disorders is selected from sacroiliitis (such as, rheumatoid arthritis), inflammatory bowel, inflammatory bowel syndrome, asthma, psoriatic, endometriosis, interstitial cystitis and prostatistis.In certain embodiments, inflammatory conditions is acute inflammatory illness (such as, by infecting the inflammation caused).In certain embodiments, inflammatory conditions is chronic inflammatory disorder (illness such as, caused by asthma, sacroiliitis and inflammatory bowel).Described compound also can be used for treating the inflammation relevant with non-inflammation myalgia to wound.Described compound also can be used for treating the inflammation relevant to cancer.
In certain embodiments, the illness of FAAH mediation is immunologic derangement.Such as autoimmunity disorder waits immunologic derangement to include but not limited to that sacroiliitis (comprises rheumatoid arthritis, SpA, urarthritis, degenerative joint disease is (as osteoarthritis, systemic lupus erythematous), Sjogren syndrome, ankylosing spondylitis, do not break up spondylitis, behcets disease, autoimmune hemolytic anemia disease, multiple sclerosis, amyotrophic lateral sclerosis, albuminoid degeneration, acute shoulder pain, psoriasis arthropathica and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin inflammatory disorders (such as, psoriatic, eczema, burn, dermatitis, pruritus (sending out overworked)), the enuresis, eosinophil driven's disease, gastrointestinal dysfunction (such as, is selected from peptide ulceration, regional enteritis, diverticulitis, gastrointestinal hemorrhage, eosinophil driven's gastrointestinal dysfunction (such as, eosinophil driven's esophagitis, eosinophilic gastritis, eosinophil driven's gastroenteritis, eosinophil driven's colitis), gastritis, diarrhoea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel (IBD) (such as, Crohn's disease, ulcerative colitis, collagenous colitis, lymphatic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, uncertain colitis) and inflammatory bowel irritable syndrome (IBS)) and gastrointestinal prokinetic agent improve disorder (such as, intestinal obstruction, intestinal obstruction during post operative ileus and sepsis, gastroesophageal reflux disease (GORD, or its synonym GERD), eosinophilic esophagitis, gastroparesis are as diabetic gastroparesis, Food intolerance and food anaphylaxis and other functional bowel disorder diseases, as non-ucler dyspepsia (NUD) and NCCP (NCCP comprises costal chondritis)).
In certain embodiments, inflammatory disorders and/or immunologic derangement are gastrointestinal dysfunction.In some embodiments, gastrointestinal dysfunction is selected from gastrointestinal dysfunction (such as, be selected from peptide ulceration, regional enteritis, diverticulitis, gastrointestinal hemorrhage, eosinophil driven's gastrointestinal dysfunction (such as, eosinophil driven's esophagitis, eosinophilic gastritis, eosinophil driven's gastroenteritis, eosinophil driven's colitis), gastritis, diarrhoea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel (IBD) (such as, Crohn's disease, ulcerative colitis, collagenous colitis, lymphatic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, uncertain colitis) and inflammatory bowel syndrome (IBS)).In certain embodiments, gastrointestinal dysfunction is inflammatory bowel (IBD).
In certain embodiments, inflammatory conditions and/or immunologic derangement are skin disorders.In some embodiments, skin disorder is pruritus (sending out overworked), psoriatic, eczema, burn or dermatitis.In certain embodiments, skin disorder is psoriatic.In certain embodiments, skin disorder is pruritus.
In certain embodiments, the illness of FAAH mediation is the disorder (CNS) (" CNS is disorderly ") of central nervous system.Exemplary CNS disorder includes but not limited to neurotoxicity and/or nerve injury, apoplexy, multiple sclerosis, Spinal injury, epilepsy, mental disorder, somnopathy, dyskinesia, feels sick and/or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and dopy.
In certain embodiments, CNS disorder is neurotoxicity and/or nerve injury, such as, as acute nerve injury (such as, traumatic brain injury (TBI), apoplexy, epilepsy) or the result of chronic neurodegenerative disorder (such as, multiple sclerosis, Parkinson's disease, lymphogranulomatosis, amyotrophic lateral sclerosis, Alzheimer's disease).In certain embodiments, compound of the present invention provides neuroprotective, such as, for acute nerve injury or chronic neurodegenerative disorder.
In certain embodiments, CNS disorder is apoplexy (such as, ishemic stroke).
In certain embodiments, CNS disorder is multiple sclerosis.
In certain embodiments, CNS disorder is Spinal injury.
In certain embodiments, CNS disorder is epilepsy.
In certain embodiments, CNS disorder is mental disorder, such as, and illness, learning disorder or schizophrenia that depression, anxiety or anxiety are relevant.
In certain embodiments, CNS disorder is depressed.Used herein, " depression " comprises depressive disorder or illness, such as major depressive disorder (such as, unipolar depression), dysthymic disorder (such as, chronic, minor depressive), bipolar disorder (such as, manicdepressive), Seasonal Affective Disorder and/or the depression relevant to dopy (such as, giving up).Depression can be clinical or subclinical depression.Depression can be relevant to premenstrual syndrome and/or premenstrual irritated disorder.
In certain embodiments, CNS disorder is anxiety.Used herein, " anxiety " includes but not limited to the illness that anxiety is relevant with anxiety, such as, after clinical anxiety, Phobias, agoraphobe, generalized anxiety disorder, specific phobias, social phobia, obsession, acute stress disorder, wound stress disorders, the adjustment disorder with anxiety feature, depressed relevant anxiety disorder, the Anxiety disorders caused because of general medical condition, anxiety disorder that material brings out, anxiety (such as, give up, rely on, recover) that dopy is relevant and feel sick and/or vomit relevant anxiety.The sleep of individuality (such as, suffering from the individuality of anxiety) can also be induced or promote to this treatment.
In certain embodiments, CNS disorder is learning disorder (such as, attention not enough disorderly (ADD)).
In certain embodiments, CNS disorder is schizophrenia.
In certain embodiments, CNS disorder is somnopathy." somnopathy " moves syndrome (DSPS), Periodic limb movement disorder (PLMD), low hypopnea syndrome, rapid eye movement behavior disorder (RBD), in shifts somnopathy (SWSD) and sleeping problems (such as after including but not limited to insomnia, narcolepsy, sleep apnea, restless leg syndrome (RLS), sleep phase, parasomnias), such as bad dream, sleep terror fright at night, somniloquy, ram, snore and trismus and inability to speak and/or grind one's teeth in sleep (bruxism).
In certain embodiments, CNS disorder is dyskinesia, such as, basal ganglion is disorderly, such as, the dyskinesia that Parkinson's disease, levodopa cause, lymphogranulomatosis, GillesdelaTourette syndrome, tardive dyskinesia and myodystonia.
In certain embodiments, CNS disorder is Alzheimer's disease.
In certain embodiments, CNS disorder is amyotrophic lateral sclerosis (ALS).
In certain embodiments, CNS disorder is felt sick and/or vomiting.
In certain embodiments, CNS disorder is dopy (such as, opioid drug, Nicotine, Cocaine, incitantia or alcohol addiction).
In other embodiments, the illness of FAAH mediation is heart disease, such as, is selected from hypertension, recycle system shock, myocardial ischemia-reperfusion injury and atherosclerosis.
In certain embodiments, the illness of FAAH mediation is metabolism disorder (such as, expendable illness, the illness relevant with obesity or its complication).
In certain embodiments, metabolism disorder is expendable illness.Used herein, " expendable illness " includes but not limited to the emaciation (such as, relevant to cancer weight loss, the weight loss of being correlated with other general curative illnesss, unsuccessfully relevant weight loss etc. of losing weight) of apocleisis and various character.
In certain embodiments, metabolism disorder is the illness relevant with obesity or its complication.Used herein, " illness relevant with obesity " includes but not limited to that obesity, undesirable body weight increase (such as, drug-induced or the body weight caused of giving up smoking increases) and excessive eating disorder is (such as, eat and drink immoderately, exessive appetite, force feed or lack appetite and control, often kind can optionally cause undesirable body weight to increase or fat).Used herein, " obesity " and " hypertrophy " refers to that the I class defined by the World Health Organization is fat, II class is fat, III class is fat and pre-obesity (such as, " overweight ").
Expection reduces fat and stores and will provide various main and/or secondary benefit (such as in individuality, suffer from the individuality of the complication relevant with obesity in diagnosis), such as, the response (such as, suffering from the individuality of type ii diabetes in diagnosis) of Regular Insulin is increased; Reduce blood pressure rising; Reduce cholesterol levels to raise; And/or reduce (or reducing risk or deterioration) ischemic heart disease, arteriovascular diseases, stenocardia, myocardial infarction, apoplexy, migraine, congestive heart failure, venous thrombosis, pulmonary infarction, gallbladdergallstonecholetithiasis, Gastroesophageal reflux disease, obstructive sleep apnea, Obesity-hypoventilation syndrome, asthma, gout, poor fluidity, back pain, erective dysfunction, the urinary incontinence, liver injury (such as, the liver injury of Fatty Liver Disease, liver cirrhosis, alcoholic cirrhosis, endotaxin mediate) or chronic renal failure.Therefore, method of the present invention is suitable for obese individuals, diabetic individual and excessive drinking individuality.
In some embodiments, the treatment illness relevant with obesity or its complication relate to the body weight alleviating individuality.In some embodiments, the treatment illness relevant with obesity or its complication relate to individual appetite control.
In other embodiments, the illness of FAAH mediation is glaucoma.
IV. use
Compound provided herein can use to be used the effective any amount for the treatment of and any route of administration.Required exact amount by look individual kind, age and generalized case, infection severity, particular composition, its mode of administration, its active patterns etc. and change with Different Individual.
Use the object with dose uniformity for facility, usually compound of the present invention is mixed with unit dosage.But should be appreciated that, total every per daily dose of the present composition is determined by attending doctor in the scope that rational medicine judges.The particular treatment effective dose level of any particular individual or organism depending on many factors, will comprise the severity of treated disease, disorder or illness and disorder; The activity of the given activity composition used; The particular composition used; Individual age, body weight, general health situation, sex and diet; Time of application; Route of administration; With the discharge rate of used given activity composition; The treatment time length; The medicine combinationally using with used given activity composition or use simultaneously; With similar factor well-known in medical field.
Compound provided herein and composition can be used by any approach, comprise in oral, intravenously, intramuscular, intraarticular, marrow, sheath be interior, subcutaneous, in ventricle, transdermal, intracutaneous, rectum, intravaginal, intraperitoneal, locally (as passed through pulvis, ointment, emulsifiable paste and/or dropping liquid), mucous membrane, nose, oral cavity, intestines, sublingual; Instiled by intratracheal instillation, segmental bronchus and/or suck; And/or use with oral spray, nose spraying and/or aerosol form.Particularly, desired approach is injection in systemic vein, uses via blood and/or lymph feed region and/or directly use affected area.In general, optimal route of administration will depending on many factors, comprises the characteristic (such as, its stability) in gastrointestinal tract environment of medicament, individual illness (such as, whether individuality can tolerate oral administration) etc.
The exact amount realizing the compound for the treatment of needed for significant quantity is by depending on individual kind, age and generalized case, side effect or the severity of disorder, the characteristic, mode of administration etc. of specific compound and changing between individuality.Required dosage can send every day three times, every day twice, once a day, every two days once, every three days once, once in a week, once every two weeks, every three weeks once or every surrounding once.In certain embodiments, required dosage can use and repeatedly use (such as, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, ten once, use for 12 times, 13 times, 14 times or more times) to send.
In certain embodiments, within one day, use one or many for the adult to 70kg, the treatment significant quantity per unit formulation of compound can be about 3000mg, about 0.0001mg-containing the 0.0001mg-that has an appointment and be about 2000mg, about 0.0001mg-and be about 1000mg, about 0.001mg-and be about 1000mg, about 0.01mg-and be about 1000mg, about 0.1mg-and be about 1000mg, about 1mg-and be about 1000mg, about 1mg-and be about 100mg, about 10mg-and be about the compounds of this invention that 1000mg or about 100mg-is about 1000mg.Should be appreciated that, dosage range as described herein provides the guidance of adult being used to pharmaceutical composition of the present invention.Can be determined by doctor or those skilled in the art such as children or teen-age amount of application, and can the be grown up amount used of comparison less or identical with it.
Be also to be understood that compound as described herein or composition can with one or more other treatment promoting agent combined administrations.Described compound or composition can be used with one or more other treatment promoting agents simultaneously, use before it or use after which.In general, each medicament is used with the dosage and/or time-histories that determine described medicament.Be also to be understood that the other treatment promoting agent that utilizes in combination can be used or with different compositions separate administration by single composition together.Therapeutic action needed for the consistency and/or wish of considering the compounds of this invention and other treatment promoting agent realize by the particular combination used in scheme.In general, the other treatment promoting agent utilized in expection combination utilizes with the amount being no more than the amount utilizing separately described promoting agent.In some embodiments, the amount utilized in combination will be less than the amount utilized separately.
Described compound or pharmaceutical composition can be used with the pharmaceutical agent combinations improving its biological usability, reduction and/or change its metabolism, suppress it to drain and/or improve its distribution in vivo.Should also be appreciated that, the therapy used can realize required effect (such as to identical disorder, described compound can with the combined administrations such as antiphlogiston, antianxiety agent and/or antidepressive), and/or it can realize not same-action (such as, controlling any adverse side effect).
Exemplary active agents includes but not limited to carcinostatic agent, microbiotic, antiviral agent, narcotic, antithrombotics, enzyme inhibitors, steroid dose, steroid or nonsteroid anti-inflammatory drugs, antihistaminic, immunosuppressor, antineoplastic agent, antigen, vaccine, antibody, decongestant, tranquilizer, opiates medicine, pain relief agents, pain killer, febrifuge, hormone, prostaglandin(PG), progestational agents, antiglaucoma agent, medicament for the eyes, cholilytic drug, antidepressive, antipsychotic drug, soporific, tranquilizer, anticonvulsive drug/antiepileptic drug (such as, gabapentin, Le Ruika, valproate (such as, Sodium Valproate) and other nerves stablize medicine), muscle relaxant, spasmolytic, Muscle contraction agent, channel blocker, miotic, secretion inhibitor agent, antithrombotic agent, antithrombotics, cholilytic drug, beta-adrenergic blocking agent, diuretic(s), cardiac vascular activity agent, vasoactive agent, vasodilator, hypotensive agent, angiogenic agent, cell-ECM matrix interaction conditioning agent (such as, cytostatic agent and anti-adhesion molecule), or DNA, RNA, protein-protein interaction, protein-receptor interaction inhibitor/intercalating agent etc.Promoting agent comprises organic molecule, such as medical compounds (such as, as federal regulations (CFR) the compound obtaining U.S. food and drugs administration approved that provides), peptide, albumen, carbohydrate, monose, oligosaccharides, polysaccharide, nucleoprotein, Saliva Orthana, lipoprotein, improvement on synthesis or albumen, the small molecules be connected with albumen, glycoprotein, steroid, nucleic acid, DNA, RNA, Nucleotide, nucleosides, oligonucleotide, antisense oligonucleotide, lipid, hormone, VITAMIN and cell.
In certain embodiments, other treatment promoting agent is pain relief agents.Exemplary pain relief agents includes but not limited to anodyne, and as non-narcotic analgesics, [such as, salicylate is as acetylsalicylic acid, Ibuprofen BP/EP ketoprofen naproxen Base acetyl aminophenol, indomethacin or narcotic analgesic agent [such as, opium analgesics is as U-26225A, fentanyl, sufentanil, morphine, hydromorphone, morphine monomethyl ether, oxycodone and buprenorphine]; NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) [such as, acetylsalicylic acid, acetyl aminophenol, cox 2 inhibitor]; Steroid or antirheumatic; Migraine preparations, as beta-2 adrenoceptor blocker, ergot derivative; Tricyclic antidepressant (such as, amitriptyline, Desipramine, imipramine); Anti-epilepsy medicine (such as, clonaxepam, valproic acid, phenylethyl barbituric acid, phenytoin Sodium, tiagaine, gabapentin, Carbamzepine, appropriate Thailand, Sodium Valproate); α 2 agonist; Selectivity serotonin reuptake inhibitors (SSRI), selectivity norepinephrine uptake inhibitors; Benzodiazepine; Mexiletine (MEXITIL); Flecainide (TAMBOCOR); Nmda receptor antagonist [such as, ketamine, Dextromethorphane Hbr, methadone]; With topical drug [such as, capsaicine (Zostrix), EMLA frost, lignocaine, prilocaine].
In other embodiments, other treatment promoting agent is antiphlogiston.Exemplary antiphlogiston includes but not limited to acetylsalicylic acid, Ibuprofen BP/EP, Ketoprofen, Naproxen Base, R-ETODOLAC cox 2 inhibitor is as celecoxib rofecoxib valdecoxib parecoxib, Etoricoxib (MK663), SC 59046, 2-(4-oxyethyl group-phenyl)-3-(4-Methanesulfonyl-phenyl)-pyrazolo [1,5-b] pyridazine, 4-(2-oxo-3-phenyl-2,3-dihydro-oxazole-4-base) benzsulfamide, Da Bufeilong, Flosulide, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide), meloxicam, nimesulide, 1-methyl sulphonyl-4-(1, 1-dimethyl-4-(4-fluorophenyl) ring penta-2, 4-diene-3-base) benzene, 4-(1, the fluoro-7-methoxyl group of 5-dihydro-6--3-(trifluoromethyl)-(2)-benzo thiopyranyl (4,3-c) pyrazol-1-yl) benzsulfamide, 4,4-dimethyl-2-phenyl-3-(4-methyl sulphonyl) phenyl) cyclobutene ketone, 4-amino-N-(4-(the fluoro-5-trifluoromethyl of 2-)-thiazol-2-yl)-benzsulfamide, 1-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzofuryl)-4-cyclopropyl fourth-1-ketone or its physiologically acceptable salt, ester or solvate, sulindac diclofenac piroxicam diflunisal naphthalene fourth closes ketone taisho) indomethacin or steroid as prednisone na phosphates oral liquid, injection methyl prednisone sodium succinate, board prednisone syrup.
The further example of antiphlogiston comprise with delayed-release tablet, with dS sheet and the Naproxen Base that the form of suspension obtains from RccheLabs, board celecoxib tablet, board rofecoxib, board Betamethasone Valerate, board penicillamine capsules, board titratable penicillamine sheet, DEPO-MEDROL board methylene diacetate prednisone injection suspension, ARAVA tMleflunomide tablet, AZULFIDIINE board sulfasalazine delayed-release tablet, board piroxicam capsule, diclofenac potassium tablet, diclofenac sodium delay slow releasing tablet, diclofenac sodium extended action tablet or etanercept product.
V. the method for biologic activity is measured
The method measuring the activity of the compound provided herein being used for various therepic use is known in the art.These include but not limited to that high flux screening is to identify the compound being combined and/or regulating separated FAAH activity with separated FAAH, and in vitro and in vivo therapy model.
The analysis that can be used for screening compound provided herein can detect the combination of inhibitor and FAAH or the release by being hydrolyzed the reaction product (such as, fatty acid amide or thanomin) that the such as substrate such as Oleoyl monoethanolamide or anandamide produces.Can mark substrate so that detect the reaction product discharged.U.S. Patent number 5,559,410 disclose the high-throughput screening method about albumen, U.S. Patent number 5,576,220 and 5, and 541,061 discloses the high-throughput screening method about part/antibodies.
Method about the screening FAAH inhibitor of anti-pain effect is known in the art.Such as, can test and test compounds in Mice Formalin test at mouse hot-plate, and the painful reaction of measurement to heat or chemical tissue injury (such as, see U.S. Patent number 6,326,156, wherein describes the method for screening anti-pain activity; Also see people such as Cravatt, Proc.Natl.Acad.Sci.U.S.A. (2001) 98:9371-9376).
Two Animal Models of Anxieties through pharmacology checking are the ultrasound emission test of O-shaped elevated labyrinth test and isolation induction.O type labyrinth is made up of the overhead ring-shaped platform with two openings and two closed quadrants, and based on animal probe into the instinct of its environment and its between the fear of open space contradiction (see, such as, Bickerdike, M.J. people is waited, Eur.J.Pharmacol, (994) 271,403-411; The people such as Shepherd, J.K., Psychopharmacology, (1994) 116,56-64).The anxiolytic medicament that such as benzene diazepine etc. use clinically makes the sendout of time spent in open compartment and the number of times entered in open compartment increases.
Second test about anxiety compound is ultrasonic vocalization model, its measure the sounding of stress-induced sent by shifting out rat children mouse in nest number of times (see, such as, Insel, T.R. people is waited, Pharmacol.Biochem.Behav., 24,1263-1267 (1986); The people such as Miczek, K.A., Psychopharmacology, 121,38-56 (1995); The people such as Winslow, J.T., Biol.Psychiatry, 15,745-757 (1991)).
The effect of compound provided herein in treatment is depressed can be tested in the anhedonia model of the slight stress-induced of rat chronic.This model is based on following observation: chronic mild stress causes the reduction gradually of the susceptibility of rewarding (such as, consume sucrose) and by reversing this reduction by dose dependent fashion with antidepressive long-term treatment.See, such as, Willner, Paul, Psychopharmacology, 1997,134,319-329.
Another test about antidepressive activity is forced swimming test (Nature266,730-732,1977).In this test, before being placed in the container of water 30 or 60 minutes by pharmacy application in animal, and static time timing is kept to it.The shortening of the rest time of mouse has indicated that antidepressive is active.
Similar test about antidepressive activity is tail suspension test (Psychopharmacology, 85,367-370,1985) carried out mouse.In this test, before suspending by tail 30 or 60 minutes by pharmacy application in animal, and record its static time.The shortening of the rest time of mouse has indicated that antidepressive is active.
Animal model can be used for studying test compounds anticonvulsive agent activity (see, such as, U.S. Patent number 6,309,406 and 6,326,156).
According to reports, suppress FAAH can induce test animal sleep (see, such as, U.S. Patent No. 6,096,784).The method of research sleep derivation compound be known in the art (see, such as, U.S. Patent No. 6,096,784 and 6,271,015).Can by compound administration test animal (such as, rat or mouse) or the mankind and can follow-up time spent by monitoring sleep (such as, close one's eyes, motor rest) (such as, start, time length).Also see WO98/24396.
For screen the method for the stiff FAAH inhibitor of induction be also well-known in the art (see, such as, the people such as Quistand, ToxicologyandAppliedPharmacology173:48-55 (2001); The people such as Cravatt, Proc.Natl.Acad.Sci.U.S.A.98:9371-9376 (2001)).
The method of evaluation appetitive behavior be known in the art (see, such as, U.S. Patent No. 6,344,474).Evaluate on a kind of method of the impact of appetitive behavior be FAAH inhibitor is used on rat and evaluate its impact on picked-up sucrose solution (see, such as, the people such as W.C.Lynch, Physiol.Behav., 1993,54,877-880).
Two neuropathic pain animal models through pharmacology checking are neuropathic pain rat models that rat spinal cord nerve ligation model (Chung model) and chemotherapy cause.Set up neuropathy in these models after, measuring as mechanical touch sense, by stimulate with vonFrey filament measure claw withdrawal threshold (see, such as, KimSH and ChungJM, Pain (1992) 50,355-63; The people such as Nozaki-TaguchiN, Pain (2001) 93,69-76).The neuropathic pain medicine used clinically, as gabapentin (Neurontin) increases the claw withdrawal threshold stimulated with vonFrey filament.
Two struvite and Mechanical Pain animal models through pharmacology checking are rat articular compact models of the adjuvant therapy with generation joint degeneration.With the antiphlogiston used clinically as Naproxen Base treatment increase to joint compression behavior reaction threshold value (see, such as, the people such as WilsonAW, Eur.J.Pain (2006) 10,537-49; IvanaviciusSA, waits people, Pain (2007) 128,272-282).
Animal model through the cancer pain of pharmacology checking is that the calcaneum of fibrosarcoma cell produces the hyperalgesic mouse model of claw.With the anodyne used clinically as Morphine treatment increase the behavior reaction to mechanical sense allergy threshold value (see, such as, the people such as Khasabova, J.Neurscience (2008) 28,11141-52).
Embodiment
Generally describe the present invention above, can more easily understand with the following Examples, embodiment, only for illustration of some aspect of the present invention and embodiment, is not intended to limit the present invention.
General synthetic method
method 1
The general condition of preparation 3-bromine-isoxazoline: alkene (1.2 equivalent) and saleratus (2.5 equivalent) are suspended in ethyl acetate (0.40M, relative to alkene).Add N, N-dibromo formoxime (1.0 equivalent), reacts and stir 14-28h at 23 DEG C.After having been judged by thin-layer chromatographic analysis, react and distributed between water and t-butyl methyl ether, organic layers with water and salt water washing, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by silica flash chromatography purifying (ethyl acetate/hexane), obtains target 3-bromine-isoxazoline.
method 2
The general condition of preparation 3-bromine-isoxazoline: add oxoethanoic acid monohydrate (1.0 equivalent) and hydroxy amine hydrochloric acid salt (1.1 equivalent) in flask.Mixture is dissolved in (2.0M, relative to oxoethanoic acid monohydrate) in water, at 23 DEG C, stir 24h.Mixture dilute with water, is extracted with ethyl acetate.Organic layers with sodium sulfate is dry, concentrated, obtains the thick oxime of target, in direct postpose cycloaddition.The oxime (1.1 equivalent) that the first step obtains is suspended in glycol dimethyl ether: in 3: 1 mixtures of water (v/v) (0.15M, relative to oxime), be cooled to 0 DEG C.Add N-bromine succinic diamide (NBS) (2.0 equivalent), react and stir 20min at 23 DEG C.Then the mixture obtained is added in alkene (1.0 equivalent) and the solution of saleratus (2.5 equivalent) in glycol dimethyl ether (1.50M, relative to alkene), reacts and stir 20h at 23 DEG C.After having been judged by thin-layer chromatographic analysis, react and distributed between water and t-butyl methyl ether, organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target 3-bromine-isoxazoline.
method 3
Preparation 3-aryloxy-isoxazoline or the general condition of 3-heteroaryloxy-isoxazoline: in microwave reaction bottle, add given 3-bromine-isoxazoline (1.0 equivalent) and alcohol (such as, phenol or pyridone) (3.0 equivalent), and be dissolved in (0.50M, relative to isoxazoline) in N-crassitude.Add the sodium hydroxide (2.0 equivalent) of pulverizing, sealed mixture, heats 30min in microwave reaction at 150 DEG C.Then react and distribute between water and t-butyl methyl ether, organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target isoxazoline.
method 4
Preparation 3-aryloxy-isoxazoline or the general condition of 3-heteroaryloxy-isoxazoline: in flask, add given 3-bromine-isoxazoline (1.0 equivalent) and alcohol (such as, phenol or pyridone) (2.0 equivalent), be dissolved in N, in dinethylformamide (0.4M, relative to isoxazoline).Add sodium hydride (2.0 equivalent), 10min is stirred in reaction, until stop releasing all gas.Then reaction is heated to 150 DEG C of maintenance 1-5h.After being completed by thin-layer chromatographic analysis assaying reaction, react and distribute between water and ethyl acetate, organic layer 1NNaOH and salt water washing, then use dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target isoxazoline.
method 5
The general condition of preparation 3-aryloxy-isoxazoline: add given 3-bromine-isoxazoline (1.0 equivalent) and alcohol (such as in flask, phenol or pyridone) (2.0 equivalent), be dissolved in N, in dinethylformamide or N-Methyl pyrrolidone (0.15M, relative to isoxazole).Add cesium carbonate (1.2-3 equivalent), react and be heated to 120 DEG C of maintenance 1h in oil bath.Then react and distribute between water and t-butyl methyl ether, organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethanol/methylene), obtains target isoxazoline.
method 6
Prepare the general condition of alkene: in nitrogen atmosphere, the 0.25M methyltriphenylphosphonium bromide be dissolved in tetrahydrofuran (THF) (1.1 equivalent) is cooled to 0 DEG C, thereafter mixture is processed by the silica-based azane sodium (NaHMDS) of hexamethyl two (1.0M, 1.2 equivalents) dripped in tetrahydrofuran (THF).Stir extra 30min at 0 DEG C after, add given aldehydes or ketones, sluggish is raised to 23 DEG C, spends the night.The saturated ammonium chloride quencher of mixture, concentrated removing tetrahydrofuran (THF).Then mixture dilute with water, is extracted with ethyl acetate.Organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target alkene.
method 7
Prepare the general condition of alkene: in nitrogen atmosphere, the 0.15M methyltriphenylphosphonium bromide be dissolved in tetrahydrofuran (THF) (1.5 equivalent) is cooled to-78 DEG C, thereafter mixture is processed by the n-Butyl Lithium (2.5M, 1.5 equivalents) dripped in hexane.Stir extra 1h at-78 DEG C after, add given aldehydes or ketones, sluggish is raised to 23 DEG C, spends the night.The saturated ammonium chloride quencher of mixture, concentrated removing tetrahydrofuran (THF).Then mixture dilute with water, is extracted with ethyl acetate.Organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target alkene.
method 8
Prepare the general condition of alkene: in nitrogen atmosphere, 0.12M methyltriphenylphosphonium bromide (2.5 equivalent) is dissolved in tetrahydrofuran (THF), divide thereafter and add potassium tert.-butoxide (4.0 equivalent) for 6 times.Stir extra 1h at 23 DEG C after, add given aldehydes or ketones, reaction is heated to 55 DEG C and keeps 2h.The saturated ammonium chloride quencher of mixture, concentrated removing tetrahydrofuran (THF).Then mixture 1NHCl is acidified to pH5-6, uses dichloromethane extraction.Organic layer washed with brine, then uses dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target alkene.
method 9
Prepare cinnamic general condition: in the dry flask in argon gas atmosphere, add aryl bromide (1.0 equivalent), vinyl potassium trifluoborate (1.2 equivalent), 1; 1 "-bis-(diphenylphosphino)-ferrocene dichloro palladium (II) dichloromethane adduct (0.02 equivalent) and triethylamine (1.0 equivalent), mixture is suspended in Virahol (0.25M, relative to aryl bromide) in, at 80 DEG C, heat 2-24h.Then mixture dilute with water, uses extracted with diethyl ether.Organic layer washed with brine, then uses dried over mgso, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target vinylbenzene.
method 10
Prepare cinnamic general condition: in the dry flask in nitrogen atmosphere, add aryl bromide (1.0 equivalent), tributylvinyl tin (1.1 equivalent), be dissolved in (0.3M, relative to bromide) in toluene.The mixture nitrogen wash 10min obtained, adds thereafter tetrakis triphenylphosphine palladium (0.1 equivalent), reaction backflow 1.5h.After being completed by TLC analysis assaying reaction, cooling, and directly install on silicagel column, by flash silica chromatography (ethyl acetate/hexane), obtain target vinylbenzene.
method 11
Pyridyl and pyridiminyl boronic acid are hydrolyzed into the general condition of corresponding phenol: in flask, add given boric acid or its ester (1.0 equivalent), are dissolved in (1.1M, 10 volumes) in tetrahydrofuran (THF).Sodium peroxoborate (1.0 equivalent) to be dissolved in water (1.1M, relative to boric acid, 10 volumes), sonic treatment 10min.Then perborate suspension is added in THF solution, uses tetrahydrofuran (THF) (1.6 volume) by the drip washing of remaining solid perborate in reaction mixture.Reaction at room temperature stirs (reacting leniently heat release), divides thereafter and adds ammonium chloride (10 equivalent) for 3 times, and reaction cools back room temperature.After 40min, reaction vacuum concentration, the true tetrahydrofuran (THF) whole to removing.The solid that collected by vacuum filtration obtains, with excessive water washing, in vacuum drying oven at 40 DEG C dry 3 days, obtains target phenol, 80% productive rate.
chirality HPLC method
The enantiomer of compound or the mixture of diastereomer can use known method preparation, comprise chiral hplc (HPLC) and chirality supercritical fluid chromatography (SFC).Exemplary chiral column for separating of this kind of mixture of the compounds of this invention includes but not limited to aD-H, oD-H, aY, RegisPack tMand S, S and LUX tMcellulose2 post.One or more in these posts are used to the enantiomeric mixture being separated the compounds of this invention, thus obtain the compound of enantiomeric pure substantially.
The synthesis of the exemplary compounds of formula I
The following describes the synthesis of exemplary compounds.Use the compound of methods analyst as people FAAH inhibitor of detailed description in embodiment 351.The activity being marked as " A " refers to K 1be less than or equal to the compound of 100nM; " B " refers to K 1for the compound of 100nM-1 μM; " C " refers to K 1be more than or equal to the compound of 1 μM.
Embodiment 1
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-1a and I-1b of 3-from vinylbenzene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝225.0m/z。Active: B
Embodiment 2
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-2a and I-2b of 3-from 4-fluorobenzene ethene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.Active: B
Embodiment 3
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-3a and I-3b of 3-from 4-chloro-styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝259.0m/z。Active: A
Embodiment 4
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-4a and I-4b of 3-from 3-chloro-styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝258.9m/z。Active: B
Embodiment 5
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-5a and I-5b of 3-from 2-chloro-styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝258.9m/z。Active: B
Embodiment 6
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-6a and I-6b of 3-from 4-methoxy styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝255.0m/z。Active: A
Embodiment 7
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-7a and I-7b of 3-from 3-methoxy styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝255.0m/z。Active: B
Embodiment 8
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-8a and I-8b of 3-from 2-methoxy styrene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝255.0m/z。Active: C
Embodiment 9
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-9a and I-9b of 3-from 4-vinyl biphenyl 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝301.6m/z。Active: A
Embodiment 10
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-10a and I-10b of 3-from 4-phenoxy group vinylbenzene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝317.0m/z。Active: A
Embodiment 11
Using method 8 forms alkene, the then cycloaddition of using method 2 from 3-phenoxy benzaldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-11a and I-11b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝317.0m/z。Active: A
Embodiment 12
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-(pyridin-3-yl oxygen base) phenyl aldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-12a and I-12b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝318.0m/z。Active: A
Embodiment 13
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-(pyrimidine-2-yloxy)-phenyl aldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-13a and I-13b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝319.0m/z。Active: A
Embodiment 14
Using method 8 forms alkene, the then cycloaddition of using method 1 from 4-trifluoro-methoxybenzaldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-14a and I-14b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝309.6m/z。Active: A
Embodiment 15
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-isopropoxide benzaldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-15a and I-15b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝238.0m/z。Active: A
Embodiment 16
Using method 7 forms alkene, the then cycloaddition of using method 2 from piperonylaldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-16a and I-16b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝269.0m/z。Active: A
Embodiment 17
Using the step similar to embodiment 10 to prepare chloro-4,5-dihydro-isoxazole I-17a and I-17b of 3-, replacing N-bromine succinic diamide except using N-chlorine succinic diamide.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝273.1m/z。Active: A
Embodiment 18
Using method 9 forms alkene, the then cycloaddition of using method 2 from 3-(4-bromine phenoxy group)-6-methyl pyridazine, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-18a and I-18b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝333.0m/z。Active: B
Embodiment 19
Using method 9 forms alkene, the then cycloaddition of using method 2 from 2-(4-bromophenyl)-5-phenyl-1,3,4-oxadiazole, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-19a and I-19b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝369.0m/z。Active: A
Embodiment 20
Using method 8 forms alkene, the then cycloaddition of using method 1 from 4-butoxybenzaldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-20a and I-20b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝297.0m/z。Active: A
Embodiment 21
From the coupling between 4-vinyl benzoic acid and benzyl alcohol, 2 steps prepare 3-bromo-4 as follows, 5-dihydro-isoxazole I-21a and I-21b: 4-vinyl benzoic acid (1.0 equivalent) is dissolved in N, in dinethylformamide (0.20M, relative to acid).Add benzyl alcohol (2.0 equivalent), then add the DMAP (0.05 equivalent) of EDC (1.05 equivalent) and catalytic amount.Reaction stirs 14h at 23 DEG C, reacts thereafter and distributes between water and t-butyl methyl ether, organic layer 0.5M citric acid solution washing (2 ×) and saturated sodium hydrogen carbonate solution washing (1 ×), by dried over mgso, and vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target ester.Then, this compound using method 1 changes into bromo-4, the 5-dihydro-isoxazoles of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝359.8m/z。Active: A
Embodiment 22
Using the step similar to embodiment 21 to prepare bromo-4,5-dihydro-isoxazole I-22a and I-22b of 3-, replacing benzyl alcohol except using benzyl amine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝358.9m/z。Active: B
Embodiment 23
Using method 3 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-23a and I-23b from Compound I-10 and phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝331.1m/z。Active: C
Embodiment 24
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-24a and I-24b from Compound I-10 and 4-fluorophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝350.3m/z。Active: C
Embodiment 25
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-25a and I-25b from Compound I-10 and 3-fluorophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝349.3m/z。Active: B
Embodiment 26
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-26a and I-26b from Compound I-10 and 3-trifloro methyl phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝400.3m/z。Active: C
Embodiment 27
Using method 3 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-27a and I-27b from Compound I-10 and 4-cyanophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝356.1m/z。Active: A
Embodiment 28
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-28a and I-28b from Compound I-10 and 2-cyanophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝357.3m/z。Active: C
Embodiment 29
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-29a and I-29b from Compound I-10 and 4-nitro 1 phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝376.8m/z。Active: B
Embodiment 30
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-30a and I-30b from Compound I-10 and 4-methyl sulphonyl phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝409.0m/z。Active: A
Embodiment 31
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-31a and I-31b from Compound I-10 and 4-methyl-3-fluorophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝364.4m/z。Active: C
Embodiment 32
Racemic compound I-10 (1.0 equivalent) and aniline (4.0 equivalent) is added in microwave reaction bottle.Sealed mixture, heats 2h in microwave reactor at 150 DEG C.Then react and distribute between water and t-butyl methyl ether, organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains amino-4,5-dihydro-isoxazole I-32a and I-32b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -330.1m/z。Active: C.
Embodiment 33
Using method 3 prepares 1-(4,5-dihydro-isoxazole-3-base) pyridine-2 (1H)-one I-33a and I-33b from racemic compound I-10 and 2 hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝332.1m/z。
Active: C
Embodiment 34
The sodium salt (2.0 equivalent) of racemic compound I-10 (1.0 equivalent) and 1,2,4-triazole is added in microwave reaction bottle.Each agent dissolves is (0.18M, relative to Compound I-10) in N-crassitude.Sealed mixture, heats 30min in microwave reactor at 100 DEG C.Add excessive water, brown solid breaks, and uses isolated by vacuum filtration, dry, obtains target 3-(1H-1,2,4-triazol-1-yl)-4,5-dihydro-isoxazole I-34a and I-34b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝306.1m/z。Active: C
Embodiment 35
Pyrazoles (3.0 equivalent) is dissolved in (0.60M, relative to pyrazoles) in DMF, adds NaH (60% dispersion, in mineral oil, 3.0 equivalents), react and stir 5min in nitrogen.Thereafter, racemic compound I-10 is added.Then, reaction is heated to 90 DEG C and keeps 14h, cools thereafter and uses methyl alcohol quencher (0.30M, relative to pyrazoles).Crude mixture is filtered by cotton and directly by half preparation property reverse-phase chromatography purifying, obtains target 3-(1H-pyrazol-1-yl)-4,5-dihydro-isoxazole I-35a and I-35b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝306.4m/z。Active: C
Embodiment 36
Using method 3 prepares 3-(pyridin-4-yl oxygen base)-4,5-dihydro-isoxazole I-36a and I-36b from Compound I-10 and 4-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝332.1m/z。Active: C
Embodiment 37
Using method 3 or method 5 prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-37a and I-37b from racemic compound I-10 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝332.1m/z。Active: A
Embodiment 38
Using method 3 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-38a and I-38b from racemic compound I-6 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝270.1m/z。Active: B
Embodiment 39
Using method 3 or method 5 prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-39a and I-39b from racemic compound I-10 and 5-hydroxy niacin methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.2m/z。Active: A
Embodiment 40
Using method 4 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-40a and I-40b from racemic compound I-10 and 5-hydroxy-2-methyl pyridine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝346.1m/z。Active: A
Embodiment 41
Using method 3 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-41a and I-41b from racemic compound I-10 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝333.1m/z。Active: A
Embodiment 42
Using method 3 prepares 3-(quinoline-3-base oxygen base)-4,5-dihydro-isoxazole I-42a and I-42b from racemic compound I-10 and 3-hydroxyquinoline 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝382.1m/z。Active: A
Embodiment 43
The fluoro-3-pyridone of using method 3 racemic compound I-10 and 5-is from preparing 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-43a and I-43b by 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝350.1m/z。Active: A
Embodiment 44
Using method 3 prepares 3-(1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-5-base oxygen base)-4,5-dihydro-isoxazole I-44a and I-44b from racemic compound I-10 and 1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-5-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝385.1m/z。Active: B
Embodiment 45
In bottle, add racemic compound I-10 (1.0 equivalent), be dissolved in (0.05M, relative to isoxazole) in methyl alcohol.Add salt of wormwood (5.0 equivalent), sealed reaction, be heated to 50 DEG C and keep 24h.Then, react and distribute between water and ethyl acetate, organic layer washed with brine, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target 3-methoxyl group-4,5-dihydro-isoxazole I-45a and I-45b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝269.1m/z。
Active: C
Embodiment 46
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-46a and I-46b from racemic compound I-14 and 5-hydroxy niacin methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝384.0m/z。
Active: B
Embodiment 47
Racemic compound I-39 is dissolved in (7.0M, in methyl alcohol, 0.02M, relative to isoxazole) in the methanol solution of ammonia.Sealed reaction, stirs 24h at 23 DEG C, removes desolventizing and excess ammonia thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-47a and I-47b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝374.0m/z。Active: B
Embodiment 48
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-48a and I-48b of 3-from 3-phenyl-1-propylene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝239.0m/z。Active: C
Embodiment 49
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-49a and I-49b of 3-from 4-phenyl-1-butylene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝253.0m/z。Active: B
Embodiment 50
Phenol (1.0 equivalent) is dissolved in ethanol (0.5M, relative to phenol), adds sodium hydroxide (1.0 equivalent), then add the bromo-1-butylene of 4-.Mixture reflux 1h, its final vacuum removes most of solvent.Then, react and distribute between water and t-butyl methyl ether, organic layer washed with brine, with dried over sodium sulfate, vacuum concentration, obtain thick alkene, using method 21 step directly changes into bromo-4,5-dihydro-isoxazole I-50a and I-50b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝269.0m/z。Active: B
Embodiment 51
Phenol (1.2 equivalent) is dissolved in N, (0.4M in dinethylformamide, relative to phenol), add cesium carbonate (1.3 equivalent), then add the bromo-1-amylene of 5-(1.0 equivalent) and tetrabutylammonium iodide (0.10 equivalent).Mixture is heated to 50 DEG C and keeps 16h.Then, react and distribute between water and t-butyl methyl ether, organic layer diluted sodium hydroxide solution, water, salt water washing, by dried over sodium sulfate, vacuum concentration.Thick alkene using method 21 step directly changes into bromo-4,5-dihydro-isoxazole I-51a and I-51b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝283.0m/z。Active: A
Embodiment 52
2-phenylethyl alcohol (1.0 equivalent) is dissolved in N, (0.8M in dinethylformamide, relative to alcohol), add broken sodium hydroxide (2.0 equivalent), then add allyl bromide 98 (1.0 equivalent) and tetrabutylammonium iodide (0.10 equivalent).Mixture at room temperature stirs 48h.Then, react and distribute between water and t-butyl methyl ether, the rare Na of organic layer 2s 2o 3solution and salt water washing, by dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture is by flash silica chromatography (ethyl acetate/hexane), and obtain target alkene, using method 11 step directly changes into bromo-4,5-dihydro-isoxazole I-52a and I-52b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝285.6m/z。Active: B
Embodiment 53
Racemic compound I-46 is dissolved in (7.0M, in methyl alcohol, 0.02M, relative to isoxazole) in the methanol solution of ammonia.Sealed reaction, stirs 72h at 23 DEG C, removes desolventizing and excess ammonia thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-53a and I-53b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝366.0m/z。Active: B
Embodiment 54
Racemic compound I-46 is dissolved in (2.0M, in tetrahydrofuran (THF), 0.02M, relative to isoxazole) in the methylamine solution of ammonia.Sealed reaction, stirs 72h at 23 DEG C, removes desolventizing and excess ammonia thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-54a and I-54b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝380.0m/z。Active: A
Embodiment 55
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-55a and I-55b from racemic compound I-46 and 5-hydroxy niacin methyl esters 1 step, as the separation of by-products of reaction in silica flash chromatography process.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝367.0m/z。Active: C
Embodiment 56
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-56a and I-56b from racemic compound I-10 and 5-hydroxyl-2-5-flumethiazine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝401.5m/z。Active: A
Embodiment 57
Using method 5 prepares 3-(1H-pyrrolo-[3,2-b] pyridine-6-base oxygen base)-4,5-dihydro-isoxazole I-57a and I-57b from racemic compound I-10 and 1H-pyrrolo-[3,2-δ] pyridine-6-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝370.0m/z。Active: A
Embodiment 58
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-58a and I-58b from racemic compound I-10 and 3-cyanophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝356.8m/z。Active: B
Embodiment 59
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-59a and I-59b from racemic compound I-10 and 2-fluorophenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝350.3m/z。Active: B
Embodiment 60
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-60a and I-60b from the fluoro-3-of racemic compound I-10 and 4-(trifluoromethyl) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.Active: C
Embodiment 61
Using method 4 is prepared from racemic compound I-10 and 3-methyl hydroxybenzoate 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed in this 3-phenoxy group-4,5-dihydro-isoxazole I-61a and I-61b literary composition.[M+H] +＝390.5m/z。Active: A
Embodiment 62
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-62a and I-62b from racemic compound I-10 and 4-HBA methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝389.7m/z。
Active: A
Embodiment 63
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-63a and I-63b from racemic compound I-10 and 3-(methyl sulphonyl) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝409.0m/z。Active: C
Embodiment 64
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-64a and I-64b from racemic compound I-10 and 3-hydroxy benzene sulfonamide 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝409.0m/z。Active: C
Embodiment 65
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-65a and I-65b from racemic compound I-10 and 5-methoxypyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝363.2m/z。
Active: A
Embodiment 66
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-66a and I-66b from racemic compound I-10 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝364.6m/z。
Active: A
Embodiment 67
Using method 3 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-67a and I-67b from racemic compound I-10 and 5-hydroxy-picolinic acid methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.1m/z。Active: A
Embodiment 68
Using method 5 prepares 3-(1H-pyrrolo-[2,3-6] pyridine-5-base oxygen base)-4,5-dihydro-isoxazole I-68a and I-68b from racemic compound I-10 and 1H-pyrrolo-[2,3-b] pyridine-5-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝370.0m/z。Active: A
Embodiment 69
Using method 5 is from racemic compound I-10 and furo [3,2-δ] pyridine-6-alcohol 2 step prepares 6-(4,5-dihydro-isoxazole-3-base oxygen base) furo [3,2-δ] pyridine I-69a and I-69b, thereafter using method 11 is from 6-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base) furo [3,2-δ] pyridine prepares furo [3,2-δ] pyridine-6-alcohol.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝374.2m/z。Active: A
Embodiment 70
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-70a and I-70b from racemic compound I-14 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝324.1m/z。
Active: A
Embodiment 71
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-71a and I-71b from the bromo-3-pyridone of racemic compound I-14 and 5-1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝402.5m/z。
Active: A
Embodiment 72
By racemic compound I-71 (1.0 equivalent), phenyl-boron dihydroxide (1.1 equivalent), potassium acetate (1.0 equivalent), cesium carbonate (3.0 equivalent) and dichloro [1,1 '-bis-(diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (14mol%) is suspended in 1mLDMSO, uses argon cleaning.Seal the mixture obtained, be heated to 80 DEG C and keep 1h.Crude mixture uses excessive water to transfer in separating funnel, with methyl tertiary butyl ether extraction (2 ×).Merge organic layer, use Na 2sO 4drying, uses flash silica chromatography (gradient 2-10%MeOH), obtains target 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-72a and I-72b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝402.3m/z。Active: B
Embodiment 73
By racemic compound I-71 (1.0 equivalent), 3-carboxylamine base phenyl-boron dihydroxide (1.1 equivalent), potassium acetate (1.0 equivalent), cesium carbonate (3.0 equivalent) and dichloro [1,1 '-bis-(diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (14mol%) is suspended in 1mLDMSO, uses argon cleaning.Seal the mixture obtained, be heated to 80 DEG C and keep 1h.Crude mixture uses excessive water to transfer in separating funnel, with methyl tertiary butyl ether extraction (2 ×).Merge organic layer, use Na 2sO 4drying, uses flash silica chromatography (gradient 2-10%MeOH), obtains target 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-73a and I-73b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝442.0m/z。Active: A
Embodiment 74
Using method 1 prepares bromo-4,5-dihydro-isoxazole I-74a and I-74b of 3-from 4-vinylbenzoate 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝283.6m/z。Active: A
Embodiment 75
Using method 6 forms alkene, the then cycloaddition of using method 1 from 4 '-(trifluoromethoxy) methyl phenyl ketone, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-75a and I-75b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝323.0m/z。Active: A
Embodiment 76
Using method 6 forms alkene, the then cycloaddition of using method 2 from 4 '-metaphenoxy acetophenone, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-76a and I-76b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝331.0m/z。Active: A
Embodiment 77
Using method 2 prepares bromo-4,5-dihydro-isoxazole I-77a and I-77b of 3-from cis-methyl allylphenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝269.0m/z。Active: C
Embodiment 78
Using method 6 forms alkene (replacing methyltriphenylphosphonium bromide except using ethyltriphenylphosphonium bromide) from 4-phenoxy benzaldehyde, and the then cycloaddition of using method 2,2 steps prepare bromo-4,5-dihydro-isoxazole I-78a and I-78b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝331.0m/z。Active: A
Embodiment 79
Bromo-4,5-dihydro-isoxazole I-82a and I-82b of 3-are prepared as follows: 4-phenoxy benzaldehyde (1.0 equivalent) is dissolved in (0.20M, relative to tetrahydrofuran (THF)) in tetrahydrofuran (THF), is cooled to 0 DEG C from 4-phenoxy benzaldehyde 3 step.Drip ethylmagnesium bromide (in 1.0M, THF, 1.2 equivalents), react thereafter and stir 2h at 23 DEG C.The saturated ammonium chloride quencher of mixture, concentrated removing tetrahydrofuran (THF).Then mixture dilute with water, extracts by t-butyl methyl ether.Organic layers with water and salt water washing, then use dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target alcohol I-80.
Then the alcohol I-80 of purifying is dissolved in (0.80M, relative to alcohol) in pyridine to add.Phosphorus oxychloride (1.1 equivalent).Mixture reflux 2h.Thereafter, reaction is cooled to 0 DEG C, adds excessive water quencher.Then mixture diluted ethyl acetate.Organic layers with water and salt water washing, then use dried over sodium sulfate, vacuum concentration.Concentrated reaction mixture, by flash silica chromatography (ethyl acetate/hexane), obtains target alkene I-81.
Then alkene 1-81 using method 2 changes into bromo-4,5-dihydro-isoxazole I-82a and I-82b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝331.0m/z。Active: B.
Embodiment 80
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-83a and I-83b from racemic compound I-14 and 3-(5-pyridone-2-base) methyl benzoate 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝460.1m/z。Active: B
Embodiment 81
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-84a and I-84b from racemic compound I-14 and 3-(5-pyridone-2-base) ethyl benzoate 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝474.1m/z。Active: B
Embodiment 82
Racemic compound I-83 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-85a and I-85b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝443.0m/z。Active: B
Embodiment 83
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-86a and I-86b from racemic compound I-14 and 6-phenylpyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝402.2m/z。
Active: B
Embodiment 84
Using method 5 racemic compound I-12 and 3-pyridone are from preparing 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-87a and I-87b by 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝333.5m/z。
Active: A
Embodiment 85
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-88a and I-88b from racemic compound I-75 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝340.2m/z。
Active: B
Embodiment 86
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-89a and I-89b from racemic compound I-76 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝348.4m/z。
Active: A
Embodiment 87
Using method 4 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-90a and I-90b from racemic compound I-10 and 4-hydroxy benzene sulfonamide 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝410.8m/z。Active: A
Embodiment 88
Using method 5 prepares cis 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-91a and I-91b from racemic compound I-78 or I-82 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝346.2m/z。Active: C
Embodiment 89
In using method 11 from 5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base) after pyridine-2-carbamate forms (5-Hydroxy-pyridine-2-base)-t-butyl carbamate, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-92a and I-92b from racemic compound I-10 and (5-Hydroxy-pyridine-2-base)-t-butyl carbamate 2 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝447.9m/z。
Active: C
Embodiment 90
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-92 are dissolved in (0.20M, relative to isoxazole) in trifluoroacetic acid, at room temperature stir 1h.Then, solvent removed in vacuo, thick resistates and methylbenzene azeotropic (2 ×), obtain the tfa salt (white solid) of I-93a and I-93b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝347.1m/z。Active: A
Embodiment 91
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-93 are dissolved in (0.03M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and diacetyl oxide (3.0 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with saturated NaHCO 3washing (2 ×) and with salt water washing (1 ×).Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains acetic ester I-94a and I-94b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝388.1m/z。Active: A
Embodiment 92
Using method 8 forms alkene, the then cycloaddition of using method 1 from 1-(4-Phenoxyphenyl) third-1-ketone, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-95a and I-95b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝347.7m/z。Active: A
Embodiment 93
3-(pyridin-3-yl oxygen base)-4 is prepared from racemic compound I-14 and 5-hydroxy-picolinic acid methyl esters 1 step according to following steps, 5-dihydro-isoxazole I-96a and I-96b: by bromo-for 3-5-(4-(trifluoromethoxy) phenyl)-4,5-dihydro-isoxazole (1.0 equivalent), 5-hydroxy-picolinic acid methyl esters (1.2 equivalent) and cesium bicarbonate (1.50 equivalent) are suspended in N, in dinethylformamide (0.32M, relative to dihydro-isoxazole).Then, mixture argon-degassed, is heated to thereafter 130 DEG C and keeps 4h, and being observed by LC/MS thereafter only has target product and corresponding acid.Reaction cool to room temperature, by quencher (30 % by weight, 0.08M, relative to dihydro-isoxazole) in the aqueous solution of pouring ammonium chloride into.Aqueous phase is extracted with ethyl acetate (2 ×), by dried over sodium sulfate, filter, concentrated generation brown solid, dehydrated alcohol recrystallization can be used, racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-96 are obtained, white solid (25% productive rate) by filtering separation.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝383.8m/z。Active: A
Embodiment 94
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-96 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid enantiomer I-97a and I-97b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝369.3m/z。Active: A
Embodiment 95
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-98a and I-98b from racemic compound I-10 and 3-(5-pyridone-2-base) methyl propionate 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝418.1m/z。Active: A
Embodiment 96
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-98 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-99a and I-99b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝402.8m/z。
Active: A
Embodiment 97
Racemic compound I-98 is dissolved in (7.0M, in methyl alcohol, 0.02M, relative to isoxazole) in the methanol solution of ammonia.Sealed reaction, stirs 72h at 23 DEG C, removes desolventizing and excess ammonia thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-100a and I-100b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝404.5m/z。Active: A
Embodiment 98
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-101a and I-101b from racemic compound I-9 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝316.8m/z。
Active: A
Embodiment 99
Using method 8 forms alkene, the then cycloaddition of using method 1 from 1-(biphenyl-4-base) ethyl ketone, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-102a and I-102b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝315.7m/z。Active: A
Embodiment 100
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-103a and I-103b from racemic compound I-9 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝318.7m/z。
Active: A
Embodiment 101
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-104a and I-104b from racemic compound I-102 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝332.6m/z。
Active: A
Embodiment 102
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-97 (1.0 equivalent) is dissolved in (0.03M, relative to isoxazole) in methylene dichloride.Add thionyl chloride (2.0 equivalent), reaction at room temperature stirs 1h, and vacuum concentration becomes beige solid thereafter, with methylbenzene azeotropic (2 ×).The solid obtained is dissolved in (0.03M, relative to isoxazole) in tetrahydrofuran (THF) again, adds thereafter methyl aminoacetate (1.5 equivalent), then adds triethylamine (3.0 equivalent).Reaction at room temperature stirs 1h, uses thereafter excessive water to transfer in separating funnel and ethyl acetate.Then, the saturated NaHCO of organic layer 3solution and salt water washing, with dried over mgso, vacuum concentration, obtain thick material, uses flash silica chromatography (ethyl acetate/hexane), obtain acid amides I-105a and I-105b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝437.5m/z。Active: A
Embodiment 103
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-105 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-106a and I-106b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝423.7m/z。Active: A
Embodiment 104
Using the step similar to embodiment 102 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-107a and I-107b, replacing methyl aminoacetate except using methylamine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝382.5m/z。Active: A
Embodiment 105
Using the step similar to embodiment 102 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-108a and I-108b, replacing methyl aminoacetate except using dimethylamine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝396.6m/z。Active: B
Embodiment 106
Using the step similar to embodiment 102 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-109a and I-109b, replacing methyl aminoacetate except using thanomin.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝409.9m/z。Active: A
Embodiment 107
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-67 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-110a and I-110b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝376.5m/z。Active: A
Embodiment 108
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-67 are dissolved in (2.0M, in tetrahydrofuran (THF), 0.02M, relative to isoxazole) in the methanol solution of dimethylamine.Sealed reaction, stirs 72h at 23 DEG C, removes desolventizing and excess dimethylamine thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-111a and I-111b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝405.1m/z。Active: A
Embodiment 109
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-112a and I-112b from racemic compound I-14 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.Active: A
Embodiment 110
By using method 5 then with embodiment 94 the same terms under be hydrolyzed and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-113a and I-113b from racemic compound I-75 and 5-hydroxy-picolinic acid methyl esters 2 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝380.7m/z。Active: A
Embodiment 111
Using and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-114a and I-114b with the similar step of embodiment 102 from racemic compound I-113, replacing methyl aminoacetate except using methylamine (2.0M, in tetrahydrofuran (THF)).These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝396.4m/z。Active: A
Embodiment 112
Using and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-115a and I-115b with the similar step of embodiment 102 from racemic compound I-113, replacing methyl aminoacetate except using ethylamine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝411.1m/z。Active: A
Embodiment 113
Using and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-116a and I-116b with the similar step of embodiment 102 from racemic compound I-113, replacing methyl aminoacetate except using trifluoroethyl amine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝461.7m/z。Active: B
Embodiment 114
Using and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-117a and I-117b with the similar step of embodiment 102 from racemic compound I-113, replacing methyl aminoacetate except using hydroxy amine hydrochloric acid salt.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝398.4m/z。Active: A
Embodiment 115
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-105 are dissolved in (7.0M, in methyl alcohol, 0.02M, relative to isoxazole) in the methanol solution of ammonia.Sealed reaction, stirs 72h at 23 DEG C, removes desolventizing and excess ammonia thereafter, obtain light tan solid, grind in hexane, obtain purposed amide I-118a and I-118b, white solid in nitrogen gas stream.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝325.1m/z。
Active: B
Embodiment 116
Using method 9 is from 4-bromo-3,3 '-DfBP changes into its corresponding alkene, then the cycloaddition of using method 1, then using method 5 5-hydroxy pyrimidine displacement, 3 step synthesis 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-119a and I-119b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝354.3m/z。Active: A
Embodiment 117
Using method 8 forms alkene, the then cycloaddition of using method 1 from the fluoro-4-of 3-(trifluoromethoxy) phenyl aldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-120a and I-120b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝327.5m/z。Active: A
Embodiment 118
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-121a and I-121b from racemic compound I-120 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝344.1m/z。
Active: A
Embodiment 119
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-122a and I-122b from racemic compound I-120 and 5-hydroxy-picolinic acid methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝400.3m/z。Active: A
Embodiment 120
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-122 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-123a and I-123b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝386.3m/z。Active: A
Embodiment 121
Using method 8 forms alkene, the then cycloaddition of using method 1 from the chloro-4-of 3-(trifluoromethoxy) phenyl aldehyde, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-124a and I-124b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝345.5m/z。Active: A
Embodiment 122
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-125a and I-125b from racemic compound I-124 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝359.7m/z。
Active: A
Embodiment 123
Using method 8 forms alkene, the then cycloaddition of using method 1 from fluoro-1, the 3-benzodioxolane-5-formaldehyde of 2,2-bis-, and 2 steps prepare bromo-4,5-dihydro-isoxazole I-126a and I-126b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝305.6m/z。Active: A
Embodiment 124
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-127a and I-127b from racemic compound I-126 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝321.8m/z。
Active: B
Embodiment 125
Preparing 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-128a and I-128b by the mode similar to the Compound I-99 in embodiment 96, replacing racemic compound I-10 except using racemic compound I-14 as raw material.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝398.2m/z。Active: A
Embodiment 126
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-129a and I-129b from racemic compound I-75 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝339.8m/z。
Active: A
Embodiment 127
Following from 4-phenoxyphenyl boronic acid and 2-bromo-3,3, coupling between 3-trifluoropropyl-1-alkene starts 2 steps and prepares 3-bromo-4,5-dihydro-isoxazole I-130a and I-130b: by the solution (0.25M of toluene in sealed tube, relative to boric acid) be cooled to 0 DEG C, add thereafter 2-bromo-3,3,3-trifluoropropyl-1-alkene (0.83 equivalent), then tetrakis triphenylphosphine palladium (2.5mol%).Mixture argon cleaning, adds thereafter 2.0M sodium carbonate solution (1.5 equivalent), then adds boric acid (1.0 equivalent) (1.0M, relative to boric acid) in methyl alcohol.Mixture argon gas second time is rinsed, and is heated to thereafter 70 DEG C and keeps 20h in oil bath.Reaction cooling, transfers in separating funnel by excessive water and ethyl acetate thereafter, washs (1 ×) and wash with water (2 ×) with 2.0M sodium carbonate solution.Organic layer is dry, and concentrated, obtain black oil, by flash silica chromatography (ethyl acetate/hexane), obtain the target alkene of oily, 35% productive rate, using method 1 directly changes into bromo-4, the 5-dihydro-isoxazole I-130 of target racemize 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝385.6m/z。Active: B
Embodiment 128
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-131a and I-131b from racemic compound I-130 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝401.4m/z。
Active: A
Embodiment 129
After first using method 11 prepares 2-(methylthio group) pyrimidine-5-alcohol from 2-(methylthio group) pyrimidine-5-ylboronic acid, using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-132a and I-132b from racemic compound I-14 and 2-(methylthio group) pyrimidine-5-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝372.2m/z。Active: B
Embodiment 130
By racemize 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-132 is dissolved in (0.5M in methylene dichloride, relative to isoxazole), add thereafter metachloroperbenzoic acid (2.0 equivalent) once, reaction at room temperature stirs 1h.After being completed by LC/MS assaying reaction, evaporate solvent.Then, crude mixture is dissolved in (0.5M) in t-butyl methyl ether again, slowly adds hexane thereafter, until separate out solid.Then, by collected by vacuum filtration solid, with 1: 1 hexane/t-butyl methyl ether washing, obtain target 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-133a and I-133b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝404.1m/z。Active: A
Embodiment 131
After first using method 11 prepares 6-(methylthio group) pyridine-3-alcohol from 6-(methylthio group) pyridin-3-yl boric acid, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-134a and I-134b from racemic compound I-14 and 6-(methylthio group) pyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝372.4m/z。Active: A
Embodiment 132
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-135a and I-135b are prepared from I-134 by the mode similar to the Compound I-133 in embodiment 130.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝403.2m/z。
Active: A
Embodiment 133
After first using method 11 prepares the fluoro-6-methoxypyridine of 5--3-alcohol from 5-fluoro-6-methoxypyridine-3-boric acid, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-136a and I-136b from the fluoro-6-methoxypyridine of racemic compound I-14 and 5--3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝373.4m/z。Active: B
Embodiment 134
Using method 8 is from 4-butoxybenzaldehyde, and then cycloaddition 3 step of using method 1 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-137a and I-137b.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy-picolinic acid methyl esters react.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝370.1m/z。
Active: A
Embodiment 135
Use and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-138a and I-138b with similar hydrolysising condition in embodiment 94 from Compound I-137 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝357.7m/z。
Active: A
Embodiment 136
Using method 8 is from 4-butoxybenzaldehyde, and then cycloaddition 3 step of using method 1 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-139a and I-139b.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy pyrimidine react.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝314.9m/z。Active: A
Embodiment 137
Using method 8 is from 4-isopropoxide benzaldehyde, and then the cycloaddition of using method 1 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-140a and I-140b by 4 steps.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy-picolinic acid methyl esters react, and then uses and is hydrolyzed with similar condition in embodiment 94.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝343.5m/z。Active: A
Embodiment 138
Using method 8 is from 4-isopropoxide benzaldehyde, and then cycloaddition 3 step of using method 1 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-141a and I-141b.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy pyrimidine react.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝299.3m/z。
Active: A
Embodiment 139
Cycloaddition condition 3 steps from acetic acid 4-vinyl phenyl ester of using method 1 prepare bromo-4,5-dihydro-isoxazole I-142a and I-142b of 3-.The acetic ester obtained is dissolved in (1.0 equivalents, 0.18M, relative to Xiu isoxazole) in tetrahydrofuran (THF), is cooled to 0 DEG C in ice bath.Add lithium hydroxide (3.0 equivalents, 1.0M, in water), 30min is stirred in reaction, transfers in separating funnel thereafter by excessive water and ethyl acetate.Organic layer saturated ammonium chloride extraction, by dried over sodium sulfate, evaporation, obtains the target phenol that productive rate can be quantitative, directly uses.Phenol (1.00 equivalent) is dissolved in (0.20M, relative to raw material) in acetonitrile, in ice bath, is cooled to 0 DEG C.Add propargyl bromide (2.0 equivalent), then add cesium carbonate (3.0 equivalent).2h is stirred in reaction, thereafter with saturated ammonium chloride quencher, and transfers in separating funnel by excessive water and ethyl acetate.Organic layers with sodium sulfate is dry and evaporate, and obtains target racemize alkynes I-142, by flash silica chromatography (ethyl acetate/hexane), obtains target racemic compound, 70% productive rate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝279.7m/z。Active: A
Embodiment 140
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-143a and I-143b from racemic compound I-142 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝296.5m/z。
Active: B
Embodiment 141
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-144a and I-144b from racemic compound I-142 and 5-hydroxy-picolinic acid methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝353.5m/z。Active: A
Embodiment 142
Use and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-145a and I-145b with similar hydrolysising condition in embodiment 94 from racemic compound I-144 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝338.8m/z。Active: A
Embodiment 143
Use and prepare 3-phenoxy group-4,5-dihydro-isoxazole I-146a and I-146b with similar hydrolysising condition in embodiment 94 from racemic compound I-61 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝376.2m/z。
Active: B
Embodiment 144
Use and prepare 3-phenoxy group-4,5-dihydro-isoxazole I-147a and I-147b with similar hydrolysising condition in embodiment 94 from racemic compound I-62 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝375.1m/z。
Active: A
Embodiment 145
Using method 1 prepares bromo-4,5-dihydro-isoxazole I-148a and I-148b of 3-from 1-bromo-4-vinyl benzene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝350.5m/z。Active: A
Embodiment 146
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-149a and I-149b from racemic compound I-148 and 5-hydroxy-picolinic acid methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝378.4m/z。Active: A
Embodiment 147
Use and prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-150a and I-150b with similar hydrolysising condition in embodiment 94 from racemic compound I-149 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝362.6m/z。Active: A
Embodiment 148
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-151a and I-151b from racemic compound I-14 and 4-hydroxy-picolinic acid methyl esters 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝384.2m/z。Active: A
Embodiment 149
Racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-151 (1.0 equivalent) is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid I-152a and I-152b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝368.9m/z。Active: A
Embodiment 150
Using method 1 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-153a and I-153b from 1-chloro-4-vinyl benzene 2 step.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy pyrimidine react.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝277.3m/z。Active: B
Embodiment 151
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-154a and I-154b from racemic compound I-75 and 6-(furans-3-base) pyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.3m/z。Active: A
Embodiment 152
3-(pyridin-3-yl oxygen base)-4 is prepared from racemic acid I-110 according to following steps; 5-dihydro-isoxazole I-155a and I-155b: in microwave reaction pipe, is dissolved in acetylhydrazide (1.0 equivalent) and sour I-110 (1.0 equivalent) in anhydrous acetonitrile and (is 0.1M).Add triphenylphosphine (3.0 equivalent) and the Trichloroacetonitrile (2.0 equivalent) of polystyrene support, sealed mixture, heats 2 hours in microwave reactor at 130 DEG C.Thereafter, do not completed by LC/MS assaying reaction, then add the triphenylphosphine resin of 1.5 equivalents, and then add the Trichloroacetonitrile of 1.0 equivalents.Sealed vessel again, reheats 2h at 130 DEG C.After completing, concentrated reaction mixture, by flash silica chromatography (hexane/ethyl acetate), obtains target Wai Xiao Xuan oxadiazole I-155.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝415.5m/z。Active: A
Embodiment 153
Use the step similar with embodiment 152 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-156a and I-156b, racemoid I-113 is used as raw material acid except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝422.0m/z。Active: A
Embodiment 154
Use the step similar with embodiment 152 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-157a and I-157b, racemoid I-97 is used as raw material acid except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝407.2m/z。Active: A
Embodiment 155
3-(pyridin-3-yl oxygen base)-4 is prepared from racemic acid 1-113 according to following steps; 5-dihydro-isoxazole I-158a and I-158b: acetylhydrazide (1.0 equivalent) and sour 1-113 (1.0 equivalent) are dissolved in (0.1Meach) in anhydrous methylene chloride; with EDC (1.05 equivalent) and DMAP (0.10 equivalent) process, reaction mixture stirs 6h at 23 DEG C thereafter.After having reacted, be diluted in separating funnel with excessive methylene dichloride and water, organic layer 0.5M aqueous citric acid solution and saturated sodium bicarbonate aqueous solution wash twice respectively.Organic layer dried over mgso, is condensed into white solid.This dissolution of solid, in anhydrous THF, adds 1.2 equivalent Lawesson reagent.Mixture is sealed in pipe, in microwave reactor, heat 30min at 115 DEG C.Concentrated reaction mixture, by flash silica chromatography (hexane/ethyl acetate), obtains target racemize thiadiazoles I-158.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝438.2m/z。Active: A
Embodiment 156
Use the step similar with embodiment 152 to prepare 3-phenoxy group-4,5-dihydro-isoxazole I-159a and I-159b, racemoid I-147 is used as raw material acid except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝413.6m/z。Active: A
Embodiment 157
Use the step similar with embodiment 152 to prepare 3-phenoxy group-4,5-dihydro-isoxazole I-160a and I-160b, racemoid I-146 is used as raw material acid except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝414.4m/z。Active: A
Embodiment 158
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-162a and I-162b are prepared: using method 5 prepares racemize dihydro-isoxazole I-161 from Compound I-14 and 6-bromopyridine-3-alcohol 1 step according to following steps.Compound I-161 is placed in microwave vial, is then dissolved in (0.02M) in diox.Add 2-(tributylstamlyl) thiazole and tetrakis triphenylphosphine palladium, reaction argon cleaning.Thereafter, react and heat 20min in microwave reactor, analyzed by TLC thereafter and determine to there is not raw material.Mixture concentrates, and by flash silica chromatography (hexane/ethyl acetate), obtains target racemize thiazole 1-162,50% productive rate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝407.3m/z。Active: A
Embodiment 159
The step similar with embodiment 158 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-163a and I-163b, except using 2-, (tributylstamlyl) oxazole replaces 2-(tributylstamlyl) thiazole.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝393.2m/z。Active: A
Embodiment 160
Using the step similar with embodiment 158 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-164a and I-164b, replacing Compound I-14 as raw material except using racemic compound I-75.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝423.4m/z。Active: A
Embodiment 161
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-165a and I-165b are prepared: racemize dihydro-isoxazole I-161 and sodium carbonate (10.0 equivalent) are placed in microwave vial according to following steps.Add 2: 2: 1 mixtures (0.02M, relative to 1-161) of toluene, second alcohol and water, then add 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate boric acid (1.5 equivalent).Mixture argon cleaning 20min, adds thereafter tetrakis triphenylphosphine palladium (4mo1%), sealed reaction, is heated to 80 DEG C and keeps 17h in oil bath.Then reaction mixture cooling, transfers in separating funnel with Excess ethyl acetate and water thereafter.Organic layers with water and saturated sodium-chloride washing.Aqueous layer with ethyl acetate is stripped.Merge organic layer, by dried over sodium sulfate, concentrated, obtain thick oil, by flash silica chromatography (hexane/ethyl acetate), obtain target racemize pyrazoles 1-165,36% productive rate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝392.4m/z。Active: C
Embodiment 162
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-166a and I-166b from racemic compound I and 5-hydroxy pyrimidine 1 step.[M-H] -＝241.5m/z。Active: B
Embodiment 163
Prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-167a and I-167b by the mode similar to the Compound I-135 in embodiment 132, racemoid I-75 is used as bromine-isoxazole raw material except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝417.3m/z。Active: A
Embodiment 164
The cycloaddition condition of using method 1 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-168a and I-168b from 1-(trifluoromethyl)-4-vinyl benzene 2 step.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy pyrimidine react, and obtains racemic compound I-168.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝309.8m/z。Active: B
Embodiment 165
The cycloaddition condition of using method 1 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-169a and I-169b from 1-(trifluoromethyl)-4-vinyl benzene 3 step.Using method 5 makes obtain bromo-4,5-dihydro-isoxazole and 6-(methylthio group) pyridine-3-alcohol (using method 11 obtains from 6-(methylthio group) pyridin-3-yl boric acid) react, and are then oxidized under the condition similar to embodiment 130.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝387.2m/z。Active: A
Embodiment 166
The cycloaddition condition of using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-170a and I-170b from 1-(trifluoromethyl)-4-vinyl benzene 3 step.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 5-hydroxy-picolinic acid methyl esters react, and then uses and is hydrolyzed with similar condition in embodiment 94.
These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝353.0m/z。Active: A
Embodiment 167
The step similar with embodiment 35 is used to prepare 1-(4,5-dihydro-isoxazole-3-base)-1H-1,2,4-triazole-3-formic acid I-171a and I-171b, racemoid I-75 is used as raw material bromine-isoxazole and 1H-1 except for the outer, and 2,4-triazole-3-methyl-formiate is used as nucleophilic reagent.In addition, in reaction or some moment for the treatment of processes, Ester hydrolysis becomes corresponding acid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝356.6m/z。Active: C
Embodiment 168
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-172a and I-172b from racemic compound I-75 and pyrazolo [1,5-α] pyridine-2-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝378.1m/z。Active: C
Embodiment 169
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-173a and I-173b, except using 2-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrroles-1-t-butyl formate replaces 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝390.6m/z。Active: A
Embodiment 170
Using method 5 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-174a and I-174b from racemic compound I-14 and 3-(1H-TETRAZOLE-5-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.3m/z。
Active: B
Embodiment 171
Using method 5 prepares 3-phenoxy group-4,5-dihydro-isoxazole I-175a and I-175b from racemic compound I-14 and 4-(1H-TETRAZOLE-5-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝391.6m/z。
Active: B
Embodiment 172
Preparation 3-phenoxy group-4,5-dihydro-isoxazole I-176a and I-176b is walked from racemic compound I-142.Using method 5 makes bromo-4,5-dihydro-isoxazole I-14 and 3-methyl hydroxybenzoate react, and then uses and is hydrolyzed with similar condition in embodiment 94.[M+H] +＝368.0m/z。Active: C
Embodiment 173
Preparation 3-phenoxy group-4,5-dihydro-isoxazole I-177a and I-177b is walked from racemic compound I-142.Using method 5 makes bromo-4,5-dihydro-isoxazole I-14 and 4-HBA methyl esters react, and then uses and is hydrolyzed with similar condition in embodiment 94.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝368.0m/z。Active: B
Embodiment 174
In using method 11 from 5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base) after pyridine carbonitrile prepares 5-pyridone formonitrile HCN, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-178a and I-178b from racemic compound I-14 and 5-pyridone formonitrile HCN 2 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝350.0m/z。Active: B
Embodiment 175
Using method 1 prepares bromo-4,5-dihydro-isoxazole I-179a and I-179b of 3-from 1-amyl group-4-vinyl benzene 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝283.6m/z。Active: A
Embodiment 176
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole I-180a and I-180b from racemic compound I-179 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝298.7m/z。
Active: A
Embodiment 177
First I-179 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the synthesis of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-181a and I-181b are prepared from racemic compound I-179 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝375.4m/z。Active: A
Embodiment 178
First I-14 and 6-(ethylmercapto group) pyridine-3-alcohol (using method 11 is from the synthesis of 6-(ethylmercapto group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-182a and I-182b are prepared from racemic compound I-14 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝417.1m/z。Active: A
Embodiment 179
First I-14 and 6-(ring penta sulfenyl) pyridine-3-alcohol (using method 11 is from the synthesis of 6-(ring penta sulfenyl) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-183a and I-183b are prepared from racemic compound I-14 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝456.8m/z。Active: B
Embodiment 180
First I-14 and 6-(isobutylthio) pyridine-3-alcohol (using method 11 is from the synthesis of 6-(isobutylthio) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-184a and I-184b are prepared from racemic compound I-14 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝444.7m/z。Active: B
Embodiment 181
The step similar with embodiment 178 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-185a and I-185b, replaces Compound I-75 as raw material except using racemic compound I-75 and uses 2-(tributylstamlyl) oxazole to replace 2-(tributylstamlyl) thiazole (as in embodiment 158).These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝407.2m/z。Active: A
Embodiment 182
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-186a and I-186b, 4-(4 is replaced except using 2-furyl boronic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.2m/z。
Active: A
Embodiment 183
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-187a and I-187b, 4-(4 is replaced except using 5-methyl furan-2-ylboronic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.3m/z。Active: A
Embodiment 184
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4, the enantiomer of 5-dihydro-isoxazole I-188a and I-188b, 4-(4 is replaced except using 5-boryl furans-2-formic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝435.5m/z。Active: C
Embodiment 185
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-189a and I-189b, except using 1-methyl-5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles replaces 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.2m/z。Active: A
Embodiment 186
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-190a and I-190b, except using 1,3-dimethyl-1H-pyrazoles-5-ylboronic acid replaces 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝419.4m/z。Active: A
Embodiment 187
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-191a and I-191b, 4-(4 is replaced except using 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-ylboronic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝473.3m/z。Active: C
Embodiment 188
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-192a and I-192b, 4-(4 is replaced except using 1H-pyrazoles-5-ylboronic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝391.4m/z。
Active: A
Embodiment 189
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-193a and I-193b, 4-(4 is replaced except using 5-boryl thiophene-2-carboxylic acid, 4,5,5-tetramethyl--1,3,2-bis-is mixed oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝450.6m/z。
Active: B
Embodiment 190
3-(pyridin-3-yl oxygen base)-4 is prepared according to following steps, 5-dihydro-isoxazole I-194a and I-194b: by racemize dihydro-isoxazole I-161, Tripotassium phosphate (3.0 equivalent), 4-(4,4,5,5-tetramethyl--1, mix oxygen pentaborane-2-base) isoxazole (1.2 equivalent) and palladium catalyst (10mol%) of 3,2-bis-is placed in microwave vial.Add diox (0.1M, relative to 1-161), mixture argon cleaning 20min, sealed reaction thereafter, in oil bath, be heated to 85 DEG C keep 17h.Then reaction mixture cooling, transfers in separating funnel with Excess ethyl acetate and water thereafter.Organic layers with water and saturated sodium-chloride washing.Aqueous layer with ethyl acetate is stripped.Merge organic layer, by dried over sodium sulfate, concentrated, obtain thick oil, by flash silica chromatography (hexane/ethyl acetate), obtain target racemize pyrazoles 1-194, < 5% productive rate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝392.2m/z。Active: A
Embodiment 191
3-(pyridin-3-yl oxygen base)-4 is prepared according to following steps, 5-dihydro-isoxazole I-195a and I-195b: racemize dihydro-isoxazole I-178 (1.0 equivalent) is dissolved in N, (0.1M in dinethylformamide, relative to isoxazole), add thereafter ammonium chloride (3.1 equivalent) and sodiumazide (1.5 equivalent).Then, react and be heated to 120 DEG C of maintenance 4h in oil bath, reaction Excess ethyl acetate and water are transferred in separating funnel thereafter.Organic layers with water and saturated sodium-chloride washing, by dried over sodium sulfate, concentrated, obtain thick oil, by flash silica chromatography (hexane/ethyl acetate), obtain target racemize tetrazolium 1-195.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝393.2m/z。Active: A
Embodiment 192
First I-75 and 6-(ethylmercapto group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(ethylmercapto group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-196a and I-196b are prepared from racemic compound I-75 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝431.3m/z。Active: A
Embodiment 193
First I-10 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-197a and I-197b are prepared from racemic compound I-10 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝411.4m/z。Active: A
Embodiment 194
In using method 11 from 2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base) after pyridine synthesis 6-(1H-pyrazol-1-yl) pyridine-3-alcohol, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-198a and I-198b from racemic compound I-75 and 6-(1H-pyrazol-1-yl) pyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝405.3m/z。Active: A
Embodiment 195
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-199a and I-199b from racemic compound I-14 and 3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.3m/z。Active: C
Embodiment 196
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-200a and I-200b from racemic compound I-14 and 4-(2-methyl-2H-tetrazolium-5-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.4m/z。Active: B
Embodiment 197
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-201a and I-201b from racemic compound I-14 and 4-(1,3,4-oxadiazole-2-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.2m/z。Active: A
Embodiment 198
3-bromo-4 is prepared according to following steps 2 step, 5-dihydro-isoxazole I-202a and I-202b:4-vinylbenzoyl chloride (1.0 equivalent) are dissolved in (0.375M in methylene dichloride, relative to vinylbenzene), add thereafter morpholine (3.0 equivalent).Reaction at room temperature stirs 14h, starts during this period to form white precipitate.Then, reaction excessive water and methylene dichloride are transferred in separating funnel.Organic layers with water (1 ×), 1NHCl (1 ×), saturated sodium bicarbonate (1 ×) and salt solution (1 ×) wash, and use dried over sodium sulfate thereafter, concentrated, obtain yellow oil.Then, thick substance migration method 1 is directly used in and forms target racemize Xiu isoxazole.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝338.7m/z。Active: B
Embodiment 199
Using the step similar with embodiment 198 to prepare bromo-4,5-dihydro-isoxazole I-203a and I-203b of 3-, replacing morpholine except using the dimethylamine (2.0M) in tetrahydrofuran (THF).These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝299.3m/z。Active: A
Embodiment 200
Using the step similar with embodiment 198 to prepare bromo-4,5-dihydro-isoxazole I-204a and I-204b of 3-, replacing morpholine except using the methylamine (2.0M) in tetrahydrofuran (THF).These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝282.6m/z。Active: B
Embodiment 201
3-bromo-4 is prepared according to following steps 2 step, 5-dihydro-isoxazole I-205a and I-205b: 4-vinyl benzene-1-SULPHURYL CHLORIDE (1.0 equivalent) is dissolved in (0.50M in methylene dichloride, relative to vinylbenzene), add thereafter morpholine (3.0 equivalent).Reaction at room temperature stirs 90min, transfers in separating funnel thereafter with excessive water and methylene dichloride.Organic layers with water (1 ×), 1NHCl (1 ×), saturated sodium bicarbonate (1 ×) and salt solution (1 ×) wash, and use dried over sodium sulfate thereafter, concentrated, obtain yellow oil.Then, thick substance migration method 1 is directly used in and forms target racemize Xiu isoxazole.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝374.6m/z。
Active: A
Embodiment 202
Using the step similar with embodiment 201 to prepare bromo-4,5-dihydro-isoxazole I-206a and I-206b of 3-, replacing morpholine except using the dimethylamine (2.0M) in THF.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝332.6m/z。Active: A
Embodiment 203
Using the step similar with embodiment 201 to prepare bromo-4,5-dihydro-isoxazole I-207a and I-207b of 3-, replacing morpholine except using the methylamine (2.0M) in THF.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝318.6m/z。
Active: A
Embodiment 204
Using the step similar with embodiment 198 to prepare bromo-4,5-dihydro-isoxazole I-208a and I-208b of 3-, replacing morpholine except using piperidines.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝339.3m/z。Active: A
Embodiment 205
Using the step similar with embodiment 198 to prepare bromo-4,5-dihydro-isoxazole I-209a and I-209b of 3-, replacing morpholine except using tetramethyleneimine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝322.6m/z。Active: A
Embodiment 206
Using the step similar with embodiment 201 to prepare bromo-4,5-dihydro-isoxazole I-210a and I-210b of 3-, replacing morpholine except using piperidines.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝472.6m/z。Active: A
Embodiment 207
Using the step similar with embodiment 201 to prepare bromo-4,5-dihydro-isoxazole I-211a and I-211b of 3-, replacing morpholine except using tetramethyleneimine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝358.6m/z。Active: A
Embodiment 208
First I-203 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-212a and I-212b are prepared from racemic compound I-203 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝390.4m/z。Active: B
Embodiment 209
First I-202 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-213a and I-213b are prepared from racemic compound I-202 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝426.2m/z。Active: A
Embodiment 210
First I-21 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-214a and I-214b are prepared from racemic compound I-21 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝352.2m/z。Active: A
Embodiment 211
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-215a and I-215b are prepared by 2 steps from racemic compound I-21.Using method 5 makes bromo-4,5-dihydro-isoxazole I-215 and 5-hydroxy-picolinic acid methyl esters react, and then uses and is hydrolyzed with similar condition in embodiment 94.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝418.3m/z。Active: B
Embodiment 212
The cycloaddition condition of using method 1 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-216a and I-216b from 1-(trifluoromethyl)-4-vinyl benzene 2 step.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and the bromo-5-pyridone of 2-react, and obtains racemic compound I-216.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝389.1m/z。Active: B
Embodiment 213
Using the step similar with embodiment 212 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-217a and I-217b, replacing the bromo-5-pyridone of 2-except using 3-(1,3,4-oxadiazole-2-base) phenol.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝376.4m/z。Active: A
Embodiment 214
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-218a and I-218b, except using 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles replaces 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝404.8m/z。Active: A
Embodiment 215
The step similar with embodiment 161 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-219a and I-219b, except using 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles replaces 4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles-1-t-butyl formate and racemize bromopyridine I-216 be used as raw material instead of I-161.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝390.3m/z。Active: A
Embodiment 216
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-220a and I-220b are prepared: sour I-97 (1.0 equivalent) is dissolved in (0.08M) in methylene dichloride according to following steps.Add oxalyl chloride (1.5 equivalent), then add 1 DMF.Reaction at room temperature stirs 20min, vacuum concentration thereafter.Then, thick material is dissolved in methylene dichloride again, adds thereafter amsacrine (1.2 equivalent), DMAP (10mol%) and triethylamine (1.5 equivalent).After 3h, analyze assaying reaction by LC/MS and complete.Then, reaction mixture Excess ethyl acetate and water are transferred in separating funnel.Organic layer 1NHCl and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain desired sulfonyl amine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝446.1m/z。Active: A
Embodiment 217
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-221a and I-221b from racemic compound I-14 and 3-(4H-1,2,4-triazole-4-yl) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.0m/z。Active: C
Embodiment 218
3-(phenoxy group)-4,5-dihydro-isoxazole I-222a and I-222b is prepared: using method 5 makes 3-methyl hydroxybenzoate and racemize Xiu isoxazole I-75 react according to following steps 3 step.The methyl esters obtained (1.0 equivalent) is dissolved in (0.08M) in methyl alcohol, adds thereafter hydrazine (50 equivalents, 50 % by weight, in water), 14h is stirred in reaction.Then, reaction mixture vacuum concentration, is directly used in next step.Add triethly orthoacetate (8.0 equivalent), sealed reaction, reflux 14h.Then reaction Excess ethyl acetate and water are transferred in separating funnel.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, and use flash silica chromatography (gradient ethyl acetate/hexane), obtaining disappears outside target revolves oxadiazole I-222.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝420.5m/z。Active: A
Embodiment 219
Using the step similar with embodiment 218 to prepare 3-(phenoxy group)-4,5-dihydro-isoxazole I-223a and I-223b, replacing Compound I-75 as raw material except using racemic compound I-15.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.5m/z。Active: A
Embodiment 220
3-(phenoxy group)-4,5-dihydro-isoxazole I-224a and I-224b is prepared: using method 5 makes the fluoro-5-methyl hydroxybenzoate of 3-and racemize Xiu isoxazole I-14 react according to following steps 3 step.The methyl esters (1.0 equivalent) obtained is dissolved in (0.08M) in methyl alcohol, adds thereafter hydrazine (50 equivalents, 50 % by weight, in water), and 14h is stirred in reaction.Then, reaction mixture vacuum concentration, is directly used in next step.Add triethly orthoacetate (8.0 equivalent), sealed reaction, reflux 14h.Then reaction Excess ethyl acetate and water are transferred in separating funnel.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, and use flash silica chromatography (gradient ethyl acetate/hexane), obtaining disappears outside target revolves oxadiazole I-224.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +424.5m/z。Active: A
Embodiment 221
Using the step similar with embodiment 220 to prepare 3-(phenoxy group)-4,5-dihydro-isoxazole I-225a and I-225b, except using triethyl orthoformate to replace triethly orthoacetate, forming Mu Biao oxadiazole.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝410.3m/z。Active: A
Embodiment 222
Using the step similar with embodiment 220 to prepare 3-(phenoxy group)-4,5-dihydro-isoxazole I-226a and I-226b, replacing the fluoro-5-methyl hydroxybenzoate of 3-except using 4-fluoro-5-methyl hydroxybenzoate in a first step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝410.4m/z。Active: A
Embodiment 223
Using the step similar with embodiment 222 to prepare 3-(phenoxy group)-4,5-dihydro-isoxazole I-227a and I-227b, replacing Compound I-14 as raw material except using racemic compound I-75.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝424.2m/z。Active: A
Embodiment 224
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-228a and I-228b are prepared: using method 5 makes 5-hydroxy niacin methyl esters and racemize Xiu isoxazole I-75 react according to following steps 3 step.The methyl esters (1.0 equivalent) obtained is dissolved in (0.08M) in methyl alcohol, adds thereafter hydrazine (50 equivalents, 50 % by weight, in water), and 14h is stirred in reaction.Then, reaction mixture vacuum concentration, is directly used in next step.Add triethyl orthoformate (8.0 equivalent), sealed reaction, reflux 14h.Then reaction Excess ethyl acetate and water are transferred in separating funnel.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, and use flash silica chromatography (gradient ethyl acetate/hexane), obtaining disappears outside target revolves oxadiazole I-228.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝407.5m/z。Active: A
Embodiment 225
Using the step similar with embodiment 224 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-229a and I-229b, except using triethly orthoacetate to replace triethyl orthoformate, forming Mu Biao oxadiazole.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝422.0m/z。Active: A
Embodiment 226
Using the step similar with embodiment 224 to prepare 3-(phenoxy group)-4,5-dihydro-isoxazole I-230a and I-230b, replacing compound 75 as raw material except using racemic compound I-14.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝393.2m/z。Active: A
Embodiment 227
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-231a and I-231b are prepared: using method 5 makes 5-hydroxy niacin methyl esters and racemize Xiu isoxazole I-75 react according to following steps 3 step.The methyl esters (1.0 equivalent) obtained is dissolved in (0.08M) in methyl alcohol, adds thereafter hydrazine (50 equivalents, 50 % by weight, in water), and 14h is stirred in reaction.Then, reaction mixture vacuum concentration, is directly used in next step.Hydrazides is dissolved in (0.12M, relative to hydrazides) in diox.Add N, N-carbonyl dimidazoles (1.2 equivalent), sealed reaction, reflux 4h.Then reaction Excess ethyl acetate and water are transferred in separating funnel.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, uses flash silica chromatography (gradient methanol/methylene dichloride), obtain target racemize 1,3,4-oxadiazole-2 (3H)-one I-231.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝423.4m/z。Active: B
Embodiment 228
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-232a and I-232b from racemic compound I-75 and 4-(1,3,4-oxadiazole-2-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.5m/z。Active: A
Embodiment 229
Using method 5 is from racemic compound I-75 and 3-hydroxy-n, and N-dimethyl benzene sulfonamide 1 step prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-233a and I-233b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝445.4m/z。Active: C
Embodiment 230
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-234a and I-234b from racemic compound I-75 and 4-(methyl sulphonyl) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝415.6m/z。
Active: B
Embodiment 231
Using method 5 is from racemic compound I-75 and 4-hydroxy-n, and N-dimethyl benzene sulfonamide 1 step prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-235a and I-235b.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝445.3m/z。Active: C
Embodiment 232
3-(pyridin-3-yl oxygen base)-4 is prepared according to following steps 3 steps, 5-dihydro-isoxazole I-236a and I-236b: racemize dihydro-isoxazole I-161 (1.0 equivalent) is dissolved in (0.1M) in DMF.Add cupric iodide (1.0 equivalent), then add trimethylsilyl acetylene (3.0 equivalent) and N, N-diisopropyl ethyl amine (2.0 equivalent).Add tetrakis triphenylphosphine palladium (15mol%), sealed reaction, in microwave reactor, at 100 DEG C, heat 1h.Reaction cooling, transfers in separating funnel with ethyl acetate and water thereafter.Then, organic layers with water and salt water washing, by dried over sodium sulfate, concentrated, by flash silica chromatography (gradient ethyl acetate/hexane).Then, by by substance dissolves in methyl alcohol (0.07M) add salt of wormwood (3.0 equivalent) and make TMS group deprotection.After at room temperature stirring 4h, reaction ethyl acetate and water are transferred in separating funnel.Then, organic layers with water and salt water washing, by dried over sodium sulfate, concentrated, by flash silica chromatography (gradient ethyl acetate/hexane).Then, by being first dissolved in pure trimethylsilyl azide (80 equivalent), use argon cleaning reaction mixture, and in microwave reactor, be heated to 110 DEG C of maintenance 3h, make the alkynes obtained change into target triazole.After reheating 4h, analyze assaying reaction by LC/MS and complete 60%, now concentrate and pass through silica flash chromatography direct purification (gradient methanol/methylene dichloride), obtaining target racemize triazole I-236.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.9m/z。Active: A
Embodiment 233
First I-148 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized under the condition similar to embodiment 130,3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-237a and I-237b are prepared from racemic compound I-148 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝396.6m/z。Active: A
Embodiment 234
The cycloaddition condition of using method 1 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-238a and I-238b from 1-(trifluoromethyl)-4-vinyl benzene 2 steps.Using method 5 makes bromo-4, the 5-dihydro-isoxazoles that obtain and 6-(methylthio group) pyridine-3-alcohol (using method 11 is prepared from 6-(methylthio group) pyridin-3-yl boric acid) react, and obtains Compound I-238.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝355.3m/z。Active: A
Embodiment 235
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-240a and I-240b are prepared: 6-bromopyridine-3-alcohol (1.0 equivalent) and sodium carbonate (10.0 equivalent) are added to microwave vial according to following steps 2 steps.Add toluene, second alcohol and water (0.16M, 2: 2: 1v/v), then add 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mix oxygen pentaborane-2-base)-1H-pyrazoles (1.5 equivalent).Mixture argon cleaning 15min, then adds tetrakis triphenylphosphine palladium (4mol%).Then, cover reaction tubes with aluminium foil, in oil bath, be heated to 80 DEG C keep 17h.After cooling, reaction excessive water and ethyl acetate are transferred in separating funnel.Then, organic layers with water (1 ×), saturated ammonium chloride (1 ×) and salt solution (1 ×) washing.Combining water layer, by ethyl acetate washing (1 ×).Then, merge organic layer, by dried over sodium sulfate, concentrated, use flash silica chromatography (gradient methanol/methylene dichloride), obtain 6-(1-methyl isophthalic acid H-pyrazoles-4-base) pyridine-3-alcohol 1-239, white solid.Then, using method 5 makes this compound and bromo-4, the 5-dihydro-isoxazole I-75 of racemize 3-react, and obtains target racemic compound I-240.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝419.3m/z。Active: A
Embodiment 236
The step similar with embodiment 235 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-241a and I-241b, except using 1-methyl-5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles replaces 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles is as the boric acid ester in the first step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.2m/z。Active: A
Embodiment 237
Using the step similar with embodiment 188 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-242a and I-242b, replacing Compound I-14 as raw material except using racemic compound I-75.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝406.3m/z。Active: A
Embodiment 238
2-(4 is prepared according to following steps 2 steps, 5-dihydro-isoxazole-3-base is amino) ethanol I-243a and I-243b: by bromo-for racemize 3-4,5-dihydro-isoxazole I-10 (1.0 equivalent) is dissolved in (0.57M) in propyl carbinol, then adds (t-butyldimethylsilyl oxygen base) methylamine (1.2 equivalent) and sodium carbonate (2.5 equivalent).Sealed reaction, heats 1h in microwave reactor at 150 DEG C, is analyzed thereafter measure few product formation by LC/MS.Then, then sealed reaction, in microwave reactor, at 120 DEG C, reheat 24h, use thereafter excessive water and t-butyl methyl ether to transfer in separating funnel.Water layer t-butyl methyl ether washing (2 ×), merges organic layer, uses salt water washing, by dried over mgso, concentrated, obtain orange solids, use flash silica chromatography (gradient ethyl acetate/hexane), obtain target silyl ether.Then, this compound (1.0 equivalent) is dissolved in (0.02M) in methyl alcohol, in ice bath, is cooled to 0 DEG C.Drip Acetyl Chloride 98Min. (50 equivalent), reaction thereafter stirs 30min at 0 DEG C.Then, except desolventizing and remaining Acetyl Chloride 98Min. in nitrogen gas stream, thick material is by flash silica chromatography (gradient ethyl acetate/methyl alcohol) thereafter, obtains racemize I-243.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝300.2m/z。Active: B
Embodiment 239
2-((4 is prepared according to following steps 2 steps, 5-dihydro-isoxazole-3-base) (methyl) amino) acetic acid I-244a with I-244b: by reacting bromo-for racemize 3-4 with sarcosine ethyl under the condition identical with embodiment 238,5-dihydro-isoxazole I-10 changes into amino-4, the 5-dihydro-isoxazoles of corresponding 3-.Then, use the condition similar to embodiment 119 that ethyl ester is hydrolyzed, obtain the mixture of racemize I-244.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝327.5m/z。Active: B
Embodiment 240
2-(4 is prepared according to following steps 1 step, 5-dihydro-isoxazole-3-base is amino) alcohol I-245a and I-245b: by bromo-for racemize 3-4,5-dihydro-isoxazole I-10 (1.0 equivalent) is dissolved in (0.64M) in propyl carbinol, then adds (S)-2-amino-1-phenylethyl alcohol (1.2 equivalent) and sodium carbonate (2.5 equivalent).Sealed reaction, is heated to 120 DEG C and keeps 18h, cool thereafter, then transfer in separating funnel by excessive water and t-butyl methyl ether in oil bath.Water layer t-butyl methyl ether washing (2 ×), merges organic layer, uses salt water washing, by dried over mgso, concentrated, obtain orange solids, use flash silica chromatography (gradient toluene/hexane is to toluene/ethyl acetate), obtain racemize I-245, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝374.20m/z。Active: C
Embodiment 241
The step similar with embodiment 240 is used to prepare 2-(4,5-dihydro-isoxazole-3-base is amino) alcohol I-246a and I-246b, except using racemize 3-bromo-4,5-dihydro-isoxazole I-14 replaces bromo-4, the 5-dihydro-isoxazole I-10 of 3-to replace (S)-2-amino-1-phenylethyl alcohol as raw material and use (R)-2-amino-1-phenylethyl alcohol.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝365.6m/z。Active: C
Embodiment 242
3-(thiophenyl)-4,5-dihydro-isoxazole I-248a and I-248b is prepared: be dissolved in tetrahydrofuran (THF) by N, N-dibromo formoxime (1.0 equivalent) according to following steps 2 steps.Add thiophenol (2.0 equivalent), then add sodium hydride (1.98 equivalent).After stirring 1h, reaction is concentrated, by flash silica chromatography (gradient ethyl acetate/hexane), obtains desired hydroxyl group sub-amido dithiocarbonic acid diphenyl ester I-247.Then dithioesters (1.0 equivalent) is dissolved in (1.0M) in acetonitrile again, then adds 1-(trifluoromethoxy)-4-vinyl benzene (2.4 equivalent), Silver Nitrate (1.0 equivalent) and salt of wormwood (1.0 equivalent).Reaction is at room temperature stirred 3 days, concentrates thereafter, by flash silica chromatography (gradient ethyl acetate/hexane), obtains racemize 3-(thiophenyl)-4,5-dihydro-isoxazole I-248.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝339.9m/z。Active: C
Embodiment 243
3-(phenylsufinyl)-4,5-dihydro-isoxazole I-249a and I-249b is prepared by oxidation racemize 3-(thiophenyl)-4,5-dihydro-isoxazole I-248.By 3-(thiophenyl)-4,5-dihydro-isoxazole I-248 (1.0 equivalent) dissolves in ethanol (0.15M), then the excess hydrogen peroxide aqueous solution (30 % by weight, > 50 equivalent) and 1NHCl (0.29M) is added.Reaction at room temperature stirs 14h, transfers in separating funnel thereafter with excessive water and methylene dichloride.Water layer is with dichloromethane extraction (1 ×), by dried over mgso, concentrated, obtains crude product, uses hexane recrystallization, obtain target racemize 3-(phenylsufinyl)-4,5-dihydro-isoxazole I-249.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝355.5m/z。Active: C
Embodiment 244
3-(phenyl sulfonyl)-4,5-dihydro-isoxazole I-250a and I-250b is prepared by oxidation racemize 3-(phenylsufinyl)-4,5-dihydro-isoxazole I-249.3-(phenylsufinyl)-4,5-dihydro-isoxazole I-249 is dissolved in (0.03M) in methylene dichloride.Divide and add metachloroperbenzoic acid (77 % by weight, 2.95 equivalents) for 2 times, reaction at room temperature stirs 14h, transfers in separating funnel thereafter with excessive water and methylene dichloride.Organic layer saturated sodium bicarbonate washing (2 ×), by dried over mgso, concentrated, obtain thick solid, use dichloromethane/hexane recrystallization, obtain target racemize 3-(phenyl sulfonyl)-4,5-dihydro-isoxazole I-250.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝371.7m/z。Active: C
Embodiment 245
Using the step similar with embodiment 242 to prepare 3-(thiophenyl)-4,5-dihydro-isoxazole I-251a and I-251b, except using 4-mercaptobenzoate to replace thiophenol, forming the sub-amido dithiocarbonates of necessary hydroxyl.Then, use and with similar condition in embodiment 94, the methyl esters cycloaddition thing obtained is hydrolyzed, obtain racemize 3-(thiophenyl)-4,5-dihydro-isoxazole I-251.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝384.1m/z。Active: C
Embodiment 246
N-ethyl, N-phenyl-4,5-dihydro-isoxazole-3-amine I-253a and I-253b is prepared: be dissolved in acetonitrile by N, N-dibromo formoxime (1.05 equivalent) according to following steps 2 steps.Add thiophenol (1.0 equivalent) and N-ethylaniline (1.0 equivalent), reaction at room temperature stirs 2.5h, adds thereafter triethylamine (5.0 equivalent).After stirring 1h, filter the solid of separating out from reaction, concentrated filtrate, directly by flash silica chromatography (gradient ethyl acetate/hexane, containing 1% triethylamine), obtain target sub-amido dithiocarbonates 1-252.Then sub-amido dithiocarbonates (1.0 equivalent) is dissolved in (1.0M) in acetonitrile again, then adds 1-(trifluoromethoxy)-4-vinyl benzene (2.4 equivalent), Silver Nitrate (1.07 equivalent) and salt of wormwood (1.17 equivalent).Reaction is at room temperature stirred 1 day, thereafter by flash silica chromatography (gradient ethyl acetate/hexane, containing 1% triethylamine), obtains racemize 4,5-dihydro-isoxazole-3-amine 1-253.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝352.1m/z。Active: C
Embodiment 247
N-Methyl-N-phenyl-4,5-dihydro-isoxazole-3-amine I-255a and I-255b is prepared: be dissolved in acetonitrile by N, N-dibromo formoxime (1.05 equivalent) according to following steps 3 steps.Add thiophenol (1.0 equivalent) and 4-(methylamino) methyl benzoate (1.0 equivalent), divide thereafter and add triethylamine (3.0 equivalent) for 3 times.After stirring 3h, reaction excessive water and methylene dichloride are transferred in separating funnel.Organic layer 1NHCl washing (2 ×), by dried over mgso, concentrated, use flash silica chromatography (gradient ethyl acetate/hexane, containing 0.5% triethylamine, then gradient methanol/methylene dichloride, containing 0.5% triethylamine), obtain target sub-amido dithiocarbonates 1-254.Then sub-amido dithiocarbonates (1.0 equivalent) is dissolved in (1.0M) in acetonitrile again, then adds 1-(trifluoromethoxy)-4-vinyl benzene (1.8 equivalent), Silver Nitrate (2.3 equivalent) and salt of wormwood (2.1 equivalent).Reaction is at room temperature stirred 1 day, thereafter by flash silica chromatography (gradient ethyl acetate/hexane, containing 0.5% triethylamine, then gradient methanol/methylene dichloride, containing 0.5% triethylamine).Then, use and with similar condition in embodiment 94, the racemic methyl ester cycloaddition thing obtained is hydrolyzed, obtain racemize N-Methyl-N-phenyl-4,5-dihydro-isoxazole-3-amine 1-255.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝381.5m/z。Active: C
Embodiment 248
Using the step similar with embodiment 238 to prepare 3-(pyrrolidin-1-yl)-4,5-dihydro-isoxazole I-256a and I-256b, replacing (S)-2-amino-1-phenylethyl alcohol except using tetramethyleneimine.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝310.3m/z。Active: C
Embodiment 249
Using method 5 prepares 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-base oxygen base)-4,5-dihydro-isoxazole I-257a and I-257b from Compound I-10 and 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝403.7m/z。Active: B
Embodiment 250
Using method 5 prepares 3-(phenoxy group)-4,5-dihydro-isoxazole I-258a and I-258b from racemic compound I-14 and 3-(1,3,4-oxadiazole-2-base) phenol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝392.4m/z。Active: A
Embodiment 251
Use the step similar with embodiment 152 to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-259a and I-259b, racemoid I-170 is used as raw material acid except for the outer.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝390.7m/z。Active: A
Embodiment 252
4,5-dihydro-isoxazole-3-yl acetate I-260a and I-260b is prepared: racemize Xiu isoxazole I-10 (1.0 equivalent) is dissolved in (1.0M) in tetrahydrofuran (THF) according to following steps 3 steps.Add 1N sodium hydroxide solution (4.0 equivalent), then add allyl alcohol (45 equivalent).Sealed reaction, is heated to 60 DEG C and keeps 3h.Reaction mixture cools, and then transfers in separating funnel by excessive water and ethyl acetate.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, uses flash silica chromatography (gradient ethyl acetate/hexane).Then by the allyl ethers obtained, (1.0 are dissolved in middle tetrahydrofuran (THF) (0.2M).Add formic acid (5.0 equivalent), then add tetrakis triphenylphosphine palladium (10mol%), react thereafter and at room temperature stir 2h.Reaction mixture excessive water and ethyl acetate are transferred in separating funnel.Organic layer saturated sodium bicarbonate and salt water washing, by dried over sodium sulfate, use flash silica chromatography (gradient ethyl acetate/hexane).Obtain isoxazoline-3-ketone (1.0 equivalent) and be dissolved in (0.3M) in methylene dichloride, add N thereafter, N-dimethyl aminopyridine (1.0 equivalent) and diacetyl oxide (1.0 equivalent).After at room temperature stirring 14h, reaction excessive water and ethyl acetate are transferred in separating funnel.Organic layer 1NHCl and salt water washing, by dried over sodium sulfate, concentrated, obtain target racemize acetic ester 1-260.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝297.8m/z。Active: D
Embodiment 253
After first using method 11 prepares 6-(methylthio group) pyridine-3-alcohol from 6-(methylthio group) pyridin-3-yl boric acid, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole I-261a and I-261b from racemic compound I-75 and 6-(methylthio group) pyridine-3-alcohol 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝386.2m/z。Active: A
Embodiment 254
Using method 2 prepares bromo-4,5-dihydro-isoxazole II-1a and II-1b of 3-from 4-vinylpridine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝226.0m/z。Active: C
Embodiment 255
Using method 2 prepares bromo-4,5-dihydro-isoxazole II-2a and II-2b of 3-from 3-vinyl pyridine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝226.0m/z。Active: C
Embodiment 256
Using method 2 prepares bromo-4,5-dihydro-isoxazole II-3a and II-3b of 3-from 2-vinyl pyridine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝226.0m/z。Active: C
Embodiment 257
Using method 8 forms alkene, the then cycloaddition of using method 2 from 1-phenyl-1H-pyrazoles-4-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-4a and II-4b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝291.0m/z。Active: B
Embodiment 258
Using method 8 forms alkene, the then cycloaddition of using method 2 from 2-phenyl-1,3-thiazoles-4-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-5a and II-5b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝308.0m/z。Active: C
Embodiment 259
Form alkene by using method 8 from 2-phenyl-1,3-thiazoles-5-formaldehyde, the then cycloaddition of using method 1, prepare bromo-4,5-dihydro-isoxazole II-6a and II-6b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝308.0m/z。Active: A
Embodiment 260
Using method 8 from 5-tolylthiophene-2-formaldehyde formed alkene, the then cycloaddition of using method 1, prepare bromo-4,5-dihydro-isoxazole II-7a and II-7b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝309.6m/z。Active: A
Embodiment 261
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-tolylthiophene-2-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-8a and II-8b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝307.0m/z。Active: A
Embodiment 262
Using method 8 forms alkene, the then cycloaddition of using method 2 from 6-quinoline aldehyde, prepares bromo-4,5-dihydro-isoxazole II-9a and II-9b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝276.0m/z。Active: A
Embodiment 263
Using method 8 forms alkene, the then cycloaddition of using method 2 from 3-quinoline aldehyde, prepares bromo-4,5-dihydro-isoxazole II-10a and II-10b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝276.0m/z。
Active: A
Embodiment 264
Using method 10 forms alkene, the then cycloaddition of using method 2 from 6-bromine quinoxaline, prepares bromo-4,5-dihydro-isoxazole II-11a and II-11b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝277.0m/z。
Active: A
Embodiment 265
Using method 9 forms alkene, the then cycloaddition of using method 2 from the bromo-1-Methyl-1H-indole of 5-, prepares bromo-4,5-dihydro-isoxazole II-12a and II-12b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝278.0m/z。Active: A
Embodiment 266
Bromo-4,5-dihydro-isoxazole II-13a and II-13b of 3-are prepared by 2 steps as follows: benzothiazole (1.0 equivalent) is dissolved in (0.12M, relative to thiazole) in methylene dichloride from the Boc-protection of 2-amino-6-bromo benzothiazole.Then add tert-Butyl dicarbonate (3.0 equivalent), then divide and add DMAP (0.20 equivalent) for 5 times.Reaction stirs 2h at 23 DEG C, is analyzed thereafter determine to there is not SM by TLC.Reaction is by adding methyl alcohol (75 equivalent) quencher and stirring 10min, thereafter react and distribute between water and methylene dichloride, organic layer 0.5M citric acid solution washs (2 ×) and washs (1 ×) with saturated sodium hydrogen carbonate solution, by dried over mgso, vacuum concentration, obtain thick solid, using method 9, then method 2 directly change into bromo-4, the 5-dihydro-isoxazoles of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝397.0m/z。Active: B
Embodiment 267
By 1-allyl group piperazine dissolved (1.1M, relative to piperazine) in methylene dichloride.Add salt of wormwood (1.5 equivalent), then add tert-Butyl dicarbonate (1.1 equivalent).16h is stirred in reaction, and distribute between water and t-butyl methyl ether thereafter, organic layer washed with brine, with dried over sodium sulfate, vacuum concentration, obtain thick alkene, using method 11 step directly changes into bromo-4,5-dihydro-isoxazole II-14a and II-14b of target 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝347.1m/z。Active: A
Embodiment 268
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-formyl piperidine-1-benzyl formate, prepares bromo-4,5-dihydro-isoxazole II-15a and II-15b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝366.1m/z。Active: B
Embodiment 269
Using method 8 forms alkene, the then cycloaddition of using method 2 from 4-formyl piperidine-1-t-butyl formate, prepares bromo-4,5-dihydro-isoxazole II-16a and II-16b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M-H] -＝332.1m/z。Active: A
Embodiment 270
Using method 8 forms alkene, the then cycloaddition of using method 1 from 2-(4-chloro-phenyl-) thiazole-5-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-17a and II-17b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝342.5m/z。Active: A
Embodiment 271
Using method 8 forms alkene, the then cycloaddition of using method 1 from 1-(2-phenyl thiazole-5-base) ethyl ketone, prepares bromo-4,5-dihydro-isoxazole II-18a and II-18b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝322.3m/z。Active: A
Embodiment 272
Using method 8 forms alkene, the then cycloaddition of using method 1 from 2-phenyl thiazole-5-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-19a and II-19b of 3-by 2 steps, replaces methyltriphenylphosphonium bromide except using ethyltriphenylphosphonium bromide.[M+H] +＝325.1m/z。Active: A
Embodiment 273
As the cis diastereomers formed in the cycloaddition of embodiment 272, isolate bromo-4,5-dihydro-isoxazole II-20a and II-20b of 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝324.9m/z。Active: C
Embodiment 274
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-21a and II-21b from racemic compound II-6 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝325.1m/z。
Active: A
Embodiment 275
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-22a and II-22b from racemic compound II-18 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝340.4m/z。
Active: A
Embodiment 276
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-23a and II-23b from racemic compound II-18 and 3-pyridone 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝339.3m/z。
Active: A
Embodiment 277
Using method 8 forms alkene, the then cycloaddition of using method 1 from 1-(4-methyl-2-phenyl thiazole-5-base) ethyl ketone, prepares bromo-4,5-dihydro-isoxazole II-24a and II-24b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝339.0m/z。Active: B
Embodiment 278
Using method 8 forms alkene, the then cycloaddition of using method 1 from 5-pyridine-3-thiophene 2-formaldehyde, prepares bromo-4,5-dihydro-isoxazole II-25a and II-25b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝310.3m/z。Active: A
Embodiment 279
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole II-26a and II-26b from racemic compound II-25 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝325.1m/z。
Active: A
Embodiment 280
Prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-27a and II-27b according to following steps from racemic compound II-25 2 steps: using method 5, then by methyl esters hydrolysis, 5-hydroxy-picolinic acid methyl esters is reacted.The methyl esters II-27 (1.0 equivalent) of racemize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazoles is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains target acid II-27a and II-27b, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.
[M+H] +＝367.5m/z。Active: A
Embodiment 281
First II-6 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then be oxidized according to following steps, 3-(pyridin-3-yl oxygen base)-4 is prepared from racemic compound II-6 2 steps, 5-dihydro-isoxazole II-28a and II-28b: by racemize 3-(6-(methylthio group) pyridin-3-yl oxygen base)-4, 5-dihydro-isoxazole is dissolved in (0.5M in methylene dichloride, relative to isoxazole), thereafter metachloroperbenzoic acid (2.0 equivalent) is added once, reaction at room temperature stirs 1h.After being completed by LC/MS assaying reaction, evaporate solvent.Then, crude mixture is dissolved in (0.5M) in t-butyl methyl ether again, slowly adds hexane thereafter, until separate out solid.Then, by collected by vacuum filtration solid, with 1: 1 hexane/MTBE washing, obtain target 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-29a and II-29b, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝404.1m/z。
Active: A
Embodiment 282
First II-18 and 6-(methylthio group) pyridine-3-alcohol (using method 11 is from the preparation of 6-(methylthio group) pyridin-3-yl boric acid) reaction is made by using method 5, then with embodiment 281 simulated condition under be oxidized, 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole II-29a and II-29b are prepared from racemic compound II-18 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝417.9m/z。Active: A
Embodiment 283
2-(4 is prepared according to following steps 1 step, 5-dihydro-isoxazole-3-base is amino) alcohol II-30a and II-30b: by bromo-for racemize 3-4,5-dihydro-isoxazole I-8 (1.0 equivalent) is dissolved in (0.64M) in propyl carbinol, then adds (5)-2-amino-1-phenylethyl alcohol (1.2 equivalent) and sodium carbonate (2.5 equivalent).Sealed reaction, is heated to 120 DEG C and keeps 18h, cool thereafter, then transfer in separating funnel by excessive water and t-butyl methyl ether in oil bath.Water layer t-butyl methyl ether washing (2 ×), merges organic layer, uses salt water washing, by dried over mgso, concentrated, obtain orange solids, use flash silica chromatography (gradient toluene/hexane is to toluene/ethyl acetate), obtain racemize II-30, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝374.20m/z。
Active: C
Embodiment 284
Using the step similar with embodiment 283 to prepare 2-(4,5-dihydro-isoxazole-3-base is amino) alcohol II-31a and II-31b, replacing (5)-2-amino-1-phenylethyl alcohol except using (R)-2-amino-1-phenylethyl alcohol.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝366.4m/z。Active: C
Embodiment 285
Using method 1 prepares bromo-4, the 5-dihydro-isoxazole III-1 of 3-from methylenecyclohexane 1 step.[M-H] -＝217.0m/z。Active: A
Embodiment 286
Using method 6 forms alkene, the then cycloaddition of using method 1 from 4-tbutylcyclohexanone, prepares bromo-4,5-dihydro-isoxazole III-2a and III-2b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝273.1m/z。Active: B
Embodiment 287
Using method 6 forms alkene, the then cycloaddition of using method 1 from 4-phenyl cyclohexanone, prepares bromo-4,5-dihydro-isoxazole III-3a and III-3b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝293.0m/z。Active: A.
Embodiment 288
Using method 6 forms alkene, the then cycloaddition of using method 1 from Isosorbide-5-Nitrae-dioxo spiro [4.5]-8-in last of the ten Heavenly stems ketone, prepares bromo-4, the 5-dihydro-isoxazole III-4 of 3-by 2 steps.[M-H] -＝275.0m/z。Active: C
Embodiment 289
Using method 3 is from the Wittig reaction preparation 4-methylenecyclohexane ethyl formate of 4-oxocyclohex alkane ethyl formate.According to following steps, this ester is reduced into compound III-5: to the diethyl ether solution (1.0M of lithium aluminum hydride (4.0 equivalent), relative to hydride) in add the diethyl ether solution (2.0M, relative to ester) of 4-oxocyclohex alkane ethyl formate.Reaction reflux 2h, cools thereafter, by adding Virahol, the 50%NaOH aqueous solution and water quencher below in ice bath.Then filtering mixt, filter cake excess diethyl ether washs.Then filtrate water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain clean oil, be not further purified during use.
Then compound III-5 (1.0 equivalent) is dissolved in (0.90M, relative to alcohol) in pyridine.Add Tosyl chloride (1.1 equivalent), 16h is stirred in reaction, thereafter with several quencher of dripping, uses excessive dchloromethane, with water, rare HCl and salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains pale solid, is not further purified during use.
Then phenol (1.2 equivalent) is dissolved in (0.20M, relative to tolysulfonyl ester) in DMF.Add cesium carbonate (1.3 equivalent), then add compound III-6 (1.0 equivalent) and TBAI (0.10 equivalent).Reaction is heated to 40 DEG C and keeps 19h, thereafter with t-butyl methyl ether dilution, with rare NaOH, water and salt water washing, then uses dried over sodium sulfate.Vacuum concentration, provides compound III-7, and clean oil is not further purified during use.
Thick alkene is directly changed into bromo-4,5-dihydro-isoxazole III-8a and III-8b of target diastereomer 3-by using method 21 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝323.6m/z。Active: A
Embodiment 290
Using method 7 forms alkene, the then cycloaddition of using method 1 or method 2 from 1-(tert-butoxycarbonyl)-4-piperidone, prepares bromo-4, the 5-dihydro-isoxazole III-9 of 3-by 2 steps.[M-H] -＝318.1m/z。Active: A.
Embodiment 291
Using method 7 forms alkene, the then cycloaddition of using method 1 from 1-(tert-butoxycarbonyl)-3-piperidone, prepares bromo-4,5-dihydro-isoxazole III-10a and III-10b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝318.1m/z。Active: C
Embodiment 292
Using method 7 forms alkene, the then cycloaddition of using method 1 from N-(tert-butoxycarbonyl)-3-pyrrolidone, prepares bromo-4,5-dihydro-isoxazole III-11a and III-11b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝304.7m/z。Active: B
Embodiment 293
Using method 7 forms alkene, the then cycloaddition of using method 1 from 1-(tert-butoxycarbonyl)-4-oxo azepan, prepares bromo-4,5-dihydro-isoxazole III-12a and III-12b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝332.1m/z。Active: A
Embodiment 294
Using method 7 forms alkene, the then cycloaddition of using method 1 from N-(tert-butoxycarbonyl)-notropinon, prepares bromo-4,5-dihydro-isoxazole III-13a and III-13b of 3-by 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝344.1m/z。Active: C
Embodiment 295
Bromo-for 3-4,5-dihydro-isoxazole III-9 are dissolved in (0.20M, relative to isoxazole) in trifluoroacetic acid, at room temperature stir 1h.Then, solvent removed in vacuo, thick resistates and methylbenzene azeotropic (2 ×), obtain the tfa salt (white solid) of III-14.[M-H] -＝218.0m/z。Active: C
Embodiment 296
Bromo-for 3-4,5-dihydro-isoxazole III-14 are dissolved in (0.03M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and diacetyl oxide (3.0 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare HCl, rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, by using flash silica chromatography (ethyl acetate/hexane), obtains acetic ester III-15, white solid.[M-H] -＝260.0m/z。Active: C
Embodiment 297
Bromo-for 3-4,5-dihydro-isoxazole III-14 are dissolved in (0.05M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and Benzoyl chloride (1.25 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare HCl, rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains acetic ester III-16, white films.[M-H] -＝332.0m/z。Active: A
Embodiment 298
Bromo-for 3-4,5-dihydro-isoxazole III-14 are dissolved in (0.05M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and benzene sulfonyl chloride (1.25 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare HCl, rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains sulphonamide III-17, white solid.[M-H] -＝358.0m/z。Active: B
Embodiment 299
Bromo-for 3-4,5-dihydro-isoxazole III-14 are dissolved in (0.05M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and chloroformic acid benzyl ester (1.25 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare HCl, rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, uses flash silica chromatography (ethyl acetate/hexane), obtains carbamate III-18, white solid.[M-H] -＝352.0m/z。Active: A.
Embodiment 300
By bromo-for 3-4,5-dihydro-isoxazole III-14 is dissolved in (0.06M in methylene dichloride, relative to isoxazole), add thereafter triethylamine (2.5 equivalent) and phenyl aldehyde (1.25 equivalent), then add sodium triacetoxy borohydride (1.5 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, uses flash silica chromatography (ethyl acetate/hexane), obtains N-benzyl piepridine III-19, white solid.[M-H] -＝308.1m/z。Active: A.
Embodiment 301
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-20 of 3-, replacing phenyl aldehyde except using 4-chlorobenzaldehyde.[M+H] +＝342.6m/z。Active: A
Embodiment 302
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-21 of 3-, replacing phenyl aldehyde except using 4-methoxybenzaldehyde.[M+H] +＝338.7m/z。Active: A
Embodiment 303
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-22 of 3-, replacing phenyl aldehyde except using 2-pyridylaldehyde.[M+H] +＝312.1m/z。Active: B
Embodiment 304
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-23 of 3-, replacing phenyl aldehyde except using 3-pyridylaldehyde.[M+H] +＝312.4m/z。Active: B
Embodiment 305
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-24 of 3-, replacing phenyl aldehyde except using 4-tolyl aldehyde.[M+H] +＝322.5m/z。Active: A
Embodiment 306
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-25 of 3-, replacing phenyl aldehyde except using 3,4-dichlorobenzaldehyde.[M+H] +＝378.6m/z。Active: A
Embodiment 307
Using the step similar to embodiment 300 to prepare bromo-4,5-dihydro-isoxazole III-26, replacing phenyl aldehyde except using 4-trifluoromethylated benzaldehyde.[M+H] +＝376.6m/z。Active: A
Embodiment 308
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-27 of 3-, replacing phenyl aldehyde except using 3-chlorobenzaldehyde.[M+H] +＝342.6m/z。Active: A
Embodiment 309
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-28 of 3-, replacing phenyl aldehyde except using hydrogen phenylacrolein.[M+H] +＝336.7m/z。Active: A
Embodiment 310
By bromo-for 3-4,5-dihydro-isoxazole III-14 is dissolved in (0.05M, relative to isoxazole) in DMF, thereafter add salt of wormwood (3.0 equivalent), then add potassiumiodide (0.2 equivalent) and 2 bromoethyl benzene (3.0 equivalent).Reaction is heated to 70 DEG C and keeps 16h in oil bath, thereafter by directly using flash silica chromatography (ethyl acetate/hexane), obtains the amine III-29 of oily.[M+H] +＝324.6m/z。Active: A
Embodiment 311
Using the step similar to embodiment 290 to prepare bromo-4, the 5-dihydro-isoxazole III-30 of 3-, replacing 1-(tert-butoxycarbonyl)-4-piperidone except using 1-phenyl-4-piperidone.[M+H] +＝297.0m/z。Active: B
Embodiment 312
Bromo-for 3-4,5-dihydro-isoxazole III-30 are dissolved in (0.01M, relative to isoxazole) in chloroform, add thereafter bromine (1.0 equivalent).16h, thereafter dilute with water are stirred in reaction, with saturated Na 2cO 3washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains III-31, yellow solid.[M+H] +＝377.0m/z。Active: B
Embodiment 313
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-32 of 3-, replacing phenyl aldehyde except using cyclohexanecarboxaldehyde.[M+H] +＝390.5m/z。Active: A
Embodiment 314
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-33 of 3-, replacing phenyl aldehyde except using valeral.[M+H] +＝290.5m/z。Active: B
Embodiment 315
Using the step similar to embodiment 297 to prepare bromo-4, the 5-dihydro-isoxazole III-34 of 3-, replacing Benzoyl chloride except using hydrocinnamic aldehyde.[M+H] +＝352.8m/z。Active: A
Embodiment 316
Using the step similar to embodiment 299 to prepare bromo-4, the 5-dihydro-isoxazole III-35 of 3-, replacing chloroformic acid benzyl ester except using methyl-chloroformate.[M+H] +＝378.8m/z。Active: B
Embodiment 317
Using the step similar to embodiment 299 to prepare bromo-4, the 5-dihydro-isoxazole III-36 of 3-, replacing chloroformic acid benzyl ester except using isobutyl chlorocarbonate.[M+H] +＝318.7m/z。Active: A
Embodiment 318
Using the step similar to embodiment 299 to prepare bromo-4, the 5-dihydro-isoxazole III-37 of 3-, replacing chloroformic acid benzyl ester except using phenyl chloroformate.[M+H] +＝340.7m/z。Active: A
Embodiment 319
Using the step similar to embodiment 299 to prepare bromo-4, the 5-dihydro-isoxazole III-38 of 3-, replacing chloroformic acid benzyl ester except using chloroformic acid 2,2,2-trichloro ethyl ester.[M+H] +＝394.5m/z。Active: B
Embodiment 320
Bromo-for 3-4,5-dihydro-isoxazole III-14 are dissolved in (0.05M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (5.0 equivalent) and carbonyl dimidazoles (1.25 equivalent).2h is stirred in reaction, adds thereafter pmethoxybenzyl alcohol (2.5 equivalent), then catalysis 4-butyl ammonium hydrogen sulfate and 50% aqueous sodium hydroxide solution (0.10M, relative to isoxazole).Heterogeneous mixture stirs 16h, uses diluted ethyl acetate thereafter.Aqueous layer with ethyl acetate washs 2 times again, merges organic layer thereafter, with dried over sodium sulfate, vacuum concentration, obtains thick material, uses flash silica chromatography (ethyl acetate/hexane), obtains carbamate III-39, white solid.[M+H] +＝382.9m/z。Active: A
Embodiment 321
Using the step similar to embodiment 320 to prepare bromo-4, the 5-dihydro-isoxazole III-40 of 3-, replacing pmethoxybenzyl alcohol except using 4-chlorobenzyl alcohol.[M+H] +＝388.8m/z。Active: A
Embodiment 322
Using the step similar to embodiment 320 to prepare bromo-4,5-dihydro-isoxazole III-41a and III-41b of 3-, replacing pmethoxybenzyl alcohol except using the secondary styroyl alcohol of racemize.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝368.8m/z。
Active: A
Embodiment 323
3-cyclopentenes-1-alcohol (1.0 equivalent) is dissolved in (0.80M, relative to alcohol) in DMF, with TBAI (0.10 equivalent) process, then processes with broken sodium hydroxide (2.0 equivalent).Then add bromotoluene (1.2 equivalent), reaction at room temperature stirs 48h.Then reaction t-butyl methyl ether is diluted, and uses rare Na 2s 2o 3with salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, and use flash silica chromatography (ethyl acetate/hexane), obtaining target cycloolefin, is water white oil.Then, this converting compounds is become bromo-4, the 5-dihydro-isoxazole III-42 of target 3-by the cycloaddition step shown in using method 1.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝295.0m/z。Active: B
Embodiment 324
Using method 1 prepares bromo-4,5-dihydro-isoxazole III-43a and III-43b of 3-from N-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles by 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M-H] -＝290.0m/z。Active: B
Embodiment 325
Bromo-for racemize 3-4,5-dihydro-isoxazole III-43 are dissolved in (0.20M, relative to isoxazole) in trifluoroacetic acid, at room temperature stir 1h.Then, solvent removed in vacuo, thick resistates and methylbenzene azeotropic (2 ×), obtain trifluoroacetate, white solid, be dissolved in (0.05M, relative to isoxazole) in methylene dichloride, add thereafter triethylamine (4.0 equivalent) and chloroformic acid benzyl ester (1.25 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare HCl, rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, uses flash silica chromatography (ethyl acetate/hexane), obtains carbamate III-44, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝324.6m/z。Active: A
Example 326
Bromo-for racemize 3-4,5-dihydro-isoxazole III-43 are dissolved in (0.20M, relative to isoxazole) in trifluoroacetic acid, at room temperature stir 1h.Then, solvent removed in vacuo, thick resistates and methylbenzene azeotropic (2 ×), obtain trifluoroacetate, white solid, is then dissolved in (0.06M, relative to isoxazole) in methylene dichloride, thereafter triethylamine (2.5 equivalent) and 4-chlorobenzaldehyde (1.25 equivalent) is added, then sodium triacetoxy borohydride (1.5 equivalent).16h is stirred in reaction, uses diluted ethyl acetate thereafter, with rare NaOH, then salt water washing.Then, organic layers with sodium sulfate is dry, and vacuum concentration, obtains thick material, uses flash silica chromatography (ethyl acetate/hexane), obtains N-benzyl piepridine III-45, white solid.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝316.6m/z。Active: C
Embodiment 327
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-46 from compound III-18 and 3-pyridone 1 step.[M+H] +＝369.4m/z。Active: A
Embodiment 328
Using method 6 forms alkene, the then cycloaddition of using method 2 from 1-(tert-butoxycarbonyl)-4-piperidone, prepares chloro-4, the 5-dihydro-isoxazole III-47 of 3-by 2 steps, replaces N-bromine succinic diamide except using N-chlorine succinic diamide.[M+H] +＝274.9m/z。Active: A
Embodiment 329
Using the step similar to embodiment 301 to prepare chloro-4, the 5-dihydro-isoxazole III-48 of 3-, replacing bromo-4, the 5-dihydro-isoxazole III-9 of 3-except using chloro-4, the 5-dihydro-isoxazole III-47 of 3-.[M+H] +＝298.6m/z。Active: A
Embodiment 330
Using the step similar to embodiment 300 to prepare bromo-4, the 5-dihydro-isoxazole III-49 of 3-, replacing phenyl aldehyde except using 4-ethynyl formaldehyde.[M+H] +＝335.1m/z。Active: A
Embodiment 331
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-50 from compound III-49 and 3-pyridone 1 step.[M+H] +＝348.6m/z。Active: A
Embodiment 332
Using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-51 from compound III-20 and 3-pyridone 1 step.[M-H] -＝358.1m/z。Active: A
Embodiment 333
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole III-52 from compound III-20 and 5-hydroxy pyrimidine 1 step.[M+H] +＝360.2m/z。Active: A
Embodiment 334
Using method 5, from compound III-9 and 5-hydroxy pyrimidine synthesis 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-53, prepares compound III-93-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole III-54 by 3 steps.Then, using the step similar to embodiment 295 to make compound III-53 deprotection, then use the step similar to embodiment 297 to change into target product III-54, replacing Benzoyl chloride except using hydrocinnamic aldehyde.
[M+H] +＝367.6m/z。Active: B
Embodiment 335
Using the step similar to embodiment 334 to prepare 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole III-55 from compound III-9 3 steps, replacing hydrocinnamic aldehyde except using 4-chloro-benzoyl chloride.[M-H] -＝372.9m/z。Active: A
Embodiment 336
The condition similar to embodiment 295 is used to synthesize 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole III-56 from compound III-53 2 steps from deprotection.Then, the trifluoroacetate (1.0 equivalent) obtained is dissolved in (0.11M, relative to isoxazole) in methylene dichloride, adds thereafter phenyl isocyanate (1.5 equivalent), then pyridine (5.0 equivalent).Reaction is at room temperature stirred and is spent the night, and reaction excessive water and methylene dichloride are transferred in separating funnel thereafter.Organic layer saturated sodium bicarbonate washing (2 ×), by dried over mgso, concentrated, obtain white solid, by flash silica chromatography (gradient ethyl acetate/methyl alcohol).[M+H] +＝353.6m/z。Active: C
Embodiment 337
The condition similar to embodiment 295 is used to synthesize 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-57 from compound III-53 2 steps from deprotection.Then, the trifluoroacetate (1.0 equivalent) obtained is dissolved in (0.11M, relative to isoxazole) in methylene dichloride, adds 5 thereafter, 5,5-trifluoro valeric acid (1.5 equivalent), EDC (1.5 equivalent) and triethylamine (3.0 equivalent).Reaction at room temperature stirs 14h, and reaction excessive water and methylene dichloride are transferred in separating funnel thereafter.Organic layer saturated sodium bicarbonate washing (2 ×), by dried over mgso, concentrated, obtain white solid, by flash silica chromatography (gradient ethyl acetate/methyl alcohol).[M+H] +＝373.7m/z。Active: C
Embodiment 338
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-58 are prepared from compound III-16 3 steps: using method 11 prepares 6-(methylthio group) pyridine-3-alcohol from 6-(methylthio group) pyridin-3-yl boric acid according to following steps.Then, using method 5 makes bromo-4,5-dihydro-isoxazole III-16 and 6-(methylthio group) pyridine-3-alcohol reactions of 3-.By the 3-(pyridin-3-yl oxygen base)-4 obtained, 5-dihydro-isoxazole is dissolved in (0.5M in methylene dichloride, relative to isoxazole), add thereafter metachloroperbenzoic acid (2.0 equivalent) once, reaction at room temperature stirs 1h.After being completed by LC/MS assaying reaction, reaction excessive water and methylene dichloride are transferred in separating funnel.Organic layer is with saturated sodium bicarbonate washing (2 ×) with 1NNaOH washing (1 ×), by dried over mgso, concentrated, obtains white solid, by flash silica chromatography (gradient ethyl acetate/methyl alcohol).[M+H] +＝415.8m/z。Active: B
Embodiment 339
3-(pyrrolidin-1-yl)-4 is prepared according to following steps 1 step, 5-dihydro-isoxazole III-59: by bromo-for 3-4,5-dihydro-isoxazole III-18 (1.0 equivalent) is dissolved in (0.64M) in propyl carbinol, then adds tetramethyleneimine (1.2 equivalent) and sodium carbonate (2.5 equivalent).Sealed reaction, is heated to 120 DEG C and keeps 18h, cool thereafter, then transfer in separating funnel by excessive water and t-butyl methyl ether in oil bath.Water layer t-butyl methyl ether washing (2 ×), merges organic layer, uses salt water washing, by dried over mgso, concentrated, obtain orange solids, use flash silica chromatography (gradient ethyl acetate/hexane), obtain III-59, white solid.[M+H] +＝345.4m/z。Active: C
Embodiment 340
According to following steps synthesis 1-(4,5-dihydro-isoxazole-3-base)-1-crassitude iodine III-60: by 3-(pyrrolidin-1-yl)-4,5-dihydro-isoxazole III-59 is dissolved in (0.044M) in methyl alcohol, then adds methyl iodide (0.022M).72h is placed in reaction, concentrates thereafter, uses high pressure lipuid chromatography (HPLC) purifying (0.1% formic acid).Target fraction freeze-drying, obtains target product and some impurity, by removing impurity with hexanes wash solid.
Active: C
Embodiment 341
According to following steps bromo-4,5-dihydro-isoxazole III-62a and III-62b of 3 step synthesis 3-: phenyl-boron dihydroxide (2.0 equivalent) is suspended in (0.23M, relative to boric acid) in toluene, heating, until form solution.Evaporating solvent, repeats this process.Then, the acid anhydrides obtained is dissolved in (0.23M) in methylene dichloride again.Add 6-hydroxyl-3,4-dihydronaphthalene-1 (2H)-one (1.0 equivalent), triethylamine (5.0 equivalent) and venus crystals (0.95 equivalent), sealed reaction, at room temperature stirs 16h.Then, mixture excessive methylene dichloride and water is transferred in separating funnel.Then, organic layers with water, dilute sodium hydroxide and salt water washing.Organic layers with sodium sulfate is dry, and concentrated, obtaining III-61, is brown oil, and using method 5, then method 1 directly change into bromo-4, the 5-dihydro-isoxazole III-62 of racemize 3-.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝359.5m/z。
Active: A
Embodiment 342
Use the step similar to embodiment 341 to prepare bromo-4,5-dihydro-isoxazole III-63a and III-63b of 3-, except use in 5-hydroxyl-2,3-dihydro-1H-1-Indanone replacement 6-hydroxyl-3,4-dihydronaphthalene-1 (2H) the-one the first step as raw material.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝343.7m/z。Active: A
Embodiment 343
Using method 5 prepares 3-(pyrimidine-5-base oxygen base)-4,5-dihydro-isoxazole III-60a and III-60b from racemic compound III-63 and 5-hydroxy pyrimidine 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝361.2m/z。
Active: A
Embodiment 344
According to following steps bromo-4,5-dihydro-isoxazole III-66a and III-66b of 4 step synthesis 3-: the 250mL round-bottomed flask with 10/30 thermometer mouth is loaded onto agitator arm, similar thermometer and Allihn prolong.Add 3-(3-(trifluoromethoxy) phenyl) propionic acid (0.22mol, 1.0 equivalents), be dissolved in (6.0 equivalent) in thionyl chloride, reflux 1h in oil bath, and during this period, temperature is 78-82 DEG C of maintenance 1 hour.Now, prolong minor axis head and the thermometer with dry argon gas stream entrance replace, by distillation removing volatile matter.When distillation completes, hexanaphthene (100mL) is added in reactor, and distills by same way, obtain the target acyl chlorides that productive rate can be quantitative, be brown oil, directly use.Then, the pressure balanced dropping funnel of mechanical stirrer, thermocouple probe and 250-mL loaded onto by the 3 neck round-bottomed flasks of 2L.Add aluminum chloride (0.233mol, 1.08 equivalents) and methylene dichloride (0.24M), then stir 45min, dissolve as much as possible.Then react and be cooled to interior temperature < 2.5 DEG C in ice bath.In 15min, acyl chlorides (1.0 equivalents, the 0.215mo1) solution in 200ml methylene dichloride is added by adding funnel.After having added, except deicing from bath, replace (bath temperature 18 DEG C) with room temperature water, reaction carries out 2h again, is now analyzed by TLC and LC/MS and shows that reaction completes.Then, reaction mixture ice (500g), then water (600mL) process, and mixture stirs 1h thereafter, until all solids dissolves.Be separated each layer, water layer is with extracted with diethyl ether (350mL).Merge organism, with water (250mL, 1 ×), half saturated sodium bicarbonate (250mL, 1 ×), salt solution (250mL, 1 ×) washs, by dried over mgso, concentrated, obtaining 5-(trifluoromethoxy)-2, the 3-dihydro-1H-1-Indanone III-65 that productive rate can be quantitative, is pink solid.Then, this material is directly changed into bromo-4, the 5-dihydro-isoxazole III-66 of racemize 3-by using method 5, then method 1.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝335.6m/z。
Active: A
Embodiment 345
After first using method 11 prepares 6-(methylthio group) pyridine-3-alcohol from 6-(methylthio group) pyridin-3-yl boric acid, using method 5 prepares 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-67a and III-67b from racemic compound III-66 and 6-(methylthio group) pyridine-3-alcohol 2 steps.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝396.7m/z。Active: A
Embodiment 346
The oxidizing condition similar with embodiment 338 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-68a and III-68b from racemic compound III-67 1 step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝429.4m/z。Active: A
Embodiment 347
3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-70a and III-70b are prepared: 6-bromopyridine-3-alcohol (1.0 equivalent) and sodium carbonate (10.0 equivalent) are added in microwave vial according to following steps 2 steps.Add toluene, second alcohol and water (0.16M, 2: 2: 1v/v), then add 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mix oxygen pentaborane-2-base)-1H-pyrazoles (1.5 equivalent).Mixture argon cleaning 15min, then adds tetrakis triphenylphosphine palladium (4mol%).Then reaction tubes aluminium foil covers, and is heated to 80 DEG C and keeps 17h in oil bath.After cooling, reaction excessive water and ethyl acetate are transferred in separating funnel.Then, organic layers with water (1 ×), saturated ammonium chloride (1 ×) and salt solution (1 ×) washing.Combining water layer, by ethyl acetate washing (1 ×).Then, merge organic layer, by dried over sodium sulfate, concentrated, use flash silica chromatography (gradient methanol/methylene dichloride), obtain 6-(1-methyl isophthalic acid H-pyrazoles-4-base) pyridine-3-alcohol III-69, white solid.Then, using method 5 makes this compound and bromo-4, the 5-dihydro-isoxazole III-66 of racemize 3-react, and obtains target racemic compound III-70.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝430.0m/z。Active: A
Embodiment 348
The step similar with embodiment 347 is used to prepare 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-71a and III-71b, except using 1-methyl-5-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles replaces 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-bis-mixes oxygen pentaborane-2-base)-1H-pyrazoles is as the boric acid ester in the first step.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H]+＝430.0m/z。Active: A
Embodiment 349
3-(pyridin-3-yl oxygen base)-4 is prepared according to following steps 3 steps, 5-dihydro-isoxazole III-73a and III-73b: 5-hydroxy niacin methyl esters (1.0 equivalent) is dissolved in (0.08M) in methyl alcohol, thereafter hydrazine (50 equivalents are added, 50 % by weight, in water), 14h is stirred in reaction.Then, reaction mixture vacuum concentration, is directly used in next step.Add triethyl orthoformate (8.0 equivalent), sealed reaction, reflux 14h.Then reaction Excess ethyl acetate and water are transferred in separating funnel.Organic layers with water and salt water washing, with dried over sodium sulfate, vacuum concentration, obtain thick material, uses flash silica chromatography (gradient methanol/methylene dichloride), obtain order mark oxadiazole III-72.Then, using method 5 makes this compound and bromo-4, the 5-dihydro-isoxazole III-66 of racemize 3-react, and obtains target racemic compound III-73.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝419.5m/z。Active: A
Embodiment 350
Enantiomer 3-(pyridin-3-yl oxygen base)-4,5-dihydro-isoxazole III-74a and III-74b are prepared: using method 5 makes racemize 3-bromine 4,5-dihydro-isoxazole III-66 and 5-hydroxy niacin methyl esters react according to following steps 2 steps.The ester (1.0 equivalent) obtained is dissolved in (0.06M) in 1: 1 tetrahydrofuran (THF)/water, adds lithium hydroxide (8.0 equivalent).Reaction at room temperature stirs 1h, and in nitrogen gas stream, remove tetrahydrofuran (THF) thereafter, surplus solution 1NHCl is acidified to pH < 2, obtains racemize target acid III-74, goes out white solid through isolated by vacuum filtration.These compounds can use chirality HPLC method known in the art to be separated.Such as, see chirality HPLC method disclosed herein.[M+H] +＝395.5m/z。Active: A
Embodiment 351
The suppression of mankind FAAH
The preparation of mankind FAAH: test the day before yesterday, COS-7 cell is assigned in 150mm × 25mm cell culture vessel (CorningInc., Cat.No.430599) with 1: 5.According to FuGENE6 transfection reagent (Roche, catalog number (Cat.No.) 11814443001) requirement, carry out transient transfection when 30-40% converges.
Transfection procedure: FuGENE transfection 6 reagent (45 μ L) is added to 1410 μ L substratum (DMEM in 15mL conical tube, serum-free is without penicillin/streptomycin (pen/strep)) in, and at room temperature cultivate 5 minutes, add FAAH plasmid DNA (15 μ g) (OriGene catalog number (Cat.No.) TC119221 subsequently, Genbank registration number NM_001441.1,0.67 μ g/ μ L), and at room temperature cultivate 15 minutes again.Gained solution is added drop-wise in the culture dish of the COS-7 cell that a 30-40% converges.Subsequently COS-7 Tissue Culture Dish is cultivated 48 hours.Gather cell subsequently.
Collect step: sucking-off substratum from culture dish also uses 10mLPBS rinsing cell.Remove PBS and 3mLPBS is added in culture dish.Cell suspending liquid, to make cell settling flux, is collected in 15ml conical tube by scraping culture dish subsequently.By within centrifugal 5 minutes, making cell become precipitation with 1200rpm in desk centrifuge.Remove PBS and in liquid nitrogen, make cell precipitation quick freezing, storing at-80 DEG C.
The purifying of COS-7 cell-FAAH:
(1) be separated: on ice, the frozen cell of transient transfection precipitation is thawed, and make its settling flux in 12.5mMHepespH8.0,100mMNaCl, 1mMEDTA (10mL/0.2g cell precipitation).Described precipitation Dounce homogenizer is homogenized and supersound process subsequently, obtain cell extract.Subsequently with 1000g eccentric cell extract to remove cell debris.Precipitation to be abandoned and by supernatant liquor with 13,000g centrifugal 20 minutes.Precipitation is containing conjunctival FAAH.Supernatant liquor is abandoned and precipitation is dissolved again.
(2) dissolve again: by paid close attention to part (13,000g, membrane portions) settling flux is in 2.3mL settling flux damping fluid (20mMHepespH7.8,10%v/v glycerine, 1mMEDTA, 1%TritonX-100), sample is placed 1 hour on ice, centrifugal to remove any particulate material subsequently.Several parts will be divided into containing the supernatant liquor of mankind FAAH dissolved and in liquid nitrogen quick freezing, store stand-by at-80 DEG C.
(3) characterize: analyze (Bradfordassay) by Bu Laide Ford and measure protein concentration.
Sds gel and western blot method determine the existence of FAAH
FAAH activity is analyzed
K mmeasuring---96 holes are analyzed
Linear dependence---96 holes are analyzed
N-compound Ki measures---and 384 holes are analyzed
Mankind FAAH analyzes; Testing program: the mankind FAAH solution making 0.1mg/mL in FAAH reaction buffer, and 24 μ l are sucked in 384 orifice plates.Add the inhibitor of 1 μ L through the 3 times of serial dilutions of DMSO liquid storage wherein.At room temperature FAAH solution and inhibitor are cultivated 30 minutes.The FAAH reaction buffer containing 40 μMs of AMC arachidonic acylamide by adding 25 μ L carrys out initial FAAH reaction; obtain the AMC-arachidonic acyl group substrate that end reaction mankind FAAH preparation that concentration is 0.05mg/mL and concentration are 20 μMs, reaction volume is 50 μ L.Reaction is at room temperature made to carry out 4 hours.Termination reaction is carried out by the α-one base heterocycle (CaymanChemicals, catalog number (Cat.No.) 10435) adding 25 μ L12 μMs.Envision microplate reader reads microtiter plate.
Be y-axis with Raw fluorescence and inhibitor concentration is mapped for x-axis, obtain dose response and suppress curve.Data and single-point competitive are suppressed equation model, the Km of people's fermentoid is chosen to be respectively 12 μMs and 9 μMs.
Suppress other analysis of FAAH to comprise for measuring compound of the present invention: the people such as (1) Manjunath, AnalyticalBiochemistry (2005) 343:143-151 record with the analysis based on fluorescence of the fatty acid amide hydrolase of high flux screening compatibility; (2) high flux screening of the inhibitor finding fatty acid amide hydrolase based on MC fluorometric analysis is used.The people such as Wang, BiomolecularScreening (2006) 1-9.
Embodiment 352
The Serine-241 of FAAH is Yu form the evidence of covalent complex between isoxazoline
A kind of crystalline texture is produced with the irreversible inhibitor methoxyl group arachidonic acidic group fluoro phosphonic acid ester process rat FAAH albumen for avtive spot, wherein methoxyl group arachidonic acidic group phosphonic acid ester and Ser-241 side chain covalent attachment (people such as Bracey, Science (2002) 298:1793-1796).
According to this data, assuming that the nucleophilic side-chains of isoxazoline compounds of the present invention and Ser-241 forms covalent complex.This hypothesis conforms to dynamics data, and the combination of proposition relates to the nucleophillic attack of avtive spot Ser-241 Dui isoxazoline electrophilic reagent, causes, from tenuigenin mouth removing leavings group, forming the enzyme-isoxazoline adducts of covalency subsequently.Active recovery will relate to de-acyl reaction subsequently, and for the enzyme-isoxazoline adducts of covalency, even if there is de-acyl reaction, it can not occur effectively.
Carry out active recovery experiment by jump dilution process, it relates to and dilutes rapidly enzyme-5 times, inhibitor complex compound at apparent below Ki, and active as the function measurement of time.Seldom or do not have enzymic activity to recover in 2 hours, irreversible suppression is substantially described, or is slowly hydrolyzed complex compound, support above-mentioned hypothesis.
Other embodiments
Those skilled in the art will recognize that, or can only use routine test to determine many equivalents of specific embodiments of the present invention as herein described.These equivalents are also intended to contain in the dependent claims.

Claims (22)

1. the compound of following formula:
Or its pharmacy acceptable salt, wherein,
R aand R cbe selected from H, C independently of one another 1-10alkyl and C 1-10whole haloalkyl;
R 16independently selected from C 1-10alkyl, C 1-10whole haloalkyl, C 2-10thiazolinyl, C 2-10alkynyl, C 3- 10carbocylic radical, 3-14 unit heterocyclic radical, C 6-14aryl and 5-14 unit heteroaryl; And
G is following formula-OR e:
2. compound as claimed in claim 1, wherein, G is the-OR of following formula e:
3. compound as claimed in claim 1, wherein, described compound is the compound of following formula, or its pharmacy acceptable salt:
4. compound as claimed in claim 1, wherein said compound is:
Or its pharmacy acceptable salt.
5. compound as claimed in claim 1, wherein said compound is:
Or its pharmacy acceptable salt.
6. the compound according to any one of claim 3-5, wherein said compound is enantiomeric pure.
7. compound as claimed in claim 6, wherein compound is (R)-enantiomer.
8. compound as claimed in claim 1, wherein said compound is
Or its pharmacy acceptable salt.
9. compound as claimed in claim 1, wherein said compound is
Or its pharmacy acceptable salt.
10. compound as claimed in claim 1, wherein said compound is
Or its pharmacy acceptable salt.
11. compounds as claimed in claim 1, wherein said compound is
Or its pharmacy acceptable salt.
12. compounds as claimed in claim 1, wherein said compound is
Or its pharmacy acceptable salt.
13. 1 kinds of pharmaceutical compositions, containing, for example the compound described in claim 1-12 or its pharmacy acceptable salt and pharmaceutically acceptable vehicle.
14. pharmaceutical compositions as claimed in claim 13, wherein said compound is
Or its pharmacy acceptable salt.
15. pharmaceutical compositions as claimed in claim 13, wherein said compound is
Or its pharmacy acceptable salt.
The application in the medicine of the illness for the preparation for the treatment of FAAH mediation of 16. compounds as described in claim 1-12 or its pharmacy acceptable salt, the illness of wherein said FAAH mediation is antalgesic, inflammatory conditions, immunologic derangement, the disorder of central nervous system, metabolism disorder, heart disease or glaucoma.
17. apply as claimed in claim 16, and wherein said antalgesic is selected from: the pain that medical procedures is relevant, arthralgia, headache and toothache.
18. apply as claimed in claim 16, wherein said antalgesic is selected from: neuropathic pain, central pain, deafferentiation pain, chronic pain, post-operative pain, preoperative pain, the stimulation of pain receptor, acute pain, non-inflammatory pain, inflammatory pain, the pain that cancer is relevant, trauma pain, burn pain, to scratch where it itches the pain caused, painful bladder syndrome, premenstrual irritated disorderly relevant pain, the pain that premenstrual syndrome is relevant, the pain that chronic fatigue syndrome is relevant, the pain that premature labor is relevant, dopy gives up the relevant pain of syndrome, arthritis ache, lumbus sacrum pain, musculoskeletal pain, migraine, myalgia, back pain, cervicodynia, tooth/Orofacial pain and visceral pain.
19. apply as claimed in claim 16, and wherein said inflammatory conditions or immunologic derangement are gastrointestinal dysfunction or skin disorder.
20. apply as claimed in claim 16, and the disorder of wherein said central nervous system is selected from as follows: neurotoxicity and/or nerve injury, apoplexy, multiple sclerosis, Spinal injury, epilepsy, mental disorder, somnopathy, dyskinesia, feel sick and/or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and dopy.
21. apply as claimed in claim 16, and wherein said metabolism disorder is selected from as follows: expendable illness, the illness relevant with obesity and its complication.
22. apply as claimed in claim 16, and wherein said heart disease is selected from as follows: hypertension, recycle system shock, myocardial ischemia-reperfusion injury and atherosclerosis.
CN201080032435.4A 2009-05-18 2010-05-18 As the inhibitor isoxazoline of fatty acid amide hydrolase Expired - Fee Related CN102459202B (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US17928309P 2009-05-18 2009-05-18
US17928009P 2009-05-18 2009-05-18
US17928509P 2009-05-18 2009-05-18
US61/179,285 2009-05-18
US61/179,280 2009-05-18
US61/179,283 2009-05-18
PCT/US2010/035309 WO2010135360A1 (en) 2009-05-18 2010-05-18 Isoxazolines as inhibitors of fatty acid amide hydrolase

Publications (2)

Publication Number Publication Date
CN102459202A CN102459202A (en) 2012-05-16
CN102459202B true CN102459202B (en) 2015-11-25

Family

ID=43126477

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201080032435.4A Expired - Fee Related CN102459202B (en) 2009-05-18 2010-05-18 As the inhibitor isoxazoline of fatty acid amide hydrolase

Country Status (16)

Country Link
EP (1) EP2432771A4 (en)
JP (1) JP2012527467A (en)
KR (1) KR20120042766A (en)
CN (1) CN102459202B (en)
AR (1) AR076687A1 (en)
AU (1) AU2010249674A1 (en)
BR (1) BRPI1011049A2 (en)
CA (1) CA2762527A1 (en)
IL (1) IL216420A0 (en)
MX (1) MX2011012263A (en)
NZ (2) NZ619076A (en)
RU (1) RU2539595C2 (en)
SG (2) SG10201402443PA (en)
TW (1) TW201043620A (en)
WO (1) WO2010135360A1 (en)
ZA (1) ZA201108657B (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2074123E (en) 2006-10-16 2013-01-22 Bionomics Ltd Novel anxiolytic compounds
US10954231B2 (en) 2006-10-16 2021-03-23 Bionomics Limited Anxiolytic compounds
US8927551B2 (en) 2009-05-18 2015-01-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US9149465B2 (en) 2009-05-18 2015-10-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US20130150346A1 (en) 2010-01-08 2013-06-13 Quest Ventures Ltd. Use of FAAH Inhibitors for Treating Parkinson's Disease and Restless Legs Syndrome
US20130224151A1 (en) 2010-03-31 2013-08-29 United States Of America Use of FAAH Inhibitors for Treating Abdominal, Visceral and Pelvic Pain
JP2014510065A (en) 2011-03-02 2014-04-24 バイオノミックス リミテッド Novel small molecules as therapeutic agents
CN103649086A (en) 2011-05-12 2014-03-19 生态学有限公司 Methods for preparing naphthyridines
WO2018112843A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
KR20200038457A (en) * 2017-08-10 2020-04-13 다이쇼 세이야꾸 가부시끼가이샤 Pyridine compound substituted with azole
AU2019362788A1 (en) * 2018-10-15 2021-04-15 Dana-Farber Cancer Institute, Inc. Transcriptional enhanced associate domain (TEAD) transcription factor inhibitors and uses thereof
CN110016142B (en) * 2019-04-30 2021-08-03 合肥工业大学 Silicone oil containing pyrimidine boric acid structure and preparation method thereof
CA3141826A1 (en) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
TW202108571A (en) 2019-05-31 2021-03-01 美商醫肯納腫瘤學公司 Tead inhibitors and uses thereof
EP4043444A1 (en) 2021-02-11 2022-08-17 Basf Se Substituted isoxazoline derivatives
AU2022219182A1 (en) 2021-02-11 2023-08-24 Basf Se Substituted isoxazoline derivatives
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
EP4238971A1 (en) 2022-03-02 2023-09-06 Basf Se Substituted isoxazoline derivatives
WO2023165854A1 (en) 2022-03-02 2023-09-07 Basf Se Substituted isoxazoline derivatives
WO2024061665A1 (en) 2022-09-20 2024-03-28 Basf Se N-(3-(aminomethyl)-phenyl)-5-(4-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine derivatives and similar compounds as pesticides
EP4342885A1 (en) 2022-09-20 2024-03-27 Basf Se N-(3-(aminomethyl)-phenyl)-5-(4-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine derivatives and similar compounds as pesticides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004044169A2 (en) * 2002-11-14 2004-05-27 The Scripps Research Institute Crystalline form of fatty acid amine hydrolase (faah)
CN1703407A (en) * 2002-10-08 2005-11-30 斯克里普斯研究学院 Inhibitors of fatty acid amide hydrolase
WO2009011904A1 (en) * 2007-07-19 2009-01-22 Renovis, Inc. Compounds useful as faah modulators and uses thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9505651D0 (en) * 1995-03-21 1995-05-10 Agrevo Uk Ltd AgrEvo UK Limited
US7807696B2 (en) * 2003-10-07 2010-10-05 The Feinstein Institute For Medical Research Isoxazole and isothiazole compounds useful in the treatment of inflammation
FR2866888B1 (en) * 2004-02-26 2006-05-05 Sanofi Synthelabo ALKYLPIPERAZINE- AND ALKYLHOMOPIPERAZINE-CARBOXYLATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
TW200633990A (en) * 2004-11-18 2006-10-01 Takeda Pharmaceuticals Co Amide compound
US20070155747A1 (en) * 2005-12-29 2007-07-05 Kadmus Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
ITMI20061279A1 (en) * 2006-06-30 2008-01-01 Consiglio Nazionale Ricerche SELECTIVE NICOTINIC AGONISTS FOR THE ALFA7 RECEPTOR SUBTIPLE, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS
JO3598B1 (en) * 2006-10-10 2020-07-05 Infinity Discovery Inc Boronic acids and esters as inhibitors of fatty acid amide hydrolase
CL2008003895A1 (en) * 2007-12-27 2010-06-25 Bial Portela & Companhia S A Compounds derived from 5-o-substituted 3-n-phenyl-1,3,4-oxadiazolones, pharmaceutical composition, preparation process, and their use for the treatment of a disorder positively influenced by the inhibition of faah such as eating disorders and neurological and psychiatric pathologies, among others.
KR20150065958A (en) * 2008-01-25 2015-06-15 이 아이 듀폰 디 네모아 앤드 캄파니 Fungicidal hetercyclic compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1703407A (en) * 2002-10-08 2005-11-30 斯克里普斯研究学院 Inhibitors of fatty acid amide hydrolase
WO2004044169A2 (en) * 2002-11-14 2004-05-27 The Scripps Research Institute Crystalline form of fatty acid amine hydrolase (faah)
WO2009011904A1 (en) * 2007-07-19 2009-01-22 Renovis, Inc. Compounds useful as faah modulators and uses thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
1,4-Diazabicyclo[2.2.2]octane (DABCO) as an Efficient Reagent for the Synthesis of Isoxazole Derivatives from Primary Nitro Compounds and Dipolarophiles: The Role of the Base;Luca Cecchi，等;《Eur. J. Org. Chem.》;20060831;第2006卷(第21期);第4853页 *
Application of a Thermal β-Elimination Reaction to N-Alkoxy-3,3-dinitroisoxazolidines:Synthesis of 3-Nitroisoxazolines;Olga A. Ivanova，等;《Synthesis》;20060125;第2006卷(第4期);第707页 *
Preparation of β-hydroxyesters from isoxazolines. A selective Ni0bpy-catalyzed electrochemical method;Viviane F. Caetano，等;《Tetrahedron Letters》;20031103;第44卷(第45期);第8218页 *
Synthesis and Biochemical Evaluation of N-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase;Stephan Rover，等;《J. Med. Chem.》;19971219;第40卷(第26期);第4379页 *
Synthesis of 3-Aminoisoxazoles via the Addition-Elimination of Amines on 3-Bromoisoxazolines;Melina Girardin，等;《Organic Letters》;20090211;第11卷(第5期);第1160页 *

Also Published As

Publication number Publication date
SG10201402443PA (en) 2014-10-30
SG176168A1 (en) 2011-12-29
NZ619076A (en) 2015-07-31
JP2012527467A (en) 2012-11-08
AR076687A1 (en) 2011-06-29
KR20120042766A (en) 2012-05-03
BRPI1011049A2 (en) 2019-09-24
NZ596585A (en) 2014-01-31
IL216420A0 (en) 2012-03-01
TW201043620A (en) 2010-12-16
MX2011012263A (en) 2012-01-30
RU2539595C2 (en) 2015-01-20
CA2762527A1 (en) 2010-11-25
ZA201108657B (en) 2013-01-30
AU2010249674A1 (en) 2011-12-15
EP2432771A4 (en) 2013-06-05
WO2010135360A1 (en) 2010-11-25
EP2432771A1 (en) 2012-03-28
CN102459202A (en) 2012-05-16
RU2011151635A (en) 2013-06-27

Similar Documents

Publication Publication Date Title
CN102459202B (en) As the inhibitor isoxazoline of fatty acid amide hydrolase
US11091492B2 (en) Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disorders
JP5637982B2 (en) Inhibitors of fatty acid amide hydrolase
JP2008543726A (en) PGD2 receptor antagonist for the treatment of inflammatory diseases
JP2023139195A (en) Ligands to cereblon (crbn)
UA120571C2 (en) Allosteric modulators of nicotinic acetylcholine receptors
NL2000336C2 (en) Spirocyclic derivatives.
CN103635458A (en) Trpv1 antagonists
CN103958474A (en) (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
TW202214587A (en) Cyclopropyl dihydroquinoline sulfonamide compounds
WO2017192841A1 (en) Methods of treatment and combination therapies using gcase activator heterobicyclic and related compounds
CN111836807A (en) Oxaspiro compounds, preparation method and application thereof
TW201245115A (en) Histone deacetylase inhibitors and compositions and methods of use thereof
JP7299382B2 (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
CN102105458B (en) 5-[5-[2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoylmethylamino]-4-(4-fluoro-2-methylphenyl)]-2-pyridinyl-2-alkyl-prolinamide as NK1 receptor antagonists
CN101663276A (en) 2-aminopyridine derivatives useful as kinase inhibitors
JP7041141B2 (en) Substituted bicyclic heteroaryl nicotinic acetylcholine receptor allosteric regulator
CN111635373B (en) Polycyclic sulfonamide ROR gamma modulators
CN101611005B (en) Substituted acetophenones useful as PDE4 inhibitors
CA3226724A1 (en) Cyanopyridine and cyanopyrimidine bcl6 degraders
CA3178647A1 (en) Substituted tricyclic amides, analogues thereof, and methods using same
WO2021083246A1 (en) Modifier of four-membered ring derivative, preparation method and application thereof
CN108884104A (en) Three and cycle compound as immunomodulator
WO2023054006A1 (en) Opioid receptor antagonist and pharmaceutical composition
KR102662215B1 (en) Substituted pyrazolo(1,5-a)pyrimidines and their use in the treatment of medical disorders

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20151125

Termination date: 20160518

CF01 Termination of patent right due to non-payment of annual fee