CN118515621A - 含有乙炔基的唑醇类化合物及其用途 - Google Patents
含有乙炔基的唑醇类化合物及其用途 Download PDFInfo
- Publication number
- CN118515621A CN118515621A CN202410581110.5A CN202410581110A CN118515621A CN 118515621 A CN118515621 A CN 118515621A CN 202410581110 A CN202410581110 A CN 202410581110A CN 118515621 A CN118515621 A CN 118515621A
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- CN
- China
- Prior art keywords
- methyl
- difluorophenyl
- amino
- ethynyl
- triazol
- 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.)
- Pending
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- -1 Azolyl alcohol compound Chemical class 0.000 title claims description 257
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 title claims description 38
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title claims description 38
- 239000003814 drug Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000000651 prodrug Substances 0.000 claims abstract description 20
- 229940002612 prodrug Drugs 0.000 claims abstract description 20
- 150000007980 azole derivatives Chemical class 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 18
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 241000233866 Fungi Species 0.000 claims description 11
- 230000000843 anti-fungal effect Effects 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229940121375 antifungal agent Drugs 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 5
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 241000222122 Candida albicans Species 0.000 claims description 4
- 241000222173 Candida parapsilosis Species 0.000 claims description 4
- 241000222178 Candida tropicalis Species 0.000 claims description 4
- 201000007336 Cryptococcosis Diseases 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 229940095731 candida albicans Drugs 0.000 claims description 3
- 229940055022 candida parapsilosis Drugs 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 241000555676 Malassezia Species 0.000 claims 6
- 241000223230 Trichosporon Species 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 201000004624 Dermatitis Diseases 0.000 claims 3
- 244000286779 Hansenula anomala Species 0.000 claims 3
- 235000014683 Hansenula anomala Nutrition 0.000 claims 3
- 241000235048 Meyerozyma guilliermondii Species 0.000 claims 3
- 241000235645 Pichia kudriavzevii Species 0.000 claims 3
- 241001045770 Trichophyton mentagrophytes Species 0.000 claims 3
- 241000228197 Aspergillus flavus Species 0.000 claims 2
- 241001225321 Aspergillus fumigatus Species 0.000 claims 2
- 241000228245 Aspergillus niger Species 0.000 claims 2
- 241000228405 Blastomyces dermatitidis Species 0.000 claims 2
- 241000079253 Byssochlamys spectabilis Species 0.000 claims 2
- 241001480036 Epidermophyton floccosum Species 0.000 claims 2
- 241000427940 Fusarium solani Species 0.000 claims 2
- 244000168141 Geotrichum candidum Species 0.000 claims 2
- 235000017388 Geotrichum candidum Nutrition 0.000 claims 2
- 241000228404 Histoplasma capsulatum Species 0.000 claims 2
- 241000228456 Leptosphaeria Species 0.000 claims 2
- 241001291474 Malassezia globosa Species 0.000 claims 2
- 241000306281 Mucor ambiguus Species 0.000 claims 2
- 241000186359 Mycobacterium Species 0.000 claims 2
- 241000893974 Nannizzia fulva Species 0.000 claims 2
- 241000893976 Nannizzia gypsea Species 0.000 claims 2
- 240000005384 Rhizopus oryzae Species 0.000 claims 2
- 235000013752 Rhizopus oryzae Nutrition 0.000 claims 2
- 241000222481 Schizophyllum commune Species 0.000 claims 2
- 241000223238 Trichophyton Species 0.000 claims 2
- 241000223229 Trichophyton rubrum Species 0.000 claims 2
- 241000222126 [Candida] glabrata Species 0.000 claims 2
- 229940091771 aspergillus fumigatus Drugs 0.000 claims 2
- 208000032343 candida glabrata infection Diseases 0.000 claims 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims 1
- 241000235389 Absidia Species 0.000 claims 1
- 235000016993 Agrimonia Nutrition 0.000 claims 1
- 244000307697 Agrimonia eupatoria Species 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 241000282465 Canis Species 0.000 claims 1
- 241001668502 Cladophialophora carrionii Species 0.000 claims 1
- 241000223205 Coccidioides immitis Species 0.000 claims 1
- 241000667819 Cunninghamella sp. Species 0.000 claims 1
- 241000223233 Cutaneotrichosporon cutaneum Species 0.000 claims 1
- 241001634927 Cutaneotrichosporon mucoides Species 0.000 claims 1
- 241000223682 Exophiala Species 0.000 claims 1
- 241000248325 Exophiala dermatitidis Species 0.000 claims 1
- 241000122864 Fonsecaea pedrosoi Species 0.000 claims 1
- 241000308514 Hortaea werneckii Species 0.000 claims 1
- 241000144128 Lichtheimia corymbifera Species 0.000 claims 1
- 241000555688 Malassezia furfur Species 0.000 claims 1
- 241001291472 Malassezia obtusa Species 0.000 claims 1
- 241001299738 Malassezia pachydermatis Species 0.000 claims 1
- 241001291477 Malassezia restricta Species 0.000 claims 1
- 241001291475 Malassezia slooffiae Species 0.000 claims 1
- 241001291478 Malassezia sympodialis Species 0.000 claims 1
- 241001480037 Microsporum Species 0.000 claims 1
- 241000893980 Microsporum canis Species 0.000 claims 1
- 241000818707 Nannizzia incurvata Species 0.000 claims 1
- 241000526686 Paracoccidioides brasiliensis Species 0.000 claims 1
- 241001057811 Paracoccus <mealybug> Species 0.000 claims 1
- 241000233872 Pneumocystis carinii Species 0.000 claims 1
- 241000223252 Rhodotorula Species 0.000 claims 1
- 241000223254 Rhodotorula mucilaginosa Species 0.000 claims 1
- 241000868102 Saccharopolyspora spinosa Species 0.000 claims 1
- 241000223598 Scedosporium boydii Species 0.000 claims 1
- 241001149963 Sporothrix schenckii Species 0.000 claims 1
- 241001085826 Sporotrichum Species 0.000 claims 1
- 241001523006 Talaromyces marneffei Species 0.000 claims 1
- 241000893969 Trichophyton benhamiae Species 0.000 claims 1
- 241000893966 Trichophyton verrucosum Species 0.000 claims 1
- 241001480050 Trichophyton violaceum Species 0.000 claims 1
- 241001634961 Trichosporon asahii Species 0.000 claims 1
- 241001634942 Trichosporon inkin Species 0.000 claims 1
- 241000221566 Ustilago Species 0.000 claims 1
- 241000645784 [Candida] auris Species 0.000 claims 1
- 241001231403 [Nectria] haematococca Species 0.000 claims 1
- 238000005452 bending Methods 0.000 claims 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims 1
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- 229940079593 drug Drugs 0.000 abstract description 26
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 166
- 238000005160 1H NMR spectroscopy Methods 0.000 description 85
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属药物合成技术领域，具体公开了一种如通式I所示的唑类衍生物，或其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其制备方法以及其在制备预防或治疗由真菌感染引起的各类疾病的药物中的用途。
Description
技术领域
本发明属药物合成技术领域，具体涉及一种唑类衍生物及其药学上可接受的盐、水合物、溶剂化物及其前药，其制备方法以及其在制备治疗由真菌感染引起的各类疾病的药物中的用途。
背景技术
真菌感染可分为浅表真菌感染和深部真菌感染，深部真菌感染又称侵袭性真菌感染，其是一类具有高发病率和死亡率的疾病，近些年来，侵袭性真菌感染在免疫缺陷、癌症、器官移植等患者群体中的发病率和死亡率逐年递增，加剧了患者和医疗行业的治疗负担。
念珠菌、隐球菌和曲霉菌是侵袭性真菌感染的三大致病菌。尽管真菌感染已对人类造成极大威胁，但临床治疗真菌感染的有效药物仍十分有限。目前临床上抗真菌药物根据作用机制的不同，可以分为抑制麦角甾醇合成的唑类药物；破坏细胞壁的棘白霉素类抗真菌药物、抑制真菌细胞膜合成的烯丙胺类药物、造成细胞膜泄漏的多烯类药物和作用于核酸的抗代谢类抗真菌药物。其中，唑类药物是临床广泛使用的一线用药，其通过作用于羊毛甾醇14α-去甲基化酶(CYP51)的活性，抑制真菌细胞膜的合成，发挥抑菌作用。目前临床上的唑类抗真菌药物主要分为三类：咪唑类药物，如咪康唑(Miconazole)、酮康唑(Ketoconazole)；三氮唑类药物，如氟康唑(Fluconazole)、伊曲康唑(Itraconazole)、伏立康唑(Voriconazole)和泊沙康唑(Posaconazole)以及四氮唑类药物，如奥特康唑(Oteseconazole)。
尽管唑类药物在临床上发挥着不可替代的作用，但是该类药物存在药效低，抗菌谱窄、联合给药易引起药物间相互作用等问题。此外真菌耐药性问题的出现，也是造成药物治疗效果不佳的原因。本发明开发新一代结构新颖、具有强效抗真菌效果的含有乙炔基的唑醇类衍生物以应对上述问题。
发明内容
本发明的目的在于提供一种新型含有乙炔基的唑醇类衍生物及其制备方法和作为抗真菌药物特别是作为CYP51抑制剂的应用。
为实现上述目的，本发明采用技术方案为：
一种唑类衍生物，所述衍生物为通式I所示的化合物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
其中，MBG是任选取代的四唑基、任选取代的三唑基、或任选取代的吡唑基，所述任选取代的指C1-4烷基取代或C1-4烷氧基取代；
Ar为取代苯环，取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代，取代基选自卤素，所述卤素为F、Cl、Br或I；
R1为氢、卤素、烷基或卤代烷基；
R2为烷基或氘代烷基；
*标识的碳原子为手性碳原子或非手性碳原子；
A环为苯基、5-7元杂芳基或5-7元杂环烷基，其中，所述杂芳基、杂环烷基含有1-3个选自N、O或S的杂原子，并且A环任选1-4个相同或不同R3取代；
R3或R4为氢或者羟基、卤素、硝基、氨基、氰基、醛基、苯基、苄氧基、C1-C6烷基、C1-C6烯基、C1-C6烷氧基、任选被羟基、氨基或卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的苯基、卤代的苄氧基、游离的、成盐的、酯化的和酰胺化的羧基、C1-C6烷基酰基、C1-C3亚烷基二氧基；
B环为苯基、5-7元杂芳基或5-7元杂环烷基，其中，所述杂芳基、杂环烷基含有1-3个选自N、O或S的杂原子，并且B环任选1-4个相同或不同R4取代；
在一个优选的实施方式中，其中，MBG选自以下结构：Ar为2,4-二氟苯基。
在一个优选的实施方式中，R1为氢或甲基；R2为甲基或氘代甲基。
在一个优选的实施方式中，其中A环为苯环；R3为氢或氟；
在一个优选的实施方式中，其中A环为吡啶环；R3为氢；
在一个优选的实施方式中，其中B环为苯环；R4选自i，ii，或iii，其中取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基。
在一个优选的实施方式中，其中B环为5-6元杂芳基，杂芳基含有1-2个选自N、O或S的杂原子；R4为氢；
在一个优选的实施方式中，其中A环为苯环，B环为5-6元杂芳基，杂芳基含有1-2个选自N、O
或S的杂原子；R3和R4为氢；
在一个优选的实施方式中，其中A环为苯环，B环为苯环；R3为氢或氟；R4选自i，ii，或iii，其中
取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基。在一个优选的实施方式中，其中A环为吡啶环，B环为苯环；R3为氢；R4选自i，ii，或iii，其中取
代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基。
在一个优选的实施方式中，所述衍生物为通式I所示的化合物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，选自：
2-(2,4-二氟苯基)-1-(甲基(4-(苯乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-2-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-3-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-4-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-5-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-3-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((4-甲氧基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-(4-乙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((4-异丙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-(叔丁基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苄腈
2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯酚
1-((4-((4-氨基苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((1,1’-联苯)-4-乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-(苄氧基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲醛
1-(4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲酸乙酯
2-(2,4-二氟苯基)-1-((4-(2-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-(3-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((2-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((3-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((2-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((3-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((2-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((3-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基((4-(2-(2-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基((4-(2-(3-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((3,5-二甲基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((3,5-双(三氟甲基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((2,5-二氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-溴-2-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(4-((2-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-溴-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((3-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-((2,4,5-三氟苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1-((4-((4-溴-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-3-((4-((4-氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-3-((4-((4-溴苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-3-((4-((4-(叔丁基)苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1-(4-(((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)苯基)乙炔基)苄腈
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-((2,4,5-三氟苯基)乙炔基)苄基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-3-((4-(4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)苯基)乙炔基)苄腈
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-3-氟苯基)乙炔基)苄腈
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-2-氟苯基)乙炔基)苄腈
4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)-3-氟苯基)乙炔基)苄腈
(2R,3R)-2-(2,4-二氟苯基)-3-((5-((2,4-二氟苯基)乙炔基)吡啶-2-基)(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-((6-((2,4-二氟苯基)乙炔基)吡啶-3-基)甲基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-2-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-3-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-(4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1-(4-(2-(4-(((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,3,4-四唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯基)乙-1-酮
2-(2,4-二氟苯基)-1-((4-(2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1-((4-((4-溴-3-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
而且，按照本发明所属领域的一些通常的方法，本发明中通式I的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式I所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式I所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式I所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
上面给出的通式I化合物的定义中，汇集所用术语一般定义如下：
任选取代的取代基：C1-C4烷基、C1-C4烷氧基。
卤素：指氟、氯、溴或碘。
烷基：直链或支链烷基，优选地，所述烷基为C1-6直链或支链烷基，例如，其可以选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基。
环烷基：取代或未取代的环状烷基，例如环丙基、环戊基或环己基。取代基如甲基、卤素等。
卤代烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被卤原子所取代，例如，氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基等。
烷氧基：直链或支链烷基，羟基的氢原子可被这些直链或支链烷基所取代，例如，甲基氧基，乙基氧基，丙基氧基，异丙基氧基等。
本发明可以含有通式I的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明通式I的化合物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来制备；本发明中的室温指环境温度，为25℃。
上述通式I所示衍生物的制备方法，所述通式I所示衍生物得到制备反应如下：
以2'-氯-2,4-二氟苯乙酮为起始原料，碱性条件下发生取代反应得到中间体2，中间体2在碱性条件下，与三甲基碘化亚砜环合得到中间体3。中间体4与甲胺发生还原胺化得到中间体5，中间体3再与中间体5在碱性条件下开环得到中间体6，随后与不同的含碘芳杂环以及不同取代基的碘苯片段发生Sonogashira偶联反应得到目标化合物7。
上述制备过程流程中对MBG、B环和R4的定义，如上文所述。
进一步的说，以2'-氯-2,4-二氟苯乙酮为起始原料，碱性条件下与三氮唑或者四氮唑发生取代反应得到中间体2，反应温度为0～70℃，优选25℃；反应中的碱可为氢化钠，三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选碳酸钾；反应中的催化剂可为苄基三乙基氯化铵，四乙基溴化铵，苄基三甲基氯化铵，聚乙二醇，最优为苄基三乙基氯化铵；反应溶剂可为乙腈，四氢呋喃，甲苯，二氯甲烷，N,N-二甲基甲酰胺，优选二氯甲烷。中间体2在高温碱性条件下，与三甲基碘化亚砜环合得到中间体3，反应溶剂可为甲苯/水，二氯甲烷/水，乙腈/水，优选二氯甲烷/水；反应温度为30～80℃，优选50℃；反应中的催化剂可为十六烷基三甲基溴化铵、十四烷基三甲基溴化胺、四丁基溴化铵、四乙基溴化铵、苄基三甲基氯化铵，优选苄基三甲基氯化铵；反应中的碱可为氢化钠，氢氧化钠，氢氧化钾，三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾等，优选氢氧化钠；中间体4与甲胺进行还原胺化得到中间体5，反应温度为0～50℃，优选25℃；反应溶剂可为甲醇，乙醇，二氯甲烷，四氢呋喃等，优选甲醇；还原剂可为硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，四异丙基钛酸酯等，优选硼氢化钠。中间体3与中间体5碱性条件下开环得到中间体6，反应溶剂可为乙醇，N,N-二甲基甲酰胺，优选乙醇；反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸钾，碳酸钠等，优选三乙胺；反应温度为50～120℃，优选80℃。中间体6分别与含碘芳杂环和不同取代基的碘苯片段发生偶联反应，分别得到目标化合物7和8，反应溶剂可为四氢呋喃，乙腈，甲醇，N,N-二甲基甲酰胺，优选乙腈，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠，优选三乙胺，反应中的催化剂可为四三苯基磷钯/碘化亚铜，双三苯基磷二氯化钯/碘化亚铜，醋酸钯/碘化亚铜，优选为四三苯基磷钯/碘化亚铜；反应温度为25～80℃，优选50℃。
以9为起始原料，与三甲基硅炔发生Sonogashira偶联反应得到中间体10，中间体10在碱性条件下脱除TMS保护得到中间体11。中间体11与含R4取代基的碘苯发生Sonogashira偶联反应得到中间体12，中间体12再与甲胺盐酸盐或甲基-d3-胺盐酸盐发生还原胺化反应得到中间体13，随后与1-[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧甲基]-1H-[1,2,4]三唑开环得到目标化合物14。
上述制备过程流程中对A环、R2、R3和R4的定义，如上文所述。
进一步的说，以9为起始原料，三甲基硅炔发生Sonogashira偶联反应得到中间体10，反应温度为0～70℃，优选30℃；反应溶剂可为四氢呋喃，乙腈，甲醇，N,N-二甲基甲酰胺，优选四氢呋喃；反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；反应中的催化剂可为四三苯基磷钯/碘化亚铜，双三苯基磷二氯化钯/碘化亚铜，醋酸钯/碘化亚铜，优选为四三苯基磷钯/碘化亚铜；中间体10在碱性条件下脱除TMS保护得到中间体11，反应溶剂可为甲醇，四氢呋喃，乙腈，甲苯，N,N-二甲基甲酰胺，优选甲醇；反应温度为0～70℃，优选30℃；反应中的碱可为，氢氧化钠，氢氧化钾，碳酸铯，碳酸钾等，优选碳酸钾；中间体11与含R4取代基的碘苯发生Sonogashira偶联反应得到中间体12，反应温度为0～70℃，优选50℃；反应溶剂可为四氢呋喃，乙腈，甲醇，N,N-二甲基甲酰胺，优选乙腈；反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；反应中的催化剂可为四三苯基磷钯/碘化亚铜，双三苯基磷二氯化钯/碘化亚铜，醋酸钯/碘化亚铜，优选为双三苯基磷二氯化钯/碘化亚铜；中间体12与甲胺盐酸盐或甲基-d3-胺盐酸盐发生还原胺化反应得到中间体13，反应温度为0～70℃，优选25℃；反应溶剂可为甲醇，乙醇，二氯甲烷，四氢呋喃等，优选甲醇；反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；还原剂可为硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，四异丙基钛酸酯等，优选硼氢化钠。中间体13与1-[(2R,3s)-2-(2,4-二氟苯基)-3-甲基环氧甲基]-1H-[1,2,4]三唑开环得到目标化合物14，反应温度为50～120℃，优选80℃；溶剂可为乙腈，四氢呋喃，叔丁醇，甲苯，异丙醇，优选为乙腈。反应中的碱可为氢氧化镁，碳酸酶，氢氧化钠，碳酸钾，碳酸钠，叔丁醇锂，叔丁醇镁，优选为叔丁醇镁；路易斯酸可为氯化锂，溴化锂，氯化镁，三氯化铁，氯化锌，氯化锰，优选为氯化镁。
本发明唑类衍生物的应用，所述通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与真菌感染有关的疾病的药物中的应用。
所述通式I所示的唑类衍生物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备抗真菌药物中的应用。
一种药用组合物，包含通式I所示的唑类衍生物及其立体异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
所述组合物在制备预防或治疗与真菌感染有关的疾病的药物中的应用。
所述组合物在制备抗真菌药物中的应用。
本发明的有益效果在于：本发明提供了一种新型唑类衍生物，其制备方法、药物组合和应用。本发明的唑类衍生物对各种浅表和深部真菌具有良好的抗真菌活性，与现有的临床应用的抗真菌药物相比，具有高效、低毒、抗菌谱广等优点，可用于制备抗真菌药物。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-600测定；所用试剂均为分析纯或化学纯。
具体实施例结构如下：
实施例1的制备路线如下所示：
具体合成步骤如下：
1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙-1-酮(2)的合成
将1,2,4-三氮唑(20.00g,0.29mol)，苄基三乙基氯化铵(2.20g,0.01mmol)，碳酸钾(41.42g,0.30mmol)加入到二氯甲烷溶液中，在冰浴条件下向其中滴加中间体1(2.00g,0.19mmol)的二氯甲烷溶液。滴毕后，移至室温搅拌反应12h，TLC监测(DCM:MeOH＝50:1)原料反应完全，过滤，滤饼用二氯甲烷洗涤，有机相浓缩，经柱层析分离得白色固体，产率80％。
1-((2-(2,4-二氟苯基)环氧乙烷-2-基)甲基)-1H-1,2,4-三唑(3)的合成
将三甲基碘化亚砜(28.29g,0.13mol)溶于NaOH水溶液中，室温反应2h，再加入中间体2(25.00g,0.11mol)，苄基三甲基氯化铵(0.99g,0.005mol)，二氯甲烷，55℃反应6h。TLC监测(DCM:MeOH＝50:1)原料反应完全，乙酸乙酯萃取，有机相减压浓缩，经柱层析分离得淡黄色固体，产率75％。
1-(4-乙炔基苯基)-N-甲基甲胺(5)的合成
将中间体4(8.86g,0.068mol)，甲胺水溶液(2.56g,0.082mol)加入到甲醇溶液中，室温反应30min，随后加入还原剂硼氢化钠(3.91g,0.102mol)，继续室温反应1h。TLC监测(DCM:MeOH＝20:1)原料反应完全，减压浓缩，经柱层析分离得白色粉末状固体，产率85％。
2-(2,4-二氟苯基)-1-((4-乙炔苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇(6)的合成
将中间体3(10.00g,0.042mol)，中间体5(7.64g,0.048mol)，三乙胺(21.32g,0.21mol)在室温条件下加入到无水乙醇溶液中，回流反应6h。TLC监测(DCM:MeOH＝30:1)原料反应完全，减压浓缩，经柱层析分离得白色固体，产率78％。
2-(2,4-二氟苯基)-1-(甲基(4-(苯乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇(实施例1)的制备
将中间体5(0.080g,0.21mmol)溶于5mL乙腈中，依次加入碘苯(0.051g,0.25mmol)和三乙胺(0.063g,0.63mmol)，双三苯基磷二氯化钯(0.014g,0.02mmol)，碘化亚铜(0.08g,0.04mmol)，氩气保护下，50℃下搅拌3h。TLC监测(DCM:MeOH＝50:1)反应完全，乙酸乙酯萃取，合并有机相，减压浓缩，制备薄层板分离(DCM:MeOH＝30:1)，得白色固体，收率49％。1HNMR(600MHz,DMSO-d6)δ8.32(s,1H),7.76(s,1H),7.56–7.52(m,2H),7.44(d,J＝3.7Hz,1H),7.43–7.41(m,4H),7.17–7.12(m,3H),6.97(td,J＝8.5,2.6Hz,1H),5.79(s,1H),4.54(dd,J＝34.9,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.45(s,1H),3.42(s,1H),3.02(d,J＝11.8Hz,1H),2.78(d,J＝13.8Hz,1H),2.10(s,3H).HRMS calcd for C27H24F2N4O,[M+H]+,459.1996；found 459.2021.
按照实施例1的方法，分别使用相应的原料制备得到实施例2-52。
实施例2：2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-2-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.60(s,1H),8.32(s,1H),7.86–7.81(m,1H),7.77(s,1H),7.62(d,J＝7.9Hz,1H),7.48(d,J＝7.8Hz,2H),7.41(dd,J＝14.6,6.9Hz,2H),7.19–7.10(m,3H),7.00–6.92(m,1H),5.78(s,1H),4.54(dd,J＝30.9,14.3Hz,2H),3.60(d,J＝13.7Hz,1H),3.44(d,J＝14.0Hz,1H),3.01(d,J＝14.1Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C26H23F2N5O,[M+H]+,460.1949；found460.1971.
实施例3：2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-3-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,Chloroform-d)δ8.76(s,1H),8.23(s,1H),7.79(d,J＝7.7Hz,2H),7.54(d,J＝8.0Hz,1H),7.43(d,J＝7.7Hz,2H),7.33(s,1H),7.10(d,J＝7.7Hz,2H),6.75(d,J＝11.4Hz,2H),5.25(s,1H),4.47(q,J＝14.2Hz,2H),3.45(d,J＝13.0Hz,1H),3.36(d,J＝13.0Hz,1H),3.05(d,J＝13.5Hz,1H),2.78(d,J＝13.5Hz,1H),2.01(s,3H).HRMS calcd for C26H23F2N5O,[M+H]+,460.1949；found 460.1985.
实施例4：2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-4-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
NMR(600MHz,DMSO-d6)δ8.64(s,1H),8.31(s,1H),7.76(s,1H),7.49(dd,J＝19.2,11.0Hz,3H),7.43(dd,J＝16.0,9.0Hz,1H),7.16(dd,J＝12.7,8.8Hz,3H),6.97(t,J＝8.6Hz,1H),5.79(s,1H),4.54(dd,J＝34.1,14.4Hz,2H),3.61(d,J＝13.8Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.8Hz,1H),2.10(s,3H).HRMS calcdfor C26H23F2N5O,[M+H]+,460.1949；found 460.1971.HRMS calcd for C26H23F2N5O,[M+H]+,460.1949；found 460.1971.
实施例5：2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.87(dd,J＝2.9,1.2Hz,1H),7.75(s,1H),7.65(dd,J＝5.0,2.9Hz,1H),7.45–7.41(m,1H),7.40(d,J＝8.1Hz,2H),7.26(dd,J＝5.0,1.2Hz,1H),7.18–7.14(m,1H),7.13(d,J＝8.1Hz,2H),6.97(td,J＝8.5,2.6Hz,1H),5.78(s,1H),4.53(dd,J＝36.7,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.43(s,1H),3.01(d,J＝15.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C25H22F2N6O,[M+Na]+,483.1721；found 483.1760.
实施例6：2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-5-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.00(s,2H),8.42(s,1H),7.84(s,1H),7.48(d,J＝7.7Hz,2H),7.43(s,1H),7.17(d,J＝7.9Hz,2H),7.14(s,1H),6.96(s,1H),5.79(s,1H),4.60–4.51(m,2H),3.61(d,J＝13.6Hz,1H),3.46(s,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.6Hz,1H),2.09(s,3H).HRMS calcd for C25H22F2N6O,[M+H]+,461.1901；found 461.1905.
实施例7：2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.66(dd,J＝5.2,1.2Hz,1H),7.45–7.40(m,4H),7.17–7.12(m,4H),6.96(td,J＝8.5,2.6Hz,1H),5.79(s,1H),4.54(dd,J＝35.9,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.01(d,J＝15.5Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C25H22F2N4OS,[M+Na]+,487.1380；found 487.1410.
实施例8：2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-3-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.87(dd,J＝2.9,1.2Hz,1H),7.75(s,1H),7.65(dd,J＝5.0,2.9Hz,1H),7.45–7.41(m,1H),7.40(d,J＝8.1Hz,2H),7.26(dd,J＝5.0,1.2Hz,1H),7.18–7.14(m,1H),7.13(d,J＝8.2Hz,2H),6.97(td,J＝8.5,2.6Hz,1H),5.78(s,1H),4.53(dd,J＝36.7,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.42(s,1H),3.01(d,J＝15.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C25H22F2N4OS,[M+Na]+,487.1380；found 487.1410.
实施例9：2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.60(dd,J＝8.6,5.6Hz,2H),7.45–7.40(m,3H),7.27(t,J＝8.9Hz,2H),7.19–7.15(m,1H),7.14(d,J＝7.8Hz,2H),6.97(td,J＝8.6,2.7Hz,1H),5.77(s,1H),4.54(dd,J＝37.7,14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.01(d,J＝15.3Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H23F3N4O,[M+H]+,477.1902；found 477.1951.
实施例10：1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.33(s,1H),7.77(s,1H),7.56(d,J＝8.3Hz,2H),7.49(d,J＝8.5Hz,2H),7.43(t,J＝10.2Hz,3H),7.16(dd,J＝18.1,5.3Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.78(s,1H),4.54(dd,J＝34.2,14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝15.2Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMScalcd for C27H23CIF2N4O,[M+H]+,493.1607；found 493.1640.
实施例11：1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.49(s,1H),7.89(s,1H),7.62(d,J＝8.0Hz,2H),7.49(d,J＝8.1Hz,2H),7.43(d,J＝7.8Hz,3H),7.15(t,J＝10.9Hz,3H),6.96(s,1H),5.77(s,1H),4.56(s,2H),3.59(d,J＝13.6Hz,1H),3.43(d,J＝13.6Hz,1H),3.01(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C27H23BrF2N4O,[M+H]+,539.1081；found 539.1096.
实施例12：2-(2,4-二氟苯基)-1-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.79(d,J＝8.4Hz,2H),7.75(s,1H),7.43(d,J＝8.2Hz,3H),7.32(d,J＝8.4Hz,2H),7.16(d,J＝2.6Hz,1H),7.13(d,J＝8.0Hz,2H),6.96(dt,J＝8.5,4.2Hz,1H),5.78(s,1H),4.54(dd,J＝36.8,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.43(d,J＝13.7Hz,1H),3.01(d,J＝15.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C27H23F2IN4O,[M+H]+,585.0963；found585.0998.
实施例13：2-(2,4-二氟苯基)-1-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.74(s,1H),7.41(t,J＝9.6Hz,5H),7.23(d,J＝7.7Hz,2H),7.16(d,J＝8.6Hz,1H),7.12(d,J＝8.1Hz,2H),6.99–6.93(m,1H),5.77(s,1H),4.53(dd,J＝37.2,14.3Hz,2H),3.58(d,J＝13.5Hz,1H),3.43(d,J＝13.6Hz,1H),3.01(d,J＝13.7Hz,1H),2.76(d,J＝13.7Hz,1H),2.33(s,3H),2.09(s,3H).HRMS calcdfor C28H26F2N4O,[M+H]+,473.2153；found 473.2181.
实施例14：2-(2,4-二氟苯基)-1-((4-((4-甲氧基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.48(d,J＝8.3Hz,2H),7.43(d,J＝7.5Hz,1H),7.39(d,J＝7.8Hz,2H),7.16(s,1H),7.12(d,J＝7.7Hz,2H),6.98(d,J＝8.2Hz,2H),5.78(s,1H),4.58–4.49(m,2H),3.80(s,3H),3.59(d,J＝13.5Hz,1H),3.43(d,J＝13.5Hz,1H),3.01(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcdfor C28H26F2N4O2,[M+H]+,489.2102；found 489.2131.
实施例15：2-(2,4-二氟苯基)-1-((4-(4-乙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.35(s,1H),7.79(s,1H),7.46(d,J＝8.1Hz,2H),7.43(s,1H),7.41(d,J＝8.1Hz,2H),7.27(d,J＝8.0Hz,2H),7.19–7.14(m,1H),7.13(d,J＝8.0Hz,2H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.54(dd,J＝32.3,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.01(d,J＝13.9Hz,1H),2.77(d,J＝13.7Hz,1H),2.64(q,J＝7.6Hz,2H),2.10(s,3H),1.19(t,J＝7.6Hz,3H).HRMS calcd forC29H28F2N4O,[M+H]+,2309；found 487.2316.
实施例16：2-(2,4-二氟苯基)-1-((4-((4-异丙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.81(s,1H),7.46(d,J＝7.9Hz,2H),7.43(d,J＝12.7Hz,1H),7.41(d,J＝7.8Hz,2H),7.30(d,J＝8.0Hz,2H),7.17(d,J＝9.6Hz,1H),7.13(d,J＝8.0Hz,2H),6.97(t,J＝7.2Hz,1H),5.77(s,1H),4.54(dd,J＝30.1,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.01(d,J＝13.8Hz,1H),2.92(dt,J＝13.8,6.9Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H),1.21(d,J＝6.9Hz,6H).HRMScalcd for C30H30F2N4O,[M+H]+,501.2466；found 501.2492.
实施例17：1-((4-((4-(叔丁基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.42(s,1H),7.84(s,1H),7.46(d,J＝11.4Hz,3H),7.44–7.39(m,4H),7.15(dd,J＝20.4,9.9Hz,3H),6.97(t,J＝8.3Hz,1H),5.77(s,1H),4.55(q,J＝14.4Hz,2H),3.59(d,J＝13.6Hz,1H),3.44(s,1H),3.01(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H),1.29(s,9H).HRMS calcd for C31H32F2N4O,[M+H]+,515.2622；found 515.2650.
实施例18：2-(2,4-二氟苯基)-1-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.79(d,J＝8.5Hz,2H),7.76(d,J＝9.8Hz,3H),7.48(d,J＝8.1Hz,2H),7.45–7.41(m,1H),7.18–7.14(m,3H),6.97(td,J＝8.5,2.3Hz,1H),5.78(s,1H),4.54(dd,J＝37.4,14.0Hz,2H),3.61(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝14.2Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcdfor C28H23F5N4O,[M+H]+,527.1870；found 527.1868.
实施例19：2-(2,4-二氟苯基)-1-(甲基(4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.68(d,J＝8.6Hz,2H),7.44(dd,J＝12.5,8.0Hz,5H),7.18–7.13(m,3H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.57(d,J＝14.3Hz,1H),4.50(d,J＝14.3Hz,1H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.02(d,J＝13.0Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcdfor C28H23F5N4O2,[M+H]+,543.1819；found 543.1865.
实施例20：4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苄腈
1H NMR(600MHz,Chloroform-d)δ8.10(s,1H),7.75(s,1H),7.62(q,J＝8.3Hz,5H),7.46(d,J＝8.1Hz,2H),7.15(d,J＝8.1Hz,2H),6.81(dtd,J＝11.7,5.5,2.5Hz,2H),4.52–4.44(m,2H),3.51(d,J＝13.3Hz,1H),3.41(d,J＝13.2Hz,1H),3.10(d,J＝13.0Hz,1H),2.83(d,J＝13.5Hz,1H),2.06(s,3H).HRMS calcd for C28H23F2N5O,[M+H]+,484.1949；found 484.1993.
实施例21：2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),8.29–8.26(m,2H),7.81(d,J＝8.6Hz,2H),7.76(s,1H),7.50(d,J＝7.8Hz,2H),7.46–7.42(m,1H),7.19–7.14(m,3H),6.97(t,J＝8.3Hz,1H),5.80(s,1H),4.59–4.50(m,2H),3.62(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.03(d,J＝13.1Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd forC27H23F2N5O3,[M+H]+,504.1847；found 504.1855.
实施例22：4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯酚
1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.30(s,1H),7.75(s,1H),7.40–7.33(m,4H),7.15(t,J＝9.1Hz,2H),7.11(d,J＝8.0Hz,2H),6.96(d,J＝7.6Hz,1H),6.80(d,J＝8.4Hz,1H),5.77(s,1H),4.54(dd,J＝36.1,14.3Hz,3H),3.58(d,J＝13.7Hz,1H),3.43(d,J＝13.6Hz,1H),3.01(d,J＝14.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcdfor C27H24F2N4O2,[M+H]+,475.1946；found 475.1980.
实施例23：1-((4-((4-氨基苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.54(s,1H),7.97(s,1H),7.42(t,J＝12.6Hz,1H),7.33(d,J＝7.8Hz,2H),7.18(d,J＝8.3Hz,2H),7.14(d,J＝10.4Hz,1H),7.09(d,J＝7.8Hz,2H),6.97(s,1H),6.55(d,J＝8.3Hz,2H),5.75(s,1H),5.55(s,2H),4.57(s,2H),3.56(d,J＝13.5Hz,1H),3.42(d,J＝13.5Hz,1H),3.00(d,J＝13.7Hz,1H),2.76(d,J＝13.6Hz,1H),2.09(s,3H).HRMS calcd for C27H25F2N5O,[M+H]+,474.2105；found474.2145.
实施例24：1-((4-((1,1’-联苯)-4-乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.76(d,J＝12.0Hz,2H),7.74–7.71(m,3H),7.63(d,J＝8.3Hz,2H),7.49(t,J＝7.7Hz,2H),7.45(t,J＝7.1Hz,3H),7.40(t,J＝7.4Hz,1H),7.16(dd,J＝12.7,8.0Hz,3H),6.98(t,J＝8.7Hz,1H),5.79(s,1H),4.59–4.51(m,2H),3.61(d,J＝13.6Hz,1H),3.45(d,J＝13.6Hz,1H),3.03(d,J＝15.5Hz,1H),2.79(d,J＝13.6Hz,1H),2.11(s,3H).HRMS calcd for C33H28F2N4O,[M+H]+,535.2309；found535.2358.
实施例25：1-((4-((4-(苄氧基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.50–7.45(m,4H),7.45–7.37(m,5H),7.35(t,J＝7.3Hz,1H),7.17(d,J＝9.3Hz,1H),7.13(t,J＝7.7Hz,2H),7.06(d,J＝8.8Hz,2H),6.97(t,J＝7.4Hz,1H),5.77(s,1H),5.15(s,2H),4.54(dd,J＝37.3,14.3Hz,2H),3.59(d,J＝13.6Hz,1H),3.43(d,J＝13.6Hz,1H),3.01(d,J＝15.5Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C34H30F2N4O2,[M+H]+,565.2415；found565.2442.
实施例26：4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲醛
1H NMR(600MHz,DMSO-d6)δ10.04(s,1H),8.39(s,1H),7.95(s,2H),7.76(s,2H),7.48(s,2H),7.43(s,1H),7.16(s,3H),6.97(s,1H),5.79(s,1H),4.55(dd,J＝28.2,14.5Hz,2H),3.61(d,J＝13.5Hz,1H),3.45(s,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.8Hz,1H),2.10(s,3H).HRMS calcd for C28H24F2N4O2,[M+H]+,487.1946；found487.1970.
实施例27：1-(4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.99(d,J＝8.4Hz,2H),7.76(s,1H),7.68(d,J＝8.4Hz,2H),7.47(d,J＝8.2Hz,2H),7.44(d,J＝6.9Hz,1H),7.15(t,J＝8.0Hz,3H),6.97(dd,J＝8.5,5.8Hz,1H),5.80(s,1H),4.54(d,J＝23.1Hz,2H),3.61(d,J＝13.7Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝15.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.60(s,3H),2.10(s,3H).HRMS calcd for C28H27F2N5O2,[M+H]+,501.2102；found 501.2130.
实施例28：4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲酸乙酯
1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.99(d,J＝8.6Hz,2H),7.81(s,1H),7.68(d,J＝8.5Hz,2H),7.47(d,J＝8.1Hz,2H),7.43(dd,J＝15.8,8.8Hz,1H),7.16(d,J＝7.9Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.55(dd,J＝29.6,14.3Hz,2H),4.33(q,J＝7.1Hz,2H),3.61(d,J＝13.6Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝13.8Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H),1.34(t,J＝7.1Hz,3H).HRMS calcd forC30H28F2N4O3,[M+H]+,531.2208；found 531.2262.
实施例29：2-(2,4-二氟苯基)-1-((4-(2-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,CDCl3)δ8.35(s,1H),7.85(s,1H),7.57(d,J＝7.7Hz,1H),7.52(t,J＝7.3Hz,1H),7.49(d,J＝7.6Hz,2H),7.32(dd,J＝13.8,7.2Hz,1H),7.15–7.09(m,4H),6.84–6.77(m,2H),5.34(s,1H),4.53(dd,J＝28.4,15.1Hz,2H),3.49(d,J＝13.1Hz,1H),3.40(d,J＝13.1Hz,1H),3.10(d,J＝13.2Hz,1H),2.82(d,J＝13.4Hz,1H),2.05(s,3H).HRMS calcd for C27H23F3N4O,[M+H]+,477.1902；found 477.1927.
实施例30：2-(2,4-二氟苯基)-1-((4-(3-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.50(s,1H),7.89(s,1H),7.49–7.43(m,4H),7.40(t,J＝7.4Hz,2H),7.27(td,J＝8.7,2.6Hz,1H),7.16(d,J＝8.3Hz,1H),7.14(d,J＝7.8Hz,2H),6.97(t,J＝7.4Hz,1H),5.78(s,1H),4.57(s,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.02(d,J＝13.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcdfor C27H23F3N4O,[M+H]+,477.1902；found 477.1930.
实施例31：1-((4-((2-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.67(dd,J＝7.5,1.8Hz,1H),7.60(dd,J＝8.0,1.4Hz,1H),7.46(d,J＝8.2Hz,2H),7.45–7.39(m,3H),7.16(d,J＝8.0Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.78(s,1H),4.54(dd,J＝35.4,14.3Hz,2H),3.61(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.03(d,J＝14.5Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H23CIF2N4O,[M+H]+,493.1607；found 493.1621.
实施例32：1-((4-((3-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.76(s,1H),7.62(s,1H),7.53–7.41(m,6H),7.15(d,J＝8.1Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.78(s,1H),4.54(dd,J＝35.0,14.5Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.6Hz,1H),3.02(d,J＝15.5Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H23CIF2N4O,[M+H]+,493.1607；found 493.1626.
实施例33：1-((4-((2-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.75(d,J＝8.6Hz,2H),7.65(d,J＝7.6Hz,1H),7.45(dd,J＝13.6,7.7Hz,4H),7.35(t,J＝7.8Hz,1H),7.16(d,J＝6.2Hz,3H),6.97(t,J＝7.3Hz,1H),5.78(s,1H),4.54(dd,J＝33.0,14.3Hz,2H),3.61(d,J＝13.6Hz,1H),3.44(d,J＝13.7Hz,1H),3.03(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMScalcd for C27H23BrF2N4O,[M+H]+,539.1081；found 539.1096.
实施例34：1-((4-((3-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.45(s,1H),7.85(s,1H),7.76(s,1H),7.63(d,J＝8.1Hz,1H),7.56(d,J＝7.7Hz,1H),7.45(d,J＝7.8Hz,2H),7.42(d,J＝6.9Hz,1H),7.39(t,J＝7.9Hz,1H),7.15(d,J＝7.8Hz,3H),6.97(t,J＝7.7Hz,1H),5.77(s,1H),4.55(q,J＝14.2Hz,2H),3.60(d,J＝13.7Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H23BrF2N4O,[M+H]+,539.1081；found 539.1103.
实施例35：2-(2,4-二氟苯基)-1-((4-((2-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.96(d,J＝6.9Hz,1H),7.75(s,1H),7.60(dd,J＝7.7,1.6Hz,1H),7.45(ddd,J＝10.2,9.8,7.4Hz,4H),7.16(d,J＝7.9Hz,4H),6.98(td,J＝8.5,2.7Hz,1H),5.78(s,1H),4.54(dd,J＝33.8,14.3Hz,2H),3.61(d,J＝13.7Hz,1H),3.44(d,J＝13.6Hz,1H),3.03(d,J＝15.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd forC27H23F2IN4O,[M+H]+,585.0963；found585.0975.
实施例36：2-(2,4-二氟苯基)-1-((4-((3-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.92(s,1H),7.79(d,J＝7.7Hz,1H),7.76(s,1H),7.56(d,J＝7.6Hz,1H),7.44(d,J＝8.0Hz,2H),7.41(d,J＝8.7Hz,1H),7.23(t,J＝7.9Hz,1H),7.19–7.15(m,1H),7.14(d,J＝7.8Hz,2H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.54(dd,J＝36.4,14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.8Hz,1H),2.10(s,3H).HRMS calcdforC27H23F2IN4O,[M+H]+,585.0963；found 585.0975.
实施例37：2-(2,4-二氟苯基)-1-(甲基((4-(2-(2-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.76(s,1H),7.49(d,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,3H),7.34–7.29(m,2H),7.23(t,J＝7.2Hz,1H),7.15(dd,J＝17.4,8.6Hz,3H),6.97(td,J＝8.4,2.6Hz,1H),5.78(s,1H),4.54(dd,J＝32.7,14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.42(s,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.46(s,3H),2.09(s,3H).HRMS calcd for C28H26F2N4O,[M+H]+,473.2153；found473.2187.
实施例38：2-(2,4-二氟苯基)-1-(甲基((4-(2-(3-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.45–7.43(m,1H),7.42(d,J＝8.2Hz,2H),7.37(s,1H),7.34(d,J＝7.6Hz,1H),7.31(t,J＝7.5Hz,1H),7.23(d,J＝7.3Hz,1H),7.18–7.15(m,1H),7.13(d,J＝7.9Hz,2H),6.97(dd,J＝8.4,5.7Hz,1H),5.78(s,1H),4.57(d,J＝14.3Hz,1H),4.51(d,J＝14.3Hz,1H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.5Hz,1H),3.02(d,J＝14.4Hz,1H),2.77(d,J＝13.7Hz,1H),2.32(s,3H),2.10(s,3H).HRMS calcd for C28H26F2N4O,[M+H]+,473.2153；found 473.2165.
实施例39：2-(2,4-二氟苯基)-1-((4-((3,5-二甲基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.41(s,3H),7.15(d,J＝13.7Hz,5H),7.04(s,1H),6.97(s,1H),5.78(s,1H),4.54(dd,J＝36.2,14.4Hz,2H),3.59(d,J＝13.5Hz,1H),3.43(d,J＝7.4Hz,1H),3.02(d,J＝13.7Hz,1H),2.77(d,J＝13.8Hz,1H),2.28(s,6H),2.09(s,3H).HRMS calcd for C29H28F2N4O,[M+H]+,487.2309；found487.2299.
实施例40：1-((4-((3,5-双(三氟甲基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.26(s,2H),8.14(s,1H),7.76(s,1H),7.52(d,J＝7.7Hz,2H),7.44(d,J＝8.1Hz,1H),7.18(d,J＝7.7Hz,2H),7.14(s,1H),6.98(t,J＝8.6Hz,1H),5.79(s,1H),4.54(d,J＝25.0Hz,2H),3.63(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.03(d,J＝13.7Hz,1H),2.78(d,J＝13.7Hz,1H),2.11(s,3H).HRMS calcdfor C29H22F8N4O,[M+H]+,595.1744；found 595.1767.
实施例41：1-((4-((2,5-二氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.75(s,1H),7.45–7.43(m,1H),7.42(d,J＝8.2Hz,2H),7.37(s,1H),7.34(d,J＝7.6Hz,1H),7.31(t,J＝7.5Hz,1H),7.23(d,J＝7.3Hz,1H),7.19–7.15(m,1H),7.13(d,J＝7.9Hz,2H),6.97(dd,J＝8.4,5.7Hz,1H),5.78(s,1H),4.54(d,J＝22.2Hz,2H),3.60(d,J＝13.5Hz,1H),3.44(d,J＝13.6Hz,1H),3.02(d,J＝13.6Hz,1H),2.77(d,J＝13.7Hz,1H),2.32(s,3H),2.10(s,3H).HRMS calcd forC27H22CI2F2N4O,[M+H]+,527.1217；found 527.1232.
实施例42：2-(2,4-二氟苯基)-1-((4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.69(dd,J＝15.0,8.5Hz,1H),7.46(d,J＝7.9Hz,2H),7.42(t,J＝9.1Hz,1H),7.32(d,J＝7.1Hz,1H),7.20(d,J＝7.9Hz,3H),7.17(d,J＝8.3Hz,1H),6.95(td,J＝8.4,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.01(d,J＝13.3Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcd for C26H22F4N4O,[M+Na]+,495.1808；found495.1839.
实施例43：1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.81(s,1H),7.65(t,J＝8.1Hz,1H),7.60(dd,J＝9.4,2.0Hz,1H),7.45(d,J＝7.9Hz,2H),7.42(d,J＝8.5Hz,1H),7.37(dd,J＝8.3,2.1Hz,1H),7.15(dd,J＝15.5,5.4Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.76(s,1H),4.55(q,J＝14.3Hz,2H),3.61(d,J＝13.6Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝13.1Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C26H22F4N4O,[M+Na]+,495.1808；found 495.1839.
实施例44：1-((4-((4-溴-2-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.42(s,1H),7.84(s,1H),7.71(dd,J＝9.1,1.9Hz,1H),7.58(t,J＝8.0Hz,1H),7.49(dd,J＝8.3,1.9Hz,1H),7.45(t,J＝9.4Hz,3H),7.15(dd,J＝16.0,5.3Hz,3H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.56(q,J＝14.2Hz,2H),3.61(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝13.7Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H22BrF3N4O,[M+H]+,557.0987；found 557.1061.
实施例45：2-(2,4-二氟苯基)-1-(4-((2-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.25(dd,J＝9.2,2.3Hz,1H),8.14(dd,J＝8.6,2.3Hz,1H),7.93–7.89(m,1H),7.76(s,1H),7.51(d,J＝7.9Hz,2H),7.44(d,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),7.17–7.13(m,1H),6.97(dt,J＝8.5,4.2Hz,1H),5.78(s,1H),4.57(d,J＝14.3Hz,1H),4.52(d,J＝14.3Hz,1H),3.63(d,J＝13.7Hz,1H),3.46(d,J＝13.8Hz,1H),3.03(d,J＝15.5Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcdfor C27H22F3N5O3,[M+H]+,522.1753；found 522.1807.
实施例46：2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.39(s,1H),7.82(s,1H),7.70–7.65(m,1H),7.50(dd,J＝19.2,8.5Hz,1H),7.45–7.40(m,4H),7.17–7.13(m,3H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.55(dd,J＝29.1,14.3Hz,2H),3.60(d,J＝13.8Hz,1H),3.44(d,J＝13.6Hz,1H),3.02(d,J＝13.2Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd forC27H22F4N4O,[M+H]+,494.1730；found 495.1840.
实施例47：1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.39(s,1H),7.95–7.72(m,1H),7.64(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.42(d,J＝8.8Hz,2H),7.14(dd,J＝12.1,5.1Hz,2H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.55(q,J＝14.3Hz,1H),3.61(d,J＝13.7Hz,1H),3.45(d,J＝13.7Hz,1H),3.02(d,J＝13.1Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,2H).HRMS calcdfor C27H22ClF3N4O,[M+H]+,511.1512；found 511.1528.
实施例48：1-((4-((4-溴-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.41(s,1H),7.84(s,1H),7.76(t,J＝7.9Hz,1H),7.59(dd,J＝9.5,1.9Hz,1H),7.45(d,J＝7.9Hz,2H),7.42(s,1H),7.34(dd,J＝8.2,1.9Hz,1H),7.17–7.13(m,3H),6.97(td,J＝8.5,2.6Hz,1H),5.77(s,1H),4.55(q,J＝14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝14.7Hz,1H),2.77(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H22BrF3N4O,[M+H]+,557.0987；found 557.1027.
实施例49：2-(2,4-二氟苯基)-1-((4-((3-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.20(t,J＝8.3Hz,1H),7.81(d,J＝11.9Hz,1H),7.76(s,1H),7.59(d,J＝8.5Hz,1H),7.50(d,J＝7.8Hz,2H),7.46–7.42(m,1H),7.16(dd,J＝22.3,8.8Hz,3H),6.97(td,J＝8.5,2.7Hz,1H),5.78(s,1H),4.58(d,J＝14.2Hz,1H),4.51(d,J＝14.3Hz,1H),3.63(d,J＝13.7Hz,1H),3.46(d,J＝13.7Hz,1H),3.03(d,J＝13.2Hz,1H),2.78(d,J＝13.7Hz,1H),2.11(s,3H).HRMS calcd forC27H22F3N5O3,[M+H]+,522.1753；found 522.1824.
实施例50：2-(2,4-二氟苯基)-1-(4-((2,4,5-三氟苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.86–7.81(m,1H),7.76(d,J＝10.0Hz,1H),7.74–7.70(m,1H),7.45–7.39(m,3H),7.14(dd,J＝13.6,5.2Hz,3H),6.96(dt,J＝8.5,2.6Hz,1H),5.77(s,1H),4.53(dd,J＝34.2,14.3Hz,2H),3.60(d,J＝13.6Hz,1H),3.44(d,J＝13.7Hz,1H),3.01(d,J＝15.4Hz,1H),2.76(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcdfor C27H21F5N4O,[M+Na]+,535.1533；found 535.1588.
实施例51：1-((4-((4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.84–7.73(m,3H),7.48–7.41(m,3H),7.19–7.13(m,3H),6.97(td,J＝8.5,2.7Hz,1H),5.79(s,1H),4.55(dd,J＝37.1,14.3Hz,2H),3.62(d,J＝13.7Hz,1H),3.46(d,J＝13.7Hz,1H),3.03(d,J＝14.8Hz,1H),2.78(d,J＝13.7Hz,1H),2.10(s,3H).HRMS calcd for C27H21ClF4N4O,[M+Na]+,551.1238；found551.1274.
实施例52：1-((4-((4-溴-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.88(dd,J＝8.5,5.8Hz,1H),7.76(s,1H),7.72(dd,J＝8.7,6.1Hz,1H),7.45(d,J＝7.9Hz,2H),7.43–7.39(m,1H),7.14(dd,J＝17.5,5.3Hz,3H),6.96(td,J＝8.5,2.6Hz,1H),5.79(s,1H),4.53(dd,J＝34.4,14.3Hz,2H),3.60(d,J＝13.8Hz,1H),3.47(s,1H),3.01(d,J＝13.0Hz,1H),2.76(d,J＝13.7Hz,1H),2.09(s,3H).HRMS calcd for C27H21ClF4N4O,[M+Na]+,551.1238；found 551.1274.
实施例53的制备路线如下所示：
具体合成步骤如下：
1-(4-乙炔基苯基)-N-甲基甲胺(5)的合成
将中间体4(8.86g,0.068mol)，甲胺水溶液(2.56g,0.082mol)加入到甲醇溶液中，室温反应30min，随后加入还原剂硼氢化钠(3.91g,0.102mol)，继续室温反应1h。TLC监测(DCM:MeOH＝20:1)原料反应完全，减压浓缩，经柱层析分离得白色粉末状固体，产率85％。
(2R,3R)-2-(2,4-二氟苯基)-3-((4-乙炔苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇(9)的合成
将中间体8(2.00g,7.97mmol)，中间体5(1.73g,11.95mmol)，叔丁醇镁(1.20g,11.95mmol)，氯化镁(1.13g,11.95mmol)，在室温条件下加入到乙腈溶液中，氩气保护下，回流反应6h。TLC监测(DCM:MeOH＝30:1)原料反应完全，减压浓缩，经柱层析分离得白色固体，产率80％。
2-(2,4-二氟苯基)-1-(甲基(4-(苯乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇(实施例53)的制备
将中间体9(0.080g,0.20mmol)溶于5mL乙腈中，依次加入4-氟碘苯(0.054g,0.25mmol)和三乙胺(0.063g,0.63mmol)，四三苯基膦钯(0.023g,0.02mmol)，碘化亚铜(0.08g,0.04mmol)，氩气保护下，50℃下搅拌3h。TLC监测(DCM:MeOH＝50:1)反应完全，乙酸乙酯萃取，合并有机相，减压浓缩，制备薄层板分离(DCM:MeOH＝30:1)，得白色固体，收率45％。1H NMR(600MHz,DMSO-d6)δ8.33(s,1H),7.67(s,1H),7.64–7.61(m,2H),7.56(d,J＝7.8Hz,2H),7.48(d,J＝7.8Hz,2H),7.28(t,J＝7.8Hz,2H),7.25(d,J＝8.8Hz,1H),7.07(ddd,J＝11.8,9.0,2.6Hz,1H),6.88(td,J＝8.4,2.6Hz,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.64(d,J＝14.5Hz,1H),3.86(d,J＝13.4Hz,1H),3.54(d,J＝13.5Hz,1H),3.30–3.27(m,1H),2.36(s,3H),0.77(d,J＝6.8Hz,3H).HRMS calcd for C28H25F3N4O,[M+Na]+,513.1878；found 513.1899.
按照实施例53的方法，分别使用相应的原料制备得到实施例54-68。
实施例54：(2R,3R)-3-((4-((4-氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.65(s,1H),7.59(d,J＝8.2Hz,2H),7.57(d,J＝7.7Hz,2H),7.49(t,J＝8.4Hz,4H),7.26(d,J＝8.1Hz,1H),7.07(t,J＝9.7Hz,1H),6.88(t,J＝7.4Hz,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.64(d,J＝14.6Hz,1H),3.86(d,J＝13.4Hz,1H),3.55(d,J＝13.5Hz,1H),3.30–3.27(m,1H),2.36(s,3H),0.77(d,J＝6.8Hz,3H).HRMS calcd for C28H25ClF2N4O,[M+Na]+,529.1583；found 529.1606.
实施例55：(2R,3R)-3-((4-((4-溴苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),7.68(s,1H),7.64(d,J＝8.1Hz,2H),7.57(d,J＝7.7Hz,2H),7.52(d,J＝8.0Hz,2H),7.48(d,J＝7.9Hz,2H),7.26(dd,J＝16.1,8.1Hz,1H),7.07(t,J＝10.5Hz,1H),6.88(t,J＝8.6Hz,1H),5.54(s,1H),4.91(d,J＝14.5Hz,1H),4.65(d,J＝14.5Hz,1H),3.86(d,J＝13.3Hz,1H),3.55(d,J＝13.5Hz,1H),3.28(d,J＝7.1Hz,1H),2.36(s,3H),0.77(d,J＝6.8Hz,3H).HRMS calcd forC28H25BrF2N4O,[M+Na]+,575.1057；found 575.1096.
实施例56：(2R,3R)-2-(2,4-二氟苯基)-3-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.80(d,J＝8.0Hz,2H),7.65(s,1H),7.56(d,J＝7.7Hz,2H),7.48(d,J＝7.8Hz,2H),7.35(d,J＝8.0Hz,2H),7.25(dd,J＝16.3,8.3Hz,1H),7.09–7.05(m,1H),6.88(td,J＝8.5,2.5Hz,1H),5.54(s,1H),4.91(d,J＝14.4Hz,1H),4.63(d,J＝14.5Hz,1H),3.86(d,J＝13.4Hz,1H),3.54(d,J＝13.5Hz,1H),3.28(dd,J＝13.9,6.9Hz,1H),2.36(s,3H),0.77(d,J＝6.8Hz,3H).HRMS calcd forC28H25F2IN4O,[M+Na]+,621.0939；found 621.0963.
实施例57：(2R,3R)-2-(2,4-二氟苯基)-3-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.66(s,1H),7.54(d,J＝8.0Hz,2H),7.48–7.44(m,4H),7.25(t,J＝8.7Hz,3H),7.07(td,J＝9.1,4.5Hz,1H),6.90–6.86(m,1H),5.54(s,1H),4.92(d,J＝14.5Hz,1H),4.64(d,J＝14.6Hz,1H),3.86(d,J＝13.4Hz,1H),3.54(d,J＝13.4Hz,1H),3.29(t,J＝6.9Hz,1H),2.36(s,3H),2.34(s,3H),0.77(d,J＝6.9Hz,3H).HRMS calcd for C29H28F2N4O,[M+Na]+,509.2129；found509.2160.
实施例58：(2R,3R)-3-((4-((4-(叔丁基)苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.64(s,1H),7.54(d,J＝7.9Hz,2H),7.50(s,1H),7.48(d,J＝6.8Hz,2H),7.46(d,J＝3.6Hz,2H),7.44(s,1H),7.25(dt,J＝9.1,6.7Hz,1H),7.07(ddd,J＝11.9,9.0,2.6Hz,1H),6.88(td,J＝8.5,2.6Hz,1H),5.54(s,1H),4.91(d,J＝14.5Hz,1H),4.63(d,J＝14.6Hz,1H),3.85(d,J＝13.4Hz,1H),3.54(d,J＝13.5Hz,1H),3.28(q,J＝6.9Hz,1H),2.36(s,3H),1.29(s,9H),0.77(d,J＝6.8Hz,3H).HRMScalcd for C32H34F2N4O,[M+Na]+,551.2598；found 551.2622.
实施例59：1-(4-(((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮
1H NMR(600MHz,DMSO-d6)δ8.33(s,1H),8.00(d,J＝8.2Hz,2H),7.71(d,J＝8.0Hz,2H),7.67(s,1H),7.60(d,J＝7.8Hz,2H),7.51(d,J＝8.0Hz,2H),7.28–7.24(m,1H),7.07(ddd,J＝11.9,9.0,2.6Hz,1H),6.88(td,J＝8.5,2.6Hz,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.65(d,J＝14.6Hz,1H),3.87(d,J＝13.5Hz,1H),3.56(d,J＝13.5Hz,1H),3.30–3.27(m,1H),2.61(s,3H),2.37(s,3H),0.78(d,J＝6.8Hz,3H).HRMS calcd forC30H28F2N4O2,[M+Na]+,537.2078；found 537.2097.
实施例60：(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.27(d,J＝8.8Hz,2H),7.83(d,J＝8.6Hz,2H),7.65(s,1H),7.63(d,J＝7.9Hz,2H),7.52(d,J＝7.8Hz,2H),7.26(dd,J＝15.8,9.0Hz,1H),7.07(ddd,J＝11.9,8.9,2.6Hz,1H),6.88(td,J＝8.5,2.6Hz,1H),5.55(s,1H),4.93(d,J＝14.5Hz,1H),4.65(d,J＝14.6Hz,1H),3.88(d,J＝13.5Hz,1H),3.56(d,J＝13.5Hz,1H),3.29(q,J＝6.9Hz,1H),2.37(s,3H),0.78(d,J＝6.9Hz,3H).HRMS calcd forC28H25F2N5O3,[M+Na]+,540.1823；found 540.1848.
实施例61：4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)苯基)乙炔基)苄腈
1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),7.90(d,J＝8.2Hz,2H),7.75(d,J＝8.1Hz,2H),7.68(s,1H),7.61(d,J＝7.9Hz,2H),7.51(d,J＝7.8Hz,2H),7.26(d,J＝8.0Hz,1H),7.09–7.05(m,1H),6.90–6.87(m,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.65(d,J＝14.5Hz,1H),3.88(d,J＝13.4Hz,1H),3.56(d,J＝13.5Hz,1H),3.28(d,J＝7.0Hz,1H),2.37(s,3H),0.78(d,J＝6.8Hz,3H).HRMS calcd for C29H25F2N5O,[M+Na]+,520.1925；found520.1954.
实施例62：(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.79(s,2H),7.64(s,1H),7.61(d,J＝7.7Hz,2H),7.51(d,J＝7.8Hz,2H),7.26(dd,J＝16.1,8.2Hz,1H),7.10–7.05(m,1H),6.90–6.85(m,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.63(d,J＝14.6Hz,1H),3.88(d,J＝13.5Hz,1H),3.56(d,J＝13.6Hz,1H),3.29(dd,J＝14.1,7.1Hz,1H),2.37(s,2H),0.78(d,J＝6.8Hz,2H).HRMS calcd for C29H25F5N4O,[M+Na]+,563.1846；found 563.1855.
实施例63：(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.71(d,J＝8.4Hz,2H),7.64(s,1H),7.58(d,J＝7.9Hz,2H),7.49(d,J＝7.8Hz,2H),7.43(d,J＝8.2Hz,2H),7.26(td,J＝9.0,6.6Hz,1H),7.07(ddd,J＝11.8,8.9,2.6Hz,1H),6.88(td,J＝8.4,2.6Hz,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.64(d,J＝14.6Hz,1H),3.87(d,J＝13.5Hz,1H),3.55(d,J＝13.5Hz,1H),3.29(q,J＝6.9Hz,1H),2.37(s,3H),0.78(d,J＝6.8Hz,3H).HRMS calcd forC29H25F5N4O2,[M+Na]+,579.1795；found 579.1855.
实施例64：(2R,3R)-2-(2,4-二氟苯基)-3-(4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.35(s,1H),7.79(s,1H),7.70(dd,J＝15.0,8.5Hz,1H),7.47–7.38(m,3H),7.21–7.17(m,1H),7.17–7.11(m,3H),6.97(td,J＝8.5,2.6Hz,1H),5.76(s,1H),4.54(q,J＝14.2Hz,1H),3.60(d,J＝13.7Hz,1H),3.44(d,J＝13.7Hz,1H),3.02(d,J＝13.8Hz,1H),2.77(d,J＝13.7Hz,1H),2.09(s,2H).HRMS calcd forC28H24F4N4O,[M+Na]+,531.1784；found 531.1813.
实施例65：(2R,3R)-2-(2,4-二氟苯基)-3-(4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.71(ddd,J＝11.3,7.7,2.0Hz,1H),7.64(s,1H),7.56(d,J＝7.9Hz,2H),7.53–7.50(m,1H),7.49(d,J＝7.9Hz,2H),7.45(dd,J＝8.4,4.2Hz,1H),7.25(d,J＝6.8Hz,1H),7.07(ddd,J＝11.9,9.0,2.6Hz,1H),6.90–6.86(m,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.62(d,J＝14.6Hz,1H),3.86(d,J＝13.5Hz,1H),3.55(d,J＝13.5Hz,1H),3.29(t,J＝6.9Hz,1H),2.36(s,3H),0.77(d,J＝6.8Hz,3H).HRMS calcd for C28H24F4N4O,[M+H]+,509.1964；found 509.2004.
实施例66：(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-((2,4,5-三氟苯基)乙炔基)苄基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.86(dd,J＝17.5,8.8Hz,1H),7.73(dd,J＝17.7,9.0Hz,1H),7.64(s,1H),7.57(d,J＝7.7Hz,2H),7.51(d,J＝7.8Hz,2H),7.27(dd,J＝16.5,8.3Hz,1H),7.07(t,J＝10.6Hz,1H),6.88(t,J＝8.6Hz,1H),5.57(s,1H),4.93(d,J＝14.5Hz,1H),4.64(d,J＝14.6Hz,1H),3.88(d,J＝13.4Hz,1H),3.55(d,J＝13.6Hz,1H),3.28(dd,J＝14.1,7.0Hz,1H),2.36(s,3H),0.78(d,J＝6.8Hz,3H).HRMS calcd forC28H24F4N4O,[M+H]+,509.1964；found 509.2004.
实施例67：(2R,3R)-3-((4-(4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.85–7.82(m,1H),7.82–7.80(m,1H),7.66(s,1H),7.59(d,J＝8.0Hz,2H),7.52(d,J＝7.9Hz,2H),7.28–7.24(m,1H),7.07(ddd,J＝11.9,9.0,2.6Hz,1H),6.88(td,J＝8.5,2.6Hz,1H),5.55(s,1H),4.92(d,J＝14.5Hz,1H),4.64(d,J＝14.6Hz,1H),3.88(d,J＝13.5Hz,1H),3.56(d,J＝13.5Hz,1H),3.28(q,J＝6.9Hz,1H),2.36(s,3H),0.78(d,J＝6.9Hz,3H).HRMS calcd for C28H23ClF4N4O,[M+Na]+,565.1394；found 565.1456.
实施例68：4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)苯基)乙炔基)苄腈
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.90(d,J＝8.0Hz,2H),7.75(d,J＝7.9Hz,2H),7.64(s,1H),7.61(d,J＝7.7Hz,2H),7.51(d,J＝7.8Hz,2H),7.26(q,J＝8.4Hz,1H),7.07(ddd,J＝11.9,8.8,2.5Hz,1H),6.88(td,J＝8.6,2.6Hz,1H),5.55(s,1H),4.92(d,J＝14.6Hz,1H),4.63(d,J＝14.6Hz,1H),3.87(d,J＝13.5Hz,1H),3.56(d,J＝13.6Hz,1H),3.28(q,J＝6.9Hz,1H),0.77(d,J＝6.8Hz,3H).HRMS calcd for C29H22D3F2N5O,[M+Na]+,523.2213；found 523.2256.
实施例69的制备路线如下所示：
具体合成步骤如下：
4-((3-氟-4-甲酰基苯基)乙炔基)苄腈-2-氟-4-((三甲基甲硅烷基)乙炔基)苯甲醛-4-溴-2-氟苯甲醛-4-乙炔基-2-氟苯甲醛(12)的合成
将中间体11(1.00g,4.92mmol)，三甲基硅炔(2.56g,9.85mmol)，DIEA(2.53g,19.61mmol)，四三苯基膦钯(0.011g,0.098mmol)，碘化亚铜(0.047g,0.024mmol)依次加入到四氢呋喃溶液中，氩气保护下，室温搅拌2h。TLC监测(PE:EA＝6:1)原料反应完全，乙酸乙酯萃取，有机相减压浓缩，经柱层析分离得黄色粉末状固体，产率80％。
4-乙炔基-2-氟苯甲醛(13)的合成
将中间体12(0.95g,4.31mmol)，碳酸钾(1.19g,8.62mmol)加入到甲醇溶液中，室温反应1h。TLC监测(PE:EA＝6:1)原料反应完全，乙酸乙酯萃取，有机相减压浓缩，经柱层析分离得白色粉末状固体，产率88％。
4-((3-氟-4-甲酰基苯基)乙炔基)苄腈(14)的合成
将中间体13(0.55g,3.71mmol)，4-碘苯乙腈(1.02g,4.45mmol)溶于5mL乙腈中，依次加入三乙胺(0.063g,11.13mmol)，四三苯基膦钯(0.043g,0.037mmol)，碘化亚铜(0.014g,0.074mmol)，氩气保护下，50℃下搅拌3h。TLC监测(PE:EA＝4:1)原料反应完全，乙酸乙酯萃取，有机相减压浓缩，经柱层析分离得白色粉末状固体，产率68％
4-((3-氟-4-(甲氨基)甲基)苯基)乙炔基)苄腈(15)的合成
将中间体14(0.20g,0.80mmol)，甲胺水溶液(0.037g,1.20mmol)加入到甲醇溶液中，室温反应30min，随后加入还原剂硼氢化钠(0.060g,1.60mmol)，继续室温反应1h。TLC监测(DCM:MeOH＝20:1)原料反应完全，减压浓缩，经柱层析分离得白色粉末状固体，产率85％。
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-3-氟苯基)乙炔基)苄腈(实施例69)的制备
将中间体15(0.08g,0.30mmol)，1-[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧甲基]-1H-[1,2,4]三唑(0.63g,0.25mmol)，叔丁醇镁(0.45g,0.45mmol)，氯化镁(0.43g,0.45mmol)，在室温条件下加入到乙腈溶液中，氩气保护下，回流反应6h。TLC监测(DCM:MeOH＝30:1)原料反应完全，减压浓缩，经柱层析分离得白色固体，产率56％。1H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.73(d,J＝8.0Hz,2H),7.63(s,1H),7.45(d,J＝7.8Hz,1H),7.42(d,J＝8.1Hz,2H),7.27–7.24(m,1H),7.07–7.02(m,2H),6.89(dd,J＝8.2,3.0Hz,1H),6.84(d,J＝12.2Hz,1H),6.77(d,J＝12.2Hz,1H),5.55(s,1H),4.84(d,J＝14.5Hz,1H),4.37(d,J＝14.6Hz,1H),3.75(d,J＝13.3Hz,1H),3.58(d,J＝13.3Hz,1H),3.29(d,J＝7.0Hz,1H),2.42(s,3H),0.77(d,J＝6.9Hz,3H).HRMS calcd for C29H24F3N5O,[M+Na]+,538.1831；found 538.1856.
按照实施例69的方法，分别使用相应的原料制备得到实施例70-75。
实施例70：4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-2-氟苯基)乙炔基)苄腈
1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.92(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.66(dd,J＝14.0,6.2Hz,1H),7.44(d,J＝10.5Hz,1H),7.37(d,J＝8.1Hz,1H),7.27(d,J＝7.4Hz,1H),7.11–7.07(m,1H),6.89(td,J＝8.3,2.9Hz,1H),5.57(s,1H),4.92(d,J＝14.6Hz,1H),4.69(d,J＝14.6Hz,1H),3.90(d,J＝13.9Hz,1H),3.59(d,J＝13.9Hz,1H),3.29–3.26(m,1H),2.36(s,2H),0.79(d,J＝6.8Hz,2H).HRMS calcd for C29H24F3N5O,[M+Na]+,538.1831；found 538.1853.
实施例71：4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)-3-氟苯基)乙炔基)苄腈
1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.95–7.89(m,2H),7.77(d,J＝8.1Hz,2H),7.64(d,J＝5.0Hz,2H),7.52–7.47(m,2H),7.28–7.24(m,1H),7.09(ddd,J＝11.8,9.0,2.6Hz,1H),6.88(dt,J＝8.5,4.2Hz,1H),5.55(s,1H),4.87(d,J＝14.6Hz,1H),4.54(d,J＝14.6Hz,1H),3.87(d,J＝13.6Hz,1H),3.65(d,J＝13.6Hz,1H),3.31(d,J＝6.9Hz,1H),0.79(d,J＝6.9Hz,3H).HRMS calcd for C29H21D3F3N5O,[M+Na]+,541.2019；found 541.2056.
实施例72：(2R,3R)-2-(2,4-二氟苯基)-3-((5-((2,4-二氟苯基)乙炔基)吡啶-2-基)(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.76(d,J＝1.9Hz,1H),8.31(s,1H),8.03(dd,J＝8.1,2.2Hz,1H),7.78–7.75(m,1H),7.68(d,J＝8.1Hz,1H),7.65(s,1H),7.47(td,J＝9.6,2.6Hz,1H),7.31–7.27(m,1H),7.24–7.21(m,1H),7.12–7.08(m,1H),6.91–6.88(m,1H),5.82(s,1H),4.92(d,J＝14.6Hz,1H),4.76(d,J＝14.8Hz,1H),4.05(d,J＝14.3Hz,1H),3.63(d,J＝14.3Hz,1H),3.24(q,J＝5.5Hz,1H),0.80(d,J＝6.8Hz,3H).HRMS calcd forC27H20D3F3N5O,[M+Na]+,535.1925；found 535.1955.
实施例73：(2R,3R)-2-(2,4-二氟苯基)-3-((6-((2,4-二氟苯基)乙炔基)吡啶-3-基)甲基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.76(d,J＝1.9Hz,1H),8.31(s,1H),8.03(dd,J＝8.1,2.2Hz,1H),7.78–7.75(m,1H),7.68(d,J＝8.1Hz,1H),7.65(s,1H),7.47(td,J＝9.6,2.6Hz,1H),7.31–7.27(m,1H),7.24–7.21(m,1H),7.12–7.08(m,1H),6.91–6.88(m,1H),5.82(s,1H),4.92(d,J＝14.6Hz,1H),4.76(d,J＝14.8Hz,1H),4.05(d,J＝14.3Hz,1H),3.63(d,J＝14.3Hz,1H),3.24(q,J＝5.5Hz,1H),0.80(d,J＝6.8Hz,3H).HRMS calcd forC27H20D3F3N5O,[M+Na]+,535.1925；found 535.1955.
实施例74：(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-2-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.74(td,J＝8.5,6.4Hz,1H),7.63(q,J＝5.8,4.0Hz,2H),7.49–7.41(m,3H),7.27–7.19(m,2H),7.09(ddd,J＝11.9,9.1,2.7Hz,1H),6.88(td,J＝8.5,2.7Hz,1H),5.56(s,1H),4.86(d,J＝14.5Hz,1H),4.52(d,J＝14.6Hz,1H),3.86(d,J＝13.6Hz,1H),3.64(d,J＝13.6Hz,1H),3.30(q,J＝6.9Hz,1H),0.78(d,J＝6.9Hz,3H).HRMS calcd for C28H20D3F5N4O,[M+Na]+,552.1878；found 552.1823.
实施例75：(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-3-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇
1H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.74(q,J＝7.8Hz,1H),7.64(d,J＝8.8Hz,2H),7.46(ddd,J＝24.5,12.4,6.4Hz,2H),7.35(d,J＝8.0Hz,1H),7.27(q,J＝8.4Hz,1H),7.21(td,J＝8.5,2.6Hz,1H),7.09(td,J＝9.2,4.4Hz,1H),6.89(dt,J＝8.7,4.2Hz,1H),5.56(s,1H),4.92(d,J＝14.5Hz,1H),4.69(d,J＝14.6Hz,1H),3.89(d,J＝13.9Hz,1H),3.59(d,J＝14.0Hz,1H),3.27(q,J＝6.9Hz,1H),0.78(d,J＝6.9Hz,3H).HRMS calcd forC28H20D3F5N4O,[M+Na]+,552.1878；found 522.1806.
参照制备实施例1的方法，将三氮唑替换为四氮唑，分别使用相应的原料制备得到实施例76-86。
实施例76：2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.60(dd,J＝8.6,5.4Hz,2H),7.44(d,J＝8.0Hz,2H),7.34–7.29(m,1H),7.27(t,J＝8.8Hz,2H),7.23–7.19(m,1H),7.18(d,J＝7.8Hz,2H),6.95(td,J＝8.4,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.60(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.8Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcd for C26H22F3N5O,[M+Na]+,500.1674；found 500.1696.
实施例77：1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.57(d,J＝8.4Hz,2H),7.49(d,J＝8.5Hz,2H),7.46(d,J＝8.2Hz,2H),7.34–7.30(m,1H),7.22(d,J＝2.6Hz,1H),7.19(d,J＝7.9Hz,2H),6.95(td,J＝8.5,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝15.4Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMScalcd for C26H22CIF2N5O,[M+Na]+,416.1379；found 516.1419.
实施例78：1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.62(d,J＝8.5Hz,2H),7.49(d,J＝8.4Hz,2H),7.45(d,J＝7.9Hz,2H),7.32(d,J＝6.8Hz,1H),7.22(d,J＝2.6Hz,1H),7.19(d,J＝8.0Hz,2H),6.95(td,J＝8.5,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.60(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.5Hz,1H),2.86(d,J＝13.7Hz,1H),2.15(s,3H).HRMS calcd for C26H22BrF2N5O,[M+Na]+,560.0873；found560.0913.
实施例79：2-(2,4-二氟苯基)-1-((4-(4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.79(d,J＝8.4Hz,2H),7.45(d,J＝8.1Hz,2H),7.33(d,J＝8.3Hz,2H),7.31(d,J＝9.0Hz,1H),7.22–7.19(m,1H),7.18(d,J＝8.2Hz,2H),6.97–6.93(m,1H),6.00(s,1H),4.83(s,2H),3.60(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.9Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcdfor C26H22F2IN5O,[M+H]+,586.0915；found 586.0982.
实施例80：2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),8.26(d,J＝8.5Hz,2H),7.81(d,J＝8.4Hz,2H),7.52(d,J＝7.8Hz,2H),7.32(dd,J＝15.8,8.9Hz,1H),7.22(d,J＝7.8Hz,2H),7.18(d,J＝2.6Hz,1H),6.95(td,J＝8.5,2.1Hz,1H),6.02(s,1H),4.83(s,2H),3.62(d,J＝13.6Hz,1H),3.51(d,J＝13.6Hz,1H),3.01(d,J＝13.8Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcd for C26H22F2N6O3,[M+Na]+,527.1619；found527.1681.
实施例81：1-(4-(2-(4-(((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,3,4-四唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯基)乙-1-酮
1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.98(d,J＝8.2Hz,2H),7.67(d,J＝8.3Hz,2H),7.49(d,J＝7.9Hz,2H),7.33(dd,J＝15.7,9.0Hz,1H),7.19(dd,J＝16.4,5.3Hz,3H),6.97–6.94(m,1H),6.01(s,1H),4.84(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.01(d,J＝13.3Hz,1H),2.87(d,J＝13.8Hz,1H),2.59(s,3H),2.15(s,3H).HRMScalcd for C28H25F2N5O2,[M+Na]+,524.1874；found 524.1877.
实施例82：2-(2,4-二氟苯基)-1-((4-(2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.69(dd,J＝15.0,8.5Hz,1H),7.46(d,J＝7.9Hz,2H),7.42(t,J＝9.1Hz,1H),7.32(d,J＝7.1Hz,1H),7.20(d,J＝7.9Hz,3H),7.17(d,J＝8.3Hz,1H),6.95(td,J＝8.4,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.01(d,J＝13.3Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcd for C26H26F4N5O,[M+Na]+,518.1580；found 518.1608.
实施例83：1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.12(s,1H),7.66(t,J＝8.1Hz,1H),7.60(dd,J＝9.4,2.1Hz,1H),7.47(d,J＝7.9Hz,2H),7.37(d,J＝8.5Hz,1H),7.35–7.31(m,1H),7.21(d,J＝7.8Hz,3H),6.96(td,J＝8.5,2.6Hz,1H),6.00(s,1H),4.84(s,2H),3.62(d,J＝13.6Hz,1H),3.51(d,J＝13.6Hz,1H),3.01(d,J＝13.5Hz,1H),2.87(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcd for C26H21ClF3N5O,[M+Na]+,534.1284；found 534.1334.
实施例84：2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.68(t,J＝9.0Hz,1H),7.51(d,J＝10.4Hz,1H),7.46(d,J＝8.0Hz,1H),7.43(s,1H),7.34–7.30(m,1H),7.19(d,J＝8.3Hz,2H),6.96(td,J＝8.5,2.6Hz,1H),5.99(s,1H),4.83(s,1H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.2Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,2H).HRMScalcd for C26H26F4N5O,[M+Na]+,518.1580；found 518.1646.
实施例85：1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.66–7.63(m,2H),7.47(d,J＝7.8Hz,2H),7.42(d,J＝7.6Hz,1H),7.32(d,J＝7.1Hz,1H),7.22(d,J＝2.5Hz,1H),7.19(s,2H),6.96(td,J＝8.5,2.6Hz,1H),6.00(s,1H),4.83(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.4Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcdfor C26H21ClF3N5O,[M+Na]+,534.1284；found 534.1298.
实施例86：1-((4-((4-溴-3-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇
1H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.77(t,J＝7.9Hz,1H),7.60(dd,J＝9.5,1.9Hz,1H),7.47(d,J＝8.0Hz,2H),7.35–7.30(m,2H),7.21(dd,J＝14.4,5.3Hz,3H),6.96(td,J＝8.5,2.6Hz,1H),5.99(s,1H),4.83(s,2H),3.61(d,J＝13.6Hz,1H),3.50(d,J＝13.6Hz,1H),3.00(d,J＝13.9Hz,1H),2.86(d,J＝13.8Hz,1H),2.15(s,3H).HRMS calcdfor C26H21BrF3N5O,[M+Na]+,556.0960；found 556.0979.
本发明部分产物的药效学研究：
实验方法：
参考常规的体外抑菌试验方法(Reference method for broth dilutionantifungal susceptibility testing of yeasts and filamentous fungi；ApprovedStandard M27-A3 and M38-A2)。
实验材料和方法：
(1)实验菌株：本实验使用了以下五种常见的人体致病标准真菌菌株作为筛选对象，真菌菌株由沈阳药科大学提供。
表1实验所用菌株及其编号
| 菌种名称 | 种属 | 菌株 |
| 白色念珠菌 | Candida albicans | SC5314 |
| 白色念珠菌 | Candida albicans | GIM 2.194 |
| 热带假丝酵母菌 | Candida tropicalis | cgmcc 2.3739 |
| 近平滑念珠菌 | Candida parapsilosis | GIM 2.190 |
| 新生隐球菌 | Cryptococcus neofrmans | GIM 2.209 |
(2)实验方法：
RPMI-1640培养基的配制：RPMI-1640 10.0g,NaHCO32.0 g，三氮吗啡琳丙磺酸(Sigma)34.5g，加800mL无菌蒸馏水溶解，l mol/L NaOH调整pH至7.0后，定容至1000mL，0.22μm微孔滤膜过滤除菌后放置4℃保存备用。
球状真菌菌悬液的制备：球状菌(白色念珠菌，热带假丝酵母菌，近平滑念珠菌，新生隐球菌)。将活化后的菌株用分区划线法接种于沙氏固体培养基平板上，于32℃恒温培养2-3天，取适量单菌落接入含l0 mL 0.85％无菌生理盐水的三角瓶中，震荡15分钟，用灭菌枪头取少量菌液于血细胞计数板上，显微镜下计数。加RPMI-1640培养基稀释，使最终菌悬液的浓度为1x106个/mL。
药液制备：称取上述实施例制备获得化合物各6.40mg，依次加入l.0mL二甲基亚砜(DMSO)，l.0mL吐温-20和8.0mL灭菌蒸馏水，混匀。配成药液浓度为0.64mg/mL。以相同方法配制阳性对照药氟康唑、伏立康唑、伊曲康唑。
接种：第一步，加RPMI-1640培养基：每行的第1孔加入180μL RPMI-1640培养基，第2-11孔加入100μL RPMI-1640培养基，第12孔加入200μL RPMI-1640培养基。第二步，加药样：向第1孔中加入20μL待测药液(即，各实施例获得化合物)，用移液枪混匀后吸取100μL至2孔，依次进行2倍稀释至第10孔后混匀弃去100μL。第三步，加菌悬液：向1-11孔中各加100μL接种菌悬液。第11孔为生长对照，第12孔为空白培养基对照。阳性对照药物不设空白药物对照，即从第1孔开始做倍比梯度稀释直至第10孔，测试浓度(μg/mL)范围32、16、8、4、2、1、0.5、0.25、0.125、0.0625。
培养和检测：以空白对照无菌生长，阳性对照生长良好作为判断试验操作是否合格的标准。每板测试8个样品，每个菌均设置阳性药物对照。待测药物稀释法同上。
表2实施例化合物最低抑菌浓度(μg/mL)
从上述实验结果可以看出，本发明所要保护的通式I的化合物及其盐类具有良好的抗真菌活性，多个化合物的抗真菌活性强于阳性对照药，与现有的抗真菌药物相比，具有结构新颖、低毒、高效、广谱等优点，因此本发明的化合物具有很好的应用前景。
本发明中通式I的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
实施例87：片剂。
实施例75化合物10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
实施例88：胶囊剂。
实施例75化合物10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。
实施例89：注射剂。
实施例75化合物10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
实施例90：气雾剂。
实施例75化合物10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
实施例91：栓剂。
实施例75化合物10g，将其研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。
实施例92：膜剂。
实施例75化合物10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将上述实施例75化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
实施例93：滴丸剂。
实施例75化合物10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
实施例94：外用搽剂。
实施例75化合物10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
实施例95：软膏剂。
实施例75化合物10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。
Claims (10)
1.通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中，MBG是任选取代的四唑基、任选取代的三唑基、或任选取代的吡唑基，所述任选取代的指C1-4烷基取代或C1-4烷氧基取代；
Ar为取代苯环，取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代，所述卤素为F、Cl、Br或I；
R1为氢、卤素、烷基或卤代烷基；
R2为烷基或氘代烷基；
*标识的碳原子为手性碳原子或非手性碳原子；
A环为苯基、5-7元杂芳基或5-7元杂环烷基，其中，杂芳基、杂环烷基含有1-3个选自N、O或S的杂原子，并且A环任选被1-4个相同或不同R3取代；
R3或R4为氢或者羟基、卤素、硝基、氨基、氰基、醛基、苯基、苄氧基、C1-C6烷基、C1-C6烯基、C1-C6烷氧基、任选被羟基、氨基或卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的苯基、卤代的苄氧基、游离的、成盐的、酯化的和酰胺化的羧基、C1-C6烷基酰基、C1-C3亚烷基二氧基；
B环为苯基、5-7元杂芳基或5-7元杂环烷基，其中，杂芳基、杂环烷基含有1-3个选自N、O或S的杂原子，并且B环任选被1-4个相同或不同R4取代。
2.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中，MBG选自以下结构：Ar为2,4-二氟苯基；或者，
其中，R1为氢或甲基；R2为甲基或氘代甲基；或者，
其中，A环为苯环或吡啶环；R3为氢或氟。
3.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中B环为苯环；
R4选自i，ii，或iii，其中取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基；或者，
其中B环为5-6元杂芳基，杂芳基含有1-2个选自N、O或S的杂原子；
R4为氢。
4.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中A环为苯环，B环为5-6元杂芳基，杂芳基含有1-2个选自N、O或S的杂原子；
R3和R4为氢。
5.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中A环为苯环，B环为苯环；
R3为氢或氟；
R4选自i，ii，或iii，其中取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基。
6.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：
其中A环为吡啶环，B环为苯环；
R3为氢；
R4选自i，ii，或iii，其中取代基位置可位于邻位、间位或对位，所述取代是单取代或多取代；
i.卤素，所述卤素为F、Cl、Br或I；
ii.1～6个碳原子的直链或支链烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、叔戊基、仲戊基或异戊基；
iii.氰基、硝基、三氟甲基、三氟甲氧基、甲酰基、乙酰基、甲氧基、苄氧基、苯基、氨基或羟基。
7.根据权利要求1所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，选自：
2-(2,4-二氟苯基)-1-(甲基(4-(苯乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-2-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-3-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(吡啶-4-乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(嘧啶-5-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-2-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(噻吩-3-基乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((4-甲氧基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-(4-乙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((4-异丙基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-(叔丁基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苄腈；
2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯酚
1-((4-((4-氨基苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((1,1’-联苯)-4-乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-(苄氧基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲醛；
1-(4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮；
4-((4-((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,4-三唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯甲酸乙酯；
2-(2,4-二氟苯基)-1-((4-(2-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-(3-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((2-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((3-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((2-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((3-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((2-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((3-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基((4-(2-(2-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基((4-(2-(3-甲基苯基)乙炔基)苯基)甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((3,5-二甲基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((3,5-双(三氟甲基)苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((2,5-二氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-溴-2-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(4-((2-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-溴-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((3-氟-4-硝基苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-((2,4,5-三氟苯基)乙炔基)苄基)氨基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
1-((4-((4-溴-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-1,2,4-三唑-1-基)丙-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-3-((4-((4-氯苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-3-((4-((4-溴苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-((4-((4-碘代苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基((4-(2-(4-甲基苯基)乙炔基)苯基)甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-3-((4-((4-(叔丁基)苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
1-(4-(((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基)氨基)甲基)苯基)乙炔基)乙-1-酮；
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)苯基)乙炔基)苄腈；
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(三氟甲基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((4-(4-(三氟甲氧基)苯基)乙炔基)苄基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-(4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-(甲基(4-((2,4,5-三氟苯基)乙炔基)苄基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-3-((4-(4-氯-2,5-二氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)苯基)乙炔基)苄腈；
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-3-氟苯基)乙炔基)苄腈；
4-((4-)((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基(甲基)氨基)甲基)-2-氟苯基)乙炔基)苄腈；
4-((((2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基)(甲基-d3)氨基)甲基)-3-氟苯基)乙炔基)苄腈；
(2R,3R)-2-(2,4-二氟苯基)-3-((5-((2,4-二氟苯基)乙炔基)吡啶-2-基)(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-((6-((2,4-二氟苯基)乙炔基)吡啶-3-基)甲基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-2-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
(2R,3R)-2-(2,4-二氟苯基)-3-((4-(2,4-二氟苯基)乙炔基)-3-氟苄基(甲基-d3)氨基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇；
2-(2,4-二氟苯基)-1-((4-(4-氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇；
1-((4-(4-氯苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇；
1-((4-(4-溴苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-(4-碘代苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-(甲基(4-(4-硝基苯基)乙炔基)苄基)氨基)-3-(1H-四唑-1-基)丙-2-醇；
1-(4-(2-(4-(((2-(2,4-二氟苯基)-2-羟基-3-(1H-1,2,3,4-四唑-1-基)丙基)(甲基)氨基)甲基)苯基)乙炔基)苯基)乙-1-酮；
2-(2,4-二氟苯基)-1-((4-(2,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇；
1-((4-((4-氯-2-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇；
2-(2,4-二氟苯基)-1-((4-((3,4-二氟苯基)乙炔基)苄基)(甲基)氨基)-3-(1H-四唑-1-基)丙-2-醇；
1-((4-((4-氯-3-氟苯基)乙炔基)苄基(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇；
1-((4-((4-溴-3-氟苯基)乙炔基)苄基)(甲基)氨基)-2-(2,4-二氟苯基)-3-(1H-四唑-1-基)丙-2-醇。
8.一种药物组合物，其特征在于：其包含权利要求1至7中任一项所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
9.一种药物制剂，其特征在于：其包含权利要求1至7中任一项所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药或者权利要求8所述的药物组合物作为活性成分。
10.权利要求1至7中任一项所述的通式I所示的唑类衍生物，或者其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药或者权利要求8所述的药物组合物或者权利要求9所述的药物制剂在制备抗真菌药物中的用途，其特征在于：优选地，所述真菌选自以下一种或多种致病真菌：伞状犁头霉(Absidia corymbifera)、荚膜阿耶罗菌(Ajellomycescapsulatus)、皮炎阿耶罗菌((Ajellomyces dermatitidis)、苯黑末节皮真菌(Arthrodermabenhamiae)、粉节皮菌(Arthrodermafulvum)、石膏样节皮菌(Arthrodermagypseum)、内弯节皮菌(Arthrodermaincurvatum)、太田节皮菌(Arthrodermaotae)、万博节皮菌(Arthrodermavanbreuseghemii)、黄曲霉(Aspergillusflavus)、烟曲霉(Aspergillus fumigatus)、黑曲霉(Aspergillus niger)、皮炎芽生菌(Blastomyces dermatitidis)、白色念珠菌(Candida albicans)、光滑念珠菌(Candidaglabrata)、季也蒙念珠菌(Candida guilliermondii)、克鲁斯念珠菌(Candida krusei)、近平滑念珠菌(Candidaparapsilosis)、热带假丝念珠菌(Candidatropicalis)、菌膜假丝酵母(Candidapelliculosa)、卡氏枝抱瓶霉(Cladophialophoracarrionii)、粗球孢子菌(Coccidioides immitis)、新生隐球菌(Cryptococcus neoformans)、小克银汉霉菌属(Cunninghamella sp.)、絮状表皮癣菌(Epidermophyton floccosum)、皮炎外瓶霉(Exophiala dermatitidis)、新型线黑粉菌(Filobasidiella neoformans)、佩德罗索氏着色芽生菌(Fonsecaeapedrosoi)、腐皮镰刀菌(Fusarium solani)、白地霉(Geotrichumcandidum)、荚膜组织胞浆菌(Histoplasma capsulatum)、威尼克外瓶霉(Hortaeawerneckii)、东方伊萨酵母(工ssatschenkiaorientalis)、灰马杜拉分枝菌(Madurellagrisae)、糠批马拉色菌(Malassezia fur fur)、球形马拉色菌(Malasseziaglobosa)、钝形马拉色菌(Malassezia obtusa)、厚皮马拉色菌(Malasseziapachydermatis)、限制性马拉色菌(Malassezia restricta)、斯洛非马拉色菌(Malassezia slooffiae)、合轴马拉色菌(Malassezia sympodialis)、犬小孢子菌(Microsporum cams)、黄褐色小孢子菌(Microsporumfulvum)、石膏样小孢子菌(Microsporumgypseum)、卷枝毛霉菌(Mucor circinelloides)、红球丛赤壳(Nectriahaematococca)、宛氏拟青霉(Paecilomycesvariotii)、巴西副球孢子菌(Paracoccidioides brasiliensis)、马尔尼菲青霉菌(Peniciliiummarneffei)、异常毕赤酵母(Pichia anomala)、季也蒙毕赤酵母(Pichia guilliermondii)、卡氏肺孢子虫(Pneumocystis carinii)、波氏假阿利什菌(Pseudallescheriaboydii)、稻根霉菌(Rhizopus oryzae)、深红酵母(Rhodotorula rubra)、尖端赛多孢子菌(Scedosporiumapiospernium)、裂褶菌(Schizophyllum commune)、申克孢子丝菌(Sporothrixschenckii)、须发癣菌(Trichophyton mentagrophytes)、红色毛癣菌(Trichophyton rubrum)、疵状癣菌(Trichophyton verrucosum)、紫色毛癣菌(Trichophyton violaceum)、阿萨希毛孢子菌(Trichosporonasahii)、皮肤毛孢子菌(Trichosporoncutaneum)、墨毛孢子菌(Trichosporoninkin)、粘状毛孢子菌(Trichosporonmucoides)或耳念珠菌(Candida auris)。
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